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Sample records for biomarker validation study

  1. Validation of New Cancer Biomarkers

    DEFF Research Database (Denmark)

    Duffy, Michael J; Sturgeon, Catherine M; Söletormos, Georg

    2015-01-01

    BACKGROUND: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. CONTENT: In this review, we discuss the key steps...... in advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance...... of the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be registered before...

  2. Validation study of genetic biomarkers of response to TNF inhibitors in rheumatoid arthritis.

    Directory of Open Access Journals (Sweden)

    Rosario Lopez-Rodriguez

    Full Text Available Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA, given their variable response to TNF inhibitors (TNFi. However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi.

  3. Genomic Biomarkers for Personalized Medicine: Development and Validation in Clinical Studies

    Directory of Open Access Journals (Sweden)

    Shigeyuki Matsui

    2013-01-01

    Full Text Available The establishment of high-throughput technologies has brought substantial advances to our understanding of the biology of many diseases at the molecular level and increasing expectations on the development of innovative molecularly targeted treatments and molecular biomarkers or diagnostic tests in the context of clinical studies. In this review article, we position the two critical statistical analyses of high-dimensional genomic data, gene screening and prediction, in the framework of development and validation of genomic biomarkers or signatures, through taking into consideration the possible different strategies for developing genomic signatures. A wide variety of biomarker-based clinical trial designs to assess clinical utility of a biomarker or a new treatment with a companion biomarker are also discussed.

  4. Validation of biomarkers for the study of environmental carcinogens: a review

    DEFF Research Database (Denmark)

    Gallo, Valentina; Khan, Aneire; Gonzales, Carlos

    2008-01-01

    There is a need for validation of biomarkers. Our aim is to review published work on the validation of selected biomarkers: bulky DNA adducts, N-nitroso compounds, 1-hydroxypyrene, and oxidative damage to DNA. A systematic literature search in PubMed was performed. Information on the variability...... and reliability of the laboratory tests used for biomarkers measurements was collected. For the evaluation of the evidence on validation we referred to the ACCE criteria. Little is known about intraindividual variation of DNA adduct measurements, but measurements have a good repeatability irrespective...... of the technique used for their identification; reproducibility improved after the correction for a laboratory factor. A high-sensitivity method is available for the measurement of 1-hydroxypyrene in urine. There is consensus on validation of biomarkers of oxidative damage DNA based on the comet assay...

  5. Application of a repeat-measure biomarker measurement error model to 2 validation studies: examination of the effect of within-person variation in biomarker measurements.

    Science.gov (United States)

    Preis, Sarah Rosner; Spiegelman, Donna; Zhao, Barbara Bojuan; Moshfegh, Alanna; Baer, David J; Willett, Walter C

    2011-03-15

    Repeat-biomarker measurement error models accounting for systematic correlated within-person error can be used to estimate the correlation coefficient (ρ) and deattenuation factor (λ), used in measurement error correction. These models account for correlated errors in the food frequency questionnaire (FFQ) and the 24-hour diet recall and random within-person variation in the biomarkers. Failure to account for within-person variation in biomarkers can exaggerate correlated errors between FFQs and 24-hour diet recalls. For 2 validation studies, ρ and λ were calculated for total energy and protein density. In the Automated Multiple-Pass Method Validation Study (n=471), doubly labeled water (DLW) and urinary nitrogen (UN) were measured twice in 52 adults approximately 16 months apart (2002-2003), yielding intraclass correlation coefficients of 0.43 for energy (DLW) and 0.54 for protein density (UN/DLW). The deattenuated correlation coefficient for protein density was 0.51 for correlation between the FFQ and the 24-hour diet recall and 0.49 for correlation between the FFQ and the biomarker. Use of repeat-biomarker measurement error models resulted in a ρ of 0.42. These models were similarly applied to the Observing Protein and Energy Nutrition Study (1999-2000). In conclusion, within-person variation in biomarkers can be substantial, and to adequately assess the impact of correlated subject-specific error, this variation should be assessed in validation studies of FFQs. © The Author 2011. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

  6. Pooled results from 5 validation studies of dietary self-report instruments using recovery biomarkers for energy and protein intake

    Science.gov (United States)

    We pooled data from 5 large validation studies of dietary self-report instruments that used recovery biomarkers as references to clarify the measurement properties of food frequency questionnaires (FFQs) and 24-hour recalls. The studies were conducted in widely differing U.S. adult populations from...

  7. Pooled results from five validation studies of dietary self-report instruments using recovery biomarkers for potassium and sodium intake

    Science.gov (United States)

    We have pooled data from five large validation studies of dietary self-report instruments that used recovery biomarkers as referents to assess food frequency questionnaires (FFQs) and 24-hour recalls. We reported on total potassium and sodium intakes, their densities, and their ratio. Results were...

  8. A Selected Reaction Monitoring Mass Spectrometry Protocol for Validation of Proteomic Biomarker Candidates in Studies of Psychiatric Disorders.

    Science.gov (United States)

    Reis-de-Oliveira, Guilherme; Garcia, Sheila; Guest, Paul C; Cassoli, Juliana S; Martins-de-Souza, Daniel

    2017-01-01

    Most biomarker candidates arising from proteomic studies of psychiatric disorders have not progressed for use in clinical studies due to insufficient validation steps. Here we describe a selective reaction monitoring mass spectrometry (SRM-MS) approach that could be used as a follow-up validation tool of proteins identified in blood serum or plasma. This protocol specifically covers the stages of peptide selection and optimization. The increasing application of SRM-MS should enable fast, sensitive, and robust methods with the potential for use in clinical studies involving sampling of serum or plasma. Understanding the molecular mechanisms and identifying potential biomarkers for risk assessment, diagnosis, prognosis, and prediction of drug response goes toward the implementation of translational medicine strategies for improved treatment of patients with psychiatric disorders and other debilitating diseases.

  9. Validation of standard operating procedures in a multicenter retrospective study to identify -omics biomarkers for chronic low back pain.

    Directory of Open Access Journals (Sweden)

    Concetta Dagostino

    Full Text Available Chronic low back pain (CLBP is one of the most common medical conditions, ranking as the greatest contributor to global disability and accounting for huge societal costs based on the Global Burden of Disease 2010 study. Large genetic and -omics studies provide a promising avenue for the screening, development and validation of biomarkers useful for personalized diagnosis and treatment (precision medicine. Multicentre studies are needed for such an effort, and a standardized and homogeneous approach is vital for recruitment of large numbers of participants among different centres (clinical and laboratories to obtain robust and reproducible results. To date, no validated standard operating procedures (SOPs for genetic/-omics studies in chronic pain have been developed. In this study, we validated an SOP model that will be used in the multicentre (5 centres retrospective "PainOmics" study, funded by the European Community in the 7th Framework Programme, which aims to develop new biomarkers for CLBP through three different -omics approaches: genomics, glycomics and activomics. The SOPs describe the specific procedures for (1 blood collection, (2 sample processing and storage, (3 shipping details and (4 cross-check testing and validation before assays that all the centres involved in the study have to follow. Multivariate analysis revealed the absolute specificity and homogeneity of the samples collected by the five centres for all genetics, glycomics and activomics analyses. The SOPs used in our multicenter study have been validated. Hence, they could represent an innovative tool for the correct management and collection of reliable samples in other large-omics-based multicenter studies.

  10. Biomarkers of Exposure to Toxic Substances. Volume 5: Biomarker Pre-validation Studies Prevalidation of Urine and Serum Biomarkers Indicative of Subclinical Kidney Damage in a Nephrotoxin Model

    Science.gov (United States)

    2009-05-01

    patients on chronic hemodialysis versus controls (Ziegelmeier et al., 2007). This study indicates that RBP4 levels correlate with c- reactive protein in...kidney injury, as well as cancer, rheumatoid arthritis , viral infections, and other chronic inflammatory diseases (Beorchia et al., 1981; Schuster...increase in plasma in dialysis patients , thought to be caused by an inflammatory response stimulated in the kidney due to interactions with hemodialysis

  11. Integrative analysis to select cancer candidate biomarkers to targeted validation

    Science.gov (United States)

    Heberle, Henry; Domingues, Romênia R.; Granato, Daniela C.; Yokoo, Sami; Canevarolo, Rafael R.; Winck, Flavia V.; Ribeiro, Ana Carolina P.; Brandão, Thaís Bianca; Filgueiras, Paulo R.; Cruz, Karen S. P.; Barbuto, José Alexandre; Poppi, Ronei J.; Minghim, Rosane; Telles, Guilherme P.; Fonseca, Felipe Paiva; Fox, Jay W.; Santos-Silva, Alan R.; Coletta, Ricardo D.; Sherman, Nicholas E.; Paes Leme, Adriana F.

    2015-01-01

    Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. PMID:26540631

  12. Derivation and Validation of a Biomarker-Based Clinical Algorithm to Rule Out Sepsis From Noninfectious Systemic Inflammatory Response Syndrome at Emergency Department Admission: A Multicenter Prospective Study.

    Science.gov (United States)

    Mearelli, Filippo; Fiotti, Nicola; Giansante, Carlo; Casarsa, Chiara; Orso, Daniele; De Helmersen, Marco; Altamura, Nicola; Ruscio, Maurizio; Castello, Luigi Mario; Colonetti, Efrem; Marino, Rossella; Barbati, Giulia; Bregnocchi, Andrea; Ronco, Claudio; Lupia, Enrico; Montrucchio, Giuseppe; Muiesan, Maria Lorenza; Di Somma, Salvatore; Avanzi, Gian Carlo; Biolo, Gianni

    2018-05-07

    To derive and validate a predictive algorithm integrating a nomogram-based prediction of the pretest probability of infection with a panel of serum biomarkers, which could robustly differentiate sepsis/septic shock from noninfectious systemic inflammatory response syndrome. Multicenter prospective study. At emergency department admission in five University hospitals. Nine-hundred forty-seven adults in inception cohort and 185 adults in validation cohort. None. A nomogram, including age, Sequential Organ Failure Assessment score, recent antimicrobial therapy, hyperthermia, leukocytosis, and high C-reactive protein values, was built in order to take data from 716 infected patients and 120 patients with noninfectious systemic inflammatory response syndrome to predict pretest probability of infection. Then, the best combination of procalcitonin, soluble phospholypase A2 group IIA, presepsin, soluble interleukin-2 receptor α, and soluble triggering receptor expressed on myeloid cell-1 was applied in order to categorize patients as "likely" or "unlikely" to be infected. The predictive algorithm required only procalcitonin backed up with soluble phospholypase A2 group IIA determined in 29% of the patients to rule out sepsis/septic shock with a negative predictive value of 93%. In a validation cohort of 158 patients, predictive algorithm reached 100% of negative predictive value requiring biomarker measurements in 18% of the population. We have developed and validated a high-performing, reproducible, and parsimonious algorithm to assist emergency department physicians in distinguishing sepsis/septic shock from noninfectious systemic inflammatory response syndrome.

  13. Towards a validation of a cellular biomarker suite in native and transplanted zebra mussels: A 2-year integrative field study of seasonal and pollution-induced variations

    Energy Technology Data Exchange (ETDEWEB)

    Guerlet, Edwige [Laboratoire Ecotoxicite, Sante Environnementale, CNRS UMR 7146, Universite Paul Verlaine-Metz, Rue General Delestraint, F-57070 Metz (France); Ledy, Karine [Laboratoire Ecotoxicite, Sante Environnementale, CNRS UMR 7146, Universite Paul Verlaine-Metz, Rue General Delestraint, F-57070 Metz (France); Meyer, Antoinette [Laboratoire Ecotoxicite, Sante Environnementale, CNRS UMR 7146, Universite Paul Verlaine-Metz, Rue General Delestraint, F-57070 Metz (France); Giamberini, Laure [Laboratoire Ecotoxicite, Sante Environnementale, CNRS UMR 7146, Universite Paul Verlaine-Metz, Rue General Delestraint, F-57070 Metz (France)]. E-mail: giamb@univ-metz.fr

    2007-03-30

    Two of the questions raised in the validation process of biomarkers are their relevance in the identification and discrimination of environmental perturbations, and the influence of seasonal factors on these biological endpoints. Determining the advantages and restrictions associated with the use of native or transplanted animals and comparing their responses is also needed. To obtain this information, a 2-year integrative field study was conducted in the vicinity of a nuclear power plant in northeastern France. A station was located in the reservoir receiving the cooling waters of the plant, and two other sites were studied 2 km upstream and 5 km downstream from the reservoir's discharge in the Moselle river. Elevated temperatures, copper contamination and a 1.4-fold-concentration factor of dissolved salts affected water quality of the reservoir. Native and transplanted zebra mussels (Dreissena polymorpha) were collected monthly and their digestive glands were processed for histochemical determinations of the lysosomal and peroxisomal systems and of the lipofuscin and neutral lipid contents. The responses were quantified using automated image analysis and stereology. Apart from neutral lipid contents, there were no systematic seasonal patterns in mussel populations or from 1 year to another. Principal Component Analyses showed a general higher discrimination potential of biological responses in transplanted organisms compared to native ones. They also pointed out the relationships between the cellular and physiological markers and abiotic factors. The present multiple biomarker integrative approach in transplanted D. polymorpha brings promising elements in their validation process as relevant biomonitoring tools.

  14. Towards a validation of a cellular biomarker suite in native and transplanted zebra mussels: A 2-year integrative field study of seasonal and pollution-induced variations

    International Nuclear Information System (INIS)

    Guerlet, Edwige; Ledy, Karine; Meyer, Antoinette; Giamberini, Laure

    2007-01-01

    Two of the questions raised in the validation process of biomarkers are their relevance in the identification and discrimination of environmental perturbations, and the influence of seasonal factors on these biological endpoints. Determining the advantages and restrictions associated with the use of native or transplanted animals and comparing their responses is also needed. To obtain this information, a 2-year integrative field study was conducted in the vicinity of a nuclear power plant in northeastern France. A station was located in the reservoir receiving the cooling waters of the plant, and two other sites were studied 2 km upstream and 5 km downstream from the reservoir's discharge in the Moselle river. Elevated temperatures, copper contamination and a 1.4-fold-concentration factor of dissolved salts affected water quality of the reservoir. Native and transplanted zebra mussels (Dreissena polymorpha) were collected monthly and their digestive glands were processed for histochemical determinations of the lysosomal and peroxisomal systems and of the lipofuscin and neutral lipid contents. The responses were quantified using automated image analysis and stereology. Apart from neutral lipid contents, there were no systematic seasonal patterns in mussel populations or from 1 year to another. Principal Component Analyses showed a general higher discrimination potential of biological responses in transplanted organisms compared to native ones. They also pointed out the relationships between the cellular and physiological markers and abiotic factors. The present multiple biomarker integrative approach in transplanted D. polymorpha brings promising elements in their validation process as relevant biomonitoring tools

  15. Addressing the Challenge of Defining Valid Proteomic Biomarkers and Classifiers

    LENUS (Irish Health Repository)

    Dakna, Mohammed

    2010-12-10

    Abstract Background The purpose of this manuscript is to provide, based on an extensive analysis of a proteomic data set, suggestions for proper statistical analysis for the discovery of sets of clinically relevant biomarkers. As tractable example we define the measurable proteomic differences between apparently healthy adult males and females. We choose urine as body-fluid of interest and CE-MS, a thoroughly validated platform technology, allowing for routine analysis of a large number of samples. The second urine of the morning was collected from apparently healthy male and female volunteers (aged 21-40) in the course of the routine medical check-up before recruitment at the Hannover Medical School. Results We found that the Wilcoxon-test is best suited for the definition of potential biomarkers. Adjustment for multiple testing is necessary. Sample size estimation can be performed based on a small number of observations via resampling from pilot data. Machine learning algorithms appear ideally suited to generate classifiers. Assessment of any results in an independent test-set is essential. Conclusions Valid proteomic biomarkers for diagnosis and prognosis only can be defined by applying proper statistical data mining procedures. In particular, a justification of the sample size should be part of the study design.

  16. Conceptual strategy for design, implementation, and validation of a biomarker-based biomonitoring capability

    Energy Technology Data Exchange (ETDEWEB)

    McCarthy, J.F.; Halbrook, R.S.; Shugart, L.R.

    1991-12-01

    This document describes a strategy for defining specific objectives for biomarker studies and for designing and implementing a biomonitoring study that focuses on these objectives. In researching this subject, it became clear to the authors that the subject of biomarkers created a great deal of interest among scientists and regulators but that general acceptance of biomarkers as a tool for environmental protection was hampered by lack of a clear notion of how to develop and apply this approach. We intend this document to be a user's guide'' that lays out a logical scheme for applying biomarkers in environmental monitoring. In addition, laboratory and field research components needed to develop and validate fundamental understanding and interpretation of biomarker responses are also described, as is a strategy for evolution of a biomarker-based biomonitoring capability. The document is divided into sections intended to lead the reader to an understanding of how biomarkers can be developed and applied.

  17. Conceptual strategy for design, implementation, and validation of a biomarker-based biomonitoring capability

    Energy Technology Data Exchange (ETDEWEB)

    McCarthy, J.F.; Halbrook, R.S.; Shugart, L.R.

    1991-12-01

    This document describes a strategy for defining specific objectives for biomarker studies and for designing and implementing a biomonitoring study that focuses on these objectives. In researching this subject, it became clear to the authors that the subject of biomarkers created a great deal of interest among scientists and regulators but that general acceptance of biomarkers as a tool for environmental protection was hampered by lack of a clear notion of how to develop and apply this approach. We intend this document to be a ``user`s guide`` that lays out a logical scheme for applying biomarkers in environmental monitoring. In addition, laboratory and field research components needed to develop and validate fundamental understanding and interpretation of biomarker responses are also described, as is a strategy for evolution of a biomarker-based biomonitoring capability. The document is divided into sections intended to lead the reader to an understanding of how biomarkers can be developed and applied.

  18. Multiple inflammatory biomarker detection in a prospective cohort study: a cross-validation between well-established single-biomarker techniques and an electrochemiluminescense-based multi-array platform.

    Directory of Open Access Journals (Sweden)

    Bas C T van Bussel

    Full Text Available BACKGROUND: In terms of time, effort and quality, multiplex technology is an attractive alternative for well-established single-biomarker measurements in clinical studies. However, limited data comparing these methods are available. METHODS: We measured, in a large ongoing cohort study (n = 574, by means of both a 4-plex multi-array biomarker assay developed by MesoScaleDiscovery (MSD and single-biomarker techniques (ELISA or immunoturbidimetric assay, the following biomarkers of low-grade inflammation: C-reactive protein (CRP, serum amyloid A (SAA, soluble intercellular adhesion molecule 1 (sICAM-1 and soluble vascular cell adhesion molecule 1 (sVCAM-1. These measures were realigned by weighted Deming regression and compared across a wide spectrum of subjects' cardiovascular risk factors by ANOVA. RESULTS: Despite that both methods ranked individuals' levels of biomarkers very similarly (Pearson's r all≥0.755 absolute concentrations of all biomarkers differed significantly between methods. Equations retrieved by the Deming regression enabled proper realignment of the data to overcome these differences, such that intra-class correlation coefficients were then 0.996 (CRP, 0.711 (SAA, 0.895 (sICAM-1 and 0.858 (sVCAM-1. Additionally, individual biomarkers differed across categories of glucose metabolism, weight, metabolic syndrome and smoking status to a similar extent by either method. CONCLUSIONS: Multiple low-grade inflammatory biomarker data obtained by the 4-plex multi-array platform of MSD or by well-established single-biomarker methods are comparable after proper realignment of differences in absolute concentrations, and are equally associated with cardiovascular risk factors, regardless of such differences. Given its greater efficiency, the MSD platform is a potential tool for the quantification of multiple biomarkers of low-grade inflammation in large ongoing and future clinical studies.

  19. A Multi-Center Prospective Study to Validate an Algorithm Using Urine and Plasma Biomarkers for Predicting Gleason ≥3+4 Prostate Cancer on Biopsy

    DEFF Research Database (Denmark)

    Albitar, Maher; Ma, Wanlong; Lund, Lars

    2017-01-01

    a prospective multicenter study recruiting patients from community-based practices. Patients and Methods: Urine and plasma samples from 2528 men were tested prospectively. Results were correlated with biopsy findings, if a biopsy was performed as deemed necessary by the practicing urologist. Of the 2528......Background: Unnecessary biopsies and overdiagnosis of prostate cancer (PCa) remain a serious healthcare problem. We have previously shown that urine- and plasma-based prostate-specific biomarkers when combined can predict high grade prostate cancer (PCa). To further validate this test, we performed...... of high grade prostate cancer with negative predictive value (NPV) of 90% to 97% for Gleason ≥3+4 and between 98% to 99% for Gleason ≥4+3....

  20. Novel automated blood separations validate whole cell biomarkers.

    Directory of Open Access Journals (Sweden)

    Douglas E Burger

    Full Text Available Progress in clinical trials in infectious disease, autoimmunity, and cancer is stymied by a dearth of successful whole cell biomarkers for peripheral blood lymphocytes (PBLs. Successful biomarkers could help to track drug effects at early time points in clinical trials to prevent costly trial failures late in development. One major obstacle is the inaccuracy of Ficoll density centrifugation, the decades-old method of separating PBLs from the abundant red blood cells (RBCs of fresh blood samples.To replace the Ficoll method, we developed and studied a novel blood-based magnetic separation method. The magnetic method strikingly surpassed Ficoll in viability, purity and yield of PBLs. To reduce labor, we developed an automated platform and compared two magnet configurations for cell separations. These more accurate and labor-saving magnet configurations allowed the lymphocytes to be tested in bioassays for rare antigen-specific T cells. The automated method succeeded at identifying 79% of patients with the rare PBLs of interest as compared with Ficoll's uniform failure. We validated improved upfront blood processing and show accurate detection of rare antigen-specific lymphocytes.Improving, automating and standardizing lymphocyte detections from whole blood may facilitate development of new cell-based biomarkers for human diseases. Improved upfront blood processes may lead to broad improvements in monitoring early trial outcome measurements in human clinical trials.

  1. Novel automated blood separations validate whole cell biomarkers.

    Science.gov (United States)

    Burger, Douglas E; Wang, Limei; Ban, Liqin; Okubo, Yoshiaki; Kühtreiber, Willem M; Leichliter, Ashley K; Faustman, Denise L

    2011-01-01

    Progress in clinical trials in infectious disease, autoimmunity, and cancer is stymied by a dearth of successful whole cell biomarkers for peripheral blood lymphocytes (PBLs). Successful biomarkers could help to track drug effects at early time points in clinical trials to prevent costly trial failures late in development. One major obstacle is the inaccuracy of Ficoll density centrifugation, the decades-old method of separating PBLs from the abundant red blood cells (RBCs) of fresh blood samples. To replace the Ficoll method, we developed and studied a novel blood-based magnetic separation method. The magnetic method strikingly surpassed Ficoll in viability, purity and yield of PBLs. To reduce labor, we developed an automated platform and compared two magnet configurations for cell separations. These more accurate and labor-saving magnet configurations allowed the lymphocytes to be tested in bioassays for rare antigen-specific T cells. The automated method succeeded at identifying 79% of patients with the rare PBLs of interest as compared with Ficoll's uniform failure. We validated improved upfront blood processing and show accurate detection of rare antigen-specific lymphocytes. Improving, automating and standardizing lymphocyte detections from whole blood may facilitate development of new cell-based biomarkers for human diseases. Improved upfront blood processes may lead to broad improvements in monitoring early trial outcome measurements in human clinical trials.

  2. COPD Exacerbation Biomarkers Validated Using Multiple Reaction Monitoring Mass Spectrometry.

    Directory of Open Access Journals (Sweden)

    Janice M Leung

    Full Text Available Acute exacerbations of chronic obstructive pulmonary disease (AECOPD result in considerable morbidity and mortality. However, there are no objective biomarkers to diagnose AECOPD.We used multiple reaction monitoring mass spectrometry to quantify 129 distinct proteins in plasma samples from patients with COPD. This analytical approach was first performed in a biomarker cohort of patients hospitalized with AECOPD (Cohort A, n = 72. Proteins differentially expressed between AECOPD and convalescent states were chosen using a false discovery rate 1.2. Protein selection and classifier building were performed using an elastic net logistic regression model. The performance of the biomarker panel was then tested in two independent AECOPD cohorts (Cohort B, n = 37, and Cohort C, n = 109 using leave-pair-out cross-validation methods.Five proteins were identified distinguishing AECOPD and convalescent states in Cohort A. Biomarker scores derived from this model were significantly higher during AECOPD than in the convalescent state in the discovery cohort (p<0.001. The receiver operating characteristic cross-validation area under the curve (CV-AUC statistic was 0.73 in Cohort A, while in the replication cohorts the CV-AUC was 0.77 for Cohort B and 0.79 for Cohort C.A panel of five biomarkers shows promise in distinguishing AECOPD from convalescence and may provide the basis for a clinical blood test to diagnose AECOPD. Further validation in larger cohorts is necessary for future clinical translation.

  3. The Growing Need for Validated Biomarkers and Endpoints for Dry Eye Clinical Research.

    Science.gov (United States)

    Roy, Neeta S; Wei, Yi; Kuklinski, Eric; Asbell, Penny A

    2017-05-01

    Biomarkers with minimally invasive and reproducible objective metrics provide the key to future paradigm shifts in understanding of the underlying causes of dry eye disease (DED) and approaches to treatment of DED. We review biomarkers and their validity in providing objective metrics for DED clinical research and patient care. The English-language literature in PubMed primarily over the last decade was surveyed for studies related to identification of biomarkers of DED: (1) inflammation, (2) point-of-care, (3) ocular imaging, and (4) genetics. Relevant studies in each group were individually evaluated for (1) methodological and analytical details, (2) data and concordance with other similar studies, and (3) potential to serve as validated biomarkers with objective metrics. Significant work has been done to identify biomarkers for DED clinical trials and for patient care. Interstudy variation among studies dealing with the same biomarker type was high. This could be attributed to biologic variations and/or differences in processing, and data analysis. Correlation with other signs and symptoms of DED was not always clear or present. Many of the biomarkers reviewed show the potential to serve as validated and objective metrics for clinical research and patient care in DED. Interstudy variation for a given biomarker emphasizes the need for detailed reporting of study methodology, including information on subject characteristics, quality control, processing, and analysis methods to optimize development of nonsubjective metrics. Biomarker development offers a rich opportunity to significantly move forward clinical research and patient care in DED. DED is an unmet medical need - a chronic pain syndrome associated with variable vision that affects quality of life, is common with advancing age, interferes with the comfortable use of contact lenses, and can diminish results of eye surgeries, such as cataract extraction, LASIK, and glaucoma procedures. It is a worldwide

  4. A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes

    DEFF Research Database (Denmark)

    Thanabalasingham, G.; Shah, N.; Vaxillaire, M.

    2011-01-01

    CRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays....... High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121......) a parts per thousand yenaEuro parts per thousand 0.91, p a parts per thousand currency signaEuro parts per thousand 1 x 10(-5)). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy...

  5. Multiple inflammatory biomarker detection in a prospective cohort study: a cross-validation between well-established single-biomarker techniques and electrochemiluminescense-based multi-array platform

    NARCIS (Netherlands)

    Bussel, van B.C.T.; Ferreira, I.; Waarenburg, M.P.H.; Greevenbroek, van M.M.J.; Kallen, van der C.J.H.; Henry, R.M.A.; Feskens, E.J.M.; Stehouwer, C.D.A.; Schalkwijk, C.G.

    2013-01-01

    Background - In terms of time, effort and quality, multiplex technology is an attractive alternative for well-established single-biomarker measurements in clinical studies. However, limited data comparing these methods are available. Methods - We measured, in a large ongoing cohort study (n = 574),

  6. Validation of Biomarkers for Prostate Cancer Prognosis

    Science.gov (United States)

    2016-11-01

    subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE...challenge, we formed the multi-institutional Canary Tissue Microarray Project. We have used rigorous clinical trial case/cohort design, taking care to...concluded that TACOMA algorithm as it currently stands, it is inadequate for automatic imaging reading. The main reason is that it still requires

  7. Validation of Biomarkers for Prostate Cancer Prognosis

    Science.gov (United States)

    2017-06-01

    been calibrated and already validated precisely for this purpose. In addition, multiparametric MRI shows good correlation with grade in that only the...StanfordUniversity, Stanford,California 2Departmentof ExperimentalandClinical Pharmacology ,UniversityofMinnesota,Minneapolis,Minnesota BACKGROUND. Protein...repeat biopsies, and more recently, MRI examinations [9–11]. This follow-up is necessitated by the inability to characterize the biological potential of

  8. Biomarkers as drug development tools: discovery, validation, qualification and use.

    Science.gov (United States)

    Kraus, Virginia B

    2018-06-01

    The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.

  9. Validation of fumonisin biomarkers in F344 rats

    International Nuclear Information System (INIS)

    Cai Qingsong; Tang Lili; Wang Jiasheng

    2007-01-01

    Fumonisins (FNs) are ubiquitous contaminants of cereal grains. Fumonisin B 1 (FB 1 ) was linked to several animal and human diseases. To validate FB 1 biomarkers for studying human disease risks, F344 rats were administered by gavage with either a single dose of 0, 10 or 25 mg FB 1 /kg body weight (BW) or repeated doses of 0, 1.0, or 2.5 mg FB 1 /kg BW/day for 5 weeks. FB 1 excretion and FB 1 -induced metabolic alterations of sphingolipids in rat urine, feces and serum were assessed. Dose-dependent urinary and fecal excretion of free FB 1 were found in both single-dose- and repeat-dose-treated rats. In the single-dose study, urinary sphinganine (Sa) to sphingosine (So) ratio (Sa/So) reached a maximum at day 7 for the high-dose group and at day 5 for the low-dose group, whereas serum Sa/So showed only marginal changes. In the repeat-dose study, urinary Sa/So was persistently elevated at 2 weeks, while serum Sa/So was unchanged. Time course changes of sphinganine 1-phosphate (SaP) and sphingosine 1-phosphate (SoP) were also examined. Although serum Sa/So and SaP/SoP ratios showed no signs of time- or dose-dependent changes, a 10-fold increase in urinary SaP/SoP was observed, suggesting that urinary SaP/SoP is a more sensitive biomarker for FB 1 exposure. The accumulation of SaP and SoP was evident in the time course of SaP/Sa and SoP/So, which may reflect activity changes of enzymes closely related to the metabolism and catabolism of SaP and SoP. These results provide concrete evidence towards the practical use of excreted FB 1 , Sa/So and SaP/SoP as biomarkers of exposure to FNs

  10. Validation of fumonisin biomarkers in F344 rats

    Energy Technology Data Exchange (ETDEWEB)

    Qingsong, Cai; Lili, Tang [Department of Environmental Toxicology and Institute of Environmental and Human Health, Box 41163, Texas Tech University, Lubbock, TX 79409-1163 (United States); Wang Jiasheng [Department of Environmental Toxicology and Institute of Environmental and Human Health, Box 41163, Texas Tech University, Lubbock, TX 79409-1163 (United States)], E-mail: js.wang@ttu.edu

    2007-11-15

    Fumonisins (FNs) are ubiquitous contaminants of cereal grains. Fumonisin B{sub 1} (FB{sub 1}) was linked to several animal and human diseases. To validate FB{sub 1} biomarkers for studying human disease risks, F344 rats were administered by gavage with either a single dose of 0, 10 or 25 mg FB{sub 1}/kg body weight (BW) or repeated doses of 0, 1.0, or 2.5 mg FB{sub 1}/kg BW/day for 5 weeks. FB{sub 1} excretion and FB{sub 1}-induced metabolic alterations of sphingolipids in rat urine, feces and serum were assessed. Dose-dependent urinary and fecal excretion of free FB{sub 1} were found in both single-dose- and repeat-dose-treated rats. In the single-dose study, urinary sphinganine (Sa) to sphingosine (So) ratio (Sa/So) reached a maximum at day 7 for the high-dose group and at day 5 for the low-dose group, whereas serum Sa/So showed only marginal changes. In the repeat-dose study, urinary Sa/So was persistently elevated at 2 weeks, while serum Sa/So was unchanged. Time course changes of sphinganine 1-phosphate (SaP) and sphingosine 1-phosphate (SoP) were also examined. Although serum Sa/So and SaP/SoP ratios showed no signs of time- or dose-dependent changes, a 10-fold increase in urinary SaP/SoP was observed, suggesting that urinary SaP/SoP is a more sensitive biomarker for FB{sub 1} exposure. The accumulation of SaP and SoP was evident in the time course of SaP/Sa and SoP/So, which may reflect activity changes of enzymes closely related to the metabolism and catabolism of SaP and SoP. These results provide concrete evidence towards the practical use of excreted FB{sub 1}, Sa/So and SaP/SoP as biomarkers of exposure to FNs.

  11. Cardiovascular biomarkers in clinical studies of type 2 diabetes

    DEFF Research Database (Denmark)

    Baldassarre, M P A; Andersen, A; Consoli, A

    2018-01-01

    biomarkers and 3) novel biomarkers (oxidative stress and endothelial dysfunction biomarkers). Within each category we present the currently best validated biomarkers with special focus on the population of interest (type 2 diabetes). For each individual biomarker, the physiological role, the validation...

  12. Validated biomarkers: The key to precision treatment in patients with breast cancer.

    Science.gov (United States)

    Duffy, Michael J; O'Donovan, Norma; McDermott, Enda; Crown, John

    2016-10-01

    Recent DNA sequencing and gene expression studies have shown that at a molecular level, almost every case of breast cancer is unique and different from other breast cancers. For optimum management therefore, every patient should receive treatment that is guided by the molecular composition of their tumor, i.e., precision treatment. While such a scenario is still some distance into the future, biomarkers are beginning to play an important role in preparing the way for precision treatment. In particular, biomarkers are increasingly being used for predicting patient outcome and informing as to the most appropriate type of systemic therapy to be administered. Mandatory biomarkers for every newly diagnosed case of breast cancer are estrogen receptors and progesterone receptors in selecting patients for endocrine treatment and HER2 for identifying patients likely to benefit from anti-HER2 therapy. Amongst the best validated prognostic biomarker tests are uPA/PAI-1, MammaPrint and Oncotype DX. Although currently, there are no biomarkers available for predicting response to specific forms of chemotherapy, uPA/PAI-1 and Oncotype DX can aid the identification of lymph node-negative patients that are most likely to benefit from adjuvant chemotherapy, in general. In order to accelerate progress towards precision treatment for women with breast cancer, we need additional predictive biomarkers, especially for enhancing the positive predictive value for endocrine and anti-HER2 therapies, as well as biomarkers for predicting response to specific forms of chemotherapy. The ultimate biomarker test for achieving the goal of precision treatment for patients with breast cancer will likely require a combination of gene sequencing and transcriptomic analysis of every patient's tumor. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. A Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers (PROVALID – Study Design and Baseline Characteristics

    Directory of Open Access Journals (Sweden)

    Susanne Eder

    2018-02-01

    Full Text Available Background/Aims: The prevalence of diabetes mellitus type 2 and kidney disease in these patients varies widely between European countries. Methods: In addition to store bio-samples the “Prospective cohort study in patients with type 2 diabetes mellitus for validation of biomarkers” collects information on history, physical status, laboratory measurements and medication in 4000 patients with diabetes mellitus type 2, being taken care of at the primary level of healthcare in 5 European countries (Austria, Hungary, Netherlands, Poland and Scotland. Next to comparing the rate of loss of eGFR between the countries, a further objective of the PROVALID study is to determine the 5-year cumulative incidence of renal and cardiovascular outcomes. Results: The mean age of the population recruited is 62.9±10 years, 54.6% are male and the mean BMI is 30.9±5.4 kg/m2. Metabolic control (median HBA1c 6.8 % (6.2; 7.5 is achieved via administration of metformin in 67.4% of the patients and insulin in 30.3%. Median systolic and diastolic blood pressure at recruitment is 135 (125; 146 and 80 (72; 85 mmHg, 65.4% of subjects received RAAS blocking agents. Mean eGFR is 80.7±29.2 ml/min/1.73m2 and median baseline albumin/creatinine ratio 8.3 mg (IQR: 3.8 and 25.1. Conclusion: PROVALID will provide information on incidence and progression of renal and cardiovascular disease and therapy in patients with type 2 diabetes mellitus in different European countries. Thus, in contrast to many other cohort studies we will be able to associate national clinical practise pattern with outcome in this highly vulnerable patient population.

  14. Validation of the Brazilian Healthy Eating Index-Revised Using Biomarkers in Children and Adolescents

    Directory of Open Access Journals (Sweden)

    Roseli B. D. Toffano

    2018-01-01

    Full Text Available The Brazilian Healthy Eating Index-Revised (BHEI-R can be used to determine overall dietary patterns. We assessed the BHEI-R scores in children and adolescents, aged from 9 to 13 years old, and associated its component scores with biomarkers of health and dietary exposure. Three 24-h recalls were used to generate BHEI-R. Biomarkers were analyzed in plasma and red blood cells. Correlation tests, agreement, and covariance analyses were used to associate BHEI-R components with biomarkers. Data from 167 subjects were used. The strongest correlations were between fruits, vegetables and legumes with omega-6 and omega-3 fatty acids, and β-carotene intakes. Milk and dairy correlated with plasma retinol and pyridoxine. All components rich in vegetable and animal protein sources correlated with plasma creatine. Total BHEI-R scores were positively associated with intakes of omega-6, omega-3, fiber and vitamin C, and inversely associated with energy and saturated fat intakes of individuals. Plasma β-carotene and riboflavin biomarkers were positively associated with total BHEI-R. An inadequate food consumption pattern was captured by both biomarkers of health and dietary exposure. BHEI-R was validated for the above dietary components and can be associated with metabolomics and nutritional epidemiological data in future pediatric studies.

  15. Potentials of single-cell biology in identification and validation of disease biomarkers.

    Science.gov (United States)

    Niu, Furong; Wang, Diane C; Lu, Jiapei; Wu, Wei; Wang, Xiangdong

    2016-09-01

    Single-cell biology is considered a new approach to identify and validate disease-specific biomarkers. However, the concern raised by clinicians is how to apply single-cell measurements for clinical practice, translate the message of single-cell systems biology into clinical phenotype or explain alterations of single-cell gene sequencing and function in patient response to therapies. This study is to address the importance and necessity of single-cell gene sequencing in the identification and development of disease-specific biomarkers, the definition and significance of single-cell biology and single-cell systems biology in the understanding of single-cell full picture, the development and establishment of whole-cell models in the validation of targeted biological function and the figure and meaning of single-molecule imaging in single cell to trace intra-single-cell molecule expression, signal, interaction and location. We headline the important role of single-cell biology in the discovery and development of disease-specific biomarkers with a special emphasis on understanding single-cell biological functions, e.g. mechanical phenotypes, single-cell biology, heterogeneity and organization of genome function. We have reason to believe that such multi-dimensional, multi-layer, multi-crossing and stereoscopic single-cell biology definitely benefits the discovery and development of disease-specific biomarkers. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  16. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema.

    Science.gov (United States)

    Lassere, Marissa N; Johnson, Kent R; Boers, Maarten; Tugwell, Peter; Brooks, Peter; Simon, Lee; Strand, Vibeke; Conaghan, Philip G; Ostergaard, Mikkel; Maksymowych, Walter P; Landewe, Robert; Bresnihan, Barry; Tak, Paul-Peter; Wakefield, Richard; Mease, Philip; Bingham, Clifton O; Hughes, Michael; Altman, Doug; Buyse, Marc; Galbraith, Sally; Wells, George

    2007-03-01

    There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Our objective was to review the literature on biomarkers and surrogates to develop a hierarchical schema that systematically evaluates and ranks the surrogacy status of biomarkers and surrogates; and to obtain feedback from stakeholders. After a systematic search of Medline and Embase on biomarkers, surrogate (outcomes, endpoints, markers, indicators), intermediate endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation level of evidence schema that evaluates biomarkers along 4 domains: Target, Study Design, Statistical Strength, and Penalties. Scores derived from 3 domains the Target that the marker is being substituted for, the Design of the (best) evidence, and the Statistical strength are additive. Penalties are then applied if there is serious counterevidence. A total score (0 to 15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. It was proposed that the term "surrogate" be restricted to markers attaining Levels 1 or 2 only. Most stakeholders agreed that this operationalization of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery, development, and approval.

  17. Validation of Candidate Serum Ovarian Cancer Biomarkers for Early Detection

    Directory of Open Access Journals (Sweden)

    Feng Su

    2007-01-01

    Full Text Available Objective: We have previously analyzed protein profi les using Surface Enhanced Laser Desorption and Ionization Time-Of-Flight Mass Spectroscopy (SELDI-TOF-MS [Kozak et al. 2003, Proc. Natl. Acad. Sci. U.S.A. 100:12343–8] and identified 3 differentially expressed serum proteins for the diagnosis of ovarian cancer (OC [Kozak et al. 2005, Proteomics, 5:4589–96], namely, apolipoprotein A-I (apoA-I, transthyretin (TTR and transferin (TF. The objective of the present study is to determine the efficacy of the three OC biomarkers for the detection of early stage (ES OC, in direct comparison to CA125.Methods: The levels of CA125, apoA-I, TTR and TF were measured in 392 serum samples [82 women with normal ovaries (N, 24 women with benign ovarian tumors (B, 85 women with ovarian tumors of low malignant potential (LMP, 126 women with early stage ovarian cancer (ESOC, and 75 women with late stage ovarian cancer (LSOC], obtained through the GOG and Cooperative Human Tissue Network. Following statistical analysis, multivariate regression models were built to evaluate the utility of the three OC markers in early detection.Results: Multiple logistic regression models (MLRM utilizing all biomarker values (CA125, TTR, TF and apoA-I from all histological subtypes (serous, mucinous, and endometrioid adenocarcinoma distinguished normal samples from LMP with 91% sensitivity (specifi city 92%, and normal samples from ESOC with a sensitivity of 89% (specifi city 92%. MLRM, utilizing values of all four markers from only the mucinous histological subtype showed that collectively, CA125, TTR, TF and apoA-I, were able to distinguish normal samples from mucinous LMP with 90% sensitivity, and further distinguished normal samples from early stage mucinous ovarian cancer with a sensitivity of 95%. In contrast, in serum samples from patients with mucinous tumors, CA125 alone was able to distinguish normal samples from LMP and early stage ovarian cancer with a sensitivity of

  18. Validation of biomarkers of food intake − critical assessment of candidate biomarkers

    DEFF Research Database (Denmark)

    Dragsted, Lars Ove; Gao, Qian; Scalbert, Augustin

    2018-01-01

    Biomarkers of food intake (BFIs) are a promising tool for limiting misclassification in nutrition research where more subjective dietary assessment instruments are used. They may also be used to assess compliance to dietary guidelines or to a dietary intervention. Biomarkers therefore hold promis...

  19. What is a biomarker? Research investments and lack of clinical integration necessitate a review of biomarker terminology and validation schema.

    Science.gov (United States)

    Ptolemy, Adam S; Rifai, Nader

    2010-01-01

    A continual trend of annual growth can be seen within research devoted to the discovery and validation of disease biomarkers within both the natural and clinical sciences. This expansion of intellectual endeavours was quantified through database searches of (a) research grant awards provided by the various branches of the National Institutes of Health (NIH) and (b) academic publications. A search of awards presented between 1986 and 2009 revealed a total of 28,856 grants awarded by the NIH containing the term "biomarker". The total funds for these awards in 2008 and 2009 alone were over $2.5 billion. During the same respective time frames, searches of "biomarker" and either "discovery", "genomics", "proteomics" or "metabolomics" yielded a total of 4,928 NIH grants whose combined funding exceeded $1.2 billion. The derived trend in NIH awards paralleled the annual expansion in "biomarker" literature. A PubMed search for the term, between 1990 and 2009, revealed a total of 441,510 published articles, with 38,457 published in 2008. These enormous investments and academic outputs however have not translated into the expected integration of new biomarkers for patient care. For example no proteomics derived biomarkers are currently being utilized in routine clinical management. This translational chasm necessitates a review of the previously proposed biomarker definitions and evaluation schema. A subsequent discussion of both the analytical and pre-analytical considerations for such research is also presented within. This required knowledge should aid scientists in their pursuit and validation of new biological markers of disease.

  20. Major depressive disorder: insight into candidate cerebrospinal fluid protein biomarkers from proteomics studies.

    Science.gov (United States)

    Al Shweiki, Mhd Rami; Oeckl, Patrick; Steinacker, Petra; Hengerer, Bastian; Schönfeldt-Lecuona, Carlos; Otto, Markus

    2017-06-01

    Major Depressive Disorder (MDD) is the leading cause of global disability, and an increasing body of literature suggests different cerebrospinal fluid (CSF) proteins as biomarkers of MDD. The aim of this review is to summarize the suggested CSF biomarkers and to analyze the MDD proteomics studies of CSF and brain tissues for promising biomarker candidates. Areas covered: The review includes the human studies found by a PubMed search using the following terms: 'depression cerebrospinal fluid biomarker', 'major depression biomarker CSF', 'depression CSF biomarker', 'proteomics depression', 'proteomics biomarkers in depression', 'proteomics CSF biomarker in depression', and 'major depressive disorder CSF'. The literature analysis highlights promising biomarker candidates and demonstrates conflicting results on others. It reveals 42 differentially regulated proteins in MDD that were identified in more than one proteomics study. It discusses the diagnostic potential of the biomarker candidates and their association with the suggested pathologies. Expert commentary: One ultimate goal of finding biomarkers for MDD is to improve the diagnostic accuracy to achieve better treatment outcomes; due to the heterogeneous nature of MDD, using bio-signatures could be a good strategy to differentiate MDD from other neuropsychiatric disorders. Notably, further validation studies of the suggested biomarkers are still needed.

  1. Calculations for Adjusting Endogenous Biomarker Levels During Analytical Recovery Assessments for Ligand-Binding Assay Bioanalytical Method Validation.

    Science.gov (United States)

    Marcelletti, John F; Evans, Cindy L; Saxena, Manju; Lopez, Adriana E

    2015-07-01

    It is often necessary to adjust for detectable endogenous biomarker levels in spiked validation samples (VS) and in selectivity determinations during bioanalytical method validation for ligand-binding assays (LBA) with a matrix like normal human serum (NHS). Described herein are case studies of biomarker analyses using multiplex LBA which highlight the challenges associated with such adjustments when calculating percent analytical recovery (%AR). The LBA test methods were the Meso Scale Discovery V-PLEX® proinflammatory and cytokine panels with NHS as test matrix. The NHS matrix blank exhibited varied endogenous content of the 20 individual cytokines before spiking, ranging from undetectable to readily quantifiable. Addition and subtraction methods for adjusting endogenous cytokine levels in %AR calculations are both used in the bioanalytical field. The two methods were compared in %AR calculations following spiking and analysis of VS for cytokines having detectable endogenous levels in NHS. Calculations for %AR obtained by subtracting quantifiable endogenous biomarker concentrations from the respective total analytical VS values yielded reproducible and credible conclusions. The addition method, in contrast, yielded %AR conclusions that were frequently unreliable and discordant with values obtained with the subtraction adjustment method. It is shown that subtraction of assay signal attributable to matrix is a feasible alternative when endogenous biomarkers levels are below the limit of quantitation, but above the limit of detection. These analyses confirm that the subtraction method is preferable over that using addition to adjust for detectable endogenous biomarker levels when calculating %AR for biomarker LBA.

  2. Discovery and validation of DNA hypomethylation biomarkers for liver cancer using HRM-specific probes.

    Directory of Open Access Journals (Sweden)

    Barbara Stefanska

    Full Text Available Poor prognosis of hepatocellular carcinoma (HCC associated with late diagnosis necessitates the development of early diagnostic biomarkers. We have previously delineated the landscape of DNA methylation in HCC patients unraveling the importance of promoter hypomethylation in activation of cancer- and metastasis-driving genes. The purpose of the present study was to test the feasibility that genes that are hypomethylated in HCC could serve as candidate diagnostic markers. We use high resolution melting analysis (HRM as a simple translatable PCR-based method to define methylation states in clinical samples. We tested seven regions selected from the shortlist of genes hypomethylated in HCC and showed that HRM analysis of several of them distinguishes methylation states in liver cancer specimens from normal adjacent liver and chronic hepatitis in the Shanghai area. Such regions were identified within promoters of neuronal membrane glycoprotein M6-B (GPM6B and melanoma antigen family A12 (MAGEA12 genes. Differences in HRM in the immunoglobulin superfamily Fc receptor (FCRL1 separated invasive tumors from less invasive HCC. The identified biomarkers differentiated HCC from chronic hepatitis in another set of samples from Dhaka. Although the main thrust in DNA methylation diagnostics in cancer is on hypermethylated genes, our study for the first time illustrates the potential use of hypomethylated genes as markers for solid tumors. After further validation in a larger cohort, the identified DNA hypomethylated regions can become important candidate biomarkers for liver cancer diagnosis and prognosis, especially in populations with high risk for HCC development.

  3. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema

    DEFF Research Database (Denmark)

    Lassere, Marissa N; Johnson, Kent R; Boers, Maarten

    2007-01-01

    endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. RESULTS: The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation...... level of evidence schema that evaluates biomarkers along 4 domains: Target, Study Design, Statistical Strength, and Penalties. Scores derived from 3 domains the Target that the marker is being substituted for, the Design of the (best) evidence, and the Statistical strength are additive. Penalties...... of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. CONCLUSION: Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery...

  4. Preclinical Validation of Salivary Biomarkers for Primary Sjogren's Syndrome

    NARCIS (Netherlands)

    Hu, Shen; Gao, Kai; Pollard, Rodney; Arellano-Garcia, Martha; Zhou, Hui; Zhang, Lei; Elashoff, David; Kallenberg, Cees G. M.; Vissink, Arjan; Wong, David T.

    2010-01-01

    Objective. Sjogren's syndrome (SS) is a systemic autoimmune disease with a variety of presenting symptoms that may delay its diagnosis. We previously discovered a number of candidate salivary biomarkers for primary SS using both mass spectrometry and expression microarray analysis. In the current

  5. Image Biomarkers and Precision Medicine: need for validation

    International Nuclear Information System (INIS)

    Marti-Bonmati, L.; Alberich-Bayarri, A.; Garcia Castro, F.

    2016-01-01

    Personalized medicine aims to improve the diagnosis, classification and the best treatment for a particular patient. Today, radiologists are challenged to translate new biological discoveries, the different mechanisms of disease and advances in preclinical research, into a clinical reality through patients, images and their associated parameters. In this article we show how digital medical imaging and computational data processing extract numerous quantitative parameters from the obtained images as virtual biopsies. To be implemented in clinical practice, biomarkers should provide useful and relevant information, improving processes diagnostic, therapeutic and monitoring, for the benefit of patients. (Author)

  6. Recommendations for adaptation and validation of commercial kits for biomarker quantification in drug development.

    Science.gov (United States)

    Khan, Masood U; Bowsher, Ronald R; Cameron, Mark; Devanarayan, Viswanath; Keller, Steve; King, Lindsay; Lee, Jean; Morimoto, Alyssa; Rhyne, Paul; Stephen, Laurie; Wu, Yuling; Wyant, Timothy; Lachno, D Richard

    2015-01-01

    Increasingly, commercial immunoassay kits are used to support drug discovery and development. Longitudinally consistent kit performance is crucial, but the degree to which kits and reagents are characterized by manufacturers is not standardized, nor are the approaches by users to adapt them and evaluate their performance through validation prior to use. These factors can negatively impact data quality. This paper offers a systematic approach to assessment, method adaptation and validation of commercial immunoassay kits for quantification of biomarkers in drug development, expanding upon previous publications and guidance. These recommendations aim to standardize and harmonize user practices, contributing to reliable biomarker data from commercial immunoassays, thus, enabling properly informed decisions during drug development.

  7. Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Richard J Perrin

    Full Text Available Ideally, disease modifying therapies for Alzheimer disease (AD will be applied during the 'preclinical' stage (pathology present with cognition intact before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1 (n = 24 and cognitively normal controls (CDR 0 (n = 24 were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA. Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs to a larger independent cohort (n = 292 that included individuals with very mild dementia (CDR 0.5. Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI] and 0.88 (0.81-0.94 CI, respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding

  8. Multicentric validation of proteomic biomarkers in urine specific for diabetic nephropathy

    DEFF Research Database (Denmark)

    Alkhalaf, Alaa; Zürbig, Petra; Bakker, Stephan J L

    2010-01-01

    /d and diabetic retinopathy (n = 66). Controls were matched for gender and diabetes duration (n = 82). METHODOLOGY/PRINCIPAL FINDINGS: Proteome analysis was performed blinded using high-resolution capillary electrophoresis coupled with mass spectrometry (CE-MS). Data were evaluated employing the previously......BACKGROUND: Urine proteome analysis is rapidly emerging as a tool for diagnosis and prognosis in disease states. For diagnosis of diabetic nephropathy (DN), urinary proteome analysis was successfully applied in a pilot study. The validity of the previously established proteomic biomarkers...... with respect to the diagnostic and prognostic potential was assessed on a separate set of patients recruited at three different European centers. In this case-control study of 148 Caucasian patients with diabetes mellitus type 2 and duration ≥5 years, cases of DN were defined as albuminuria >300 mg...

  9. Testing of the OMERACT 8 draft validation criteria for a soluble biomarker reflecting structural damage in rheumatoid arthritis: a systematic literature search on 5 candidate biomarkers

    DEFF Research Database (Denmark)

    Syversen, Silje W; Landewe, Robert; van der Heijde, Désirée

    2009-01-01

    OBJECTIVE: To test the OMERACT 8 draft validation criteria for soluble biomarkers by assessing the strength of literature evidence in support of 5 candidate biomarkers. METHODS: A systematic literature search was conducted on the 5 soluble biomarkers RANKL, osteoprotegerin (OPG), matrix...... metalloprotease (MMP-3), urine C-telopeptide of types I and II collagen (U-CTX-I and U CTX-II), focusing on the 14 OMERACT 8 criteria. Two electronic voting exercises were conducted to address: (1) strength of evidence for each biomarker as reflecting structural damage according to each individual criterion...

  10. Validation of α-Synuclein as a CSF Biomarker for Sporadic Creutzfeldt-Jakob Disease.

    Science.gov (United States)

    Llorens, Franc; Kruse, Niels; Karch, André; Schmitz, Matthias; Zafar, Saima; Gotzmann, Nadine; Sun, Ting; Köchy, Silja; Knipper, Tobias; Cramm, Maria; Golanska, Ewa; Sikorska, Beata; Liberski, Pawel P; Sánchez-Valle, Raquel; Fischer, Andre; Mollenhauer, Brit; Zerr, Inga

    2018-03-01

    The analysis of cerebrospinal fluid (CSF) biomarkers gains importance in the differential diagnosis of prion diseases. However, no single diagnostic tool or combination of them can unequivocally confirm prion disease diagnosis. Electrochemiluminescence (ECL)-based immunoassays have demonstrated to achieve high diagnostic accuracy in a variety of sample types due to their high sensitivity and dynamic range. Quantification of CSF α-synuclein (a-syn) by an in-house ECL-based ELISA assay has been recently reported as an excellent approach for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), the most prevalent form of human prion disease. In the present study, we validated a commercially available ECL-based a-syn ELISA platform as a diagnostic test for correct classification of sCJD cases. CSF a-syn was analysed in 203 sCJD cases with definite diagnosis and in 445 non-CJD cases. We investigated reproducibility and stability of CSF a-syn and made recommendations for its analysis in the sCJD diagnostic workup. A sensitivity of 98% and a specificity of 97% were achieved when using an optimal cut-off of 820 pg/mL a-syn. Moreover, we were able to show a negative correlation between a-syn levels and disease duration suggesting that CSF a-syn may be a good prognostic marker for sCJD patients. The present study validates the use of a-syn as a CSF biomarker of sCJD and establishes the clinical and pre-analytical parameters for its use in differential diagnosis in clinical routine. Additionally, the current test presents some advantages compared to other diagnostic approaches: it is fast, economic, requires minimal amount of CSF and a-syn levels are stable along disease progression.

  11. Resonance Raman Spectroscopic Evaluation of Skin Carotenoids as a Biomarker of Carotenoid Status for Human Studies

    Science.gov (United States)

    Mayne, Susan T.; Cartmel, Brenda; Scarmo, Stephanie; Jahns, Lisa; Ermakov, Igor V.; Gellermann, Werner

    2013-01-01

    Resonance Raman Spectroscopy (RRS) is a non-invasive method that has been developed to assess carotenoid status in human tissues including human skin in vivo. Skin carotenoid status has been suggested as a promising biomarker for human studies. This manuscript describes research done relevant to the development of this biomarker, including its reproducibility, validity, feasibility for use in field settings, and factors that affect the biomarker such as diet, smoking, and adiposity. Recent studies have evaluated the response of the biomarker to controlled carotenoid interventions, both supplement-based and dietary [e.g., provision of a high-carotenoid fruit and vegetable (F/V)-enriched diet], demonstrating consistent response to intervention. The totality of evidence supports the use of skin carotenoid status as an objective biomarker of F/V intake, although in the cross-sectional setting, diet explains only some of the variation in this biomarker. However, this limitation is also a strength in that skin carotenoids may effectively serve as an integrated biomarker of health, with higher status reflecting greater F/V intake, lack of smoking, and lack of adiposity. Thus, this biomarker holds promise as both a health biomarker and an objective indicator of F/V intake, supporting its further development and utilization for medical and public health purposes. PMID:23823930

  12. External validation of a biomarker and clinical prediction model for hospital mortality in acute respiratory distress syndrome.

    Science.gov (United States)

    Zhao, Zhiguo; Wickersham, Nancy; Kangelaris, Kirsten N; May, Addison K; Bernard, Gordon R; Matthay, Michael A; Calfee, Carolyn S; Koyama, Tatsuki; Ware, Lorraine B

    2017-08-01

    Mortality prediction in ARDS is important for prognostication and risk stratification. However, no prediction models have been independently validated. A combination of two biomarkers with age and APACHE III was superior in predicting mortality in the NHLBI ARDSNet ALVEOLI trial. We validated this prediction tool in two clinical trials and an observational cohort. The validation cohorts included 849 patients from the NHLBI ARDSNet Fluid and Catheter Treatment Trial (FACTT), 144 patients from a clinical trial of sivelestat for ARDS (STRIVE), and 545 ARDS patients from the VALID observational cohort study. To evaluate the performance of the prediction model, the area under the receiver operating characteristic curve (AUC), model discrimination, and calibration were assessed, and recalibration methods were applied. The biomarker/clinical prediction model performed well in all cohorts. Performance was better in the clinical trials with an AUC of 0.74 (95% CI 0.70-0.79) in FACTT, compared to 0.72 (95% CI 0.67-0.77) in VALID, a more heterogeneous observational cohort. The AUC was 0.73 (95% CI 0.70-0.76) when FACTT and VALID were combined. We validated a mortality prediction model for ARDS that includes age, APACHE III, surfactant protein D, and interleukin-8 in a variety of clinical settings. Although the model performance as measured by AUC was lower than in the original model derivation cohort, the biomarker/clinical model still performed well and may be useful for risk assessment for clinical trial enrollment, an issue of increasing importance as ARDS mortality declines, and better methods are needed for selection of the most severely ill patients for inclusion.

  13. Early-Phase Studies of Biomarkers

    DEFF Research Database (Denmark)

    Pepe, Margaret S.; Janes, Holly; Li, Christopher I.

    2016-01-01

    of a positive biomarker test in cases (true positive) to cost associated with a positive biomarker test in controls (false positive). Guidance is offered on soliciting the cost/benefit ratio. The calculations are based on the longstanding decision theory concept of providing a net benefit on average...... impact on patient outcomes of using the biomarker to make clinical decisions....

  14. Mass Spectrometry-Based Serum Proteomics for Biomarker Discovery and Validation.

    Science.gov (United States)

    Bhosale, Santosh D; Moulder, Robert; Kouvonen, Petri; Lahesmaa, Riitta; Goodlett, David R

    2017-01-01

    Blood protein measurements are used frequently in the clinic in the assessment of patient health. Nevertheless, there remains the need for new biomarkers with better diagnostic specificities. With the advent of improved technology for bioanalysis and the growth of biobanks including collections from specific disease risk cohorts, the plasma proteome has remained a target of proteomics research toward the characterization of disease-related biomarkers. The following protocol presents a workflow for serum/plasma proteomics including details of sample preparation both with and without immunoaffinity depletion of the most abundant plasma proteins and methodology for selected reaction monitoring mass spectrometry validation.

  15. Three-Dimensionally Functionalized Reverse Phase Glycoprotein Array for Cancer Biomarker Discovery and Validation.

    Science.gov (United States)

    Pan, Li; Aguilar, Hillary Andaluz; Wang, Linna; Iliuk, Anton; Tao, W Andy

    2016-11-30

    Glycoproteins have vast structural diversity that plays an important role in many biological processes and have great potential as disease biomarkers. Here, we report a novel functionalized reverse phase protein array (RPPA), termed polymer-based reverse phase glycoprotein array (polyGPA), to capture and profile glycoproteomes specifically, and validate glycoproteins. Nitrocellulose membrane functionalized with globular hydroxyaminodendrimers was used to covalently capture preoxidized glycans on glycoproteins from complex protein samples such as biofluids. The captured glycoproteins were subsequently detected using the same validated antibodies as in RPPA. We demonstrated the outstanding specificity, sensitivity, and quantitative capabilities of polyGPA by capturing and detecting purified as well as endogenous α-1-acid glycoprotein (AGP) in human plasma. We further applied quantitative N-glycoproteomics and the strategy to validate a panel of glycoproteins identified as potential biomarkers for bladder cancer by analyzing urine glycoproteins from bladder cancer patients or matched healthy individuals.

  16. Identification and validation of candidate epigenetic biomarkers in lung adenocarcinoma

    DEFF Research Database (Denmark)

    Daugaard, Iben; Dominguez, Diana; Kjeldsen, Tina E

    2016-01-01

    -adjacent normal lung tissue from four lung adenocarcinoma (LAC) patients using DNA methylation microarrays and identified 74 differentially methylated regions (DMRs). Eighteen DMRs were selected for validation in a cohort comprising primary tumors from 52 LAC patients and tumor-adjacent normal lung tissue from 32...... patients by methylation-sensitive high resolution melting (MS-HRM) analysis. Significant increases in methylation were confirmed for 15 DMRs associated with the genes and genomic regions: OSR1, SIM1, GHSR, OTX2, LOC648987, HIST1H3E, HIST1H3G/HIST1H2BI, HIST1H2AJ/HIST1H2BM, HOXD10, HOXD3, HOXB3/HOXB4, HOXA3...

  17. Mass spectrometry based biomarker discovery, verification, and validation--quality assurance and control of protein biomarker assays.

    Science.gov (United States)

    Parker, Carol E; Borchers, Christoph H

    2014-06-01

    In its early years, mass spectrometry (MS)-based proteomics focused on the cataloging of proteins found in different species or different tissues. By 2005, proteomics was being used for protein quantitation, typically based on "proteotypic" peptides which act as surrogates for the parent proteins. Biomarker discovery is usually done by non-targeted "shotgun" proteomics, using relative quantitation methods to determine protein expression changes that correlate with disease (output given as "up-or-down regulation" or "fold-increases"). MS-based techniques can also perform "absolute" quantitation which is required for clinical applications (output given as protein concentrations). Here we describe the differences between these methods, factors that affect the precision and accuracy of the results, and some examples of recent studies using MS-based proteomics to verify cancer-related biomarkers. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  18. Validation of SCT Methylation as a Hallmark Biomarker for Lung Cancers.

    Science.gov (United States)

    Zhang, Yu-An; Ma, Xiaotu; Sathe, Adwait; Fujimoto, Junya; Wistuba, Ignacio; Lam, Stephen; Yatabe, Yasushi; Wang, Yi-Wei; Stastny, Victor; Gao, Boning; Larsen, Jill E; Girard, Luc; Liu, Xiaoyun; Song, Kai; Behrens, Carmen; Kalhor, Neda; Xie, Yang; Zhang, Michael Q; Minna, John D; Gazdar, Adi F

    2016-03-01

    The human secretin gene (SCT) encodes secretin, a hormone with limited tissue distribution. Analysis of the 450k methylation array data in The Cancer Genome Atlas (TCGA) indicated that the SCT promoter region is differentially hypermethylated in lung cancer. Our purpose was to validate SCT methylation as a potential biomarker for lung cancer. We analyzed data from TCGA and developed and applied SCT-specific bisulfite DNA sequencing and quantitative methylation-specific polymerase chain reaction assays. The analyses of TCGA 450K data for 801 samples showed that SCT hypermethylation has an area under the curve (AUC) value greater than 0.98 that can be used to distinguish lung adenocarcinomas or squamous cell carcinomas from nonmalignant lung tissue. Bisulfite sequencing of lung cancer cell lines and normal blood cells allowed us to confirm that SCT methylation is highly discriminative. By applying a quantitative methylation-specific polymerase chain reaction assay, we found that SCT hypermethylation is frequently detected in all major subtypes of malignant non-small cell lung cancer (AUC = 0.92, n = 108) and small cell lung cancer (AUC = 0.93, n = 40) but is less frequent in lung carcinoids (AUC = 0.54, n = 20). SCT hypermethylation appeared in samples of lung carcinoma in situ during multistage pathogenesis and increased in invasive samples. Further analyses of TCGA 450k data showed that SCT hypermethylation is highly discriminative in most other types of malignant tumors but less frequent in low-grade malignant tumors. The only normal tissue with a high level of methylation was the placenta. Our findings demonstrated that SCT methylation is a highly discriminative biomarker for lung and other malignant tumors, is less frequent in low-grade malignant tumors (including lung carcinoids), and appears at the carcinoma in situ stage. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  19. Identification and Validation of Plasma Biomarkers in California Sea Lions

    Science.gov (United States)

    2014-04-24

    clinical studies to proceed. Several studies have suggested that domoic acid causes temporal lobe epilepsy in humans, rats, and sea lions. Temporal ...neatly into expression profiles of temporal lobe epilepsy and may be specific to excitotoxic injury in sea lions or denote some novel mechanistic... lobe epilepsy is partially characterized by a widening of the dentate gyrus granular cell layer known as granular cell dispersion (GCD). However, in

  20. Three-dimensionally Functionalized Reverse Phase Glycoprotein Array for Cancer Biomarker Discovery and Validation

    OpenAIRE

    Pan, Li; Aguilar, Hillary Andaluz; Wang, Linna; Iliuk, Anton; Tao, W. Andy

    2016-01-01

    Glycoproteins have vast structural diversity which plays an important role in many biological processes and have great potential as disease biomarkers. Here we report a novel functionalized reverse phase protein array (RPPA), termed polymer-based reverse phase GlycoProtein Array (polyGPA), to specifically capture and profile glycoproteomes, and validate glycoproteins. Nitrocellulose membrane functionalized with globular hydroxyaminodendrimers was used to covalently capture pre-oxidized glycan...

  1. Biomarkers for Early Detection of Clinically Relevant Prostate Cancer: A Multi-Institutional Validation Trial

    Science.gov (United States)

    2015-10-01

    biomarkers; prediction models; PCA3; TMPRSS2: ERG ; kallikreins; 4KScore; OncotypeDX; 5 3. ACCOMPLISHMENTS What were the major goals and...urine, alone or in combination with TMPRSS2: ERG mRNA. (Lead site: FHCRC) Milestone 10. Urine specimens identified for analysis. Due 12/30/2014...COMPLETED Milestone 11. PCA3 and TMPRSS2: ERG validation complete in PASS cohort. Due 12/30/2015 Milestone 12. Manuscript submission of PCA3 and TMPRSS2: ERG

  2. EEG-based motor network biomarkers for identifying target patients with stroke for upper limb rehabilitation and its construct validity.

    Directory of Open Access Journals (Sweden)

    Chun-Chuan Chen

    Full Text Available Rehabilitation is the main therapeutic approach for reducing poststroke functional deficits in the affected upper limb; however, significant between-patient variability in rehabilitation efficacy indicates the need to target patients who are likely to have clinically significant improvement after treatment. Many studies have determined robust predictors of recovery and treatment gains and yielded many great results using linear approachs. Evidence has emerged that the nonlinearity is a crucial aspect to study the inter-areal communication in human brains and abnormality of oscillatory activities in the motor system is linked to the pathological states. In this study, we hypothesized that combinations of linear and nonlinear (cross-frequency network connectivity parameters are favourable biomarkers for stratifying patients for upper limb rehabilitation with increased accuracy. We identified the biomarkers by using 37 prerehabilitation electroencephalogram (EEG datasets during a movement task through effective connectivity and logistic regression analyses. The predictive power of these biomarkers was then tested by using 16 independent datasets (i.e. construct validation. In addition, 14 right handed healthy subjects were also enrolled for comparisons. The result shows that the beta plus gamma or theta network features provided the best classification accuracy of 92%. The predictive value and the sensitivity of these biomarkers were 81.3% and 90.9%, respectively. Subcortical lesion, the time poststroke and initial Wolf Motor Function Test (WMFT score were identified as the most significant clinical variables affecting the classification accuracy of this predictive model. Moreover, 12 of 14 normal controls were classified as having favourable recovery. In conclusion, EEG-based linear and nonlinear motor network biomarkers are robust and can help clinical decision making.

  3. Imaging biomarker roadmap for cancer studies

    NARCIS (Netherlands)

    O'Connor, James P. B.; Aboagye, Eric O.; Adams, Judith E.; Aerts, Hugo J. W. L.; Barrington, Sally F.; Beer, Ambros J.; Boellaard, Ronald; Bohndiek, Sarah E.; Brady, Michael; Brown, Gina; Buckley, David L.; Chenevert, Thomas L.; Clarke, Laurence P.; Collette, Sandra; Cook, Gary J.; Desouza, Nandita M.; Dickson, John C.; Dive, Caroline; Evelhoch, Jeffrey L.; Faivre-Finn, Corinne; Gallagher, Ferdia A.; Gilbert, Fiona J.; Gillies, Robert J.; Goh, Vicky; Griffiths, J. R.; Groves, Ashley M.; Halligan, Steve; Harris, Adrian L.; Hawkes, David J.; Hoekstra, Otto S.; Huang, Erich P.; Hutton, Brian F.; Jackson, Edward F.; Jayson, Gordon C.; Jones, Andrew; Koh, Dow-Mu; Lacombe, Denis; Lambin, Philippe; Lassau, Nathalie; Leach, Martin O.; Lee, Ting-Yim; Leen, Edward L.; Lewis, Jason S.; Liu, Yan; Lythgoe, Mark F.; Manoharan, Prakash; Maxwell, Ross J.; Miles, Kenneth A.; Morgan, Bruno; Morris, Steve; Ng, Tony; Padhani, Anwar R.; Parker, Geoff J. M.; Partridge, Mike; Pathak, Arvind P.; Peet, Andrew C.; Punwani, Shonit; Reynolds, Andrew R.; Robinson, Simon P.; Shankar, Lalitha K.; Sharma, Ricky A.; Soloviev, Dmitry; Stroobants, Sigrid G.; Sullivan, Daniel C.; Taylor, Stuart A.; Tofts, Paul S.; Tozer, Gillian M.; van Herk, Marcel B.; Walker-Samuel, Simon; Wason, James; Williams, Kaye J.; Workman, Paul; Yankeelov, Thomas E.; Brindle, Kevin M.; McShane, Lisa M.; Jackson, Alan; Waterton, John C.

    Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and

  4. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema

    NARCIS (Netherlands)

    Lassere, Marissa N.; Johnson, Kent R.; Boers, Maarten; Tugwell, Peter; Brooks, Peter; Simon, Lee; Strand, Vibeke; Conaghan, Philip G.; Ostergaard, Mikkel; Maksymowych, Walter P.; Landewe, Robert; Bresnihan, Barry; Tak, Paul-Peter; Wakefield, Richard; Mease, Philip; Bingham, Clifton O.; Hughes, Michael; Altman, Doug; Buyse, Marc; Galbraith, Sally; Wells, George

    2007-01-01

    OBJECTIVE: There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Our objective was to review the literature on biomarkers and surrogates to

  5. Strategies to design clinical studies to identify predictive biomarkers in cancer research.

    Science.gov (United States)

    Perez-Gracia, Jose Luis; Sanmamed, Miguel F; Bosch, Ana; Patiño-Garcia, Ana; Schalper, Kurt A; Segura, Victor; Bellmunt, Joaquim; Tabernero, Josep; Sweeney, Christopher J; Choueiri, Toni K; Martín, Miguel; Fusco, Juan Pablo; Rodriguez-Ruiz, Maria Esperanza; Calvo, Alfonso; Prior, Celia; Paz-Ares, Luis; Pio, Ruben; Gonzalez-Billalabeitia, Enrique; Gonzalez Hernandez, Alvaro; Páez, David; Piulats, Jose María; Gurpide, Alfonso; Andueza, Mapi; de Velasco, Guillermo; Pazo, Roberto; Grande, Enrique; Nicolas, Pilar; Abad-Santos, Francisco; Garcia-Donas, Jesus; Castellano, Daniel; Pajares, María J; Suarez, Cristina; Colomer, Ramon; Montuenga, Luis M; Melero, Ignacio

    2017-02-01

    The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Systematic biomarker discovery and coordinative validation for different primary nephrotic syndromes using gas chromatography-mass spectrometry.

    Science.gov (United States)

    Lee, Jung-Eun; Lee, Yu Ho; Kim, Se-Yun; Kim, Yang Gyun; Moon, Ju-Young; Jeong, Kyung-Hwan; Lee, Tae Won; Ihm, Chun-Gyoo; Kim, Sooah; Kim, Kyoung Heon; Kim, Dong Ki; Kim, Yon Su; Kim, Chan-Duck; Park, Cheol Whee; Lee, Do Yup; Lee, Sang-Ho

    2016-07-01

    The goal of this study is to identify systematic biomarker panel for primary nephrotic syndromes from urine samples by applying a non-target metabolite profiling, and to validate their utility in independent sampling and analysis by multiplex statistical approaches. Nephrotic syndrome (NS) is a nonspecific kidney disorder, which is mostly represented by minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous glomerulonephritis (MGN). Since urine metabolites may mirror disease-specific functional perturbations in kidney injury, we examined urine samples for distinctive metabolic changes to identify biomarkers for clinical applications. We developed unbiased multi-component covarianced models from a discovery set with 48 samples (12 healthy controls, 12 MCD, 12 FSGS, and 12 MGN). To extensively validate their diagnostic potential, new batch from 54 patients with primary NS were independently examined a year after. In the independent validation set, the model including citric acid, pyruvic acid, fructose, ethanolamine, and cysteine effectively discriminated each NS using receiver operating characteristic (ROC) analysis except MCD-MGN comparison; nonetheless an additional metabolite multi-composite greatly improved the discrimination power between MCD and MGN. Finally, we proposed the re-constructed metabolic network distinctively dysregulated by the different NSs that may deepen comprehensive understanding of the disease mechanistic, and help the enhanced identification of NS and therapeutic plans for future. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. The BioFIND study: Characteristics of a clinically typical Parkinson's disease biomarker cohort

    Science.gov (United States)

    Goldman, Jennifer G.; Alcalay, Roy N.; Xie, Tao; Tuite, Paul; Henchcliffe, Claire; Hogarth, Penelope; Amara, Amy W.; Frank, Samuel; Rudolph, Alice; Casaceli, Cynthia; Andrews, Howard; Gwinn, Katrina; Sutherland, Margaret; Kopil, Catherine; Vincent, Lona; Frasier, Mark

    2016-01-01

    ABSTRACT Background Identifying PD‐specific biomarkers in biofluids will greatly aid in diagnosis, monitoring progression, and therapeutic interventions. PD biomarkers have been limited by poor discriminatory power, partly driven by heterogeneity of the disease, variability of collection protocols, and focus on de novo, unmedicated patients. Thus, a platform for biomarker discovery and validation in well‐characterized, clinically typical, moderate to advanced PD cohorts is critically needed. Methods BioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson's Disease) is a cross‐sectional, multicenter biomarker study that established a repository of clinical data, blood, DNA, RNA, CSF, saliva, and urine samples from 118 moderate to advanced PD and 88 healthy control subjects. Inclusion criteria were designed to maximize diagnostic specificity by selecting participants with clinically typical PD symptoms, and clinical data and biospecimen collection utilized standardized procedures to minimize variability across sites. Results We present the study methodology and data on the cohort's clinical characteristics. Motor scores and biospecimen samples including plasma are available for practically defined off and on states and thus enable testing the effects of PD medications on biomarkers. Other biospecimens are available from off state PD assessments and from controls. Conclusion Our cohort provides a valuable resource for biomarker discovery and validation in PD. Clinical data and biospecimens, available through The Michael J. Fox Foundation for Parkinson's Research and the National Institute of Neurological Disorders and Stroke, can serve as a platform for discovering biomarkers in clinically typical PD and comparisons across PD's broad and heterogeneous spectrum. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society PMID:27113479

  8. Crowdsourcing Disease Biomarker Discovery Research: The IP4IC Study.

    Science.gov (United States)

    Chancellor, Michael B; Bartolone, Sarah N; Veerecke, Andrew; Lamb, Laura E

    2018-05-01

    Biomarker discovery is limited by readily assessable, cost efficient human samples available in large numbers that represent the entire heterogeneity of the disease. We developed a novel, active participation crowdsourcing method to determine BP-RS (Bladder Permeability Defect Risk Score). It is based on noninvasive urinary cytokines to discriminate patients with interstitial cystitis/bladder pain syndrome who had Hunner lesions from controls and patients with interstitial cystitis/bladder pain syndrome but without Hunner lesions. We performed a national crowdsourcing study in cooperation with the Interstitial Cystitis Association. Patients answered demographic, symptom severity and urinary frequency questionnaires on a HIPAA (Health Insurance Portability and Accountability Act) compliant website. Urine samples were collected at home, stabilized with a preservative and sent to Beaumont Hospital for analysis. The expression of 3 urinary cytokines was used in a machine learning algorithm to develop BP-RS. The IP4IC study collected a total of 448 urine samples, representing 153 patients (147 females and 6 males) with interstitial cystitis/bladder pain syndrome, of whom 54 (50 females and 4 males) had Hunner lesions. A total of 159 female and 136 male controls also participated, who were age matched. A defined BP-RS was calculated to predict interstitial cystitis/bladder pain syndrome with Hunner lesions or a bladder permeability defect etiology with 89% validity. In this novel participation crowdsourcing study we obtained a large number of urine samples from 46 states, which were collected at home, shipped and stored at room temperature. Using a machine learning algorithm we developed BP-RS to quantify the risk of interstitial cystitis/bladder pain syndrome with Hunner lesions, which is indicative of a bladder permeability defect etiology. To our knowledge BP-RS is the first validated urine biomarker assay for interstitial cystitis/bladder pain syndrome and one of the

  9. Validation of photosynthetic-fluorescence parameters as biomarkers for isoproturon toxic effect on alga Scenedesmus obliquus

    Energy Technology Data Exchange (ETDEWEB)

    Dewez, David; Didur, Olivier; Vincent-Heroux, Jonathan [University of Quebec in Montreal, Department of Chemistry, Environmental Toxicology Research Center - TOXEN, 2101, Jeanne-Mance, Montreal, Quebec H2X 2J6 (Canada); Popovic, Radovan [University of Quebec in Montreal, Department of Chemistry, Environmental Toxicology Research Center - TOXEN, 2101, Jeanne-Mance, Montreal, Quebec H2X 2J6 (Canada)], E-mail: popovic.radovan@uqam.ca

    2008-01-15

    Photosynthetic-fluorescence parameters were investigated to be used as valid biomarkers of toxicity when alga Scenedesmus obliquus was exposed to isoproturon [3-(4-isopropylphenyl)-1,1-dimethylurea] effect. Chlorophyll fluorescence induction of algal cells treated with isoproturon showed inactivation of photosystem II (PSII) reaction centers and strong inhibition of PSII electron transport. A linear correlation was found (R{sup 2} {>=} 0.861) between the change of cells density affected by isoproturon and the change of effective PSII quantum yield ({phi}{sub M'}), photochemical quenching (q{sub P}) and relative photochemical quenching (q{sub P(rel)}) values. The cells density was also linearly dependent (R{sup 2} = 0.838) on the relative unquenched fluorescence parameter (UQF{sub (rel)}). Non-linear correlation was found (R{sup 2} = 0.937) only between cells density and the energy transfer efficiency from absorbed light to PSII reaction center (ABS/RC). The order of sensitivity determined by the EC-50% was: UQF{sub (rel)} > {phi}{sub M'} > q{sub P} > q{sub P(rel)} > ABS/RC. Correlations between cells density and those photosynthetic-fluorescence parameters provide supporting evidence to use them as biomarkers of toxicity for environmental pollutants. - Photosynthetic-fluorescence parameters are reliable biomarkers of isoproturon toxicity.

  10. Validation of photosynthetic-fluorescence parameters as biomarkers for isoproturon toxic effect on alga Scenedesmus obliquus

    International Nuclear Information System (INIS)

    Dewez, David; Didur, Olivier; Vincent-Heroux, Jonathan; Popovic, Radovan

    2008-01-01

    Photosynthetic-fluorescence parameters were investigated to be used as valid biomarkers of toxicity when alga Scenedesmus obliquus was exposed to isoproturon [3-(4-isopropylphenyl)-1,1-dimethylurea] effect. Chlorophyll fluorescence induction of algal cells treated with isoproturon showed inactivation of photosystem II (PSII) reaction centers and strong inhibition of PSII electron transport. A linear correlation was found (R 2 ≥ 0.861) between the change of cells density affected by isoproturon and the change of effective PSII quantum yield (Φ M' ), photochemical quenching (q P ) and relative photochemical quenching (q P(rel) ) values. The cells density was also linearly dependent (R 2 = 0.838) on the relative unquenched fluorescence parameter (UQF (rel) ). Non-linear correlation was found (R 2 = 0.937) only between cells density and the energy transfer efficiency from absorbed light to PSII reaction center (ABS/RC). The order of sensitivity determined by the EC-50% was: UQF (rel) > Φ M' > q P > q P(rel) > ABS/RC. Correlations between cells density and those photosynthetic-fluorescence parameters provide supporting evidence to use them as biomarkers of toxicity for environmental pollutants. - Photosynthetic-fluorescence parameters are reliable biomarkers of isoproturon toxicity

  11. Use of a food frequency questionnaire to assess diets of Jamaican adults: validation and correlation with biomarkers

    Science.gov (United States)

    2011-01-01

    Background Assessment of habitual diet is important in investigations of diet-disease relationships. Many epidemiological studies use the food frequency questionnaire (FFQ) to evaluate dietary intakes but few studies validate the instrument against biological markers. The aim of this study was to assess the validity and reproducibility of a previously validated 70-item food frequency questionnaire (FFQ) that was expanded to 120-items to assess diet - cancer relations. Methods Relative validity of the FFQ was assessed against twelve 24-hour recalls administered over 12 months in 70 subjects. The FFQ was repeated after one year (FFQ2) to assess reproducibility. The validity of the FFQ was evaluated by comparing nutrient and food group intakes from 24-hour recalls with the first and second FFQ. In addition, FFQ validity for cholesterol and folate were determined through correlation with biomarkers (serum cholesterol, serum folate and whole blood folate) in 159 control subjects participating in a case-control prostate cancer study. Results Compared to recalls the FFQ tended to overestimate energy and carbohydrate intakes but gave no differences in intake for protein and fat. Quartile agreement for energy-adjusted nutrient intakes between FFQ2 and recalls ranged from 31.8% - 77.3% for the lowest quartile and 20.8% - 81.0% in the highest quartile. Gross misclassification of nutrients was low with the exceptions of protein, vitamin E and retinol and weighted kappa values ranged from 0.33 to 0.64 for other nutrients. Validity correlations for energy-adjusted nutrients (excluding retinol) were moderate to high (0.38- 0.86). Correlation coefficients between multiple recalls and FFQ1 ranged from 0.27 (fruits) to 0.55 (red meat); the second FFQ gave somewhat higher coefficients (0.30 to 0.61). Reproducibility correlations for the nutrients ranged from 0.50 to 0.84. Calibration of the FFQ with biochemical markers showed modest correlations with serum cholesterol (0.24), serum

  12. Reverse-translational biomarker validation of Abnormal Repetitive Behaviors in mice: an illustration of the 4P's modeling approach.

    Science.gov (United States)

    Garner, Joseph P; Thogerson, Collette M; Dufour, Brett D; Würbel, Hanno; Murray, James D; Mench, Joy A

    2011-06-01

    The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Pre-emption, Personalization, and Populations) and biomarker-based medicine requires a radical shift in animal modeling methodology. In particular 4P's models will be non-determinant (i.e. disease severity will depend on secondary environmental and genetic factors); and validated by reverse-translation of animal homologues to human biomarkers. A powerful consequence of the biomarker approach is that different closely related disorders have a unique fingerprint of biomarkers. Animals can be validated as a highly specific model of a single disorder by matching this 'fingerprint'; or as a model of a symptom seen in multiple disorders by matching common biomarkers. Here we illustrate this approach with two Abnormal Repetitive Behaviors (ARBs) in mice: stereotypies and barbering (hair pulling). We developed animal versions of the neuropsychological biomarkers that distinguish human ARBs, and tested the fingerprint of the different mouse ARBs. As predicted, the two mouse ARBs were associated with different biomarkers. Both barbering and stereotypy could be discounted as models of OCD (even though they are widely used as such), due to the absence of limbic biomarkers which are characteristic of OCD and hence are necessary for a valid model. Conversely barbering matched the fingerprint of trichotillomania (i.e. selective deficits in set-shifting), suggesting it may be a highly specific model of this disorder. In contrast stereotypies were correlated only with a biomarker (deficits in response shifting) correlated with stereotypies in multiple disorders, suggesting that animal stereotypies model stereotypies in multiple disorders. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Validation of podocalyxin-like protein as a biomarker of poor prognosis in colorectal cancer

    International Nuclear Information System (INIS)

    Larsson, Anna; Fridberg, Marie; Gaber, Alexander; Nodin, Björn; Levéen, Per; Jönsson, Göran; Uhlén, Mathias; Birgisson, Helgi; Jirström, Karin

    2012-01-01

    Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and adverse outcome in several cancer types. We recently demonstrated that overexpression of PODXL is an independent factor of poor prognosis in colorectal cancer (CRC). The aim of this study was to validate these results in two additional independent patient cohorts and to examine the correlation between PODXL mRNA and protein levels in a subset of tumours. PODXL protein expression was analyzed by immunohistochemistry in tissue microarrays with tumour samples from a consecutive, retrospective cohort of 270 CRC patients (cohort 1) and a prospective cohort of 337 CRC patients (cohort 2). The expression of PODXL mRNA was measured by real-time quantitative PCR in a subgroup of 62 patients from cohort 2. Spearman´;s Rho and Chi-Square tests were used for analysis of correlations between PODXL expression and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between PODXL expression and time to recurrence (TTR), disease free survival (DFS) and overall survival (OS). High PODXL protein expression was significantly associated with unfavourable clinicopathological characteristics in both cohorts. In cohort 1, high PODXL expression was associated with a significantly shorter 5-year OS in both univariable (HR = 2.28; 95% CI 1.43-3.63, p = 0.001) and multivariable analysis (HR = 2.07; 95% CI 1.25-3.43, p = 0.005). In cohort 2, high PODXL expression was associated with a shorter TTR (HR = 2.93; 95% CI 1.26-6.82, p = 0.013) and DFS (HR = 2.44; 95% CI 1.32-4.54, p = 0.005), remaining significant in multivariable analysis, HR = 2.50; 95% CI 1.05-5.96, p = 0.038 for TTR and HR = 2.11; 95% CI 1.13-3.94, p = 0.019 for DFS. No significant correlation could be found between mRNA levels and protein expression of PODXL and there was no association between mRNA levels

  14. Biomarker Discovery in Human Prostate Cancer: an Update in Metabolomics Studies

    Directory of Open Access Journals (Sweden)

    Ana Rita Lima

    2016-08-01

    Full Text Available Prostate cancer (PCa is the most frequently diagnosed cancer and the second leading cause of cancer death among men in Western countries. Current screening techniques are based on the measurement of serum prostate specific antigen (PSA levels and digital rectal examination. A decisive diagnosis of PCa is based on prostate biopsies; however, this approach can lead to false-positive and false-negative results. Therefore, it is important to discover new biomarkers for the diagnosis of PCa, preferably noninvasive ones. Metabolomics is an approach that allows the analysis of the entire metabolic profile of a biological system. As neoplastic cells have a unique metabolic phenotype related to cancer development and progression, the identification of dysfunctional metabolic pathways using metabolomics can be used to discover cancer biomarkers and therapeutic targets. In this study, we review several metabolomics studies performed in prostatic fluid, blood plasma/serum, urine, tissues and immortalized cultured cell lines with the objective of discovering alterations in the metabolic phenotype of PCa and thus discovering new biomarkers for the diagnosis of PCa. Encouraging results using metabolomics have been reported for PCa, with sarcosine being one of the most promising biomarkers identified to date. However, the use of sarcosine as a PCa biomarker in the clinic remains a controversial issue within the scientific community. Beyond sarcosine, other metabolites are considered to be biomarkers for PCa, but they still need clinical validation. Despite the lack of metabolomics biomarkers reaching clinical practice, metabolomics proved to be a powerful tool in the discovery of new biomarkers for PCa detection.

  15. Optimisation and validation of a HS-SPME-GC-IT/MS method for analysis of carbonyl volatile compounds as biomarkers in human urine: Application in a pilot study to discriminate individuals with smoking habits.

    Science.gov (United States)

    Calejo, Isabel; Moreira, Nathalie; Araújo, Ana Margarida; Carvalho, Márcia; Bastos, Maria de Lourdes; de Pinho, Paula Guedes

    2016-02-01

    A new and simple analytical approach consisting of an automated headspace solid-phase microextraction (HS-SPME) sampler coupled to gas chromatography-ion trap/mass spectrometry detection (GC-IT/MS) with a prior derivatization step with O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride (PFBHA) was developed to detect volatile carbonyl metabolites with low molecular weights in human urine. A central composite design (CCD) was used to optimise the PFBHA concentration and extraction conditions that affect the efficiency of the SPME procedure. With a sample volume of 1 mL, optimal conditions were achieved by adding 300 mg/L of PFBHA and allowing the sample to equilibrate for 6 min at 62°C and then extracting the samples for 51 min at the same temperature, using a divinylbenzene/polydimethylsiloxane (DVB/PDMS) fibre. The method allowed the simultaneous identification and quantification of 44 carbonyl compounds consisting of aldehydes, dialdehydes, heterocyclic aldehydes and ketones. The method was validated with regards to the linearity, inter- and intra-day precision and accuracy. The detection limits ranged from 0.009 to 0.942 ng/mL, except for 4-hydroxy-2-nonenal (15 ng/mL), and the quantification limits varied from 0.029 to 1.66 ng/mL, except for butanal (2.78 ng/mL), 2-butanone (2.67 ng/mL), 4-heptanone (3.14 ng/mL) and 4-hydroxy-2-nonenal (50.0 ng/mL). The method accuracy was satisfactory, with recoveries ranging from 90 to 107%. The proof of applicability of the methodology was performed in a pilot target analysis of urine samples obtained from 18 healthy smokers and 18 healthy non-smokers (control group). Chemometric supervised analysis was performed using the volatile patterns acquired for these samples and clearly showed the potential of the volatile carbonyl profiles to discriminate urine from smoker and non-smoker subjects. 5-Methyl-2-furfural (p<0.0001), 2-methylpropanal, nonanal and 2-methylbutanal (p<0.05) were identified as potentially useful

  16. Validation of photosynthetic-fluorescence parameters as biomarkers for isoproturon toxic effect on alga Scenedesmus obliquus.

    Science.gov (United States)

    Dewez, David; Didur, Olivier; Vincent-Héroux, Jonathan; Popovic, Radovan

    2008-01-01

    Photosynthetic-fluorescence parameters were investigated to be used as valid biomarkers of toxicity when alga Scenedesmus obliquus was exposed to isoproturon [3-(4-isopropylphenyl)-1,1-dimethylurea] effect. Chlorophyll fluorescence induction of algal cells treated with isoproturon showed inactivation of photosystem II (PSII) reaction centers and strong inhibition of PSII electron transport. A linear correlation was found (R2>or=0.861) between the change of cells density affected by isoproturon and the change of effective PSII quantum yield (PhiM'), photochemical quenching (qP) and relative photochemical quenching (qP(rel)) values. The cells density was also linearly dependent (R2=0.838) on the relative unquenched fluorescence parameter (UQF(rel)). Non-linear correlation was found (R2=0.937) only between cells density and the energy transfer efficiency from absorbed light to PSII reaction center (ABS/RC). The order of sensitivity determined by the EC-50% was: UQF(rel)>PhiM'>qP>qP(rel)>ABS/RC. Correlations between cells density and those photosynthetic-fluorescence parameters provide supporting evidence to use them as biomarkers of toxicity for environmental pollutants.

  17. Development of a multi-institutional cohort to facilitate cardiovascular disease biomarker validation using existing biorepository samples linked to electronic health records.

    Science.gov (United States)

    Cross, Deanna S; McCarty, Catherine A; Steinhubl, Steven R; Carey, David J; Erlich, Porat M

    2013-08-01

    Emerging biomarkers for acute myocardial infarction (AMI) may enhance conventional risk-prediction algorithms if they are informative and associated with risk independently of established predictors. In this study, we constructed a cohort for testing emerging biomarkers for AMI in managed-care populations using existing biospecimen repositories linked to electronic health records (EHR). Electronic health record-based biorepositories collected by healthcare systems can be federated to provide large, methodologically sound testing sets for biomarker validation. Subjects ages 40 to 80 years were selected from 2 existing population-based biospecimen repositories. Incident AMI status and covariates were ascertained from the EHR. An ad hoc model for AMI risk was parameterized and validated. Simulation was used to test incremental gains in performance due to the inclusion of biomarkers in this model. Gains in performance were assessed in terms of area under the receiver operating characteristic curve (ROC-AUC) and case reclassification. A total of 18 329 individuals (57% female) contributed 108 400 person-years of EHR follow-up. The crude AMI incidence was 10.8 and 5.0 per 1000 person-years among males and females, respectively. Compared with the model with risk factors alone, inclusion of a simulated biomarker yielded substantial gains in sensitivity without loss of specificity. Furthermore, a net ROC-AUC gain of 13.3% was observed, as well as correct reclassification of 9.8% of incident cases (79 of 806) that were otherwise not considered statin-indicated at baseline under the National Cholesterol Education Program Adult Treatment Panel III criteria. More research is needed to assess incremental contribution of emerging biomarkers for AMI prediction in managed-care populations. © 2013 Wiley Periodicals, Inc.

  18. Urinary Excretion of Sodium, Nitrogen, and Sugar Amounts Are Valid Biomarkers of Dietary Sodium, Protein, and High Sugar Intake in Nonobese Adolescents.

    Science.gov (United States)

    Moore, Lori B; Liu, Sarah V; Halliday, Tanya M; Neilson, Andrew P; Hedrick, Valisa E; Davy, Brenda M

    2017-12-01

    Background: Objective indicators of dietary intake (e.g., biomarkers) are needed to overcome the limitations of self-reported dietary intake assessment methods in adolescents. To our knowledge, no controlled feeding studies to date have evaluated the validity of urinary sodium, nitrogen, or sugar excretion as dietary biomarkers in adolescents. Objective: This investigation aimed to evaluate the validity of urinary sodium, nitrogen, and total sugars (TS) excretion as biomarkers for sodium, protein, and added sugars (AS) intake in nonobese adolescents. Methods: In a crossover controlled feeding study design, 33 adolescents [12-18 y of age, 47 ± 25th percentile (mean ± SD) of body mass index (BMI; in kg/m 2 ) for age] consumed 5% AS [low added sugars (LAS)] and 25% AS [high added sugars (HAS)] isocaloric, macronutrient-matched (55% carbohydrate, 30% fat, and 15% protein) diets for 7 d each, in a randomly assigned order, with a 4-wk washout period between diets. On the final 2 d of each diet period, 24-h urine samples were collected. Thirty-two adolescents completed all measurements (97% retention). Results: Urinary sodium was not different from the expected 90% recovery (mean ± SD: 88% ± 18%, P = 0.50). Urinary nitrogen was correlated with protein intake ( r = 0.69, P sodium appears to be a valid biomarker for sodium intake in nonobese adolescents. Urinary nitrogen is associated with protein intake, but nitrogen excretion rates were less than previously reported for adults, possibly owing to adolescent growth rates. TS excretion reflects AS at 25% AS intake and was responsive to the change in AS intake. Thus, urinary biomarkers are promising objective indicators of dietary intake in adolescents, although larger-scale feeding trials are needed to confirm these findings. This trial was registered at clinicaltrials.gov as NCT02455388. © 2017 American Society for Nutrition.

  19. Skin carotenoids as biomarker for vegetable and fruit intake: Validation of the reflection-spectroscopy based “Veggie Meter”

    Science.gov (United States)

    Skin is a relatively stable storage medium for carotenoids; non-invasive optical measurements of carotenoids in this tissue via Resonance Raman spectroscopy (RRS) serve as a non-invasive biomarker for fruit and vegetable (F/V) intake. The RRS method has been validated with HPLC-based measurements of...

  20. Profiling and initial validation of urinary microRNAs as biomarkers in IgA nephropathy

    Directory of Open Access Journals (Sweden)

    Nannan Wang

    2015-06-01

    Full Text Available Background. MicroRNAs (miRNAs have been found in virtually all body fluids and used successfully as biomarkers for various diseases. Evidence indicates that miRNAs have important roles in IgA nephropathy (IgAN, a major cause of renal failure. In this study, we looked for differentially expressed miRNAs in IgAN and further evaluated the correlations between candidate miRNAs and the severity of IgAN.Methods. Microarray and RT-qRCR (real-time quantitative polymerase chain reaction were sequentially used to screen and further verify miRNA expression profiles in urinary sediments of IgAN patients in two independent cohorts. The screening cohort consisted of 32 urine samples from 18 patients with IgAN, 4 patients with MN (membranous nephropathy, 4 patients with MCD (minimal changes disease and 6 healthy subjects; the validation cohort consisted of 102 IgAN patients, 41 MN patients, 27 MCD patients and 34 healthy subjects. The renal pathological lesions of patients with IgAN were evaluated according to Lee’s grading system and Oxford classification.Results. At the screening phase, significance analysis of microarrays analysis showed that no miRNA was differentially expressed in the IgAN group compared to all control groups. But IgAN grade I–II and III subgroups (according to Lee’s grading system shared dysregulation of two miRNAs (miR-3613-3p and miR-4668-5p. At the validation phase, RT-qPCR results showed that urinary level of miR-3613-3p was significantly lower in IgAN than that in MN, MCD and healthy controls (0.47, 0.44 and 0.24 folds, respectively, all P < 0.01 by Mann–Whitney U test; urinary level of miR-4668-5p was also significantly lower in IgAN than that in healthy controls (0.49 fold, P < 0.01. Significant correlations were found between urinary levels of miR-3613-3p with 24-hour urinary protein excretion (Spearman r = 0.50, P = 0.034, eGFR (estimated glomerular filtration rate (r = − 0.48, P = 0.043 and Lee’s grades (r = 0.57, P

  1. Development and validation of a Luminex assay for detection of a predictive biomarker for PROSTVAC-VF therapy

    Science.gov (United States)

    Lucas, Julie L.; Tacheny, Erin A.; Ferris, Allison; Galusha, Michelle; Srivastava, Apurva K.; Ganguly, Aniruddha; Williams, P. Mickey; Sachs, Michael C.; Thurin, Magdalena; Tricoli, James V.; Ricker, Winnie; Gildersleeve, Jeffrey C.

    2017-01-01

    Cancer therapies can provide substantially improved survival in some patients while other seemingly similar patients receive little or no benefit. Strategies to identify patients likely to respond well to a given therapy could significantly improve health care outcomes by maximizing clinical benefits while reducing toxicities and adverse effects. Using a glycan microarray assay, we recently reported that pretreatment serum levels of IgM specific to blood group A trisaccharide (BG-Atri) correlate positively with overall survival of cancer patients on PROSTVAC-VF therapy. The results suggested anti-BG-Atri IgM measured prior to treatment could serve as a biomarker for identifying patients likely to benefit from PROSTVAC-VF. For continued development and clinical application of serum IgM specific to BG-Atri as a predictive biomarker, a clinical assay was needed. In this study, we developed and validated a Luminex-based clinical assay for measuring serum IgM specific to BG-Atri. IgM levels were measured with the Luminex assay and compared to levels measured using the microarray for 126 healthy individuals and 77 prostate cancer patients. This assay provided reproducible and consistent results with low %CVs, and tolerance ranges were established for the assay. IgM levels measured using the Luminex assay were found to be highly correlated to the microarray results with R values of 0.93–0.95. This assay is a Laboratory Developed Test (LDT) and is suitable for evaluating thousands of serum samples in CLIA certified laboratories that have validated the assay. In addition, the study demonstrates that discoveries made using neoglycoprotein-based microarrays can be readily migrated to a clinical assay. PMID:28771597

  2. A short food frequency questionnaire to assess intake of seafood and n-3 supplements: validation with biomarkers

    Directory of Open Access Journals (Sweden)

    Dahl Lisbeth

    2011-11-01

    Full Text Available Abstract Background Seafood intake is associated with beneficial effects for human health. Seafood provides a number of nutrients beyond the traditionally known long chain marine n-3 fatty acids EPA, DPA and DHA, such as protein, vitamin D, iodine, selenium and vitamin B12. Valid assessment of dietary seafood and n-3 supplement intakes are becoming increasingly crucial when giving recommendations to populations as seafood consumption is regarded as an important part of a healthy and balanced diet. Methods The aim was to validate a short FFQ developed for assessment of dietary intake of seafood and n-3 supplements using the biomarkers marine n-3 fatty acids in erythrocytes and 25(OHD in serum. Results Fifty-three healthy Norwegians aged 30-64 years with a mean BMI of 25 kg/m2 were compliant with the study protocol. 70% reported eating seafood for dinner one to two times per week, and 45% reported to eat seafood as spread, in salads or as snack meal three to five times or more per week. The FFQ correlated significantly with both the levels of marine n-3 fatty acids (r = 0.73, p Conclusion The present short FFQ predicted strongly the levels of marine n-3 fatty acids in erythrocytes, and predicted fairly good the level of serum 25(OHD and may therefore be a valid method for assessment of seafood and n-3 supplements intake among adults.

  3. Biomarkers in differentiating clinical dengue cases: A prospective cohort study

    Directory of Open Access Journals (Sweden)

    Gary Kim Kuan Low

    2015-12-01

    Full Text Available Objective: To evaluate five biomarkers (neopterin, vascular endothelial growth factor-A, thrombomodulin, soluble vascular cell adhesion molecule 1 and pentraxin 3 in differentiating clinical dengue cases. Methods: A prospective cohort study was conducted whereby the blood samples were obtained at day of presentation and the final diagnosis were obtained at the end of patients’ follow-up. All patients included in the study were 15 years old or older, not pregnant, not infected by dengue previously and did not have cancer, autoimmune or haematological disorder. Median test was performed to compare the biomarker levels. A subgroup Mann-Whitney U test was analysed between severe dengue and non-severe dengue cases. Monte Carlo method was used to estimate the 2-tailed probability (P value for independent variables with unequal number of patients. Results: All biomarkers except thrombomodulin has P value < 0.001 in differentiating among the healthy subjects, non-dengue fever, dengue without warning signs and dengue with warning signs/severe dengue. Subgroup analysis for all the biomarkers between severe dengue and non-severe dengue cases was not statistically significant except vascular endothelial growth factor-A (P < 0.05. Conclusions: Certain biomarkers were able to differentiate the clinical dengue cases. This could be potentially useful in classifying and determining the severity of dengue infected patients in the hospital.

  4. The validation of an invitro colonic motility assay as a biomarker for gastrointestinal adverse drug reactions

    International Nuclear Information System (INIS)

    Keating, Christopher; Martinez, Vicente; Ewart, Lorna; Gibbons, Stephen; Grundy, Luke; Valentin, Jean-Pierre; Grundy, David

    2010-01-01

    Motility-related gastrointestinal adverse drug reactions (GADRs), such as constipation and diarrhea, are some of the most frequently reported adverse events associated with the clinical development of new chemical entities, and for marketed drugs. However, biomarkers capable of detecting such GADRs are lacking. Here, we describe an in vitro assay developed to detect and quantify changes in intestinal motility as a surrogate biomarker for constipation/diarrhea-type GADRs. In vitro recordings of intraluminal pressure were used to monitor the presence of colonic peristaltic motor complexes (CPMCs) in mouse colonic segments. CPMC frequency, contractile and total mechanical activity were assessed. To validate the assay, two experimental protocols were conducted. Initially, five drugs with known gastrointestinal effects were tested to determine optimal parameters describing excitation and inhibition as markers for disturbances in colonic motility. This was followed by a 'blinded' evaluation of nine drugs associated with or without clinically identified constipation/diarrhea-type GADRs. Concentration-response relationships were determined for these drugs and the effects were compared with their maximal free therapeutic plasma concentration in humans. The assay detected stimulatory and inhibitory responses, likely correlating to the occurrence of diarrhea or constipation. Concentration-related effects were identified and potential mechanisms of action were inferred for several drugs. Based on the results from the fourteen drugs assessed, the sensitivity of the assay was calculated at 90%, with a specificity of 75% and predictive capacity of 86%. These results support the potential use of this assay in screening for motility-related GADRs during early discovery phase, safety pharmacology assessment.

  5. Validations of SCT Methylation as a Hallmark Biomarker for Lung Cancers

    Science.gov (United States)

    Fujimoto, Junya; Wistuba, Ignacio; Lam, Stephen; Yatabe, Yasushi; Wang, Yi-Wei; Stastny, Victor; Gao, Boning; Larsen, Jill E; Girard, Luc; Liu, Xiaoyun; Song, Kai; Behrens, Carmen; Kalhor, Neda; Xie, Yang; Zhang, Michael Q; Minna, John D; Gazdar, Adi F

    2016-01-01

    Background The human secretin (SCT) gene encodes secretin, a hormone with limited tissue distribution. Analysis of The Cancer Genome Atlas (TCGA) 450K methylation array data indicated that the SCT promoter region is differentially hypermethylated in lung cancer. Our purpose was to validate SCT methylation as a potential cancer biomarker for lung cancer. Methods We analyzed TCGA data, and developed and applied SCT-specific bisulfite DNA sequencing and quantitative methylation specific PCR (qMSP) assays. Results The analyses of TCGA 450K data of 801 samples showed that SCT hypermethylation has an area under curve (AUC) value >0.98 to distinguish lung adenocarcinomas or squamous cell carcinomas from non-malignant lung. We confirmed the highly discriminative SCT methylation by bisulfite sequencing of lung cancer cell lines and normal blood cells. By applying qMSP, we found that SCT hypermethylation was frequently detected in all major subtypes of malignant NSCLC (AUC=0.92, n=108) and SCLC cancers (AUC=0.93, n=40) but less frequently present in lung carcinoids (AUC=0.54, n=20). SCT hypermethylation appeared in lung carcinoma in situ samples during multistage pathogenesis and increased in invasive samples. Further analyses of TCGA 450K data showed that SCT hypermethylation is highly discriminative in most types of other malignant tumors but less frequently present in low-grade malignant tumors. The only normal tissue with high methylation was the placenta. Conclusions Our findings demonstrated that SCT methylation is a highly discriminative biomarker for lung and other malignant tumors, and less frequently present in low-grade malignant tumors including lung carcinoids, and appears at the carcinoma in situ stage. PMID:26725182

  6. Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease.

    Science.gov (United States)

    Wagner, M; Wolf, S; Reischies, F M; Daerr, M; Wolfsgruber, S; Jessen, F; Popp, J; Maier, W; Hüll, M; Frölich, L; Hampel, H; Perneczky, R; Peters, O; Jahn, H; Luckhaus, C; Gertz, H-J; Schröder, J; Pantel, J; Lewczuk, P; Kornhuber, J; Wiltfang, J

    2012-02-07

    To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale-Revised. CSF was obtained from all patients. A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Aβ(1-42)/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD- patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.

  7. Identification and Validation of PCAT14 as Prognostic Biomarker in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Sudhanshu Shukla

    2016-08-01

    Full Text Available Rapid advances in the discovery of long noncoding RNAs (lncRNAs have identified lineage- and cancer-specific biomarkers that may be relevant in the clinical management of prostate cancer (PCa. Here we assembled and analyzed a large RNA-seq dataset, from 585 patient samples, including benign prostate tissue and both localized and metastatic PCa to discover and validate differentially expressed genes associated with disease aggressiveness. We performed Sample Set Enrichment Analysis (SSEA and identified genes associated with low versus high Gleason score in the RNA-seq database. Comparing Gleason 6 versus 9+ PCa samples, we identified 99 differentially expressed genes with variable association to Gleason grade as well as robust expression in prostate cancer. The top-ranked novel lncRNA PCAT14, exhibits both cancer and lineage specificity. On multivariate analysis, low PCAT14 expression independently predicts for BPFS (P = .00126, PSS (P = .0385, and MFS (P = .000609, with trends for OS as well (P = .056. An RNA in-situ hybridization (ISH assay for PCAT14 distinguished benign vs malignant cases, as well as high vs low Gleason disease. PCAT14 is transcriptionally regulated by AR, and endogenous PCAT14 overexpression suppresses cell invasion. Thus, Using RNA-sequencing data we identify PCAT14, a novel prostate cancer and lineage-specific lncRNA. PCAT14 is highly expressed in low grade disease and loss of PCAT14 predicts for disease aggressiveness and recurrence.

  8. Validation of the 18-gene classifier as a prognostic biomarker of distant metastasis in breast cancer.

    Directory of Open Access Journals (Sweden)

    Skye Hung-Chun Cheng

    Full Text Available We validated an 18-gene classifier (GC initially developed to predict local/regional recurrence after mastectomy in estimating distant metastasis risk. The 18-gene scoring algorithm defines scores as: <21, low risk; ≥21, high risk. Six hundred eighty-three patients with primary operable breast cancer and fresh frozen tumor tissues available were included. The primary outcome was the 5-year probability of freedom from distant metastasis (DMFP. Two external datasets were used to test the predictive accuracy of 18-GC. The 5-year rates of DMFP for patients classified as low-risk (n = 146, 21.7% and high-risk (n = 537, 78.6% were 96.2% (95% CI, 91.1%-98.8% and 80.9% (74.6%-81.9%, respectively (median follow-up interval, 71.8 months. The 5-year rates of DMFP of the low-risk group in stage I (n = 62, 35.6%, stage II (n = 66, 20.1%, and stage III (n = 18, 10.3% were 100%, 94.2% (78.5%-98.5%, and 90.9% (50.8%-98.7%, respectively. Multivariate analysis revealed that 18-GC is an independent prognostic factor of distant metastasis (adjusted hazard ratio, 5.1; 95% CI, 1.8-14.1; p = 0.0017 for scores of ≥21. External validation showed that the 5-year rate of DMFP in the low- and high-risk patients was 94.1% (82.9%-100% and 80.3% (70.7%-89.9%, p = 0.06 in a Singapore dataset, and 89.5% (81.9%-94.1% and 73.6% (67.2%-79.0%, p = 0.0039 in the GEO-GSE20685 dataset, respectively. In conclusion, 18-GC is a viable prognostic biomarker for breast cancer to estimate distant metastasis risk.

  9. Urine stability studies for novel biomarkers of acute kidney injury.

    Science.gov (United States)

    Parikh, Chirag R; Butrymowicz, Isabel; Yu, Angela; Chinchilli, Vernon M; Park, Meyeon; Hsu, Chi-Yuan; Reeves, W Brian; Devarajan, Prasad; Kimmel, Paul L; Siew, Edward D; Liu, Kathleen D

    2014-04-01

    The study of novel urinary biomarkers of acute kidney injury has expanded exponentially. Effective interpretation of data and meaningful comparisons between studies require awareness of factors that can adversely affect measurement. We examined how variations in short-term storage and processing might affect the measurement of urine biomarkers. Cross-sectional prospective. Hospitalized patients from 2 sites: Yale New Haven Hospital (n=50) and University of California, San Francisco Medical Center (n=36). We tested the impact of 3 urine processing conditions on these biomarkers: (1) centrifugation and storage at 4°C for 48 hours before freezing at -80°C, (2) centrifugation and storage at 25°C for 48 hours before freezing at -80°C, and (3) uncentrifuged samples immediately frozen at -80°C. Urine concentrations of 5 biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), and cystatin C. We measured urine biomarkers by established enzyme-linked immunosorbent assay methods. Biomarker values were log-transformed, and agreement with a reference standard of immediate centrifugation and storage at -80°C was compared using concordance correlation coefficients (CCCs). Neither storing samples at 4°C for 48 hours nor centrifugation had a significant effect on measured levels, with CCCs higher than 0.9 for all biomarkers tested. For samples stored at 25°C for 48 hours, excellent CCC values (>0.9) also were noted between the test sample and the reference standard for NGAL, cystatin C, L-FABP and KIM-1. However, the CCC for IL-18 between samples stored at 25°C for 48 hours and the reference standard was 0.81 (95% CI, 0.66-0.96). No comparisons to fresh, unfrozen samples; no evaluation of the effect of protease inhibitors. All candidate markers tested using the specified assays showed high stability with both short-term storage at 4°C and without centrifugation

  10. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema

    DEFF Research Database (Denmark)

    Lassere, Marissa N; Johnson, Kent R; Boers, Maarten

    2007-01-01

    endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. RESULTS: The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation...... of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. CONCLUSION: Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery...... are then applied if there is serious counterevidence. A total score (0 to 15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. It was proposed that the term "surrogate" be restricted to markers attaining Levels 1 or 2 only. Most stakeholders agreed that this operationalization...

  11. Biomarker case-detection and prediction with potential for functional psychosis screening: development and validation of a model related to biochemistry, sensory neural timing and end organ performance.

    Directory of Open Access Journals (Sweden)

    Stephanie eFryar-Williams

    2016-04-01

    Full Text Available The Mental Health Biomarker Project aimed to discover case-predictive biomarkers for functional psychosis. In a retrospective, cross-sectional study, candidate marker results from 67, highly-characterized symptomatic participants were compared with results from 67 gender and age matched controls. Urine samples were analysed for catecholamines, their metabolites and hydroxylpyrolline-2-one, an oxidative stress marker. Blood samples were analyzed for vitamin and trace element cofactors of enzymes in the catecholamine synthesis and metabolism pathways. Cognitive, auditory and visual processing measures were assessed using a simple 45 minute, office-based procedure. Receiver Operating Curve (ROC and Odds Ratio analysis discovered biomarkers for deficits in folate, vitamin D and B6 and elevations in free copper to zinc ratio, catecholamines and the oxidative stress marker. Deficits were discovered in peripheral visual and auditory end-organ function, intra-cerebral auditory and visual processing speed and dichotic-listening performance. 15 ROC biomarker variables were divided into 5 functional domains. Through a repeated ROC process, individual ROC variables, followed by domains and finally the overall 15 set model, were dichotomously scored and tallied for abnormal results upon which it was found that ≥ 3 out of 5 abnormal domains achieved an AUC of 0.952 with a sensitivity of 84 per cent and a specificity of 90 percent. Six additional middle ear biomarkers in a 21 biomarker set increased sensitivity to 94% percent. Fivefold cross-validation yielded a mean sensitivity of 85% for the 15 biomarker set. Non-parametric regression analysis confirmed that ≥ 3 out of 5 abnormally scored domains predicted > 50% risk of case-ness whilst 4 abnormally-scored domains predicted 88% risk of case-ness and 100% diagnostic certainty was reached when all 5 domains were abnormally scored. These findings require validation in prospective cohorts and other mental

  12. Validation of HAV biomarker 2A for differential diagnostic of hepatitis A infected and vaccinated individuals using multiplex serology.

    Science.gov (United States)

    Bohm, Katrin; Filomena, Angela; Schneiderhan-Marra, Nicole; Krause, Gérard; Sievers, Claudia

    2017-10-13

    Worldwide about 1.5 million clinical cases of hepatitis A virus (HAV) infections occur every year and increasingly countries are introducing HAV vaccination into the childhood immunization schedule with a single dose instead of the originally licenced two dose regimen. Diagnosis of acute HAV infection is determined serologically by anti-HAV-IgM detection using ELISA. Additionally anti-HAV-IgG can become positive during the early phase of symptoms, but remains detectable after infection and also after vaccination against HAV. Currently no serological marker allows the differentiation of HAV vaccinated individuals and those with a past infection with HAV. Such differentiation would greatly improve evaluation of vaccination campaigns and risk assessment of HAV outbreaks. Here we tested the HAV non-structural protein 2A, important for the capsid assembly, as a biomarker for the differentiation of the immune status in previously infected and vaccinated individuals. HAV antigens were recombinantly expressed as glutathione-S-transferase (GST) fusion proteins. Using glutathione tagged, magnetic fluorescent beads (Luminex®), the proteins were affinity purified and used in a multiplex serological assay. The multiplex HAV assay was validated using 381 reference sera in which the immune status HAV negative, vaccinated or infected was established using the Abbott ARCHITECT® HAVAb-IgM or IgG, the commercial HAV ELISA from Abnova and documentation in vaccination cards. HAV multiplex serology showed a sensitivity of 99% and specificity of 95% to detect anti-HAV IgG/IgM positive individuals. HAV biomarker 2A allowed the differentiation between previously infected and vaccinated individuals. HAV vaccinated individuals and previously infected individuals could be identified with 92% accuracy. HAV biomarker 2A can be used to differentiate between previously HAV-vaccinated and naturally infected individuals. Within a multiplex serological approach this assay can provide valuable

  13. Circulating Long Noncoding RNAs as Potential Biomarkers of Sepsis: A Preliminary Study.

    Science.gov (United States)

    Dai, Yu; Liang, Zhixin; Li, Yulin; Li, Chunsun; Chen, Liangan

    2017-11-01

    Long noncoding RNAs (lncRNAs) are becoming promising biomarker candidates in various diseases as assessed via sequencing technologies. Sepsis is a life-threatening disease without ideal biomarkers. The aim of this study was to investigate the expression profile of lncRNAs in the peripheral blood of sepsis patients and to find potential biomarkers of sepsis. A lncRNA expression profile was performed using peripheral blood from three sepsis patients and three healthy volunteers using microarray screening. The differentially expressed lncRNAs were validated by real-time quantitative polymerase chain reaction (qRT-PCR) in a further set of 22 sepsis patients and 22 healthy volunteers. Among 1316 differentially expressed lncRNAs, 771 were downregulated and 545 were upregulated. Results of the qRT-PCR were consistent with the microarray data. lncRNA ENST00000452391.1, uc001vji.1, and uc021zxw.1 were significantly differentially expressed between sepsis patients and healthy volunteers. Moreover, lncRNA ENST00000504301.1 and ENST00000452391.1 were significantly differentially expressed between sepsis survivors and nonsurvivors. The lncRNA expression profile in the peripheral blood of sepsis patients significantly differed from that of healthy volunteers. Circulating lncRNAs may be good candidates for sepsis biomarkers.

  14. Parkinsons Disease-related Circulating microRNA Biomarkers——a Validation Study

    Directory of Open Access Journals (Sweden)

    David Petillo

    2015-02-01

    Full Text Available Parkinson's disease (PD is the second most common neurodegenerative disease. One of the major challenges in studying this progressive neurological disorder is to identify and develop biomarkers for early detection. Recently, several blood-based microRNA (miRNA biomarkers for PD have been reported. However, follow-up studies with new, independent cohorts have been rare. Previously, we identified a panel of four circulating miRNA biomarkers for PD (miR-1826, miR-450b-3p, miR-505, and miR-626 with biomarker performance of 91% sensitivity and 100% specificity. However, the expression of miR-450b-3p could not be detected in a new, independent validation set. In our current study, we improved the detection power by including a non-biased pre-amplification step in quantitative real-time PCR (qRT-PCR and reevaluated the biomarker performance. We found the panel of four PD-related miRNAs achieved the predictive power of 83% sensitivity and 75% specificity in our validation set. This is the first biomarker validation study of PD which showed reproducibility and robustness of plasma-based circulating miRNAs as molecular biomarkers and qRT-PCR as potential diagnostic assay.

  15. Identification and validation of cetuximab resistance associated long noncoding RNA biomarkers in metastatic colorectal cancer.

    Science.gov (United States)

    Peng, Ke; Liu, Ruiqi; Yu, Yiyi; Liang, Li; Yu, Shan; Xu, Xiaojing; Liu, Tianshu

    2018-01-01

    Cetuximab is one of the most widely used epidermal growth factor receptor (EGFR) inhibitors to treat patients with metastatic colorectal cancer (mCRC) harboring wild-type of RAS/RAF status. However, primary and acquired resistance to cetuximab is often found during target therapy. To gain insights into the functions of long non-coding RNA (lncRNA) in cetuximab resistance, we used a lncRNA-mining approach to distinguish lncRNA specific probes in Affymetrix HG-U133A 2.0 arrays. Then we performed lncRNA expression profiling in a cetuximab treated mCRC cohort from Gene Expression Ominus (GEO). The potential lncRNAs were further validated in acquired cetuximab resistant cell lines and clinical samples of our hospital. The functions and associated pathways of the prognostic lncRNA were predicted by GO and KEGG analyses. 249 lncRNA-specific probe sets (corresponding to 212 lncRNAs) were represented in Affymetrix HG-U133A 2.0 arrays. We found that 9 lncRNAs were differentially expressed between disease control group (DCG) and non-responders, and 5 of these 9 lncRNAs were significantly related with the progression-free survival (PFS) of the patients. Among those 5 lncRNAs, POU5F1P4 was also down-regulated in acquired cetuximab resistant cells, as well as in cetuximab resistant patients. Downregulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab. Our findings indicate the potential roles of lncRNAs in cetuximab resistance, and may provide the useful information for discovery of new biomarkers and therapeutic targets. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Accounting for control mislabeling in case-control biomarker studies.

    Science.gov (United States)

    Rantalainen, Mattias; Holmes, Chris C

    2011-12-02

    In biomarker discovery studies, uncertainty associated with case and control labels is often overlooked. By omitting to take into account label uncertainty, model parameters and the predictive risk can become biased, sometimes severely. The most common situation is when the control set contains an unknown number of undiagnosed, or future, cases. This has a marked impact in situations where the model needs to be well-calibrated, e.g., when the prediction performance of a biomarker panel is evaluated. Failing to account for class label uncertainty may lead to underestimation of classification performance and bias in parameter estimates. This can further impact on meta-analysis for combining evidence from multiple studies. Using a simulation study, we outline how conventional statistical models can be modified to address class label uncertainty leading to well-calibrated prediction performance estimates and reduced bias in meta-analysis. We focus on the problem of mislabeled control subjects in case-control studies, i.e., when some of the control subjects are undiagnosed cases, although the procedures we report are generic. The uncertainty in control status is a particular situation common in biomarker discovery studies in the context of genomic and molecular epidemiology, where control subjects are commonly sampled from the general population with an established expected disease incidence rate.

  17. Ionizing radiation biomarkers for potential use in epidemiological studies

    International Nuclear Information System (INIS)

    Pernot, Eileen; Cardis, Elisabeth; Hall, Janet; Baatout, Sarah; El Saghire, Houssein; Mohammed Abderrafi Benotmane; Roel Quintens; Blanchardon, Eric; Bouffler, Simon; Gomolka, Maria; Guertler, Anne; Kreuzer, Michaela; Harms-Ringdahl, Mats; Jeggo, Penny; Laurier, Dominique; Lindholm, Carita; Mkacher, Radhia; Sabatier, Laure; Tapio, Soile; De Vathaire, Florent

    2012-01-01

    Ionizing radiation is a known human carcinogen that can induce a variety of biological effects depending on the physical nature, duration, doses and dose-rates of exposure. However, the magnitude of health risks at low doses and dose-rates (below 100 mSv and/or 0.1 mSv min -1 ) remains controversial due to a lack of direct human evidence. It is anticipated that significant insights will emerge from the integration of epidemiological and biological research, made possible by molecular epidemiology studies incorporating biomarkers and bioassays. A number of these have been used to investigate exposure, effects and susceptibility to ionizing radiation, albeit often at higher doses and dose rates, with each reflecting time-limited cellular or physiological alterations. This review summarises the multidisciplinary work undertaken in the framework of the European project DoReMi (Low Dose Research towards Multidisciplinary Integration) to identify the most appropriate biomarkers for use in population studies. In addition to logistical and ethical considerations for conducting large-scale epidemiological studies, we discuss the relevance of their use for assessing the effects of low dose ionizing radiation exposure at the cellular and physiological level. We also propose a temporal classification of biomarkers that may be relevant for molecular epidemiology studies which need to take into account the time elapsed since exposure. Finally, the integration of biology with epidemiology requires careful planning and enhanced discussions between the epidemiology, biology and dosimetry communities in order to determine the most important questions to be addressed in light of pragmatic considerations including the appropriate population to be investigated (occupationally, environmentally or medically exposed), and study design. The consideration of the logistics of biological sample collection, processing and storing and the choice of biomarker or bioassay, as well as awareness of

  18. Clinical studies of biomarkers in suicide prediction

    OpenAIRE

    Jokinen, Jussi

    2007-01-01

    Suicide is a major clinical problem in psychiatry and suicidal behaviours can be seen as a nosological entity per se. Predicting suicide is difficult due to its low base-rate and the limited specificity of clinical predictors. Prospective biological studies suggest that dysfunctions in the hypothalamo pituitary adrenal (HPA) axis and the serotonergic system have predictive power for suicide in mood disorders. Suicide attempt is the most robust clinical predictor making suici...

  19. Development of a biomarkers database for the National Children's Study

    Energy Technology Data Exchange (ETDEWEB)

    Lobdell, Danelle T [US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Human Studies Division, Epidemiology and Biomarkers Branch, MD 58A, Research Triangle Park, NC 27711 (United States); Mendola, Pauline [US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Human Studies Division, Epidemiology and Biomarkers Branch, MD 58A, Research Triangle Park, NC 27711 (United States)

    2005-08-07

    The National Children's Study (NCS) is a federally-sponsored, longitudinal study of environmental influences on the health and development of children across the United States (www.nationalchildrensstudy.gov). Current plans are to study approximately 100,000 children and their families beginning before birth up to age 21 years. To explore potential biomarkers that could be important measurements in the NCS, we compiled the relevant scientific literature to identify both routine or standardized biological markers as well as new and emerging biological markers. Although the search criteria encouraged examination of factors that influence the breadth of child health and development, attention was primarily focused on exposure, susceptibility, and outcome biomarkers associated with four important child health outcomes: autism and neurobehavioral disorders, injury, cancer, and asthma. The Biomarkers Database was designed to allow users to: (1) search the biomarker records compiled by type of marker (susceptibility, exposure or effect), sampling media (e.g., blood, urine, etc.), and specific marker name; (2) search the citations file; and (3) read the abstract evaluations relative to our search criteria. A searchable, user-friendly database of over 2000 articles was created and is publicly available at: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=85844. PubMed was the primary source of references with some additional searches of Toxline, NTIS, and other reference databases. Our initial focus was on review articles, beginning as early as 1996, supplemented with searches of the recent primary research literature from 2001 to 2003. We anticipate this database will have applicability for the NCS as well as other studies of children's environmental health.

  20. Development of a biomarkers database for the National Children's Study

    International Nuclear Information System (INIS)

    Lobdell, Danelle T.; Mendola, Pauline

    2005-01-01

    The National Children's Study (NCS) is a federally-sponsored, longitudinal study of environmental influences on the health and development of children across the United States (www.nationalchildrensstudy.gov). Current plans are to study approximately 100,000 children and their families beginning before birth up to age 21 years. To explore potential biomarkers that could be important measurements in the NCS, we compiled the relevant scientific literature to identify both routine or standardized biological markers as well as new and emerging biological markers. Although the search criteria encouraged examination of factors that influence the breadth of child health and development, attention was primarily focused on exposure, susceptibility, and outcome biomarkers associated with four important child health outcomes: autism and neurobehavioral disorders, injury, cancer, and asthma. The Biomarkers Database was designed to allow users to: (1) search the biomarker records compiled by type of marker (susceptibility, exposure or effect), sampling media (e.g., blood, urine, etc.), and specific marker name; (2) search the citations file; and (3) read the abstract evaluations relative to our search criteria. A searchable, user-friendly database of over 2000 articles was created and is publicly available at: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=85844. PubMed was the primary source of references with some additional searches of Toxline, NTIS, and other reference databases. Our initial focus was on review articles, beginning as early as 1996, supplemented with searches of the recent primary research literature from 2001 to 2003. We anticipate this database will have applicability for the NCS as well as other studies of children's environmental health

  1. Role of the adverse outcome pathway framework in the validation of predictive biomarkers

    Science.gov (United States)

    Gene expression, enzyme activities, changes in endogenous metabolite or hormone titers, altered histology, etc. are widely used as biomarkers, but rarely, if ever, used for regulatory decision-making or to define management objectives. The disconnect between the measurements comm...

  2. Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Platinum Chemotherapy in Muscle Invasive Urothelial Carcinoma.

    Directory of Open Access Journals (Sweden)

    Alexander S Baras

    of both these protein biomarkers detected by IHC in biopsy specimens along with the relevant clinical parameters resulted in a prediction model able to significantly stratify the likelihood of NAC resistance in our cohort (n = 37 into two well separated halves: low-26% n = 19 and high-89% n = 18, Fisher's exact p = 0.0002.We illustrate the feasibility of translating a gene expression signature of NAC response from a discovery cohort into immunohistochemical markers readily applicable to MIBC biopsy specimens in our independent cohort. The results from this study are being characterized in additional validation cohorts. Additionally, we anticipate that emerging somatic mutations in MIBC will also be important for NAC response prediction. The relationship of the findings in this study to the current understanding of variant histologic subtypes of MIBC along with the evolving molecular subtypes of MIBC as it relates to NAC response remains to be fully characterized.

  3. Validation of beverage intake methods vs. hydration biomarker: a short review

    OpenAIRE

    Nissensohn, Mariela; Ruano, Cristina; Serra-Majem, Lluis

    2013-01-01

    Introduction: Fluid intake is difficult to monitor. Biomarkers of beverage intake are able to assess dietary intake / hydration status without the bias of self-reported dietary intake errors and also the intra-individual variability. Various markers have been proposed to assess hydration, however, to date; there is a lack of universally accepted biomarker that reflects changes of hydration status in response to changes in beverage intake. Aim: We conduct a review to find out the questionnaire...

  4. Validation of biomarkers for loin meat quality (m. longissimus) of pigs

    NARCIS (Netherlands)

    Pierzchala, M.; Hoekman, A.J.W.; Urbanski, P.; Kruijt, L.; Kristensen, L.; Young, L.; Oksbjerg, N.; Goluch, D.; Pas, te M.F.W.

    2014-01-01

    The aim of this study was to validate previously reported associations between microarray gene expression levels and pork quality traits using real-time PCR. Meat samples and meat quality data from 100 pigs were collected from a different pig breed to the one tested by microarray (Large White versus

  5. Development and validation of a skin fibroblast biomarker profile for schizophrenic patients

    Directory of Open Access Journals (Sweden)

    Marianthi Logotheti

    2016-12-01

    Full Text Available Gene expression profiles of non-neural tissues through microarray technology could be used in schizophrenia studies, adding more information to the results from similar studies on postmortem brain tissue. The ultimate goal of such studies is to develop accessible biomarkers. Supervised machine learning methodologies were used, in order to examine if the gene expression from skin fibroblast cells could be exploited for the classification of schizophrenic subjects. A dataset of skin fibroblasts gene expression of schizophrenia patients was obtained from Gene Expression Omnibus database. After applying statistical criteria, we concluded to genes that present a differential expression between the schizophrenic patients and the healthy controls. Based on those genes, functional profiling was performed with the BioInfoMiner web tool. After the statistical analysis, 63 genes were identified as differentially expressed. The functional profiling revealed interesting terms and pathways, such as mitogen activated protein kinase and cyclic adenosine monophosphate signaling pathways, as well as immune-related mechanisms. A subset of 16 differentially expressed genes from fibroblast gene expression profiling that occurred after Support Vector Machines Recursive Feature Elimination could efficiently separate schizophrenic from healthy controls subjects. These findings suggest that through the analysis of fibroblast based gene expression signature and with the application of machine learning methodologies we might conclude to a diagnostic classification model in schizophrenia.

  6. Biomarkers of Pediatric Brain Tumors

    Directory of Open Access Journals (Sweden)

    Mark D Russell

    2013-03-01

    Full Text Available Background and Need for Novel Biomarkers: Brain tumors are the leading cause of death by solid tumors in children. Although improvements have been made in their radiological detection and treatment, our capacity to promptly diagnose pediatric brain tumors in their early stages remains limited. This contrasts several other cancers where serum biomarkers such as CA 19-9 and CA 125 facilitate early diagnosis and treatment. Aim: The aim of this article is to review the latest literature and highlight biomarkers which may be of clinical use in the common types of primary pediatric brain tumor. Methods: A PubMed search was performed to identify studies reporting biomarkers in the bodily fluids of pediatric patients with brain tumors. Details regarding the sample type (serum, cerebrospinal fluid or urine, biomarkers analyzed, methodology, tumor type and statistical significance were recorded. Results: A total of 12 manuscripts reporting 19 biomarkers in 367 patients vs. 397 controls were identified in the literature. Of the 19 biomarkers identified, 12 were isolated from cerebrospinal fluid, 2 from serum, 3 from urine, and 2 from multiple bodily fluids. All but one study reported statistically significant differences in biomarker expression between patient and control groups.Conclusions: This review identifies a panel of novel biomarkers for pediatric brain tumors. It provides a platform for the further studies necessary to validate these biomarkers and, in addition, highlights several techniques through which new biomarkers can be discovered.

  7. Identification and Validation of a Diagnostic and Prognostic Multi-Gene Biomarker Panel for Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Klett, Hagen; Fuellgraf, Hannah; Levit-Zerdoun, Ella; Hussung, Saskia; Kowar, Silke; Küsters, Simon; Bronsert, Peter; Werner, Martin; Wittel, Uwe; Fritsch, Ralph; Busch, Hauke; Boerries, Melanie

    2018-01-01

    Late diagnosis and systemic dissemination essentially contribute to the invariably poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Therefore, the development of diagnostic biomarkers for PDAC are urgently needed to improve patient stratification and outcome in the clinic. By studying the transcriptomes of independent PDAC patient cohorts of tumor and non-tumor tissues, we identified 81 robustly regulated genes, through a novel, generally applicable meta-analysis. Using consensus clustering on co-expression values revealed four distinct clusters with genes originating from exocrine/endocrine pancreas, stromal and tumor cells. Three clusters were strongly associated with survival of PDAC patients based on TCGA database underlining the prognostic potential of the identified genes. With the added information of impact of survival and the robustness within the meta-analysis, we extracted a 17-gene subset for further validation. We show that it did not only discriminate PDAC from non-tumor tissue and stroma in fresh-frozen as well as formalin-fixed paraffin embedded samples, but also detected pancreatic precursor lesions and singled out pancreatitis samples. Moreover, the classifier discriminated PDAC from other cancers in the TCGA database. In addition, we experimentally validated the classifier in PDAC patients on transcript level using qPCR and exemplify the usage on protein level for three proteins (AHNAK2, LAMC2, TFF1) using immunohistochemistry and for two secreted proteins (TFF1, SERPINB5) using ELISA-based protein detection in blood-plasma. In conclusion, we present a novel robust diagnostic and prognostic gene signature for PDAC with future potential applicability in the clinic.

  8. Identification and Validation of a Diagnostic and Prognostic Multi-Gene Biomarker Panel for Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Hagen Klett

    2018-04-01

    Full Text Available Late diagnosis and systemic dissemination essentially contribute to the invariably poor prognosis of pancreatic ductal adenocarcinoma (PDAC. Therefore, the development of diagnostic biomarkers for PDAC are urgently needed to improve patient stratification and outcome in the clinic. By studying the transcriptomes of independent PDAC patient cohorts of tumor and non-tumor tissues, we identified 81 robustly regulated genes, through a novel, generally applicable meta-analysis. Using consensus clustering on co-expression values revealed four distinct clusters with genes originating from exocrine/endocrine pancreas, stromal and tumor cells. Three clusters were strongly associated with survival of PDAC patients based on TCGA database underlining the prognostic potential of the identified genes. With the added information of impact of survival and the robustness within the meta-analysis, we extracted a 17-gene subset for further validation. We show that it did not only discriminate PDAC from non-tumor tissue and stroma in fresh-frozen as well as formalin-fixed paraffin embedded samples, but also detected pancreatic precursor lesions and singled out pancreatitis samples. Moreover, the classifier discriminated PDAC from other cancers in the TCGA database. In addition, we experimentally validated the classifier in PDAC patients on transcript level using qPCR and exemplify the usage on protein level for three proteins (AHNAK2, LAMC2, TFF1 using immunohistochemistry and for two secreted proteins (TFF1, SERPINB5 using ELISA-based protein detection in blood-plasma. In conclusion, we present a novel robust diagnostic and prognostic gene signature for PDAC with future potential applicability in the clinic.

  9. CTF Void Drift Validation Study

    Energy Technology Data Exchange (ETDEWEB)

    Salko, Robert K. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Gosdin, Chris [Pennsylvania State Univ., University Park, PA (United States); Avramova, Maria N. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Gergar, Marcus [Pennsylvania State Univ., University Park, PA (United States)

    2015-10-26

    This milestone report is a summary of work performed in support of expansion of the validation and verification (V&V) matrix for the thermal-hydraulic subchannel code, CTF. The focus of this study is on validating the void drift modeling capabilities of CTF and verifying the supporting models that impact the void drift phenomenon. CTF uses a simple turbulent-diffusion approximation to model lateral cross-flow due to turbulent mixing and void drift. The void drift component of the model is based on the Lahey and Moody model. The models are a function of two-phase mass, momentum, and energy distribution in the system; therefore, it is necessary to correctly model the ow distribution in rod bundle geometry as a first step to correctly calculating the void distribution due to void drift.

  10. Validation of methylation biomarkers that distinguish normal colon mucosa from cancer patients from normal colon mucosa of patients without cancer

    Science.gov (United States)

    Cesaroni, Matteo; Powell, Jasmine; Sapienza, Carmen

    2014-01-01

    We have validated differences in DNA methylation levels of candidate genes previously reported to discriminate between normal colon mucosa of colon cancer patients and normal colon mucosa of individuals without cancer. Here, we report that CpG sites in 16 of the 30 candidate genes selected show significant differences in mean methylation level in normal colon mucosa of 24 cancer patients and 24 controls. A support vector machine trained on these data and data for an additional 66 CpGs yielded an 18-gene signature, composed of 10 of the validated candidate genes plus eight additional candidates. This model exhibited 96% sensitivity and 100% specificity in a 40-sample training set and classified all eight samples in the test set correctly. Moreover, we found a moderate-strong correlation (Pearson coefficients r=0.253-0.722) between methylation levels in colon mucosa and methylation levels in peripheral blood for seven of the 18 genes in the support vector model. These seven genes, alone, classified 44 of the 48 patients in the validation set correctly and five CpGs selected from only two of the seven genes classified 41 of the 48 patients in the discovery set correctly. These results suggest that methylation biomarkers may be developed that will, at minimum, serve as useful objective and quantitative diagnostic complements to colonoscopy as a cancer-screening tool. These data also suggest that it may be possible to monitor biomarker methylation levels in tissues collected much less invasively than by colonoscopy. PMID:24806665

  11. Development and validation of a multiplex add-on assay for sepsis biomarkers using xMAP technology

    DEFF Research Database (Denmark)

    Kofoed, Kristian; Schneider, Uffe Vest; Scheel, Troels

    2006-01-01

    BACKGROUND: Sepsis is a common and often fatal disease. Because sepsis can be caused by many different organisms, biomarkers that can aid in diagnosing sepsis and monitoring treatment efficacy are highly warranted. New sepsis markers may provide additional information to complement the currently...... triggering receptor expressed on myeloid cells-1 (sTREM-1), and macrophage migration inhibiting factor (MIF) was developed and validated in-house. This 3-plex assay was added to a commercially available interleukin-1beta (IL-1beta), IL-6, IL-8, granulocyte/macrophage colony-stimulating factor, and tumor...

  12. Development and validation of a multiplex add-on assay of biomarkers related to sepsis using xMAP technology

    DEFF Research Database (Denmark)

    Kofoed, Kristian; Vest Schneider, Uffe; Scheel, Troels

    2006-01-01

    BACKGROUND: Sepsis is a common and often fatal disease. Because sepsis can be caused by many different organisms, biomarkers that can aid in diagnosing sepsis and monitoring treatment efficacy are highly warranted. New sepsis markers may provide additional information to complement the currently...... triggering receptor expressed on myeloid cells-1 (sTREM-1), and macrophage migration inhibiting factor (MIF) was developed and validated in-house. This 3-plex assay was added to a commercially available interleukin-1beta (IL-1beta), IL-6, IL-8, granulocyte/macrophage colony-stimulating factor, and tumor...

  13. Hemostasis biomarkers and incident cognitive impairment: the REGARDS study.

    Science.gov (United States)

    Gillett, S R; McClure, L A; Callas, P W; Thacker, E L; Unverzagt, F W; Wadley, V G; Letter, A J; Cushman, M

    2018-05-07

    Vascular risk factors are associated with cognitive impairment, a condition with substantial public health burden. We hypothesized that hemostasis biomarkers related to vascular disease would be associated with risk of incident cognitive impairment. We performed a nested case control study including 1,082 participants with 3.5 years of follow-up in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a longitudinal cohort study of 30,239 black and white Americans ≥45 years old. Participants were free of stroke or cognitive impairment at baseline. Baseline D-dimer, fibrinogen, factor VIII, and protein C were measured in 495 cases who developed cognitive impairment during follow-up (based on abnormal scores on ≥2 of 3 cognitive tests) and 587 controls. Unadjusted ORs for incident cognitive impairment were 1.32 (95% CI 1.02, 1.70) for D-dimer >0.50 μg/mL, 1.83 (CI 1.24, 2.71) for fibrinogen >90 th percentile, 1.63 (CI 1.11, 2.38) for factor VIII >90 th percentile and 1.10 (CI 0.73, 1.65) for protein C impairment, with an adjusted OR 1.73 (CI 1.10, 2.69). Elevated D-dimer, fibrinogen, and factor VIII were not associated with occurrence of cognitive impairment after multivariable adjustment; however, having at least 2 abnormal biomarkers was associated, suggesting the burden of these biomarkers is relevant. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  14. Prediction potential of candidate biomarker sets identified and validated on gene expression data from multiple datasets

    Directory of Open Access Journals (Sweden)

    Karacali Bilge

    2007-10-01

    Full Text Available Abstract Background Independently derived expression profiles of the same biological condition often have few genes in common. In this study, we created populations of expression profiles from publicly available microarray datasets of cancer (breast, lymphoma and renal samples linked to clinical information with an iterative machine learning algorithm. ROC curves were used to assess the prediction error of each profile for classification. We compared the prediction error of profiles correlated with molecular phenotype against profiles correlated with relapse-free status. Prediction error of profiles identified with supervised univariate feature selection algorithms were compared to profiles selected randomly from a all genes on the microarray platform and b a list of known disease-related genes (a priori selection. We also determined the relevance of expression profiles on test arrays from independent datasets, measured on either the same or different microarray platforms. Results Highly discriminative expression profiles were produced on both simulated gene expression data and expression data from breast cancer and lymphoma datasets on the basis of ER and BCL-6 expression, respectively. Use of relapse-free status to identify profiles for prognosis prediction resulted in poorly discriminative decision rules. Supervised feature selection resulted in more accurate classifications than random or a priori selection, however, the difference in prediction error decreased as the number of features increased. These results held when decision rules were applied across-datasets to samples profiled on the same microarray platform. Conclusion Our results show that many gene sets predict molecular phenotypes accurately. Given this, expression profiles identified using different training datasets should be expected to show little agreement. In addition, we demonstrate the difficulty in predicting relapse directly from microarray data using supervised machine

  15. Biomarkers of Acute Stroke Etiology (BASE) Study Methodology.

    Science.gov (United States)

    Jauch, Edward C; Barreto, Andrew D; Broderick, Joseph P; Char, Doug M; Cucchiara, Brett L; Devlin, Thomas G; Haddock, Alison J; Hicks, William J; Hiestand, Brian C; Jickling, Glen C; June, Jeff; Liebeskind, David S; Lowenkopf, Ted J; Miller, Joseph B; O'Neill, John; Schoonover, Tim L; Sharp, Frank R; Peacock, W Frank

    2017-05-05

    Acute ischemic stroke affects over 800,000 US adults annually, with hundreds of thousands more experiencing a transient ischemic attack. Emergent evaluation, prompt acute treatment, and identification of stroke or TIA (transient ischemic attack) etiology for specific secondary prevention are critical for decreasing further morbidity and mortality of cerebrovascular disease. The Biomarkers of Acute Stroke Etiology (BASE) study is a multicenter observational study to identify serum markers defining the etiology of acute ischemic stroke. Observational trial of patients presenting to the hospital within 24 h of stroke onset. Blood samples are collected at arrival, 24, and 48 h later, and RNA gene expression is utilized to identify stroke etiology marker candidates. The BASE study began January 2014. At the time of writing, there are 22 recruiting sites. Enrollment is ongoing, expected to hit 1000 patients by March 2017. The BASE study could potentially aid in focusing the initial diagnostic evaluation to determine stroke etiology, with more rapidly initiated targeted evaluations and secondary prevention strategies.Clinical Trial Registration Clinicaltrials.gov NCT02014896 https://clinicaltrials.gov/ct2/show/NCT02014896?term=biomarkers+of+acute+stroke+etiology&rank=1.

  16. Validity and Reliability of Perinatal Biomarkers after Storage as Dry Blood Spots on Paper

    Science.gov (United States)

    Mihalopoulos, Nicole L.; Phillips, Terry M.; Slater, Hillarie; Thomson, J. Anne; Varner, Michael W.; Moyer-Mileur, Laurie J.

    2013-01-01

    Ojective To validate use of chip-based immunoaffinity capillary electrophoresis on dry blood spot samples (DBSS) to measure obesity-related cytokines. Methods Chip-based immunoaffinity capillary electrophoresis was used to measure adiponectin, leptin and insulin in serum and DBSS in pregnant women, cord blood, and infant heelstick at birth and 6 weeks. Concordance of measurements was determined with Pearson's correlation. Results We report high concordance between results obtained from serum and DBSS with the exception of cord blood specimens. Conclusions Ease of sample collection and storage makes DBSS an optimal method for use in studies involving neonates and young children. PMID:21735507

  17. Biomarkers for Early Detection of Clinically Relevant Prostate Cancer. A Multi-Institutional Validation Trial

    Science.gov (United States)

    2016-10-01

    aim 2: Evaluate a panel of four-kallikrein plasma-based markers to determine the presence of or progression to clinically relevant prostate cancer...and sent to Genomic Health, Inc. for processing. Task 3: Analysis of scientific Aim 2: Evaluate a panel of four-kallikrein plasma-based markers to...site: FHCRC) PCA3 and the TMPRSS2:ERG fusion are prostate cancer-specific biomarkers that hold promise for stratifying risk in the setting of AS

  18. Biomarkers for Early Detection of Clinically Relevant Prostate Cancer: A Multi-Institutional Validation Trial

    Science.gov (United States)

    2015-10-01

    provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently ...biomarker platforms in our multi-center, prospectively accrued prostate cancer active surveillance cohort – the Canary Prostate Active Surveillance...prostate cancers currently diagnosed are low risk tumors for which there is substantial evidence that the cancer will not cause harm if left untreated

  19. Field validation of a battery of biomarkers to assess sediment quality in Spanish ports

    Energy Technology Data Exchange (ETDEWEB)

    Martin-Diaz, M.L. [Departamento de Quimica Fisica, Facultad de Ciencias del Mar y Ambientales, Poligono Rio San Pedro s/n, 11510 Puerto Real, Cadiz (Spain); Consejo Superior de Investigaciones Cientificas, Instituto de Ciencias Marinas de Andalucia, Poligono Rio San Pedro s/n, 11510 Puerto Real, Cadiz (Spain)], E-mail: laura.martin@uca.es; Blasco, J. [Consejo Superior de Investigaciones Cientificas, Instituto de Ciencias Marinas de Andalucia, Poligono Rio San Pedro s/n, 11510 Puerto Real, Cadiz (Spain); Sales, D. [Departamento Ciencias Ambientales y Tecnologia de los Alimentos, Facultad de Ciencias del Mar y Ambientales, Poligono Rio San Pedro s/n, 11510 Puerto Real, Cadiz (Spain); DelValls, T.A. [Departamento de Quimica Fisica, Facultad de Ciencias del Mar y Ambientales, Poligono Rio San Pedro s/n, 11510 Puerto Real, Cadiz (Spain)

    2008-02-15

    Two marine invertebrates, the crab Carcinus maenas and the clam Ruditapes philippinarum, were used as bioindicator species to assess contamination when exposed in situ to sediment from different sites from four Spanish ports Cadiz (SW Spain), Huelva (SW Spain), Bilbao (NE Spain) and Pasajes (NE Spain). In an attempt to determine sediments toxicity, a combination of exposure biomarkers was analyzed in both species: metallothionein-like-proteins (MTLPs), ethoxyresorufin O-deethylase (EROD), glutathione S-transferase activity (GST), glutathione peroxidase (GPX) and glutathione reductase (GR). In parallel, physical and chemical characterization of the different sediments was performed and biological responses related to the contaminants. Significant induction of MTLPs was observed when organisms were exposed to metal contaminated sediments (port of Huelva), and EROD and GPX activities after exposure to sediments containing organic compounds (port of Bilbao and Pasajes). No significant interspecies differences were observed in biomarker responses except for the GST and GR. - A battery of biomarkers shows exposure to metals and organic compounds.

  20. Field validation of a battery of biomarkers to assess sediment quality in Spanish ports

    International Nuclear Information System (INIS)

    Martin-Diaz, M.L.; Blasco, J.; Sales, D.; DelValls, T.A.

    2008-01-01

    Two marine invertebrates, the crab Carcinus maenas and the clam Ruditapes philippinarum, were used as bioindicator species to assess contamination when exposed in situ to sediment from different sites from four Spanish ports Cadiz (SW Spain), Huelva (SW Spain), Bilbao (NE Spain) and Pasajes (NE Spain). In an attempt to determine sediments toxicity, a combination of exposure biomarkers was analyzed in both species: metallothionein-like-proteins (MTLPs), ethoxyresorufin O-deethylase (EROD), glutathione S-transferase activity (GST), glutathione peroxidase (GPX) and glutathione reductase (GR). In parallel, physical and chemical characterization of the different sediments was performed and biological responses related to the contaminants. Significant induction of MTLPs was observed when organisms were exposed to metal contaminated sediments (port of Huelva), and EROD and GPX activities after exposure to sediments containing organic compounds (port of Bilbao and Pasajes). No significant interspecies differences were observed in biomarker responses except for the GST and GR. - A battery of biomarkers shows exposure to metals and organic compounds

  1. Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criteria for Alzheimer’s disease

    Science.gov (United States)

    Jack, Clifford R; Barkhof, Frederik; Bernstein, Matt A; Cantillon, Marc; Cole, Patricia E; DeCarli, Charles; Dubois, Bruno; Duchesne, Simon; Fox, Nick C; Frisoni, Giovanni B; Hampel, Harald; Hill, Derek LG; Johnson, Keith; Mangin, Jean-François; Scheltens, Philip; Schwarz, Adam J; Sperling, Reisa; Suhy, Joyce; Thompson, Paul M; Weiner, Michael; Foster, Norman L

    2012-01-01

    Background The promise of Alzheimer’s disease (AD) biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging (MRI) measure in AD and thus represents the most rational target for an initial effort at standardization. Methods and Results The authors of this position paper propose a path toward this goal. The steps include: 1) Establish and empower an oversight board to manage and assess the effort, 2) Adopt the standardized definition of anatomic hippocampal boundaries on MRI arising from the EADC-ADNI hippocampal harmonization effort as a Reference Standard, 3) Establish a scientifically appropriate, publicly available Reference Standard Dataset based on manual delineation of the hippocampus in an appropriate sample of subjects (ADNI), and 4) Define minimum technical and prognostic performance metrics for validation of new measurement techniques using the Reference Standard Dataset as a benchmark. Conclusions Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent is to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry is envisioned as a template that could be applied to other imaging biomarkers. PMID:21784356

  2. Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis

    DEFF Research Database (Denmark)

    Teunissen, Charlotte; Menge, Til; Altintas, Ayse

    2013-01-01

    The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus......). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use...

  3. [Collaborative projects with academia for regulatory science studies on biomarkers].

    Science.gov (United States)

    Saito, Yoshiro; Nakamura, Ryosuke; Maekawa, Keiko

    2014-01-01

    Biomarkers are useful tools to be utilized as indicators/predictors of disease severity and drug responsiveness/safety, and thus are expected to promote efficient drug development and to accelerate proper use of approved drugs. Many academic achievements have been reported, but only a small number of biomarkers are used in clinical trials and drug treatments. Regulatory sciences on biomarkers for their secure development and proper qualification are necessary to facilitate their practical application. We started to collaborate with Tohoku University and Nagoya City University for sample quality, biomarker identification, evaluation of their usage, and making guidances. In this short review, scheme and progress of these projects are introduced.

  4. Smoking reduction and biomarkers in two longitudinal studies

    DEFF Research Database (Denmark)

    Godtfredsen, Nina; Prescott, Eva; Vestbo, Jørgen

    2006-01-01

    AIMS: To measure reduction in exposure to smoke in two population-based studies of self-reported smoking reduction not using nicotine replacement. DESIGN: Cross-sectional analyses of biomarkers and smoking. SETTING: Data from two time-points in the Copenhagen City Heart Study (CCHS), 1981....../83 and 1991/94, and the Copenhagen Male Study (CMS) in 1976 and 1985/86, respectively. PARTICIPANTS: There were 3026 adults who were smokers at both time-points in the CCHS and 1319 men smoking at both time-points in the CMS. MEASUREMENTS: Smoking status and tobacco consumption were assessed by self...... a reduction in cigarettes per day of 50% or more without quitting were compared with continuing medium, heavy and light smokers (1-14 g/day) using linear regression. Sex (CCHS only), age, self-reported inhalation of smoke, duration of smoking, type of tobacco and amount smoked were included as covariates...

  5. Utilization of never-medicated bipolar disorder patients towards development and validation of a peripheral biomarker profile.

    Directory of Open Access Journals (Sweden)

    Catherine L Clelland

    Full Text Available There are currently no biological tests that differentiate patients with bipolar disorder (BPD from healthy controls. While there is evidence that peripheral gene expression differences between patients and controls can be utilized as biomarkers for psychiatric illness, it is unclear whether current use or residual effects of antipsychotic and mood stabilizer medication drives much of the differential transcription. We therefore tested whether expression changes in first-episode, never-medicated BPD patients, can contribute to a biological classifier that is less influenced by medication and could potentially form a practicable biomarker assay for BPD. We employed microarray technology to measure global leukocyte gene expression in first-episode (n=3 and currently medicated BPD patients (n=26, and matched healthy controls (n=25. Following an initial feature selection of the microarray data, we developed a cross-validated 10-gene model that was able to correctly predict the diagnostic group of the training sample (26 medicated patients and 12 controls, with 89% sensitivity and 75% specificity (p<0.001. The 10-gene predictor was further explored via testing on an independent cohort consisting of three pairs of monozygotic twins discordant for BPD, plus the original enrichment sample cohort (the three never-medicated BPD patients and 13 matched control subjects, and a sample of experimental replicates (n=34. 83% of the independent test sample was correctly predicted, with a sensitivity of 67% and specificity of 100% (although this result did not reach statistical significance. Additionally, 88% of sample diagnostic classes were classified correctly for both the enrichment (p=0.015 and the replicate samples (p<0.001. We have developed a peripheral gene expression biomarker profile, that can classify healthy controls from patients with BPD receiving antipsychotic or mood stabilizing medication, which has both high sensitivity and specificity

  6. EDRN Pre-Validation of Multiplex Biomarker in Urine — EDRN Public Portal

    Science.gov (United States)

    The goal of this proposal is to begin to establish an EDRN “pre-validation” trial of a multiplex set of transcripts, including the ETS gene fusions, in post-DRE urine sediments. As can be evidenced by our preliminary data, we have established the utility of this multiplex urine test (which includes TMPRSS-ERG, SPINK1, PCA3 and GOLPH2) in a cohort of prospectively collected urine sediments from the University of Michigan EDRN CEVC site (collected by co-I, Dr. John Wei). In this proposal, we will run this multiplex assay on prospectively collected post-DRE urines collected from other EDRN sites. The idea is to couple this “pre-validation” study with an EDRN validation trial under consideration for the Gen-Probe PCA3 urine test (directed by Drs. John Wei and Harry Rittenhouse).

  7. Prognostic biomarkers in osteoarthritis

    Science.gov (United States)

    Attur, Mukundan; Krasnokutsky-Samuels, Svetlana; Samuels, Jonathan; Abramson, Steven B.

    2013-01-01

    Purpose of review Identification of patients at risk for incident disease or disease progression in osteoarthritis remains challenging, as radiography is an insensitive reflection of molecular changes that presage cartilage and bone abnormalities. Thus there is a widely appreciated need for biochemical and imaging biomarkers. We describe recent developments with such biomarkers to identify osteoarthritis patients who are at risk for disease progression. Recent findings The biochemical markers currently under evaluation include anabolic, catabolic, and inflammatory molecules representing diverse biological pathways. A few promising cartilage and bone degradation and synthesis biomarkers are in various stages of development, awaiting further validation in larger populations. A number of studies have shown elevated expression levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma). These chemical biomarkers are under evaluation in combination with imaging biomarkers to predict early onset and the burden of disease. Summary Prognostic biomarkers may be used in clinical knee osteoarthritis to identify subgroups in whom the disease progresses at different rates. This could facilitate our understanding of the pathogenesis and allow us to differentiate phenotypes within a heterogeneous knee osteoarthritis population. Ultimately, such findings may help facilitate the development of disease-modifying osteoarthritis drugs (DMOADs). PMID:23169101

  8. Validation of methylation biomarkers that distinguish normal colon mucosa of cancer patients from normal colon mucosa of patients without cancer.

    Science.gov (United States)

    Cesaroni, Matteo; Powell, Jasmine; Sapienza, Carmen

    2014-07-01

    We have validated differences in DNA methylation levels of candidate genes previously reported to discriminate between normal colon mucosa of patients with colon cancer and normal colon mucosa of individuals without cancer. Here, we report that CpG sites in 16 of the 30 candidate genes selected show significant differences in mean methylation level in normal colon mucosa of 24 patients with cancer and 24 controls. A support vector machine trained on these data and data for an additional 66 CpGs yielded an 18-gene signature, composed of ten of the validated candidate genes plus eight additional candidates. This model exhibited 96% sensitivity and 100% specificity in a 40-sample training set and classified all eight samples in the test set correctly. Moreover, we found a moderate-strong correlation (Pearson coefficients r = 0.253-0.722) between methylation levels in colon mucosa and methylation levels in peripheral blood for seven of the 18 genes in the support vector model. These seven genes, alone, classified 44 of the 48 patients in the validation set correctly and five CpGs selected from only two of the seven genes classified 41 of the 48 patients in the discovery set correctly. These results suggest that methylation biomarkers may be developed that will, at minimum, serve as useful objective and quantitative diagnostic complements to colonoscopy as a cancer-screening tool. These data also suggest that it may be possible to monitor biomarker methylation levels in tissues collected much less invasively than by colonoscopy. ©2014 American Association for Cancer Research.

  9. Application of bio-marker to study on tumor radiosensitivity

    International Nuclear Information System (INIS)

    Guo Wanfeng; Ding Guirong; Han Liangfu

    2001-01-01

    To definite tumor radiosensitivity is important for applying the schedules of individualization of patient radiotherapy. Many laboratories were carrying on the research which predict the tumor radiosensitivity with one bio-marker or/and multi-bio-marker in various levels. At present has not witnessed the specific bio-marker, but it provides an excellent model for predicting tumor radiosensitivity

  10. Perceived age as clinically useful biomarker of ageing: cohort study

    DEFF Research Database (Denmark)

    Christensen, Kaare; Thinggaard, Mikael; McGue, Matt

    2009-01-01

    OBJECTIVE: To determine whether perceived age correlates with survival and important age related phenotypes. DESIGN: Follow-up study, with survival of twins determined up to January 2008, by which time 675 (37%) had died. SETTING: Population based twin cohort in Denmark. PARTICIPANTS: 20 nurses, 10...... young men, and 11 older women (assessors); 1826 twins aged >or=70. MAIN OUTCOME MEASURES: Assessors: perceived age of twins from photographs. Twins: physical and cognitive tests and molecular biomarker of ageing (leucocyte telomere length). RESULTS: For all three groups of assessors, perceived age...... increased with increasing discordance in perceived age within the twin pair-that is, the bigger the difference in perceived age within the pair, the more likely that the older looking twin died first. Twin analyses suggested that common genetic factors influence both perceived age and survival. Perceived...

  11. Development and validation of a prognostic model using blood biomarker information for prediction of survival of non-small-cell lung cancer patients treated with combined chemotherapy and radiation or radiotherapy alone (NCT00181519, NCT00573040, and NCT00572325).

    Science.gov (United States)

    Dehing-Oberije, Cary; Aerts, Hugo; Yu, Shipeng; De Ruysscher, Dirk; Menheere, Paul; Hilvo, Mika; van der Weide, Hiska; Rao, Bharat; Lambin, Philippe

    2011-10-01

    Currently, prediction of survival for non-small-cell lung cancer patients treated with (chemo)radiotherapy is mainly based on clinical factors. The hypothesis of this prospective study was that blood biomarkers related to hypoxia, inflammation, and tumor load would have an added prognostic value for predicting survival. Clinical data and blood samples were collected prospectively (NCT00181519, NCT00573040, and NCT00572325) from 106 inoperable non-small-cell lung cancer patients (Stages I-IIIB), treated with curative intent with radiotherapy alone or combined with chemotherapy. Blood biomarkers, including lactate dehydrogenase, C-reactive protein, osteopontin, carbonic anhydrase IX, interleukin (IL) 6, IL-8, carcinoembryonic antigen (CEA), and cytokeratin fragment 21-1, were measured. A multivariate model, built on a large patient population (N = 322) and externally validated, was used as a baseline model. An extended model was created by selecting additional biomarkers. The model's performance was expressed as the area under the curve (AUC) of the receiver operating characteristic and assessed by use of leave-one-out cross validation as well as a validation cohort (n = 52). The baseline model consisted of gender, World Health Organization performance status, forced expiratory volume, number of positive lymph node stations, and gross tumor volume and yielded an AUC of 0.72. The extended model included two additional blood biomarkers (CEA and IL-6) and resulted in a leave-one-out AUC of 0.81. The performance of the extended model was significantly better than the clinical model (p = 0.004). The AUC on the validation cohort was 0.66 and 0.76, respectively. The performance of the prognostic model for survival improved markedly by adding two blood biomarkers: CEA and IL-6. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy.

    Directory of Open Access Journals (Sweden)

    Anne Hansen Ree

    Full Text Available Following the demonstration that histone deacetylase inhibitors enhanced experimental radiation-induced clonogenic suppression, the Pelvic Radiation and Vorinostat (PRAVO phase 1 study, combining fractionated radiotherapy with daily vorinostat for pelvic carcinoma, was designed to evaluate both clinical and novel biomarker endpoints, the latter relating to pharmacodynamic indicators of vorinostat action in clinical radiotherapy.Potential biomarkers of vorinostat radiosensitizing action, not simultaneously manifesting molecular perturbations elicited by the radiation itself, were explored by gene expression array analysis of study patients' peripheral blood mononuclear cells (PBMC, sampled at baseline (T0 and on-treatment two and 24 hours (T2 and T24 after the patients had received vorinostat.This strategy revealed 1,600 array probes that were common for the comparisons T2 versus T0 and T24 versus T2 across all of the patients, and furthermore, that no significantly differential expression was observed between the T0 and T24 groups. Functional annotation analysis of the array data showed that a significant number of identified genes were implicated in gene regulation, the cell cycle, and chromatin biology. Gene expression was validated both in patients' PBMC and in vorinostat-treated human carcinoma xenograft models, and transient repression of MYC was consistently observed.Within the design of the PRAVO study, all of the identified genes showed rapid and transient induction or repression and therefore, in principle, fulfilled the requirement of being pharmacodynamic biomarkers of vorinostat action in fractionated radiotherapy, possibly underscoring the role of MYC in this therapeutic setting.

  13. The past and the future of Alzheimer’s disease CSF biomarkers – a journey towards validated biochemical tests covering the whole spectra of molecular events

    Directory of Open Access Journals (Sweden)

    Kaj eBlennow

    2015-09-01

    Full Text Available This paper gives a short review on cerebrospinal fluid (CSF biomarkers for Alzheimer’s disease (AD, from early developments to high-precision validated assays on fully automated lab analyzers. We also discuss developments on novel biomarkers, such as synaptic proteins and Aβ oligomers. Our vision for the future is that assaying a set of biomarkers in a single CSF tube can monitor the whole spectra of AD molecular pathogenic events. CSF biomarkers will have a central position not only for clinical diagnosis, but also for the understanding of the sequence of molecular events in the pathogenic process underlying AD and as tools to monitor the effects of novel drug candidates targeting these different mechanisms.

  14. Biomarkers in patients with Chronic Obstructive Pulmonary Disease in general practice: A prospective cohort study

    DEFF Research Database (Denmark)

    Waldorff, Frans Boch; Halling, Anders; Ledderer, Loni

    Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a common chronic disease primarily treated in primary care. It is a complex and heterogeneous disease and the trajectory is difficult to predict. The overall aim of this study is to investigate predictors of the trajectory of COPD...... were a diagnosis of COPD (ICPC code R95-), age ≥ 40 years, Danish language speaking, no severe psychiatric or cognitive disease and ability to visit the GP surgery. Prevalent as well as incident patients diagnosed with COPD were eligible. Baseline data included a patient questionnaire and validated...... treated in primary care and to determine the added value of selected biomarkers such as microfibrillar-associated protein 4 (MFAP4) and surfactant protein D (SP-D). Methods: Prospective cohort study comprising COPD patients. A total of 38 Danish practices were included in the study. Criteria for inclusion...

  15. Evaluation of flavonoids and enterolactone in overnight urine as intake biomarkers of fruits, vegetables and beverages in the Inter99 cohort study using the method of triads

    DEFF Research Database (Denmark)

    Krogholm, Kirstine Suszkiewicz; Bysted, Anette; Brantsaeter, A. L.

    2012-01-01

    in 24 h urine as an alternative and more feasible biomarker of fruit, vegetable and beverage intake. A total of 191 individuals in the Inter99 cohort in Denmark completed the validation study. Concentrations of nine urinary flavonoid aglycones (quercetin, isorhamnetin, tamarixetin, kaempferol......, hesperetin, naringenin, eriodictyol, phloretin and apigenin) and enterolactone were determined in overnight and 24 h urine samples, and their validity as biomarkers of fruit, vegetable and beverage intake was evaluated in relation to two independent reference methods (Inter99 FFQ data and plasma carotenoids...

  16. Validation of Early Detection Ovarian Cancer Biomarkers (Team Project) — EDRN Public Portal

    Science.gov (United States)

    Early detection of Ovarian Cancer (OC) is one of the key clinical problems in this disease. We propose a team EDRN project to address the issue of early detection of OC by performing a validation study on candidate protein markers already identified in previous EDRN research or in the literature (e.g. protein products of TCGA identified mutations specific to ovarian cancer). (See appendix for full listing) Biospecimen sources have been identified which include samples obtained at diagnosis and matched controls (Urban, Godwin, Marks, Skates), and longitudinal samples obtained prior to diagnosis (Urban, Skates, Godwin). Bioinformatic filters will be applied to rank the candidates (Diamandis). In order of ranking, candidate proteins for which high quality antibodies are available will be measured by development of ELISAs at JHU (Chan/Zhang) or through NAPPA at DFCI (Anderson/LaBaer), while for other candidates mass spectrometry based selective reaction monitoring (SRM) assays will be developed at PNNL (Rodland). Three milestones are defined. The first two milestones are to assemble the necessary specimens and to develop the qualifying assay(s). The final milestone is to estimate the markers’ sensitivity one year prior to diagnosis at a given high specificity.

  17. Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro.

    Science.gov (United States)

    Schmeits, Peter C J; Shao, Jia; van der Krieken, Danique A; Volger, Oscar L; van Loveren, Henk; Peijnenburg, Ad A C M; Hendriksen, Peter J M

    2015-07-01

    Previously, we identified 25 classifier genes that were able to assess immunotoxicity using human Jurkat T cells. The present study aimed to validate these classifiers. For that purpose, Jurkat cells were exposed for 6 h to subcytotoxic doses of nine immunotoxicants, five non-immunotoxicants and four compounds for which human immunotoxicity has not yet been fully established. RNA was isolated and subjected to Fluidigm quantitative real time (qRT)-PCR analysis. The sensitivity, specificity and accuracy of the screening assay as based on the nine immunotoxicants and five non-immunotoxicants used in this study were 100%, 80% and 93%, respectively, which is better than the performance in our previous study. Only one compound was classified as false positive (benzo-e-pyrene). Of the four potential (non-)immunotoxicants, chlorantraniliprole and Hidrasec were classified immunotoxic and Sunset yellow and imidacloprid as non-immunotoxic. ToxPi analysis of the PCR data provided insight in the molecular pathways that were affected by the compounds. The immunotoxicants 2,3-dichloro-propanol and cypermethrin, although structurally different, affected protein metabolism and cholesterol biosynthesis and transport. In addition, four compounds, i.e. chlorpyrifos, aldicarb, benzo-e-pyrene and anti-CD3, affected genes in cholesterol metabolism and transport, protein metabolism and transcription regulation. qRT-PCR on eight additional genes coding for similar processes as defined in ToxPi analyzes, supported these results. In conclusion, the 25 immunotoxic classifiers performed very well in a screening with new non-immunotoxic and immunotoxic compounds. Therefore, the Jurkat screening assay has great promise to be applied within a tiered approach for animal free testing of human immunotoxicity. Copyright © 2014 John Wiley & Sons, Ltd.

  18. Ambient temperature and cardiovascular biomarkers in a repeated-measure study in healthy adults: A novel biomarker index approach.

    Science.gov (United States)

    Wu, Shaowei; Yang, Di; Pan, Lu; Shan, Jiao; Li, Hongyu; Wei, Hongying; Wang, Bin; Huang, Jing; Baccarelli, Andrea A; Shima, Masayuki; Deng, Furong; Guo, Xinbiao

    2017-07-01

    Associations of ambient temperature with cardiovascular morbidity and mortality have been well documented in numerous epidemiological studies, but the underlying pathways remain unclear. We investigated whether systemic inflammation, coagulation, systemic oxidative stress, antioxidant activity and endothelial function may be the mechanistic pathways associated with ambient temperature. Forty study participants underwent repeated blood collections for 12 times in Beijing, China in 2010-2011. Ambient temperature and air pollution data were measured in central monitors close to student residences. We created five indices as the sum of weighted biomarker percentiles to represent the overall levels of 15 cardiovascular biomarkers in five pathways (systemic inflammation: hs-CRP, TNF-α and fibrinogen; coagulation: fibrinogen, PAI-1, tPA, vWF and sP-selectin; systemic oxidative stress: Ox-LDL and sCD36: antioxidant activity: EC-SOD and GPX1; and endothelial function: ET-1, E-selectin, ICAM-1 and VCAM-1). We used generalized mixed-effects models to estimate temperature effects controlling for air pollution and other covariates. There were significant decreasing trends in the adjusted means of biomarker indices over the lowest to the highest quartiles of daily temperatures before blood collection. A 10°C decrease at 2-d average daily temperature were associated with increases of 2.5% [95% confidence interval (CI): 0.7, 4.2], 1.6% (95% CI: 0.1, 3.1), 2.7% (95% CI: 0.5, 4.8), 5.5% (95% CI: 3.8, 7.3) and 2.0% (95% CI: 0.3, 3.8) in the indices for systemic inflammation, coagulation, systemic oxidative stress, antioxidant activity and endothelial function, respectively. In contrast, the associations between ambient temperature and individual biomarkers had substantial variation in magnitude and strength. The altered cardiovascular biomarker profiles in healthy adults associated with ambient temperature changes may help explain the temperature-related cardiovascular morbidity

  19. Cross-validation of biomarkers for the early differential diagnosis and prognosis of dementia in a clinical setting

    International Nuclear Information System (INIS)

    Perani, Daniela; Cerami, Chiara; Caminiti, Silvia Paola; Santangelo, Roberto; Coppi, Elisabetta; Ferrari, Laura; Magnani, Giuseppe; Pinto, Patrizia; Passerini, Gabriella; Falini, Andrea; Iannaccone, Sandro; Cappa, Stefano Francesco; Comi, Giancarlo; Gianolli, Luigi

    2016-01-01

    The aim of this study was to evaluate the supportive role of molecular and structural biomarkers (CSF protein levels, FDG PET and MRI) in the early differential diagnosis of dementia in a large sample of patients with neurodegenerative dementia, and in determining the risk of disease progression in subjects with mild cognitive impairment (MCI). We evaluated the supportive role of CSF Aβ 42 , t-Tau, p-Tau levels, conventional brain MRI and visual assessment of FDG PET SPM t-maps in the early diagnosis of dementia and the evaluation of MCI progression. Diagnosis based on molecular biomarkers showed the best fit with the final diagnosis at a long follow-up. FDG PET SPM t-maps had the highest diagnostic accuracy in Alzheimer's disease and in the differential diagnosis of non-Alzheimer's disease dementias. The p-tau/Aβ 42 ratio was the only CSF biomarker providing a significant classification rate for Alzheimer's disease. An Alzheimer's disease-positive metabolic pattern as shown by FDG PET SPM in MCI was the best predictor of conversion to Alzheimer's disease. In this clinical setting, FDG PET SPM t-maps and the p-tau/Aβ 42 ratio improved clinical diagnostic accuracy, supporting the importance of these biomarkers in the emerging diagnostic criteria for Alzheimer's disease dementia. FDG PET using SPM t-maps had the highest predictive value by identifying hypometabolic patterns in different neurodegenerative dementias and normal brain metabolism in MCI, confirming its additional crucial exclusionary role. (orig.)

  20. Cross-validation of biomarkers for the early differential diagnosis and prognosis of dementia in a clinical setting

    Energy Technology Data Exchange (ETDEWEB)

    Perani, Daniela [Vita-Salute San Raffaele University, Milan (Italy); San Raffaele Scientific Institute, Division of Neuroscience, Milan (Italy); San Raffaele Hospital, Nuclear Medicine Unit, Milan (Italy); Cerami, Chiara [Vita-Salute San Raffaele University, Milan (Italy); San Raffaele Scientific Institute, Division of Neuroscience, Milan (Italy); San Raffaele Hospital, Clinical Neuroscience Department, Milan (Italy); Caminiti, Silvia Paola [Vita-Salute San Raffaele University, Milan (Italy); San Raffaele Scientific Institute, Division of Neuroscience, Milan (Italy); Santangelo, Roberto; Coppi, Elisabetta; Ferrari, Laura; Magnani, Giuseppe [San Raffaele Hospital, Department of Neurology, Milan (Italy); Pinto, Patrizia [Papa Giovanni XXIII Hospital, Department of Neurology, Bergamo (Italy); Passerini, Gabriella [Servizio di Medicina di Laboratorio OSR, Milan (Italy); Falini, Andrea [Vita-Salute San Raffaele University, Milan (Italy); San Raffaele Scientific Institute, Division of Neuroscience, Milan (Italy); San Raffaele Hospital, CERMAC - Department of Neuroradiology, Milan (Italy); Iannaccone, Sandro [San Raffaele Hospital, Clinical Neuroscience Department, Milan (Italy); Cappa, Stefano Francesco [San Raffaele Scientific Institute, Division of Neuroscience, Milan (Italy); IUSS Pavia, Pavia (Italy); Comi, Giancarlo [Vita-Salute San Raffaele University, Milan (Italy); San Raffaele Hospital, Department of Neurology, Milan (Italy); Gianolli, Luigi [San Raffaele Hospital, Nuclear Medicine Unit, Milan (Italy)

    2016-03-15

    The aim of this study was to evaluate the supportive role of molecular and structural biomarkers (CSF protein levels, FDG PET and MRI) in the early differential diagnosis of dementia in a large sample of patients with neurodegenerative dementia, and in determining the risk of disease progression in subjects with mild cognitive impairment (MCI). We evaluated the supportive role of CSF Aβ{sub 42}, t-Tau, p-Tau levels, conventional brain MRI and visual assessment of FDG PET SPM t-maps in the early diagnosis of dementia and the evaluation of MCI progression. Diagnosis based on molecular biomarkers showed the best fit with the final diagnosis at a long follow-up. FDG PET SPM t-maps had the highest diagnostic accuracy in Alzheimer's disease and in the differential diagnosis of non-Alzheimer's disease dementias. The p-tau/Aβ{sub 42} ratio was the only CSF biomarker providing a significant classification rate for Alzheimer's disease. An Alzheimer's disease-positive metabolic pattern as shown by FDG PET SPM in MCI was the best predictor of conversion to Alzheimer's disease. In this clinical setting, FDG PET SPM t-maps and the p-tau/Aβ{sub 42} ratio improved clinical diagnostic accuracy, supporting the importance of these biomarkers in the emerging diagnostic criteria for Alzheimer's disease dementia. FDG PET using SPM t-maps had the highest predictive value by identifying hypometabolic patterns in different neurodegenerative dementias and normal brain metabolism in MCI, confirming its additional crucial exclusionary role. (orig.)

  1. Omega-3 polyunsaturated fatty acid biomarkers and coronary heart disease: Pooling project of 19 cohort studies

    Science.gov (United States)

    The role of omega-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. This study sought to evaluate biomarkers of seafood-derived eicosapentaenoic acid ...

  2. 76 FR 82306 - Draft Guidance for Industry on Use of Histology in Biomarker Qualification Studies; Availability

    Science.gov (United States)

    2011-12-30

    ...] Draft Guidance for Industry on Use of Histology in Biomarker Qualification Studies; Availability AGENCY... announcing the availability of a draft guidance for industry entitled ``Use of Histology in Biomarker... studies for which histology is a reference standard. This guidance discusses the processes that should be...

  3. Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher disease.

    Science.gov (United States)

    Murugesan, Vagishwari; Liu, Jun; Yang, Ruhua; Lin, Haiquin; Lischuk, Andrew; Pastores, Gregory; Zhang, Xiaokui; Chuang, Wei-Lien; Mistry, Pramod K

    2018-02-01

    In the spleens of Gaucher disease mice and patients, there is a striking elevation of expression of glycoprotein non-Metastatic Melanoma B (gpNMB). We conducted a study in a large cohort of patients with Gaucher disease to assess the utility of serum levels of soluble fragment of gpNMB as a biomarker of disease activity. There was >15-fold elevation of gpNMB in sera of untreated patients with Gaucher disease. gpNMB levels correlated with overall disease severity as well as the severity of individual organ compartments: liver, spleen, bone and hematological disease. Imiglucerase enzyme replacement therapy resulted in significant reduction of gpNMB. Serum levels of gpNMB were highly correlated with accumulation of bioactive lipid substrate of Gaucher disease, glucosylsphingosine as well as established biomarkers, chitotriosidase and chemokine, CCL18. Our results suggest utility of gpNMB as a biomarker of Gaucher disease to monitor individual patients and cohorts of patients for disease progression or response to therapy. Investigation of gpNMB in Gaucher disease pathophysiology is likely to illuminate our understanding disease mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. The utility of collateral student drinking reports: Evidence from a biomarker study.

    Science.gov (United States)

    Fendrich, Michael; Fuhrmann, Daniel; Berger, Lisa; Plate, Charles; Lewis, Douglas; Jones, Joseph

    2015-11-01

    Researchers have increasingly used collateral informants to validate the reports provided by primary research subjects. We assessed the utility of collateral informants for college students in a study that incorporates biomarkers to validate student reports of recent drinking behavior. Students from a Midwestern university were randomly selected for a study in which they provided 90-day Timeline Followback data, hair and fingernail specimens for ethylglucuronide (EtG) testing, and information about collateral (friends or peers) informants who were familiar with their drinking behavior. We compared summary measures of recent drinking to collateral informant reports for the subset of 72 students who were selected to participate in the collateral validation process who had complete measures. Kappa, weighted kappa, and McNemar tests were performed to evaluate levels of agreement. We compared levels of use indicated by each informant within the context of EtG findings. We also compared respondent and collateral reports with respect to heavy drinking directly to EtG test results. There was considerable overlap between the reports provided by the student participants and their collateral informants. Within the context of EtG-informed analyses, collaterals rarely provided new information about heavy use beyond that provided by the study subjects. Collateral informants have limited utility in non-clinical studies of heavy drinking in randomly selected college students. Copyright © 2015. Published by Elsevier Ltd.

  5. Development and validation of a rapid multi-biomarker liquid chromatography/tandem mass spectrometry method to assess human exposure to mycotoxins.

    Science.gov (United States)

    Warth, Benedikt; Sulyok, Michael; Fruhmann, Philipp; Mikula, Hannes; Berthiller, Franz; Schuhmacher, Rainer; Hametner, Christian; Abia, Wilfred Angie; Adam, Gerhard; Fröhlich, Johannes; Krska, Rudolf

    2012-07-15

    Mycotoxins regularly occur in food worldwide and pose serious health risks to consumers. Since individuals can be exposed to a variety of these toxic secondary metabolites of fungi at the same time, there is a demand for proper analytical methods to assess human exposure by suitable biomarkers. This study reports on the development of a liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for the quantitative measurement of 15 mycotoxins and key metabolites in human urine using polarity switching. Deoxynivalenol (DON), DON-3-O-glucuronide, DON-15-O-glucuronide (D15GlcA), de-epoxy DON, nivalenol (NIV), T-2 toxin, HT-2 toxin, zearalenone, zearalenone-14-O-glucuronide, α- and β-zearalenol, fumonisins B(1) and B(2) (FB(1), FB(2)), ochratoxin A (OTA) and aflatoxin M(1) (AFM(1)) were determined without the need for any cleanup using a rapid and simple dilute and shoot approach. Validation was performed in the range of 0.005-40 µg L(-1) depending on the analyte and expected urinary concentration levels. Apparent recoveries between 78 and 119% and interday precisions of 2-17% relative standard deviation (RSD) were achieved. The applicability of the method was demonstrated by the analysis of urine samples obtained from Cameroon. In naturally contaminated urine samples up to six biomarkers of exposure (AFM(1), DON, D15GlcA, NIV, FB(1), and OTA) were detected simultaneously. We conclude that the developed LC/MS/MS method is well suited to quantify multiple mycotoxin biomarkers in human urine down to the sub-ppb range within 18 min and without any prior cleanup. The co-occurrence of several mycotoxins in the investigated samples clearly emphasizes the great potential and importance of this method to assess exposure of humans and animals to naturally occurring mycotoxins. Copyright © 2012 John Wiley & Sons, Ltd.

  6. Biomarkers of oxidative stress and DNA damage in agricultural workers: A pilot study

    International Nuclear Information System (INIS)

    Muniz, Juan F.; McCauley, Linda; Scherer, J.; Lasarev, M.; Koshy, M.; Kow, Y.W.; Nazar-Stewart, Valle; Kisby, G.E.

    2008-01-01

    Oxidative stress and DNA damage have been proposed as mechanisms linking pesticide exposure to health effects such as cancer and neurological diseases. A study of pesticide applicators and farmworkers was conducted to examine the relationship between organophosphate pesticide exposure and biomarkers of oxidative stress and DNA damage. Urine samples were analyzed for OP metabolites and 8-hydroxy-2'-deoxyguanosine (8-OH-dG). Lymphocytes were analyzed for oxidative DNA repair activity and DNA damage (Comet assay), and serum was analyzed for lipid peroxides (i.e., malondialdehyde, MDA). Cellular damage in agricultural workers was validated using lymphocyte cell cultures. Urinary OP metabolites were significantly higher in farmworkers and applicators (p < 0.001) when compared to controls. 8-OH-dG levels were 8.5 times and 2.3 times higher in farmworkers or applicators (respectively) than in controls. Serum MDA levels were 4.9 times and 24 times higher in farmworkers or applicators (respectively) than in controls. DNA damage (Comet assay) and oxidative DNA repair were significantly greater in lymphocytes from applicators and farmworkers when compared with controls. Markers of oxidative stress (i.e., increased reactive oxygen species and reduced glutathione levels) and DNA damage were also observed in lymphocyte cell cultures treated with an OP. The findings from these in vivo and in vitro studies indicate that organophosphate pesticides induce oxidative stress and DNA damage in agricultural workers. These biomarkers may be useful for increasing our understanding of the link between pesticides and a number of health effects

  7. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients

    DEFF Research Database (Denmark)

    Győrffy, Balázs; Lánczky, András; Szállási, Zoltán

    2012-01-01

    was set up using gene expression data and survival information of 1287 ovarian cancer patients downloaded from Gene Expression Omnibus and The Cancer Genome Atlas (Affymetrix HG-U133A, HG-U133A 2.0, and HG-U133 Plus 2.0 microarrays). After quality control and normalization, only probes present on all......). A Kaplan–Meier survival plot was generated and significance was computed. The tool can be accessed online at www.kmplot.com/ovar. We used this integrative data analysis tool to validate the prognostic power of 37 biomarkers identified in the literature. Of these, CA125 (MUC16; P=3.7x10–5, hazard ratio (HR...... biomarker validation platform that mines all available microarray data to assess the prognostic power of 22 277 genes in 1287 ovarian cancer patients. We specifically used this tool to evaluate the effect of 37 previously published biomarkers on ovarian cancer prognosis....

  8. Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects.

    Directory of Open Access Journals (Sweden)

    Mark Pimentel

    Full Text Available Diarrhea-predominant irritable bowel syndrome (IBS is diagnosed through clinical criteria after excluding "organic" conditions, and can be precipitated by acute gastroenteritis. Cytolethal distending toxin B (CdtB is produced by bacteria that cause acute gastroenteritis, and a post-infectious animal model demonstrates that host antibodies to CdtB cross-react with vinculin in the host gut, producing an IBS-like phenotype. Therefore, we assessed circulating anti-CdtB and anti-vinculin antibodies as biomarkers for D-IBS in human subjects. Subjects with D-IBS based on Rome criteria (n=2375 were recruited from a large-scale multicenter clinical trial for D-IBS (TARGET 3. Subjects with inflammatory bowel disease (IBD (n=142, subjects with celiac disease (n=121, and healthy controls (n=43 were obtained for comparison. Subjects with IBD and celiac disease were recruited based on the presence of intestinal complaints and histologic confirmation of chronic inflammatory changes in the colon or small intestine. Subjects with celiac disease were also required to have an elevated tTG and biopsy. All subjects were aged between 18 and 65 years. Plasma levels of anti-CdtB and anti-vinculin antibodies were determined by ELISA, and compared between groups. Anti-CdtB titers were significantly higher in D-IBS subjects compared to IBD, healthy controls and celiac disease (P<0.001. Anti-vinculin titers were also significantly higher in IBS (P<0.001 compared to the other groups. The area-under-the-receiver operating curves (AUCs were 0.81 and 0.62 for diagnosis of D-IBS against IBD for anti-CdtB and anti-vinculin, respectively. Both tests were less specific in differentiating IBS from celiac disease. Optimization demonstrated that for anti-CdtB (optical density≥2.80 the specificity, sensitivity and likelihood ratio were 91.6%, 43.7 and 5.2, respectively, and for anti-vinculin (OD≥1.68 were 83.8%, 32.6 and 2.0, respectively. These results confirm that anti-CdtB and

  9. Traumatic brain injury produced by exposure to blasts, a critical problem in current wars: biomarkers, clinical studies, and animal models

    Science.gov (United States)

    Dixon, C. Edward

    2011-06-01

    Traumatic brain injury (TBI) resulting from exposure to blast energy released by Improvised Explosive Devices (IEDs) has been recognized as the "signature injury" of Operation Iraqi Freedom and Operation Enduring Freedom. Repeated exposure to mild blasts may produce subtle deficits that are difficult to detect and quantify. Several techniques have been used to detect subtle brain dysfunction including neuropsychological assessments, computerized function testing and neuroimaging. Another approach is based on measurement of biologic substances (e.g. proteins) that are released into the body after a TBI. Recent studies measuring biomarkers in CSF and serum from patients with severe TBI have demonstrated the diagnostic, prognostic, and monitoring potential. Advancement of the field will require 1) biochemical mining for new biomarker candidates, 2) clinical validation of utility, 3) technical advances for more sensitive, portable detectors, 4) novel statistical approach to evaluate multiple biomarkers, and 5) commercialization. Animal models have been developed to simulate elements of blast-relevant TBI including gas-driven shock tubes to generate pressure waves similar to those produced by explosives. These models can reproduce hallmark clinical neuropathological responses such as neuronal degeneration and inflammation, as well as behavioral impairments. An important application of these models is to screen novel therapies and conduct proteomic, genomic, and lipodomic studies to mine for new biomarker candidates specific to blast relevant TBI.

  10. Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study

    NARCIS (Netherlands)

    Daan, Nadine M P; Koster, Maria P H; de Wilde, Marlieke A; Dalmeijer, Gerdien W; Evelein, Annemieke M V; Fauser, Bart C J M; de Jager, Wilco

    2016-01-01

    OBJECTIVE: To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring. DESIGN: Cross-sectional comparison of serum biomarkers. SETTING: University Medical Center Utrecht. PATIENTS: Hyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n

  11. ACE inhibition with perindopril and biomarkers of atherosclerosis and thrombosis : Results from the PERTINENT study

    NARCIS (Netherlands)

    Ceconi, C.; Fox, K.M.; Remme, W.J.; Simoons, M.L.; Deckers, J.W.; Bertrand, M.; Parrinello, G.; Kluft, C.; Blann, A.; Cokkinos, D.; Ferrari, R.

    2009-01-01

    The PERTINENT study measured biomarkers of atherosclerosis and thrombosis in a stable coronary artery disease population from EUROPA receiving ACE inhibition with perindopril 8 mg/day or placebo. Biomarkers of inflammation, C-reactive protein (CRP), fibrinogen, and tumor necrosis factor-alpha

  12. Biomarker kinetics in the prediction of VAP diagnosis: results from the BioVAP study

    NARCIS (Netherlands)

    Póvoa, Pedro; Martin-Loeches, Ignacio; Ramirez, Paula; Bos, Lieuwe D.; Esperatti, Mariano; Silvestre, Joana; Gili, Gisela; Goma, Gema; Berlanga, Eugenio; Espasa, Mateu; Gonçalves, Elsa; Torres, Antoni; Artigas, Antonio

    2016-01-01

    Prediction of diagnosis of ventilator-associated pneumonia (VAP) remains difficult. Our aim was to assess the value of biomarker kinetics in VAP prediction. We performed a prospective, multicenter, observational study to evaluate predictive accuracy of biomarker kinetics, namely C-reactive protein

  13. Saliva levels of Abeta1-42 as potential biomarker of Alzheimer's disease: a pilot study

    Directory of Open Access Journals (Sweden)

    Antequera Desiree

    2010-11-01

    Full Text Available Abstract Background Simple, non-invasive tests for early detection of degenerative dementia by use of biomarkers are urgently required. However, up to the present, no validated extracerebral diagnostic markers for the early diagnosis of Alzheimer disease (AD are available. The clinical diagnosis of probable AD is made with around 90% accuracy using modern clinical, neuropsychological and imaging methods. A biochemical marker that would support the clinical diagnosis and distinguish AD from other causes of dementia would therefore be of great value as a screening test. A total of 126 samples were obtained from subjects with AD, and age-sex-matched controls. Additionally, 51 Parkinson's disease (PD patients were used as an example of another neurodegenerative disorder. We analyzed saliva and plasma levels of β amyloid (Aβ using a highly sensitive ELISA kit. Results We found a small but statistically significant increase in saliva Aβ42 levels in mild AD patients. In addition, there were not differences in saliva concentration of Aβ42 between patients with PD and healthy controls. Saliva Aβ40 expression was unchanged within all the studied sample. The association between saliva Aβ42 levels and AD was independent of established risk factors, including age or Apo E, but was dependent on sex and functional capacity. Conclusions We suggest that saliva Aβ42 levels could be considered a potential peripheral marker of AD and help discrimination from other types of neurodegenerative disorders. We propose a new and promising biomarker for early AD.

  14. Validating polyphenol intake estimates from a food-frequency questionnaire by using repeated 24-h dietary recalls and a unique method-of-triads approach with 2 biomarkers.

    Science.gov (United States)

    Burkholder-Cooley, Nasira M; Rajaram, Sujatha S; Haddad, Ella H; Oda, Keiji; Fraser, Gary E; Jaceldo-Siegl, Karen

    2017-03-01

    Background: The assessment of polyphenol intake in free-living subjects is challenging, mostly because of the difficulty in accurately measuring phenolic content and the wide presence of phenolics in foods. Objective: The aims of this study were to evaluate the validity of polyphenol intake estimated from food-frequency questionnaires (FFQs) by using the mean of 6 measurements of a 24-h dietary recall (24-HR) as a reference and to apply a unique method-of-triads approach to assess validity coefficients (VCs) between latent "true" dietary estimates, total urinary polyphenol (TUP) excretion, and a surrogate biomarker (plasma carotenoids). Design: Dietary intake data from 899 adults of the Adventist Health Study 2 (AHS-2; 43% blacks and 67% women) were obtained. Pearson correlation coefficients ( r ), corrected for attenuation from within-person variation in the recalls, were calculated between 24-HRs and FFQs and between 24-HRs and TUPs. VCs and 95% CIs between true intake and polyphenol intakes from FFQs, 24-HRs, and the biomarkers TUPs and plasma carotenoids were calculated. Results: Mean ± SD polyphenol intakes were 717 ± 646 mg/d from FFQs and 402 ± 345 mg/d from 24-HRs. The total polyphenol intake from 24-HRs was correlated with FFQs in crude ( r = 0.51, P < 0.001) and deattenuated ( r = 0.63; 95% CI: 0.61, 0.69) models . In the triad model, the VC between the FFQs and theoretical true intake was 0.46 (95% CI: 0.20, 0.93) and between 24-HRs and true intake was 0.61 (95% CI: 0.38, 1.00). Conclusions: The AHS-2 FFQ is a reasonable indicator of total polyphenol intake in the AHS-2 cohort. Urinary polyphenol excretion is limited by genetic variance, metabolism, and bioavailability and should be used in addition to rather than as a replacement for dietary intake assessment. © 2017 American Society for Nutrition.

  15. Multimodal lung cancer screening using the ITALUNG biomarker panel and low dose computed tomography. Results of the ITALUNG biomarker study.

    Science.gov (United States)

    Carozzi, Francesca Maria; Bisanzi, Simonetta; Carrozzi, Laura; Falaschi, Fabio; Lopes Pegna, Andrea; Mascalchi, Mario; Picozzi, Giulia; Peluso, Marco; Sani, Cristina; Greco, Luana; Ocello, Cristina; Paci, Eugenio

    2017-07-01

    Asymptomatic high-risk subjects, randomized in the intervention arm of the ITALUNG trial (1,406 screened for lung cancer), were enrolled for the ITALUNG biomarker study (n = 1,356), in which samples of blood and sputum were analyzed for plasma DNA quantification (cut off 5 ng/ml), loss of heterozygosity and microsatellite instability. The ITALUNG biomarker panel (IBP) was considered positive if at least one of the two biomarkers included in the panel was positive. Subjects with and without lung cancer diagnosis at the end of the screening cycle with LDCT (n = 517) were evaluated. Out of 18 baseline screen detected lung cancer cases, 17 were IBP positive (94%). Repeat screen-detected lung cancer cases were 18 and 12 of them positive at baseline IBP test (66%). Interval cancer cases (2-years) and biomarker tests after a suspect Non Calcific Nodule follow-up were investigated. The single test versus multimodal screening measures of accuracy were compared in a simulation within the screened ITALUNG intervention arm, considering screen-detected and interval cancer cases. Sensitivity was 90% at baseline screening. Specificity was 71 and 61% for LDCT and IBP as baseline single test, and improved at 89% with multimodal, combined screening. The positive predictive value was 4.3% for LDCT at baseline and 10.6% for multimodal screening. Multimodal screening could improve the screening efficiency at baseline and strategies for future implementation are discussed. If IBP was used as primary screening test, the LDCT burden might decrease of about 60%. © 2017 UICC.

  16. Heritability of Biomarkers of Oxidized Lipoproteins: Twin Pair Study.

    Science.gov (United States)

    Rao, Fangwen; Schork, Andrew J; Maihofer, Adam X; Nievergelt, Caroline M; Marcovina, Santica M; Miller, Elizabeth R; Witztum, Joseph L; O'Connor, Daniel T; Tsimikas, Sotirios

    2015-07-01

    To determine whether biomarkers of oxidized lipoproteins are genetically determined. Lipoprotein(a) (Lp[a]) is a heritable risk factor and carrier of oxidized phospholipids (OxPL). We measured oxidized phospholipids on apolipoprotein B-containing lipoproteins (OxPL-apoB), Lp(a), IgG, and IgM autoantibodies to malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes in 386 monozygotic and dizygotic twins to estimate trait heritability (h(2)) and determine specific genetic effects among traits. A genome-wide linkage study followed by genetic association was performed. The h(2) (scale: 0-1) for Lp(a) was 0.91±0.01 and for OxPL-apoB 0.87±0.02, which were higher than physiological, inflammatory, or lipid traits. h(2) of IgM malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes were 0.69±0.04, 0.67±0.05, and 0.80±0.03, respectively, and for IgG malondialdehyde-modified low-density lipoprotein, copper oxidized low-density lipoprotein, and apoB-immune complexes 0.62±0.05, 0.52±0.06, and 0.53±0.06, respectively. There was an inverse correlation between the major apo(a) isoform and OxPL-apoB (R=-0.49; Plipoprotein and copper oxidized low-density lipoprotein, and apoB-immune complexes. Sib-pair genetic linkage of the Lp(a) trait revealed that single nucleotide polymorphism rs10455872 was significantly associated with OxPL-apoB after adjusting for Lp(a). OxPL-apoB and other biomarkers of oxidized lipoproteins are highly heritable cardiovascular risk factors that suggest novel genetic origins of atherothrombosis. © 2015 American Heart Association, Inc.

  17. Biomarkers study in rainbow trout exposed to industrially contaminated groundwater

    Directory of Open Access Journals (Sweden)

    Nadjet Benchalgo

    2014-03-01

    Full Text Available The spill of liquid industrial waste from chemical and petrochemical industries in Mercier lagoons located 20 km south of Montreal, Quebec, caused a major groundwater contamination by industrial contaminants. The aim of this study was to investigate the toxic effects of Mercier groundwater, following 4 and 14 days of exposure to graded concentrations from three wells at increasing distances 1.2, 2.7 and 5.4 km from the source of contamination. Rainbow trout were examined for several biomarkers of defense [ethoxyresorufin O-deethylase (EROD and gluthatione S-transferase (GST activities] and those of tissue damage [lipid peroxidation (LPO and DNA strand breaks]. The results showed that EROD activity was significantly enhanced in hepatic tissue at 1.2 and 5.4 km, whereas inhibition in activity was observed in group at 2.7 km. Therefore, GST activity was significantly increased at 3.1% concentration for the 2.7 km well. No change in LPO was observed. However, a significant induction of DNA strand breaks in liver was obtained at each distance. In conclusion, the data suggest that the release of these contaminants in groundwater leads to increased biotransformation for coplanar aromatic hydrocarbons and DNA damage in groundwater.

  18. NVN 5694 intra laboratory validation. Feasibility study for interlaboratory- validation

    International Nuclear Information System (INIS)

    Voors, P.I.; Baard, J.H.

    1998-11-01

    Within the project NORMSTAR 2 a number of Dutch prenormative protocols have been defined for radioactivity measurements. Some of these protocols, e.g. the Dutch prenormative protocol NVN 5694, titled Methods for radiochemical determination of polonium-210 and lead-210, have not been validated, neither by intralaboratory nor interlaboratory studies. Validation studies are conducted within the framework of the programme 'Normalisatie and Validatie van Milieumethoden 1993-1997' (Standardization and Validation of test methods for environmental parameters) of the Dutch Ministry of Housing, Physical Planning and the Environment (VROM). The aims of this study were (a) a critical evaluation of the protocol, (b) investigation on the feasibility of an interlaboratory study, and (c) the interlaboratory validation of NVN 5694. The evaluation of the protocol resulted in a list of deficiencies varying from missing references to incorrect formulae. From the survey by interview it appeared that for each type of material, there are 4 to 7 laboratories willing to participate in a interlaboratory validation study. This reflects the situation in 1997. Consequently, if 4 or 6 (the minimal number) laboratories are participating and each laboratory analyses 3 subsamples, the uncertainty in the repeatability standard deviation is 49 or 40 %, respectively. If the ratio of reproducibility standard deviation to the repeatability standard deviation is equal to 1 or 2, then the uncertainty in the reproducibility standard deviation increases from 42 to 67 % and from 34 to 52 % for 4 or 6 laboratories, respectively. The intralaboratory validation was established on four different types of materials. Three types of materials (milkpowder condensate and filter) were prepared in the laboratory using the raw material and certified Pb-210 solutions, and one (sediment) was obtained from the IAEA. The ECN-prepared reference materials were used after testing on homogeneity. The pre-normative protocol can

  19. Clinical usefulness of a biomarker-based diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study.

    Science.gov (United States)

    Laskowitz, Daniel T; Kasner, Scott E; Saver, Jeffrey; Remmel, Kerri S; Jauch, Edward C

    2009-01-01

    One of the significant limitations in the evaluation and management of patients with suspected acute cerebral ischemia is the absence of a widely available, rapid, and sensitive diagnostic test. The objective of the current study was to assess whether a test using a panel of biomarkers might provide useful diagnostic information in the early evaluation of stroke by differentiating patients with cerebral ischemia from other causes of acute neurological deficit. A total of 1146 patients presenting with neurological symptoms consistent with possible stroke were prospectively enrolled at 17 different sites. Timed blood samples were assayed for matrix metalloproteinase 9, brain natriuretic factor, d-dimer, and protein S100beta. A separate cohort of 343 patients was independently enrolled to validate the multiple biomarker model approach. A diagnostic tool incorporating the values of matrix metalloproteinase 9, brain natriuretic factor, d-dimer, and S-100beta into a composite score was sensitive for acute cerebral ischemia. The multivariate model demonstrated modest discriminative capabilities with an area under the receiver operating characteristic curve of 0.76 for hemorrhagic stroke and 0.69 for all stroke (likelihood test P<0.001). When the threshold for the logistic model was set at the first quartile, this resulted in a sensitivity of 86% for detecting all stroke and a sensitivity of 94% for detecting hemorrhagic stroke. Moreover, results were reproducible in a separate cohort tested on a point-of-care platform. These results suggest that a biomarker panel may add valuable and time-sensitive diagnostic information in the early evaluation of stroke. Such an approach is feasible on a point-of-care platform. The rapid identification of patients with suspected stroke would expand the availability of time-limited treatment strategies. Although the diagnostic accuracy of the current panel is clearly imperfect, this study demonstrates the feasibility of incorporating a

  20. Big-data-based edge biomarkers: study on dynamical drug sensitivity and resistance in individuals.

    Science.gov (United States)

    Zeng, Tao; Zhang, Wanwei; Yu, Xiangtian; Liu, Xiaoping; Li, Meiyi; Chen, Luonan

    2016-07-01

    Big-data-based edge biomarker is a new concept to characterize disease features based on biomedical big data in a dynamical and network manner, which also provides alternative strategies to indicate disease status in single samples. This article gives a comprehensive review on big-data-based edge biomarkers for complex diseases in an individual patient, which are defined as biomarkers based on network information and high-dimensional data. Specifically, we firstly introduce the sources and structures of biomedical big data accessible in public for edge biomarker and disease study. We show that biomedical big data are typically 'small-sample size in high-dimension space', i.e. small samples but with high dimensions on features (e.g. omics data) for each individual, in contrast to traditional big data in many other fields characterized as 'large-sample size in low-dimension space', i.e. big samples but with low dimensions on features. Then, we demonstrate the concept, model and algorithm for edge biomarkers and further big-data-based edge biomarkers. Dissimilar to conventional biomarkers, edge biomarkers, e.g. module biomarkers in module network rewiring-analysis, are able to predict the disease state by learning differential associations between molecules rather than differential expressions of molecules during disease progression or treatment in individual patients. In particular, in contrast to using the information of the common molecules or edges (i.e.molecule-pairs) across a population in traditional biomarkers including network and edge biomarkers, big-data-based edge biomarkers are specific for each individual and thus can accurately evaluate the disease state by considering the individual heterogeneity. Therefore, the measurement of big data in a high-dimensional space is required not only in the learning process but also in the diagnosing or predicting process of the tested individual. Finally, we provide a case study on analyzing the temporal expression

  1. Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies.

    Science.gov (United States)

    Dear, James W; Clarke, Joanna I; Francis, Ben; Allen, Lowri; Wraight, Jonathan; Shen, Jasmine; Dargan, Paul I; Wood, David; Cooper, Jamie; Thomas, Simon H L; Jorgensen, Andrea L; Pirmohamed, Munir; Park, B Kevin; Antoine, Daniel J

    2018-02-01

    Paracetamol overdose is common but patient stratification is suboptimal. We investigated the usefulness of new biomarkers that have either enhanced liver specificity (microRNA-122 [miR-122]) or provide mechanistic insights (keratin-18 [K18], high mobility group box-1 [HMGB1], and glutamate dehydrogenase [GLDH]). The use of these biomarkers could help stratify patients for their risk of liver injury at hospital presentation. Using data from two prospective cohort studies, we assessed the potential for biomarkers to stratify patients who overdose with paracetamol. We completed two independent prospective studies: a derivation study (MAPP) in eight UK hospitals and a validation study (BIOPAR) in ten UK hospitals. Patients in both cohorts were adults (≥18 years in England, ≥16 years in Scotland), were diagnosed with paracetamol overdose, and gave written informed consent. Patients who needed intravenous acetylcysteine treatment for paracetamol overdose had circulating biomarkers measured at hospital presentation. The primary endpoint was acute liver injury indicating need for continued acetylcysteine treatment beyond the standard course (alanine aminotransferase [ALT] activity >100 U/L). Receiver operating characteristic (ROC) curves, category-free net reclassification index (cfNRI), and integrated discrimination index (IDI) were applied to assess endpoint prediction. Between June 2, 2010, and May 29, 2014, 1187 patients who required acetylcysteine treatment for paracetamol overdose were recruited (985 in the MAPP cohort; 202 in the BIOPAR cohort). In the derivation and validation cohorts, acute liver injury was predicted at hospital presentation by miR-122 (derivation cohort ROC-area under the curve [AUC] 0·97 [95% CI 0·95-0·98]), HMGB1 (0·95 [0·93-0·98]), and full-length K18 (0·95 [0·92-0·97]). Results were similar in the validation cohort (miR-122 AUC 0·97 [95% CI 0·95-0·99], HMGB1 0·98 [0·96-0·99], and full-length K18 0·93 [0·86-0·99]). A

  2. Cable SGEMP Code Validation Study

    Energy Technology Data Exchange (ETDEWEB)

    Ballard, William Parker [Sandia National Lab. (SNL-CA), Livermore, CA (United States). Center for CA Weapons Systems Engineering

    2013-05-01

    This report compared data taken on the Modular Bremsstrahlung Simulator using copper jacketed (cujac) cables with calculations using the RHSD-RA Cable SGEMP analysis tool. The tool relies on CEPXS/ONBFP to perform radiation transport in a series of 1D slices through the cable, and then uses a Green function technique to evaluate the expected current drive on the center conductor. The data were obtained in 2003 as part of a Cabana verification and validation experiment using 1-D geometries, but were not evaluated until now. The agreement between data and model is not adequate unless gaps between the dielectric and outer conductor (ground) are assumed, and these gaps are large compared with what is believed to be in the actual cable.

  3. Applying Data-driven Imaging Biomarker in Mammography for Breast Cancer Screening: Preliminary Study

    OpenAIRE

    Kim, Eun-Kyung; Kim, Hyo-Eun; Han, Kyunghwa; Kang, Bong Joo; Sohn, Yu-Mee; Woo, Ok Hee; Lee, Chan Wha

    2018-01-01

    We assessed the feasibility of a data-driven imaging biomarker based on weakly supervised learning (DIB; an imaging biomarker derived from large-scale medical image data with deep learning technology) in mammography (DIB-MG). A total of 29,107 digital mammograms from five institutions (4,339 cancer cases and 24,768 normal cases) were included. After matching patients’ age, breast density, and equipment, 1,238 and 1,238 cases were chosen as validation and test sets, respectively, and the remai...

  4. CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study

    Science.gov (United States)

    Kang, Ju-Hee; Mollenhauer, Brit; Coffey, Christopher S.; Toledo, Jon B.; Weintraub, Daniel; Galasko, Douglas R.; Irwin, David J.; Van Deerlin, Vivianna; Chen-Plotkin, Alice S.; Caspell-Garcia, Chelsea; Waligórska, Teresa; Taylor, Peggy; Shah, Nirali; Pan, Sarah; Zero, Pawel; Frasier, Mark; Marek, Kenneth; Kieburtz, Karl; Jennings, Danna; Tanner, Caroline M.; Simuni, Tanya; Singleton, Andrew; Toga, Arthur W.; Chowdhury, Sohini; Trojanowski, John Q.; Shaw, Leslie M.

    2016-01-01

    The development of biomarkers to predict the progression of Parkinson’s disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson’s Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1–42 (Aβ1–42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1–42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1–42, or highest t-tau/Aβ1–42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1–42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance. PMID:27021906

  5. CHURCHILL COUNTY, NEVADA ARSENIC STUDY: WATER CONSUMPTION AND EXPOSURE BIOMARKERS

    Science.gov (United States)

    The US Environmental Protection Agency is required to reevaluate the Maximum Contaminant Level (MCL) for arsenic in 2006. To provide data for reducing uncertainties in assessing health risks associated with exposure to low levels (<200 g/l) of arsenic, a large scale biomarker st...

  6. Extracellular miRNA-21 as a novel biomarker in glioma: evidence from meta-analysis, clinical validation and experimental investigations

    Science.gov (United States)

    Liu, Tian; Wang, Zhixin; Tai, Minghui; Meng, Fandi; Zhang, Jingyao; Wan, Yong; Mao, Ping; Dong, Xiaoqun; Liu, Chang; Niu, Wenquan; Dong, Shunbin

    2016-01-01

    Evidence is accumulating highlighting the importance of extracellular miRNA as a novel biomarker for diagnosing various kinds of malignancies. MiR-21 is one of the most studied miRNAs and is over-expressed in cancer tissues. To explore the clinical implications and secretory mechanisms of extracellular miR-21, we firstly meta-analyzed the diagnostic efficiency of extracellular miR-21 in different cancer types. Eighty-one studies based on 59 articles were finally included. In our study, extracellular miR-21 was observed to exhibit an outstanding diagnostic accuracy in detecting brain cancer (area under the summary receiver operating characteristic curve or AUC = 0.94), and this accuracy was more obvious in glioma diagnosis (AUC = 0.95). Our validation study (n = 45) further confirmed the diagnostic and prognostic role of miR-21 in cerebrospinal fluid (CSF) for glioma. These findings inspired us to explore the biological function of miR-21. We next conducted mechanistic investigations to explain the secretory mechanisms of extracellular miR-21 in glioma. TGF-β/Smad3 signaling was identified to participate in mediating the release of miR-21 from glioma cells. Further targeting TGF-β/Smad3 signaling using galunisertib, an inhibitor of the TGF-β type I receptor kinase, can attenuate the secretion of miR-21 from glioma cells. Taken together, CSF-based miR-21 might serve as a potential biomarker for diagnosing brain cancer, especially for patients with glioma. Moreover, extracellular levels of miR-21 were affected by exogenous TGF-β activity and galunisertib treatment. PMID:27166186

  7. Molecular biomarkers for the study of childhood leukemia

    International Nuclear Information System (INIS)

    Smith, Martyn T.; McHale, Cliona M.; Wiemels, Joseph L.; Zhang, Luoping; Wiencke, John K.; Zheng, Shichun; Gunn, Laura; Skibola, Christine F.; Ma, Xiaomei; Buffler, Patricia A.

    2005-01-01

    Various specific chromosome rearrangements, including t(8;21), t(15;17), and inv(16), are found in acute myeloid leukemia (AML) and in childhood acute lymphocytic leukemia (ALL), t(12;21) and t(1;19) are common. We sequenced the translocation breakpoints of 56 patients with childhood ALL or AML harboring t(12;21), t(8;21), t(15;17), inv(16), and t(1;19), and demonstrated, with the notable exception of t(1;19), that these rearrangements are commonly detected in the neonatal blood spots (Guthrie cards) of the cases. These findings show that most childhood leukemias begin before birth and that maternal and perinatal exposures such as chemical and infectious agents are likely to be critical. Indeed, we have reported that exposure to indoor pesticides during pregnancy and the first year of life raises leukemia risk, but that later exposures do not. We have also examined aberrant gene methylation in different cytogenetic subgroups and have found striking differences between them, suggesting that epigenetic events are also important in the development of some forms of childhood leukemia. Further, at least two studies now show that the inactivating NAD(P)H:quinone acceptor oxidoreductase (NQO1) C609T polymorphism is positively associated with leukemias arising in the first 1-2 years of life and polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been associated with adult and childhood ALL. Thus, low folate intake and compounds that are detoxified by NQO1 may be important in elevating leukemia risk in children. Finally, we are exploring the use of proteomics to subclassify leukemia, because cytogenetic analysis is costly and time-consuming. Several proteins have been identified that may serve as useful biomarkers for rapidly identifying different forms of childhood leukemia

  8. Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study.

    Science.gov (United States)

    Wang, Thomas J; Wollert, Kai C; Larson, Martin G; Coglianese, Erin; McCabe, Elizabeth L; Cheng, Susan; Ho, Jennifer E; Fradley, Michael G; Ghorbani, Anahita; Xanthakis, Vanessa; Kempf, Tibor; Benjamin, Emelia J; Levy, Daniel; Vasan, Ramachandran S; Januzzi, James L

    2012-09-25

    Biomarkers for predicting cardiovascular events in community-based populations have not consistently added information to standard risk factors. A limitation of many previously studied biomarkers is their lack of cardiovascular specificity. To determine the prognostic value of 3 novel biomarkers induced by cardiovascular stress, we measured soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I in 3428 participants (mean age, 59 years; 53% women) in the Framingham Heart Study. We performed multivariable-adjusted proportional hazards models to assess the individual and combined ability of the biomarkers to predict adverse outcomes. We also constructed a "multimarker" score composed of the 3 biomarkers in addition to B-type natriuretic peptide and high-sensitivity C-reactive protein. During a mean follow-up of 11.3 years, there were 488 deaths, 336 major cardiovascular events, 162 heart failure events, and 142 coronary events. In multivariable-adjusted models, the 3 new biomarkers were associated with each end point (Pstatistic (P=0.005 or lower) and net reclassification improvement (P=0.001 or lower). Multiple biomarkers of cardiovascular stress are detectable in ambulatory individuals and add prognostic value to standard risk factors for predicting death, overall cardiovascular events, and heart failure.

  9. Simultaneous determination of renal function biomarkers in urine using a validated paper-based microfluidic analytical device.

    Science.gov (United States)

    Rossini, Eduardo Luiz; Milani, Maria Izabel; Carrilho, Emanuel; Pezza, Leonardo; Pezza, Helena Redigolo

    2018-01-02

    In this paper, we describe a validated paper-based microfluidic analytical device for the simultaneous quantification of two important biomarkers of renal function in urine. This paper platform provides an inexpensive, simple, and easy to use colorimetric method for the quantification of creatinine (CRN) and uric acid (UA) in urine samples. The microfluidic paper-based analytical device (μPAD) consists of a main channel with three identical arms, each containing a circular testing zone and a circular uptake zone. Creatinine detection is based on the Jaffé reaction, in which CRN reacts with picrate to form an orange-red product. Uric acid quantification is based on the reduction of Fe 3+ to Fe 2+ by UA, which is detected in a colorimetric reaction using 1,10-phenanthroline. Under optimum conditions, obtained through chemometrics, the concentrations of the analytes showed good linear correlations with the effective intensities, and the method presented satisfactory repeatability. The limits of detection and the linear ranges, respectively, were 15.7 mg L -1 and 50-600 mg L -1 for CRN and 16.5 mg L -1 and 50-500 mg L -1 for UA. There were no statistically significant differences between the results obtained using the μPAD and a chromatographic comparative method (Student's t-test at 95% confidence level). Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Asthma characteristics and biomarkers from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) longitudinal profiling study

    DEFF Research Database (Denmark)

    Silkoff, P E; Strambu, I; Laviolette, M

    2015-01-01

    BACKGROUND: Asthma is a heterogeneous disease and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. The purpose of the ADEPT study was to correlate clinical features and biomarkers with molecular characteristics, by profiling asthma (NCT01274507). This re...

  11. Multiple Sclerosis Cerebrospinal Fluid Biomarkers

    Directory of Open Access Journals (Sweden)

    Gavin Giovannoni

    2006-01-01

    Full Text Available Cerebrospinal fluid (CSF is the body fluid closest to the pathology of multiple sclerosis (MS. For many candidate biomarkers CSF is the only fluid that can be investigated. Several factors need to be standardized when sampling CSF for biomarker research: time/volume of CSF collection, sample processing/storage, and the temporal relationship of sampling to clinical or MRI markers of disease activity. Assays used for biomarker detection must be validated so as to optimize the power of the studies. A formal method for establishing whether or not a particular biomarker can be used as a surrogate end-point needs to be adopted. This process is similar to that used in clinical trials, where the reporting of studies has to be done in a standardized way with sufficient detail to permit a critical review of the study and to enable others to reproduce the study design. A commitment must be made to report negative studies so as to prevent publication bias. Pre-defined consensus criteria need to be developed for MS-related prognostic biomarkers. Currently no candidate biomarker is suitable as a surrogate end-point. Bulk biomarkers of the neurodegenerative process such as glial fibrillary acidic protein (GFAP and neurofilaments (NF have advantages over intermittent inflammatory markers.

  12. Biomarkers for Detecting Mitochondrial Disorders

    Directory of Open Access Journals (Sweden)

    Josef Finsterer

    2018-01-01

    Full Text Available (1 Objectives: Mitochondrial disorders (MIDs are a genetically and phenotypically heterogeneous group of slowly or rapidly progressive disorders with onset from birth to senescence. Because of their variegated clinical presentation, MIDs are difficult to diagnose and are frequently missed in their early and late stages. This is why there is a need to provide biomarkers, which can be easily obtained in the case of suspecting a MID to initiate the further diagnostic work-up. (2 Methods: Literature review. (3 Results: Biomarkers for diagnostic purposes are used to confirm a suspected diagnosis and to facilitate and speed up the diagnostic work-up. For diagnosing MIDs, a number of dry and wet biomarkers have been proposed. Dry biomarkers for MIDs include the history and clinical neurological exam and structural and functional imaging studies of the brain, muscle, or myocardium by ultrasound, computed tomography (CT, magnetic resonance imaging (MRI, MR-spectroscopy (MRS, positron emission tomography (PET, or functional MRI. Wet biomarkers from blood, urine, saliva, or cerebrospinal fluid (CSF for diagnosing MIDs include lactate, creatine-kinase, pyruvate, organic acids, amino acids, carnitines, oxidative stress markers, and circulating cytokines. The role of microRNAs, cutaneous respirometry, biopsy, exercise tests, and small molecule reporters as possible biomarkers is unsolved. (4 Conclusions: The disadvantages of most putative biomarkers for MIDs are that they hardly meet the criteria for being acceptable as a biomarker (missing longitudinal studies, not validated, not easily feasible, not cheap, not ubiquitously available and that not all MIDs manifest in the brain, muscle, or myocardium. There is currently a lack of validated biomarkers for diagnosing MIDs.

  13. Biological impact of polycyclic aromatic hydrocarbons (PAH) on european eel Definition and validation of bio-marker useful in situ; Impact biologique des hydrocarbures aromatiques polycycliques (HAP) sur l'anguille europeenne. Definition et validation de biomarqueurs in situ

    Energy Technology Data Exchange (ETDEWEB)

    Buet, A.

    2002-02-15

    In the natural environment, especially in aquatic ecosystems, the presence of polycyclic aromatic hydrocarbons (PAH) can have deleterious effects. The aim of this project was to assess the biological impact of PAH on the European eel (Anguilla anguilla) and to define a series of bio-markers useful in situ. The originality of this field study comes from the variety of the considered factors and the choice of a protected site. Bio-markers validation requires the knowledge of normal variations of the selected parameters. Therefore, the first objective of our study was to assess the effects of natural factors on the eco-physiological characteristics of an eel population collected from the National Reserve of Camargue. Bio-metric and metabolic parameters were measured as well as enzymatic markers of contamination: biotransformation activities (EROD, GST, UDPHT), oxidative stress activities (CAT, SOD, GPx, SeGPx) and membrane activities (ATPases, AChE). The temporal evolutions and the nutritional state influenced significantly the answer of these indicators of contamination in the studied population. On the other hand, the effect of sexual maturity and parasitism by the nematode Anguillicola crassus was reduced. After confirming a local atmospheric contribution in PAH, we tried to understand the accumulation patterns of these compounds within organisms and organs. Therefore, the analysis of PAH were performed on the bile, the liver and the muscle samples of European eels. Whatever the season, the sampling site, the sexual maturity and the sanitary state of eels, the PAH tissue contamination was general but fluctuating. The localization of the contamination gives information about its persistence. Chronologically, bile accumulation reflects a recent intoxication, whereas the liver gives a medium-term contamination image and the muscle impregnation represents a longer-term storage. The PAH concentrated in fat tissues but these concentrations were not systematically

  14. Identification and Validation of Established and Novel Biomarkers for Infections in Burns

    Science.gov (United States)

    2015-10-01

    studies of asthma, COPD, and respiratory viruses; 2) Investigate the pathways and mechanisms of action of airway diseases in lung tissue (mucosal...from multiple oxidative stressors, e.g., pollen antigens (NADPH oxidases), ultra-fine carbon particles (air pollution mimetic), and respiratory ... disease which needs to be treated as early as possible. The studies described here will improve clinical care for the severely burned Wounded

  15. Pharmacogenomic Biomarkers

    Directory of Open Access Journals (Sweden)

    Sandra C. Kirkwood

    2002-01-01

    Full Text Available Pharmacogenomic biomarkers hold great promise for the future of medicine and have been touted as a means to personalize prescriptions. Genetic biomarkers for disease susceptibility including both Mendelian and complex disease promise to result in improved understanding of the pathophysiology of disease, identification of new potential therapeutic targets, and improved molecular classification of disease. However essential to fulfilling the promise of individualized therapeutic intervention is the identification of drug activity biomarkers that stratify individuals based on likely response to a particular therapeutic, both positive response, efficacy, and negative response, development of side effect or toxicity. Prior to the widespread clinical application of a genetic biomarker multiple scientific studies must be completed to identify the genetic variants and delineate their functional significance in the pathophysiology of a carefully defined phenotype. The applicability of the genetic biomarker in the human population must then be verified through both retrospective studies utilizing stored or clinical trial samples, and through clinical trials prospectively stratifying patients based on the biomarker. The risk conferred by the polymorphism and the applicability in the general population must be clearly understood. Thus, the development and widespread application of a pharmacogenomic biomarker is an involved process and for most disease states we are just at the beginning of the journey towards individualized therapy and improved clinical outcome.

  16. BIOMarkers for occupational diesel exhaust exposure monitoring (BIOMODEM) - a study in underground mining

    DEFF Research Database (Denmark)

    Scheepers, P.T.J.; Coggon, D.; Knudsen, Lisbeth E.

    2002-01-01

    Methods for the assessment of exposures to diesel exhaust were evaluated, including various biomarkers of internal exposure and early biological effects. The impact of possible biomarkers of susceptibility was also explored. Underground workers (drivers of diesel-powered excavators) at an oil sha...... bulky DNA adducts determined by 32P-postlabelling, or in DNA damage. The study indicated that smoking, diet and residential indoor air pollution are important non-occupational factors to consider when interpreting biomonitoring results....

  17. Clinical Translation and Validation of a Predictive Biomarker for Patritumab, an Anti-human Epidermal Growth Factor Receptor 3 (HER3) Monoclonal Antibody, in Patients With Advanced Non-small Cell Lung Cancer.

    Science.gov (United States)

    Mendell, Jeanne; Freeman, Daniel J; Feng, Wenqin; Hettmann, Thore; Schneider, Matthias; Blum, Sabine; Ruhe, Jens; Bange, Johannes; Nakamaru, Kenji; Chen, Shuquan; Tsuchihashi, Zenta; von Pawel, Joachim; Copigneaux, Catherine; Beckman, Robert A

    2015-03-01

    During early clinical development, prospective identification of a predictive biomarker and validation of an assay method may not always be feasible. Dichotomizing a continuous biomarker measure to classify responders also leads to challenges. We present a case study of a prospective-retrospective approach for a continuous biomarker identified after patient enrollment but defined prospectively before the unblinding of data. An analysis of the strengths and weaknesses of this approach and the challenges encountered in its practical application are also provided. HERALD (NCT02134015) was a double-blind, phase 2 study in patients with non-small cell lung cancer (NSCLC) randomized to erlotinib with placebo or with high or low doses of patritumab, a monoclonal antibody targeted against human epidermal growth factor receptor 3 (HER3). While the primary objective was to assess safety and progression-free survival (PFS), a secondary objective was to determine a single predictive biomarker hypothesis to identify subjects most likely to benefit from the addition of patritumab. Although not identified as the primary biomarker in the study protocol, on the basis of preclinical results from 2 independent laboratories, expression levels of the HER3 ligand heregulin (HRG) were prospectively declared the predictive biomarker before data unblinding but after subject enrollment. An assay to measure HRG mRNA was developed and validated. Other biomarkers, such as epidermal growth factor receptor (EGFR) mutation status, were also evaluated in an exploratory fashion. The cutoff value for high vs. low HRG mRNA levels was set at the median delta threshold cycle. A maximum likelihood analysis was performed to evaluate the provisional cutoff. The relationship of HRG values to PFS hazard ratios (HRs) was assessed as a measure of internal validation. Additional NSCLC samples were analyzed to characterize HRG mRNA distribution. The subgroup of patients with high HRG mRNA levels ("HRG

  18. Potential diagnostic biomarkers for chronic kidney disease of unknown etiology (CKDu) in Sri Lanka: a pilot study.

    Science.gov (United States)

    Sayanthooran, Saravanabavan; Magana-Arachchi, Dhammika N; Gunerathne, Lishanthe; Abeysekera, Tilak

    2017-01-19

    In Sri Lanka, there exists chronic kidney disease of both known (CKD) and unknown etiologies (CKDu). Identification of novel biomarkers that are customized to the specific causative factors would lead to early diagnosis and clearer prognosis of the diseases. This study aimed to find genetic biomarkers in blood to distinguish and identify CKDu from CKD as well as healthy populations from CKDu endemic and non-endemic areas of Sri Lanka. The expression patterns of a selected panel of 12 potential genetic biomarkers were analyzed in blood using RT-qPCR. Fold changes of gene expressions in early and late stages of CKD and CKDu patients, and an apparently healthy population of a CKDu endemic area, Girandurukotte (GH) were calculated relative to apparently healthy volunteers from a CKDu non-endemic area, Kandy (KH) of Sri Lanka, using the comparative CT method. Significant differences were observed between KH and early stage CKDu for both the insulin-like growth factor binding protein 1 (IGFBP1; p = 0.012) and kidney injury molecule-1 (KIM1; p = 0.003) genes, and KH and late stage CKD and CKDu for the glutathione-S-transferase mu 1 (GSTM1; p CKDu (p CKDu, whereas these genes in addition with FN1, IGFBP3 and KLK1 could be used to monitor progression of CKDu. The regulation of these genes has to be studied on larger populations to validate their efficiency for further clinical use.

  19. Biomarkers for Early Detection of Clinically Relevant Prostate Cancer: A Multi-Institutional Validation Trial

    Science.gov (United States)

    2017-10-01

    size, diagnostic Gleason (3+3 or 3+4), BMI ( obese , overweight or normal), race (Caucasian, African American or other), ethnicity (Hispanic versus...results were presented at the 2016 Meeting of the American Urological Association (AUA) and have been published in European Urology (v72, pp448-454.) A...prostate cancer in men in the Canary Prostate Active Surveillance Study (PASS).” Annual Meeting of the American Urological Association; 2016 May 6-10, San

  20. Pilot Study on the Investigation of Tear Fluid Biomarkers as an Indicator of Ocular, Neurological, and Immunological Health in Astronauts

    Science.gov (United States)

    Morton, Stephen; Crucian, Brian; Hagan, Suzanne; Satyamitra, Merriline; Daily, Anna

    2018-01-01

    The purpose of this pilot study is to investigate the collection, preparation, and analysis of tear biomarkers as a means of assessing ocular, neurological, and immunological health. At present, no published data exists on the cytokine profiles of tears from astronauts exposed to long periods of microgravity and space irradiations. In addition, no published data exist on cytokine (biomarker) profiles of tears that have been collected from irradiated non-human biological systems (primates and other animal models). A goal for the proposed pilot study is to discover novel tear biomarkers which can help inform researchers, clinicians, epidemiologist and healthcare providers about the health status of a living biological system, as well as informing them when a disease state is triggered. This would be done via analysis of the onset of expression of pro-inflammatory cytokines, leading up to the full progression of a disease (i.e. cancer, loss of vision, radiation-induced oxidative stress, cardiovascular disorders, fibrosis in major organs, bone loss). Another goal of this pilot study is to investigate the state of disease against proposed medical countermeasures, in order to determine whether the countermeasures are efficacious in preventing or mitigating these injuries. An example of an up and coming tear biomarker technology, Ascendant Dx, a clinical stage diagnostic company, is developing a screening test to detect breast cancer using proteins from tears. The team utilized Liquid Chromatography -Mass Spectrometry with Mass analysis (LC MS/MS) as a discovery platform followed by validation with ELISA to come up with a panel of protein biomarkers that can differentiate breast cancer samples from control ("cancer free") samples with results far surpassing the results of imaging techniques in use today. Continued research into additional proteins is underway to increase the sensitivity and specificity of the test and development efforts are on the way to transfer the

  1. Testing of the preliminary OMERACT validation criteria for a biomarker to be regarded as reflecting structural damage endpoints in rheumatoid arthritis clinical trials: the example of C-reactive protein

    NARCIS (Netherlands)

    Keeling, Stephanie O.; Landewe, Robert; van der Heijde, Desiree; Bathon, Joan; Boers, Maarten; Garnero, Patrick; Geusens, Piet; El-Gabalawy, Hani; Inman, Robert D.; Kraus, Virginia B.; Kvien, Tore K.; Mease, Philip J.; Ostergaard, Mikkel; Ritchlin, Chris; Syversen, Silje W.; Maksymowych, Walter P.

    2007-01-01

    A list of 14 criteria for guiding the validation of a soluble biomarker as reflecting structural damage endpoints in rheumatoid arthritis (RA) clinical trials was drafted by an international working group after a Delphi consensus exercise. C-reactive protein (CRP), a soluble biomarker extensively

  2. Validity of physiological biomarkers for maternal behavior in cows--a comparison of beef and dairy cattle.

    Science.gov (United States)

    Geburt, Katrin; Friedrich, Morten; Piechotta, Marion; Gauly, Matthias; König von Borstel, Uta

    2015-02-01

    The objectives of the present study were to evaluate the suitability of potential biomarkers for maternal ability in cattle, and in addition to test the hypothesis that dairy cows have a less pronounced motherliness than beef cows. Therefore, maternal behavior of 20 Simmental beef-type (S) and 20 German Black Pied (dairy-type) Cattle (BP) was assessed on the 2nd and again on the 3rd day of the calf's life. Measurements included the frequency of interactions between cow and calf, the cow's willingness to defend her calf, the overall maternal behavior, saliva cortisol, saliva oxytocin, heart rate, and thermal images of the eye (ET). Mixed model analysis revealed that BP had significantly (Pcows. Simmental (beef) cows showed more defensive behavior (3.5±0.2 vs. 2.7±0.2 scores), but fewer total interactions between cow and calf (8.1±1.4 vs. 13.8±1.4), compared to BP (dairy). However, with the exception of heart rate and overall maternal behavior, breed differences tended to diminish from the 2nd to the 3rd day of the calf's life. Repeatabilities ranged from 9±23% (ET) to 77±7% (maternal behavior measured on a visual analogue scale), and correlations between physiological parameters and behavior differed between breeds and were generally at a low level. In conclusion, beef cows do not seem to be per se more maternal compared to dairy cows, and the assessed parameters are of limited use as biomarkers for maternal behavior. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Validation of the Diet Quality Index for Adolescents by Comparison with Biomarkers, Nutrient and Food Intakes

    DEFF Research Database (Denmark)

    Vyncke, Krishna; Cruz Fernandez, Estefania; Fajó-Pascual, Marta

    2013-01-01

    in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Study. Dietary intake was assessed by two, non-consecutive 24 h recalls. A DQI-A score, considering the components' dietary quality, diversity and equilibrium, was calculated. Associations between the DQI-A and food and nutrient intakes...... with energy-dense and low-nutritious foods. On the nutrient level, the DQI-A was positively related to the intake of water, fibre and most minerals and vitamins. No association was found between the DQI-A and total fat intake. Furthermore, a positive association was observed with 25-hydroxyvitamin D, holo...

  4. Phase II cancer clinical trials for biomarker-guided treatments.

    Science.gov (United States)

    Jung, Sin-Ho

    2018-01-01

    The design and analysis of cancer clinical trials with biomarker depend on various factors, such as the phase of trials, the type of biomarker, whether the used biomarker is validated or not, and the study objectives. In this article, we demonstrate the design and analysis of two Phase II cancer clinical trials, one with a predictive biomarker and the other with an imaging prognostic biomarker. Statistical testing methods and their sample size calculation methods are presented for each trial. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint.

  5. New biomarkers of coffee consumption identified by the non-targeted metabolomic profiling of cohort study subjects.

    Directory of Open Access Journals (Sweden)

    Joseph A Rothwell

    Full Text Available Coffee contains various bioactives implicated with human health and disease risk. To accurately assess the effects of overall consumption upon health and disease, individual intake must be measured in large epidemiological studies. Metabolomics has emerged as a powerful approach to discover biomarkers of intake for a large range of foods. Here we report the profiling of the urinary metabolome of cohort study subjects to search for new biomarkers of coffee intake. Using repeated 24-hour dietary records and a food frequency questionnaire, 20 high coffee consumers (183-540 mL/d and 19 low consumers were selected from the French SU.VI.MAX2 cohort. Morning spot urine samples from each subject were profiled by high-resolution mass spectrometry. Partial least-square discriminant analysis of multidimensional liquid chromatography-mass spectrometry data clearly distinguished high consumers from low via 132 significant (p-value<0.05 discriminating features. Ion clusters whose intensities were most elevated in the high consumers were annotated using online and in-house databases and their identities checked using commercial standards and MS-MS fragmentation. The best discriminants, and thus potential markers of coffee consumption, were the glucuronide of the diterpenoid atractyligenin, the diketopiperazine cyclo(isoleucyl-prolyl, and the alkaloid trigonelline. Some caffeine metabolites, such as 1-methylxanthine, were also among the discriminants, however caffeine may be consumed from other sources and its metabolism is subject to inter-individual variation. Receiver operating characteristics curve analysis showed that the biomarkers identified could be used effectively in combination for increased sensitivity and specificity. Once validated in other cohorts or intervention studies, these specific single or combined biomarkers will become a valuable alternative to assessment of coffee intake by dietary survey and finally lead to a better understanding of

  6. Evolution of M. bovis BCG Vaccine: Is Niacin Production Still a Valid Biomarker?

    Directory of Open Access Journals (Sweden)

    Sarman Singh

    2015-01-01

    Full Text Available BCG vaccine is usually considered to be safe though rarely serious complications have also been reported, often incriminating contamination of the seed strain with pathogenic Mycobacterium tuberculosis. In such circumstances, it becomes prudent to rule out the contamination of the vaccine seed. M. bovis BCG can be confirmed by the absence of nitrate reductase, negative niacin test, and resistance to pyrazinamide and cycloserine. Recently in India, some stocks were found to be niacin positive which led to a national controversy and closer of a vaccine production plant. This prompted us to write this review and the comparative biochemical and genotypic studies were carried out on the these contentious vaccine stocks at the Indian vaccine plant and other seeds and it was found that some BCG vaccine strains and even some strains of M. bovis with eugenic-growth characteristics mainly old laboratory strains may give a positive niacin reaction. Most probably, the repeated subcultures lead to undefined changes at the genetic level in these seed strains. These changing biological characteristics envisage reevaluation of biochemical characters of existing BCG vaccine seeds and framing of newer guidelines for manufacturing, production, safety, and effectiveness of BCG vaccine.

  7. Alarmins as biomarkers of gastrointestinal surgical injury - a pilot study.

    Science.gov (United States)

    Maca, Jan; Holub, Michal; Bursa, Filip; Ihnat, Peter; Reimer, Petr; Svagera, Zdenek; Burda, Michal; Sevcik, Pavel

    2018-02-01

    The dysregulation of inflammatory response to surgical injury affects outcomes. Alarmins, the earliest bioactive substances from damaged cells, play a crucial role in initiating the inflammation. We analyzed serum levels of alarmins (S100A8, S100A12, high mobility group box, and heat shock protein 70) after major abdominal surgery (MAS) in surgical (S) (n = 82) and nonsurgical (NS) groups (n = 35). The main objective was determining a role of selected alarmins in host response to MAS. The secondary objectives were (i) evaluation of the relationship among alarmins and selected biomarkers (C-reactive protein, interleukin-6), (ii) influence of the place of gastrointestinal resection, and (iii) role of alarmins in MAS for cancer. Except for HMGB1, the levels of all alarmins were higher in the S group compared with the NS group. In the S group, positive correlations were found between S100A8 and both IL-6 and CRP. Additionally, the S100A8 level was higher (p < 0.01) in patients who underwent upper gastrointestinal tract (GIT) surgery compared to middle and lower GIT resections. Alarmins levels did not differ between cancer and noncancer patients. MAS is able to elicit increase in alarmin levels. S100A8 can be considered a potential biomarker of surgical injury, especially in the upper part of the GIT. © 2018 APMIS. Published by John Wiley & Sons Ltd.

  8. Cohort profile of BIOMArCS: the BIOMarker study to identify the Acute risk of a Coronary Syndrome-a prospective multicentre biomarker study conducted in the Netherlands.

    Science.gov (United States)

    Oemrawsingh, Rohit M; Akkerhuis, K Martijn; Umans, Victor A; Kietselaer, Bas; Schotborgh, Carl; Ronner, Eelko; Lenderink, Timo; Liem, Anho; Haitsma, David; van der Harst, Pim; Asselbergs, Folkert W; Maas, Arthur; Oude Ophuis, Anton J; Ilmer, Ben; Dijkgraaf, Rene; de Winter, Robbert-Jan; The, S Hong Kie; Wardeh, Alexander J; Hermans, Walter; Cramer, Etienne; van Schaik, Ron H; Hoefer, Imo E; Doevendans, Pieter A; Simoons, Maarten L; Boersma, Eric

    2016-12-23

    Progression of stable coronary artery disease (CAD) towards acute coronary syndrome (ACS) is a dynamic and heterogeneous process with many intertwined constituents, in which a plaque destabilising sequence could lead to ACS within short time frames. Current CAD risk assessment models, however, are not designed to identify increased vulnerability for the occurrence of coronary events within a precise, short time frame at the individual patient level. The BIOMarker study to identify the Acute risk of a Coronary Syndrome (BIOMArCS) was designed to evaluate whether repeated measurements of multiple biomarkers can predict such 'vulnerable periods'. BIOMArCS is a multicentre, prospective, observational study of 844 patients presenting with ACS, either with or without ST-elevation and at least one additional cardiovascular risk factor. We hypothesised that patterns of circulating biomarkers that reflect the various pathophysiological components of CAD, such as distorted lipid metabolism, vascular inflammation, endothelial dysfunction, increased thrombogenicity and ischaemia, diverge in the days to weeks before a coronary event. Divergent biomarker patterns, identified by serial biomarker measurements during 1-year follow-up might then indicate 'vulnerable periods' during which patients with CAD are at high short-term risk of developing an ACS. Venepuncture was performed every fortnight during the first half-year and monthly thereafter. As prespecified, patient enrolment was terminated after the primary end point of cardiovascular death or hospital admission for non-fatal ACS had occurred in 50 patients. A case-cohort design will explore differences in temporal patterns of circulating biomarkers prior to the repeat ACS. Follow-up and event adjudication have been completed. Prespecified biomarker analyses are currently being performed and dissemination through peer-reviewed publications and conference presentations is expected from the third quarter of 2016. Should

  9. The δ13C Value of Fingerstick Blood Is a Valid, Reliable, and Sensitive Biomarker of Sugar-Sweetened Beverage Intake in Children and Adolescents.

    Science.gov (United States)

    MacDougall, Carly R; Hill, Catelyn E; Jahren, A Hope; Savla, Jyoti; Riebl, Shaun K; Hedrick, Valisa E; Raynor, Hollie A; Dunsmore, Julie C; Frisard, Madlyn I; Davy, Brenda M

    2018-01-01

    Reliance on self-reported dietary intake methods is a commonly cited research limitation, and dietary misreporting is a particular problem in children and adolescents. Objective indicators of dietary intake, such as dietary biomarkers, are needed to overcome this research limitation. The added sugar (AS) biomarker δ13C, which measures the relative abundance of 13C to 12C, has demonstrated preliminary validity in adults. The purpose of this investigation was to determine the comparative validity, test-retest reliability, and sensitivity of the δ13C biomarker to detect AS and sugar-sweetened beverage (SSB) intake using fingerstick blood samples in children and adolescents. Children (aged 6-11 y, n = 126, 56% male, mean ± SD age: 9 ± 2 y) and adolescents (aged 12-18 y, n = 200, 44% male, mean ± SD age: 15 ± 2 y) completed 4 testing sessions within a 3-wk period. Participants' height, weight, demographic characteristics, and health history were determined at the first session; 24-h recalls were obtained at each visit and fingerstick blood samples were collected at visits 1 and 3. Samples were analyzed for δ13C value using natural abundance stable isotope mass spectrometry. δ13C value was compared with dietary outcomes in the full sample, and in child and adolescent subgroups. t Tests and correlational analyses were used to assess biomarker validity and reliability, whereas logistic regression and area under the receiver-operator characteristic curve (AUC) were used to evaluate sensitivity. Reported mean ± SD AS consumption was 82.2 ± 35.8 g/d and 329 ± 143 kcal/d, and SSB consumption was 222 ± 243 mL/d and 98 ± 103 kcal/d. Mean δ13C value was -19.65 ± 0.69‰, and was lower in children than in adolescents (-19.80 ± 0.67‰ compared with -19.56 ± 0.67‰, P = 0.002). δ13C values were similar across sessions (visit 1: -19.66 ± 0.68‰; visit 3: -19.64 ± 0.68‰; r = 0.99, P AUC (0.75 and 0.62, respectively). The δ13C biomarker is a promising

  10. A tool to facilitate clinical biomarker studies - a tissue dictionary based on the Human Protein Atlas

    Directory of Open Access Journals (Sweden)

    Kampf Caroline

    2012-09-01

    Full Text Available Abstract The complexity of tissue and the alterations that distinguish normal from cancer remain a challenge for translating results from tumor biological studies into clinical medicine. This has generated an unmet need to exploit the findings from studies based on cell lines and model organisms to develop, validate and clinically apply novel diagnostic, prognostic and treatment predictive markers. As one step to meet this challenge, the Human Protein Atlas project has been set up to produce antibodies towards human protein targets corresponding to all human protein coding genes and to map protein expression in normal human tissues, cancer and cells. Here, we present a dictionary based on microscopy images created as an amendment to the Human Protein Atlas. The aim of the dictionary is to facilitate the interpretation and use of the image-based data available in the Human Protein Atlas, but also to serve as a tool for training and understanding tissue histology, pathology and cell biology. The dictionary contains three main parts, normal tissues, cancer tissues and cells, and is based on high-resolution images at different magnifications of full tissue sections stained with H & E. The cell atlas is centered on immunofluorescence and confocal microscopy images, using different color channels to highlight the organelle structure of a cell. Here, we explain how this dictionary can be used as a tool to aid clinicians and scientists in understanding the use of tissue histology and cancer pathology in diagnostics and biomarker studies.

  11. Validation studies of nursing diagnoses in neonatology

    Directory of Open Access Journals (Sweden)

    Pavlína Rabasová

    2016-03-01

    Full Text Available Aim: The objective of the review was the analysis of Czech and foreign literature sources and professional periodicals to obtain a relevant comprehensive overview of validation studies of nursing diagnoses in neonatology. Design: Review. Methods: The selection criterion was studies concerning the validation of nursing diagnoses in neonatology. To obtain data from relevant sources, the licensed professional databases EBSCO, Web of Science and Scopus were utilized. The search criteria were: date of publication - unlimited; academic periodicals - full text; peer-reviewed periodicals; search language - English, Czech and Slovak. Results: A total of 788 studies were found. Only 5 studies were eligible for content analysis, dealing specifically with validation of nursing diagnoses in neonatology. The analysis of the retrieved studies suggests that authors are most often concerned with identifying the defining characteristics of nursing diagnoses applicable to both the mother (parents and the newborn. The diagnoses were validated in the domains Role Relationship; Coping/Stress tolerance; Activity/Rest, and Elimination and Exchange. Diagnoses represented were from the field of dysfunctional physical needs as well as the field of psychosocial and spiritual needs. The diagnoses were as follows: Parental role conflict (00064; Impaired parenting (00056; Grieving (00136; Ineffective breathing pattern (00032; Impaired gas exchange (00030; and Impaired spontaneous ventilation (00033. Conclusion: Validation studies enable effective planning of interventions with measurable results and support clinical nursing practice.

  12. Validation of the long-term assessment of hypothalamic-pituitary-adrenal activity in rats using hair corticosterone as a biomarker.

    Science.gov (United States)

    Scorrano, Fabrizio; Carrasco, Javier; Pastor-Ciurana, Jordi; Belda, Xavier; Rami-Bastante, Alicia; Bacci, Maria Laura; Armario, Antonio

    2015-03-01

    The evaluation of chronic activity of the hypothalamic-pituitary-adrenal (HPA) axis is critical for determining the impact of chronic stressful situations. However, current methods have important limitations. The potential use of hair glucocorticoids as a noninvasive retrospective biomarker of long-term HPA activity is gaining acceptance in humans and wild animals. However, there is no study examining hair corticosterone (HC) in laboratory animals. The present study validates a method for measuring HC in rats and demonstrates that it properly reflects chronic HPA activity. The HC concentration was similar in male and female rats, despite higher total plasma corticosterone levels in females, tentatively suggesting that it reflects free rather than total plasma corticosterone. Exposure of male rats to 2 different chronic stress protocols (chronic immobilization and chronic unpredictable stress) resulted in similarly higher HC levels compared to controls (1.8-fold). HC also increased after a mild chronic stressor (30 min daily restraint). Chronic administration of 2 different doses of a long-acting ACTH preparation dramatically increased HC (3.1- and 21.5-fold, respectively), demonstrating that a ceiling effect in HC accumulation is unlikely under other more natural conditions. Finally, adrenalectomy significantly reduced HC. In conclusion, HC measurement in rats appears appropriate to evaluate integrated chronic changes in circulating corticosterone. © FASEB.

  13. Reconstructing exposures from biomarkers using exposure-pharmacokinetic modeling--A case study with carbaryl.

    Science.gov (United States)

    Brown, Kathleen; Phillips, Martin; Grulke, Christopher; Yoon, Miyoung; Young, Bruce; McDougall, Robin; Leonard, Jeremy; Lu, Jingtao; Lefew, William; Tan, Yu-Mei

    2015-12-01

    Sources of uncertainty involved in exposure reconstruction for short half-life chemicals were characterized using computational models that link external exposures to biomarkers. Using carbaryl as an example, an exposure model, the Cumulative and Aggregate Risk Evaluation System (CARES), was used to generate time-concentration profiles for 500 virtual individuals exposed to carbaryl. These exposure profiles were used as inputs into a physiologically based pharmacokinetic (PBPK) model to predict urinary biomarker concentrations. These matching dietary intake levels and biomarker concentrations were used to (1) compare three reverse dosimetry approaches based on their ability to predict the central tendency of the intake dose distribution; and (2) identify parameters necessary for a more accurate exposure reconstruction. This study illustrates the trade-offs between using non-iterative reverse dosimetry methods that are fast, less precise and iterative methods that are slow, more precise. This study also intimates the necessity of including urine flow rate and elapsed time between last dose and urine sampling as part of the biomarker sampling collection for better interpretation of urinary biomarker data of short biological half-life chemicals. Resolution of these critical data gaps can allow exposure reconstruction methods to better predict population-level intake doses from large biomonitoring studies. Published by Elsevier Inc.

  14. Mycotoxin exposure in rural residents in northern Nigeria: a pilot study using multi-urinary biomarkers.

    Science.gov (United States)

    Ezekiel, Chibundu N; Warth, Benedikt; Ogara, Isaac M; Abia, Wilfred A; Ezekiel, Victoria C; Atehnkeng, Joseph; Sulyok, Michael; Turner, Paul C; Tayo, Grace O; Krska, Rudolf; Bandyopadhyay, Ranajit

    2014-05-01

    A pilot, cross-sectional, correlational study was conducted in eight rural communities in northern Nigeria to investigate mycotoxin exposures in 120 volunteers (19 children, 20 adolescents and 81 adults) using a modern LC-MS/MS based multi-biomarker approach. First morning urine samples were analyzed and urinary biomarker levels correlated with mycotoxin levels in foods consumed the day before urine collection. A total of eight analytes were detected in 61/120 (50.8%) of studied urine samples, with ochratoxin A, aflatoxin M1 and fumonisin B1 being the most frequently occurring biomarkers of exposure. These mycotoxin biomarkers were present in samples from all age categories, suggestive of chronic (lifetime) exposures. Rough estimates of mycotoxin intake suggested some exposures were higher than the tolerable daily intake. Overall, rural consumer populations from Nasarawa were more exposed to several mixtures of mycotoxins in their diets relative to those from Kaduna as shown by food and urine biomarker data. This study has shown that mycotoxin co-exposure may be a major public health challenge in rural Nigeria; this calls for urgent intervention. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Diagnostic and prognostic epigenetic biomarkers in cancer.

    Science.gov (United States)

    Costa-Pinheiro, Pedro; Montezuma, Diana; Henrique, Rui; Jerónimo, Carmen

    2015-01-01

    Growing cancer incidence and mortality worldwide demands development of accurate biomarkers to perfect detection, diagnosis, prognostication and monitoring. Urologic (prostate, bladder, kidney), lung, breast and colorectal cancers are the most common and despite major advances in their characterization, this has seldom translated into biomarkers amenable for clinical practice. Epigenetic alterations are innovative cancer biomarkers owing to stability, frequency, reversibility and accessibility in body fluids, entailing great potential of assay development to assist in patient management. Several studies identified putative epigenetic cancer biomarkers, some of which have been commercialized. However, large multicenter validation studies are required to foster translation to the clinics. Herein we review the most promising epigenetic detection, diagnostic, prognostic and predictive biomarkers for the most common cancers.

  16. Candidate Biomarkers in Children with Autism Spectrum Disorder: A Review of MRI Studies

    Institute of Scientific and Technical Information of China (English)

    Dongyun Li; Hans-Otto Karnath; Xiu Xu

    2017-01-01

    Searching for effective biomarkers is one of the most challenging tasks in the research field of Autism Spectrum Disorder (ASD).Magnetic resonance imaging (MRI) provides a non-invasive and powerful tool for investigating changes in the structure,function,maturation,connectivity,and metabolism of the brain of children with ASD.Here,we review the more recent MRI studies in young children with ASD,aiming to provide candidate biomarkers for the diagnosis of childhood ASD.The review covers structural imaging methods,diffusion tensor imaging,resting-state functional MRI,and magnetic reso nance spectroscopy.Future advances in neuroimaging techniques,as well as cross-disciplinary studies and largescale collaborations will be needed for an integrated approach linking neuroimaging,genetics,and phenotypic data to allow the discovery of new,effective biomarkers.

  17. Monitoring Progression of Amyotrophic Lateral Sclerosis Using Ultrasound Morpho-Textural Muscle Biomarkers: A Pilot Study.

    Science.gov (United States)

    Martínez-Payá, Jacinto J; Ríos-Díaz, José; Medina-Mirapeix, Francesc; Vázquez-Costa, Juan F; Del Baño-Aledo, María Elena

    2018-01-01

    The need is increasing for progression biomarkers that allow the loss of motor neurons in amyotrophic lateral sclerosis (ALS) to be monitored in clinical trials. In this prospective longitudinal study, muscle thickness, echointensity, echovariation and gray level co-occurrence matrix textural features are examined as possible progression ultrasound biomarkers in ALS patients during a 5-mo follow-up period. We subjected 13 patients to 3 measurements for 20 wk. They showed a significant loss of muscle, an evident tendency to loss of thickness and increased echointensity and echovariation. In regard to textural parameters, muscle heterogeneity tended to increase as a result of the neoformation of non-contractile tissue through denervation. Considering some limitations of the study, the quantitative muscle ultrasound biomarkers evaluated showed a promising ability to monitor patients affected by ALS. Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.

  18. BIOMOVS: an international model validation study

    International Nuclear Information System (INIS)

    Haegg, C.; Johansson, G.

    1988-01-01

    BIOMOVS (BIOspheric MOdel Validation Study) is an international study where models used for describing the distribution of radioactive and nonradioactive trace substances in terrestrial and aquatic environments are compared and tested. The main objectives of the study are to compare and test the accuracy of predictions between such models, explain differences in these predictions, recommend priorities for future research concerning the improvement of the accuracy of model predictions and act as a forum for the exchange of ideas, experience and information. (author)

  19. BIOMOVS: An international model validation study

    International Nuclear Information System (INIS)

    Haegg, C.; Johansson, G.

    1987-01-01

    BIOMOVS (BIOspheric MOdel Validation Study) is an international study where models used for describing the distribution of radioactive and nonradioactive trace substances in terrestrial and aquatic environments are compared and tested. The main objectives of the study are to compare and test the accuracy of predictions between such models, explain differences in these predictions, recommend priorities for future research concerning the improvement of the accuracy of model predictions and act as a forum for the exchange of ideas, experience and information. (orig.)

  20. Research strategies and the use of nutrient biomarkers in studies of diet and chronic disease.

    Science.gov (United States)

    Prentice, Ross L; Sugar, Elizabeth; Wang, C Y; Neuhouser, Marian; Patterson, Ruth

    2002-12-01

    To provide an account of the state of diet and chronic disease research designs and methods; to discuss the role and potential of aggregate and analytical observational studies and randomised controlled intervention trials; and to propose strategies for strengthening each type of study, with particular emphasis on the use of nutrient biomarkers in cohort study settings. Observations from diet and disease studies conducted over the past 25 years are used to identify the strengths and weaknesses of various study designs that have been used to associate nutrient consumption with chronic disease risk. It is argued that a varied research programme, employing multiple study designs, is needed in response to the widely different biases and constraints that attend aggregate and analytical epidemiological studies and controlled intervention trials. Study design modifications are considered that may be able to enhance the reliability of aggregate and analytical nutritional epidemiological studies. Specifically, the potential of nutrient biomarker measurements that provide an objective assessment of nutrient consumption to enhance analytical study reliability is emphasised. A statistical model for combining nutrient biomarker data with self-report nutrient consumption estimates is described, and related ongoing work on odds ratio parameter estimation is outlined briefly. Finally, a recently completed nutritional biomarker study among 102 postmenopausal women in Seattle is mentioned. The statistical model will be applied to biomarker data on energy expenditure, urinary nitrogen, selected blood fatty acid measurements and various blood micronutrient concentrations, and food frequency self-report data, to identify study subject characteristics, such as body mass, age or socio-economic status, that may be associated with the measurement properties of food frequency nutrient consumption estimates. This information will be crucial for the design of a potential larger nutrient

  1. Consensus Guidelines for CSF and Blood Biobanking for CNS Biomarker Studies

    Directory of Open Access Journals (Sweden)

    Charlotte E. Teunissen

    2011-01-01

    Full Text Available There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in cerebrospinal fluid (CSF are being used in clinical practice. Anti-aquaporin-4 antibodies in serum are currently useful for the diagnosis of neuromyelitis optica (NMO, but we could expect novel CSF biomarkers that help define prognosis and response to treatment for this disease. One of the most critical factors in biomarker research is the inadequate powering of studies performed by single centers. Collaboration between investigators is needed to establish large biobanks of well-defined samples. A key issue in collaboration is to establish standardized protocols for biobanking to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by pre-analytical factors. Here, consensus guidelines for CSF collection and biobanking are presented, based on the guidelines that have been published by the BioMS-eu network for CSF biomarker research. We focussed on CSF collection procedures, pre-analytical factors and high quality clinical and paraclinical information. Importantly, the biobanking protocols are applicable for CSF biobanks for research targeting any neurological disease.

  2. Biomarkers for predicting complete debulking in ovarian cancer

    DEFF Research Database (Denmark)

    Fagö-Olsen, Carsten Lindberg; Ottesen, Bent; Christensen, Ib Jarle

    2014-01-01

    AIM: We aimed to construct and validate a model based on biomarkers to predict complete primary debulking surgery for ovarian cancer patients. PATIENTS AND METHODS: The study consisted of three parts: Part I: Biomarker data obtained from mass spectrometry, baseline data and, surgical outcome were...... used to construct predictive indices for complete tumour resection; Part II: sera from randomly selected patients from part I were analyzed using enzyme-linked immunosorbent assay (ELISA) to investigate the correlation to mass spectrometry; Part III: the indices from part I were validated in a new.......64. CONCLUSION: Our validated model based on biomarkers was unable to predict surgical outcome for patients with ovarian cancer....

  3. Biomarkers in Czech workers exposed to 1,3-butadiene: a transitional epidemiologic study

    NARCIS (Netherlands)

    Albertini, Richard J.; Srám, Radim J.; Vacek, Pamela M.; Lynch, Jeremiah; Nicklas, Janice A.; van Sittert, Nico J.; Boogaard, Peter J.; Henderson, Rogene F.; Swenberg, James A.; Tates, Ad D.; Ward, Jonathan B.; Wright, Michael; Ammenheuser, Marinel M.; Binkova, Blanka; Blackwell, Walter; de Zwart, Franz A.; Krako, Dean; Krone, Jennifer; Megens, Hendricus; Musilová, Petra; Rajská, Gabriela; Ranasinghe, Asoka; Rosenblatt, Judah I.; Rössner, Pavel; Rubes, Jiri; Sullivan, Linda; Upton, Patricia; Zwinderman, Ailko H.

    2003-01-01

    A multiinstitutional, transitional epidemiologic study was conducted with a worker population in the Czech Republic to evaluate the utility of a continuum of non-disease biological responses as biomarkers of exposure to 1,3-butadiene (BD)* in an industrial setting. The study site included two BD

  4. Multicollinearity may lead to artificial interaction: an example from a cross sectional study of biomarkers.

    Science.gov (United States)

    Sithisarankul, P; Weaver, V M; Diener-West, M; Strickland, P T

    1997-06-01

    Collinearity is the situation which arises in multiple regression when some or all of the explanatory variables are so highly correlated with one another that it becomes very difficult, if not impossible, to disentangle their influences and obtain a reasonably precise estimate of their effects. Suppressor variable is one of the extreme situations of collinearity that one variable can substantially increase the multiple correlation when combined with a variable that is only modestly correlated with the response variable. In this study, we describe the process by which we disentangled and discovered multicollinearity and its consequences, namely artificial interaction, using the data from cross-sectional quantification of several biomarkers. We showed how the collinearity between one biomarker (blood lead level) and another (urinary trans, trans-muconic acid) and their interaction (blood lead level* urinary trans, trans-muconic acid) can lead to the observed artificial interaction on the third biomarker (urinary 5-aminolevulinic acid).

  5. Evidence that iron accelerates Alzheimer's pathology: a CSF biomarker study.

    Science.gov (United States)

    Ayton, Scott; Diouf, Ibrahima; Bush, Ashley Ian

    2018-05-01

    To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF β-amyloid (Aβ) and tau. Mixed-effects models of CSF Aβ 1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aβ 1-42 for up to 5 years. In subjects with biomarker-confirmed Alzheimer's pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aβ 1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aβ 1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aβ deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aβ from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aβ over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aβ levels to the average level of Alzheimer's subjects from 18.8 to 10.8 years. Iron might facilitate Aβ deposition in Alzheimer's and accelerate the disease process. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  6. Development and validation of a multiplex add-on assay for sepsis biomarkers using xMAP technology

    DEFF Research Database (Denmark)

    Kofoed, Kristian; Schneider, Uffe Vest; Scheel, Troels

    2006-01-01

    Sepsis is a common and often fatal disease. Because sepsis can be caused by many different organisms, biomarkers that can aid in diagnosing sepsis and monitoring treatment efficacy are highly warranted. New sepsis markers may provide additional information to complement the currently used markers....

  7. A Japanese cross-sectional multicentre study of biomarkers associated with cardiovascular disease in smokers and non-smokers

    OpenAIRE

    L?dicke, Frank; Magnette, John; Baker, Gizelle; Weitkunat, Rolf

    2015-01-01

    Abstract We performed a cross-sectional, multicentre study in Japan to detect the differences in biomarkers of exposure and cardiovascular biomarkers between smokers and non-smokers. Several clinically relevant cardiovascular biomarkers differed significantly between smokers and non-smokers, including lipid metabolism (high-density lipoprotein cholesterol concentrations ? lower in smokers), inflammation (fibrinogen and white blood cell count ? both higher in smokers), oxidative stress (8-epi-...

  8. A new approach towards biomarker selection in estimation of human exposure to chiral chemicals: a case study of mephedrone.

    Science.gov (United States)

    Castrignanò, Erika; Mardal, Marie; Rydevik, Axel; Miserez, Bram; Ramsey, John; Shine, Trevor; Pantoș, G Dan; Meyer, Markus R; Kasprzyk-Hordern, Barbara

    2017-11-02

    Wastewater-based epidemiology is an innovative approach to estimate public health status using biomarker analysis in wastewater. A new compound detected in wastewater can be a potential biomarker of an emerging trend in public health. However, it is currently difficult to select new biomarkers mainly due to limited human metabolism data. This manuscript presents a new framework, which enables the identification and selection of new biomarkers of human exposure to drugs with scarce or unknown human metabolism data. Mephedrone was targeted to elucidate the assessment of biomarkers for emerging drugs of abuse using a four-step analytical procedure. This framework consists of: (i) identification of possible metabolic biomarkers present in wastewater using an in-vivo study; (ii) verification of chiral signature of the target compound; (iii) confirmation of human metabolic residues in in-vivo/vitro studies and (iv) verification of stability of biomarkers in wastewater. Mephedrone was selected as a suitable biomarker due to its high stability profile in wastewater. Its enantiomeric profiling was studied for the first time in biological and environmental matrices, showing stereoselective metabolism of mephedrone in humans. Further biomarker candidates were also proposed for future investigation: 4'-carboxy-mephedrone, 4'-carboxy-normephedrone, 1-dihydro-mephedrone, 1-dihydro-normephedrone and 4'-hydroxy-normephedrone.

  9. Metabolite Profiling in the Pursuit of Biomarkers for IVF Outcome: The Case for Metabolomics Studies

    Directory of Open Access Journals (Sweden)

    C. McRae

    2013-01-01

    Full Text Available Background. This paper presents the literature on biomarkers of in vitro fertilisation (IVF outcome, demonstrating the progression of these studies towards metabolite profiling, specifically metabolomics. The need for more, and improved, metabolomics studies in the field of assisted conception is discussed. Methods. Searches were performed on ISI Web of Knowledge SM for literature associated with biomarkers of oocyte and embryo quality, and biomarkers of IVF outcome in embryo culture medium, follicular fluid (FF, and blood plasma in female mammals. Results. Metabolomics in the field of female reproduction is still in its infancy. Metabolomics investigations of embryo culture medium for embryo selection have been the most common, but only within the last five years. Only in 2012 has the first metabolomics investigation of FF for biomarkers of oocyte quality been reported. The only metabolomics studies of human blood plasma in this context have been aimed at identifying women with polycystic ovary syndrome (PCOS. Conclusions. Metabolomics is becoming more established in the field of assisted conception, but the studies performed so far have been preliminary and not all potential applications have yet been explored. With further improved metabolomics studies, the possibility of identifying a method for predicting IVF outcome may become a reality.

  10. Adipocytokines, hepatic and inflammatory biomarkers and incidence of type 2 diabetes. the CoLaus study.

    Directory of Open Access Journals (Sweden)

    Pedro Marques-Vidal

    Full Text Available CONTEXT: There is contradictory information regarding the prognostic importance of adipocytokines, hepatic and inflammatory biomarkers on the incidence of type 2 diabetes. The objective was to assess the prognostic relevance of adipocytokine and inflammatory markers (C-reactive protein - CRP; interleukin-1beta - IL-1β; interleukin-6- IL-6; tumour necrosis factor-α - TNF-α; leptin and adiponectin and gamma-glutamyl transpeptidase (γGT on the incidence of type 2 diabetes. METHODS: Prospective, population-based study including 3,842 non-diabetic participants (43.3% men, age range 35 to 75 years, followed for an average of 5.5 years (2003-2008. The endpoint was the occurrence of type 2 diabetes. RESULTS: 208 participants (5.4%, 66 women developed type 2 diabetes during follow-up. On univariate analysis, participants who developed type 2 diabetes had significantly higher baseline levels of IL-6, CRP, leptin and γGT, and lower levels of adiponectin than participants who remained free of type 2 diabetes. After adjusting for a validated type 2 diabetes risk score, only the associations with adiponectin: Odds Ratio and (95% confidence interval: 0.97 (0.64-1.47, 0.84 (0.55-1.30 and 0.64 (0.40-1.03 for the second, third and forth gender-specific quartiles respectively, remained significant (P-value for trend = 0.05. Adding each marker to a validated type 2 diabetes risk score (including age, family history of type 2 diabetes, height, waist circumference, resting heart rate, presence of hypertension, HDL cholesterol, triglycerides, fasting glucose and serum uric acid did not improve the area under the ROC or the net reclassification index; similar findings were obtained when the markers were combined, when the markers were used as continuous (log-transformed variables or when gender-specific quartiles were used. CONCLUSION: Decreased adiponectin levels are associated with an increased risk for incident type 2 diabetes, but they seem to add little

  11. Effect of vitamin levels on biomarkers of exposure and oxidative damage – The EXPAH study

    Czech Academy of Sciences Publication Activity Database

    Šrám, Radim; Farmer, P.; Singh, R.; Garte, S.; Kalina, I.; Popov, T. A.; Binková, Blanka; Ragin, C.; Taioli, E.

    2009-01-01

    Roč. 672, č. 2 (2009), s. 129-134 ISSN 1383-5718 Institutional research plan: CEZ:AV0Z50390512 Keywords : molecular epidemiology * cross-sectional study * biomarkers of exposure Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.552, year: 2009

  12. Metabolism and Biomarkers of Heterocyclic Aromatic Amines in Molecular Epidemiology Studies: Lessons Learned from Aromatic Amines

    Science.gov (United States)

    2011-01-01

    Aromatic amines and heterocyclic aromatic amines (HAAs) are structurally related classes of carcinogens that are formed during the combustion of tobacco or during the high-temperature cooking of meats. Both classes of procarcinogens undergo metabolic activation by N-hydroxylation of the exocyclic amine group, to produce a common proposed intermediate, the arylnitrenium ion, which is the critical metabolite implicated in toxicity and DNA damage. However, the biochemistry and chemical properties of these compounds are distinct and different biomarkers of aromatic amines and HAAs have been developed for human biomonitoring studies. Hemoglobin adducts have been extensively used as biomarkers to monitor occupational and environmental exposures to a number of aromatic amines; however, HAAs do not form hemoglobin adducts at appreciable levels and other biomarkers have been sought. A number of epidemiologic studies that have investigated dietary consumption of well-done meat in relation to various tumor sites reported a positive association between cancer risk and well-done meat consumption, although some studies have shown no associations between well-done meat and cancer risk. A major limiting factor in most epidemiological studies is the uncertainty in quantitative estimates of chronic exposure to HAAs and, thus, the association of HAAs formed in cooked meat and cancer risk has been difficult to establish. There is a critical need to establish long-term biomarkers of HAAs that can be implemented in molecular epidemioIogy studies. In this review article, we highlight and contrast the biochemistry of several prototypical carcinogenic aromatic amines and HAAs to which humans are chronically exposed. The biochemical properties and the impact of polymorphisms of the major xenobiotic-metabolizing enzymes on the biological effects of these chemicals are examined. Lastly, the analytical approaches that have been successfully employed to biomonitor aromatic amines and HAAs, and

  13. Urinary Proteomics Pilot Study for Biomarker Discovery and Diagnosis in Heart Failure with Reduced Ejection Fraction.

    Directory of Open Access Journals (Sweden)

    Kasper Rossing

    Full Text Available Biomarker discovery and new insights into the pathophysiology of heart failure with reduced ejection fraction (HFrEF may emerge from recent advances in high-throughput urinary proteomics. This could lead to improved diagnosis, risk stratification and management of HFrEF.Urine samples were analyzed by on-line capillary electrophoresis coupled to electrospray ionization micro time-of-flight mass spectrometry (CE-MS to generate individual urinary proteome profiles. In an initial biomarker discovery cohort, analysis of urinary proteome profiles from 33 HFrEF patients and 29 age- and sex-matched individuals without HFrEF resulted in identification of 103 peptides that were significantly differentially excreted in HFrEF. These 103 peptides were used to establish the support vector machine-based HFrEF classifier HFrEF103. In a subsequent validation cohort, HFrEF103 very accurately (area under the curve, AUC = 0.972 discriminated between HFrEF patients (N = 94, sensitivity = 93.6% and control individuals with and without impaired renal function and hypertension (N = 552, specificity = 92.9%. Interestingly, HFrEF103 showed low sensitivity (12.6% in individuals with diastolic left ventricular dysfunction (N = 176. The HFrEF-related peptide biomarkers mainly included fragments of fibrillar type I and III collagen but also, e.g., of fibrinogen beta and alpha-1-antitrypsin.CE-MS based urine proteome analysis served as a sensitive tool to determine a vast array of HFrEF-related urinary peptide biomarkers which might help improving our understanding and diagnosis of heart failure.

  14. Use of biomarkers in ALS drug development and clinical trials.

    Science.gov (United States)

    Bakkar, Nadine; Boehringer, Ashley; Bowser, Robert

    2015-05-14

    The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process. This article is part of a Special Issue entitled ALS complex pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Chasing the effects of Pre-analytical Confounders - a Multicentre Study on CSF-AD biomarkers

    Directory of Open Access Journals (Sweden)

    Maria Joao Leitao

    2015-07-01

    Full Text Available Core cerebrospinal fluid (CSF biomarkers-Aβ42, Tau and pTau–have been recently incorporated in the revised criteria for Alzheimer’s disease (AD. However, their widespread clinical application lacks standardization. Pre-analytical sample handling and storage play an important role in the reliable measurement of these biomarkers across laboratories. In this study, we aim to surpass the efforts from previous studies, by employing a multicentre approach to assess the impact of less studied CSF pre-analytical confounders in AD-biomarkers quantification. Four different centres participated in this study and followed the same established protocol. CSF samples were analysed for three biomarkers (Aβ42, Tau and pTau and tested for different spinning conditions (temperature: Room temperature (RT vs. 4oC; speed: 500g vs. 2000g vs. 3000g, storage volume variations (25%, 50% and 75% of tube total volume as well as freezing-thaw cycles (up to 5 cyles. The influence of sample routine parameters, inter-centre variability and relative value of each biomarker (reported as normal/abnormal, was analysed. Centrifugation conditions did not influence biomarkers levels, except for samples with a high CSF total protein content, where either non centrifugation or centrifugation at RT, compared to 4ºC, led to higher Aβ42 levels. Reducing CSF storage volume from 75% to 50% of total tube capacity, decreased Aβ42 concentration (within analytical CV of the assay, whereas no change in Tau or pTau was observed. Moreover, the concentration of Tau and pTau appears to be stable up to 5 freeze-thaw cycles, whereas Aβ42 levels decrease if CSF is freeze-thawed more than 3 times. This systematic study reinforces the need for CSF centrifugation at 4ºC prior to storage and highlights the influence of storage conditions in Aβ42 levels. This study contributes to the establishment of harmonized standard operating procedures that will help reducing inter-lab variability of CSF

  16. Blood-borne biomarkers of mortality risk: systematic review of cohort studies.

    Directory of Open Access Journals (Sweden)

    Evelyn Barron

    Full Text Available Lifespan and the proportion of older people in the population are increasing, with far reaching consequences for the social, political and economic landscape. Unless accompanied by an increase in health span, increases in age-related diseases will increase the burden on health care resources. Intervention studies to enhance healthy ageing need appropriate outcome measures, such as blood-borne biomarkers, which are easily obtainable, cost-effective, and widely accepted. To date there have been no systematic reviews of blood-borne biomarkers of mortality.To conduct a systematic review to identify available blood-borne biomarkers of mortality that can be used to predict healthy ageing post-retirement.Four databases (Medline, Embase, Scopus, Web of Science were searched. We included prospective cohort studies with a minimum of two years follow up and data available for participants with a mean age of 50 to 75 years at baseline.From a total of 11,555 studies identified in initial searches, 23 fulfilled the inclusion criteria. Fifty-one blood borne biomarkers potentially predictive of mortality risk were identified. In total, 20 biomarkers were associated with mortality risk. Meta-analyses of mortality risk showed significant associations with C-reactive protein (Hazard ratios for all-cause mortality 1.42, p<0.001; Cancer-mortality 1.62, p<0.009; CVD-mortality 1.31, p = 0.033, N Terminal-pro brain natriuretic peptide (Hazard ratios for all-cause mortality 1.43, p<0.001; CHD-mortality 1.58, p<0.001; CVD-mortality 1.67, p<0.001 and white blood cell count (Hazard ratios for all-cause mortality 1.36, p = 0.001. There was also evidence that brain natriuretic peptide, cholesterol fractions, erythrocyte sedimentation rate, fibrinogen, granulocytes, homocysteine, intercellular adhesion molecule-1, neutrophils, osteoprotegerin, procollagen type III aminoterminal peptide, serum uric acid, soluble urokinase plasminogen activator receptor, tissue inhibitor of

  17. Plasma soluble prion protein, a potential biomarker for sport-related concussions: a pilot study.

    Science.gov (United States)

    Pham, Nam; Akonasu, Hungbo; Shishkin, Rhonda; Taghibiglou, Changiz

    2015-01-01

    Sport-related mild traumatic brain injury (mTBI) or concussion is a significant health concern to athletes with potential long-term consequences. The diagnosis of sport concussion and return to sport decision making is one of the greatest challenges facing health care clinicians working in sports. Blood biomarkers have recently demonstrated their potential in assisting the detection of brain injury particularly, in those cases with no obvious physical injury. We have recently discovered plasma soluble cellular prion protein (PrP(C)) as a potential reliable biomarker for blast induced TBI (bTBI) in a rodent animal model. In order to explore the application of this novel TBI biomarker to sport-related concussion, we conducted a pilot study at the University of Saskatchewan (U of S) by recruiting athlete and non-athlete 18 to 30 year-old students. Using a modified quantitative ELISA method, we first established normal values for the plasma soluble PrP(C) in male and female students. The measured plasma soluble PrP(C) in confirmed concussion cases demonstrated a significant elevation of this analyte in post-concussion samples. Data collected from our pilot study indicates that the plasma soluble PrP(C) is a potential biomarker for sport-related concussion, which may be further developed into a clinical diagnostic tool to assist clinicians in the assessment of sport concussion and return-to-play decision making.

  18. Inflammatory biomarkers and academic performance in youth. The UP & DOWN Study.

    Science.gov (United States)

    Esteban-Cornejo, Irene; Martinez-Gomez, David; Gómez-Martínez, Sonia; Del Campo-Vecino, Juan; Fernández-Santos, Jorge; Castro-Piñero, Jose; Marcos, Ascensión; Veiga, Oscar L

    2016-05-01

    Inflammation influences cognitive development in infants and older adults, however, how inflammation may affect academic development during childhood and adolescence remains to be elucidated. This study aimed to examine the association between inflammatory biomarkers and academic performance in children and adolescents. A total of 494 youth (238 girls) aged 10.6 ± 3.4 years participated in the study. Four inflammatory biomarkers were selected: C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and white blood cell (WBC) count. An inflammatory index was created using the above mentioned biomarkers. Academic performance was assessed through schools records. Results showed that three of the four inflammatory biomarkers (CRP, IL-6 and WBC) and the inflammatory index were negatively associated with all academic indicators (β values ranging from -0.094 to -0.217, all Pacademic indicators compared with youth in the middle tertile (scores ranging from -0.578 to -0.344) and in the lowest tertile (scores ranging from -0.678 to -0.381). In conclusion, inflammation may impair academic performance independently of body fat levels in youth. Our results are of importance because the consequences of childhood and adolescence inflammation tend to continue into adulthood. Lifestyle interventions in youth may be promising in reducing levels of inflammation beyond the reduction in body fat in order to achieve cognitive benefits. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Plasma soluble prion protein, a potential biomarker for sport-related concussions: a pilot study.

    Directory of Open Access Journals (Sweden)

    Nam Pham

    Full Text Available Sport-related mild traumatic brain injury (mTBI or concussion is a significant health concern to athletes with potential long-term consequences. The diagnosis of sport concussion and return to sport decision making is one of the greatest challenges facing health care clinicians working in sports. Blood biomarkers have recently demonstrated their potential in assisting the detection of brain injury particularly, in those cases with no obvious physical injury. We have recently discovered plasma soluble cellular prion protein (PrP(C as a potential reliable biomarker for blast induced TBI (bTBI in a rodent animal model. In order to explore the application of this novel TBI biomarker to sport-related concussion, we conducted a pilot study at the University of Saskatchewan (U of S by recruiting athlete and non-athlete 18 to 30 year-old students. Using a modified quantitative ELISA method, we first established normal values for the plasma soluble PrP(C in male and female students. The measured plasma soluble PrP(C in confirmed concussion cases demonstrated a significant elevation of this analyte in post-concussion samples. Data collected from our pilot study indicates that the plasma soluble PrP(C is a potential biomarker for sport-related concussion, which may be further developed into a clinical diagnostic tool to assist clinicians in the assessment of sport concussion and return-to-play decision making.

  20. Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study.

    Directory of Open Access Journals (Sweden)

    Richard W D Welford

    Full Text Available Niemann-Pick disease type C (NP-C is a devastating, neurovisceral lysosomal storage disorder which is characterised by variable manifestation of visceral signs, progressive neuropsychiatric deterioration and premature death, caused by mutations in the NPC1 and NPC2 genes. Due to the complexity of diagnosis and the availability of an approved therapy in the EU, improved detection of NP-C may have a huge impact on future disease management. At the cellular level dysfunction or deficiency of either the NPC1 or NPC2 protein leads to a complex intracellular endosomal/lysosomal trafficking defect, and organ specific patterns of sphingolipid accumulation. Lysosphingolipids have been shown to be excellent biomarkers of sphingolipidosis in several enzyme deficient lysosomal storage disorders. Additionally, in a recent study the lysosphingolipids, lysosphingomyelin (SPC and glucosylsphingosine (GlcSph, appeared to be elevated in the plasma of three adult NP-C patients. In order to investigate the clinical utility of SPC and GlcSph as diagnostic markers, an in-depth fit for purpose biomarker assay validation for measurement of these biomarkers in plasma by liquid chromatography-tandem mass spectrometry was performed. Plasma SPC and GlcSph are stable and can be measured accurately, precisely and reproducibly. In a retrospective analysis of 57 NP-C patients and 70 control subjects, median plasma SPC and GlcSph were significantly elevated in NP-C by 2.8-fold and 1.4-fold respectively. For miglustat-naïve NP-C patients, aged 2-50 years, the area under the ROC curve was 0.999 for SPC and 0.776 for GlcSph. Plasma GlcSph did not correlate with SPC levels in NP-C patients. The data indicate excellent potential for the use of lysosphingomyelin in NP-C diagnosis, where it could be used to identify NP-C patients for confirmatory genetic testing.

  1. Dietary long-chain fatty acids and carbohydrate biomarker evaluation in a controlled feeding study in participants from the Women's Health Initiative cohort.

    Science.gov (United States)

    Song, Xiaoling; Huang, Ying; Neuhouser, Marian L; Tinker, Lesley F; Vitolins, Mara Z; Prentice, Ross L; Lampe, Johanna W

    2017-06-01

    Background: Biomarkers of macronutrient intake are lacking. Controlled human feeding studies that preserve the normal variation in nutrient and food consumption are necessary for the development and validation of robust nutritional biomarkers. Objective: We aimed to assess the utility of serum phospholipid fatty acids (PLFAs) as biomarkers of dietary intakes of fatty acids, total fat, and carbohydrate. Design: We used an individualized controlled feeding study in which 153 postmenopausal women from the Women's Health Initiative (WHI) were provided with a 2-wk controlled diet that mimicked each individual's habitual food intake. A total of 41 PLFAs were measured with the use of gas chromatography in end-of-feeding-period fasting serum samples and expressed in both relative and absolute concentrations. R 2 values (percentages of variation explained) from linear regressions of (ln-transformed) consumed fatty acids (individual, groups, and broad categories) on (ln-transformed) corresponding measures of serum PLFAs alone and together with selected participant-related variables (age, race/ethnicity, body mass index, season of study participation, education level, and estimated energy intake from doubly labeled water) were used for evaluation against established urinary recovery biomarkers of energy and protein intake as benchmarks. Models to predict intakes of other nutrients were also explored. Results: Intakes of eicosapentaenoic acid and docosahexaenoic acid achieved the benchmark of R 2 > 36% with or without covariates. When all 41 serum PLFAs and participant-related covariates were initially included in the model for selection, cross-validated R 2 achieved >36% for consumed total carbohydrate (grams per day), total saturated fatty acids (SFAs), percentage of energy from SFAs, and total trans fatty acids with serum PLFAs in both relative and absolute concentrations. Conclusions: Serum PLFA biomarkers perform similarly to established energy and protein urinary

  2. Applying Data-driven Imaging Biomarker in Mammography for Breast Cancer Screening: Preliminary Study.

    Science.gov (United States)

    Kim, Eun-Kyung; Kim, Hyo-Eun; Han, Kyunghwa; Kang, Bong Joo; Sohn, Yu-Mee; Woo, Ok Hee; Lee, Chan Wha

    2018-02-09

    We assessed the feasibility of a data-driven imaging biomarker based on weakly supervised learning (DIB; an imaging biomarker derived from large-scale medical image data with deep learning technology) in mammography (DIB-MG). A total of 29,107 digital mammograms from five institutions (4,339 cancer cases and 24,768 normal cases) were included. After matching patients' age, breast density, and equipment, 1,238 and 1,238 cases were chosen as validation and test sets, respectively, and the remainder were used for training. The core algorithm of DIB-MG is a deep convolutional neural network; a deep learning algorithm specialized for images. Each sample (case) is an exam composed of 4-view images (RCC, RMLO, LCC, and LMLO). For each case in a training set, the cancer probability inferred from DIB-MG is compared with the per-case ground-truth label. Then the model parameters in DIB-MG are updated based on the error between the prediction and the ground-truth. At the operating point (threshold) of 0.5, sensitivity was 75.6% and 76.1% when specificity was 90.2% and 88.5%, and AUC was 0.903 and 0.906 for the validation and test sets, respectively. This research showed the potential of DIB-MG as a screening tool for breast cancer.

  3. Urinary collagen IV and πGST: potential biomarkers for detecting localized kidney injury in diabetes--a pilot study.

    LENUS (Irish Health Repository)

    Cawood, T J

    2010-01-01

    Urinary biomarkers can identify damage to specific parts of the nephron. We performed a cross-sectional study to characterise the pattern of diabetic nephropathy using urinary biomarkers of glomerular fibrosis (collagen IV), proximal tubular damage (α-glutathione-S-transferase, GST) and distal tubular damage (πGST).

  4. Mass spectrometry for biomarker development

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Chaochao; Liu, Tao; Baker, Erin Shammel; Rodland, Karin D.; Smith, Richard D.

    2015-06-19

    Biomarkers potentially play a crucial role in early disease diagnosis, prognosis and targeted therapy. In the past decade, mass spectrometry based proteomics has become increasingly important in biomarker development due to large advances in technology and associated methods. This chapter mainly focuses on the application of broad (e.g. shotgun) proteomics in biomarker discovery and the utility of targeted proteomics in biomarker verification and validation. A range of mass spectrometry methodologies are discussed emphasizing their efficacy in the different stages in biomarker development, with a particular emphasis on blood biomarker development.

  5. A simulation study on estimating biomarker-treatment interaction effects in randomized trials with prognostic variables.

    Science.gov (United States)

    Haller, Bernhard; Ulm, Kurt

    2018-02-20

    To individualize treatment decisions based on patient characteristics, identification of an interaction between a biomarker and treatment is necessary. Often such potential interactions are analysed using data from randomized clinical trials intended for comparison of two treatments. Tests of interactions are often lacking statistical power and we investigated if and how a consideration of further prognostic variables can improve power and decrease the bias of estimated biomarker-treatment interactions in randomized clinical trials with time-to-event outcomes. A simulation study was performed to assess how prognostic factors affect the estimate of the biomarker-treatment interaction for a time-to-event outcome, when different approaches, like ignoring other prognostic factors, including all available covariates or using variable selection strategies, are applied. Different scenarios regarding the proportion of censored observations, the correlation structure between the covariate of interest and further potential prognostic variables, and the strength of the interaction were considered. The simulation study revealed that in a regression model for estimating a biomarker-treatment interaction, the probability of detecting a biomarker-treatment interaction can be increased by including prognostic variables that are associated with the outcome, and that the interaction estimate is biased when relevant prognostic variables are not considered. However, the probability of a false-positive finding increases if too many potential predictors are included or if variable selection is performed inadequately. We recommend undertaking an adequate literature search before data analysis to derive information about potential prognostic variables and to gain power for detecting true interaction effects and pre-specifying analyses to avoid selective reporting and increased false-positive rates.

  6. A validated LC-MS/MS method for the quantitative measurement of creatinine as an endogenous biomarker in human plasma.

    Science.gov (United States)

    Zhao, Yue; Liu, Guowen; Angeles, Aida; Christopher, Lisa J; Wang, Zhaoqing; Arnold, Mark E; Shen, Jim X

    2016-10-01

    Creatinine is an endogenous compound generated from creatine by normal muscular metabolism. It is an important indicator of renal function and the serum level is routinely monitored in clinical labs. Results & methodology: Surrogate analyte (d3-creatinine) was used for calibration standard and quality control preparation and the relative instrument response ratio between creatinine and d3-creatinine was used to calculate the endogenous creatinine concentrations. A fit-for-purpose strategy of using a surrogate analyte and authentic matrix was adopted for this validation. The assay was the first human plasma assay using such strategy and was successfully applied to a clinical study to confirm a transient elevation of creatinine observed using an existing clinical assay.

  7. Image Biomarkers and Precision Medicine: need for validation; Los biomarcadores de imagen y la Medicina de Precision: necesidad de validacion

    Energy Technology Data Exchange (ETDEWEB)

    Marti-Bonmati, L.; Alberich-Bayarri, A.; Garcia Castro, F.

    2016-08-01

    Personalized medicine aims to improve the diagnosis, classification and the best treatment for a particular patient. Today, radiologists are challenged to translate new biological discoveries, the different mechanisms of disease and advances in preclinical research, into a clinical reality through patients, images and their associated parameters. In this article we show how digital medical imaging and computational data processing extract numerous quantitative parameters from the obtained images as virtual biopsies. To be implemented in clinical practice, biomarkers should provide useful and relevant information, improving processes diagnostic, therapeutic and monitoring, for the benefit of patients. (Author)

  8. Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1.

    Science.gov (United States)

    Yee, S W; Giacomini, M M; Hsueh, C-H; Weitz, D; Liang, X; Goswami, S; Kinchen, J M; Coelho, A; Zur, A A; Mertsch, K; Brian, W; Kroetz, D L; Giacomini, K M

    2016-11-01

    Transporter-mediated drug-drug interactions (DDIs) are a major cause of drug toxicities. Using published genome-wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter-mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  9. Dietary intake and biological measurement of folate: A qualitative review of validation studies

    NARCIS (Netherlands)

    Park, Y.H.; Vollset, S.E.; Boonstra, A.; Chajes, V.; Ueland, P.M.; Slimani, N.

    2013-01-01

    Folate is a nutrient of major health significance, but its dietary intake assessment is particularly complex to quantify through traditional approaches. Attempts have been made to validate dietary instruments for assessing folate intake against circulating concentration biomarkers. However, this

  10. Discriminant validity study of Achilles enthesis ultrasound.

    Science.gov (United States)

    Expósito Molinero, María Rosa; de Miguel Mendieta, Eugenio

    2016-01-01

    We want to know if the ultrasound examination of the Achilles tendon in spondyloarthritis is different compared to other rheumatic diseases. We studied 97 patients divided into five groups: rheumatoid arthritis, spondyloarthritis, gout, chondrocalcinosis and osteoarthritis, exploring six elementary lesions in 194 Achilles entheses examined. In our study the total index ultrasonographic Achilles is higher in spondyloarthritis with significant differences. The worst elementary spondyloarthritis lesions for discriminations against other pathologies were calcification. This study aims to demonstrate the discriminant validity of Achilles enthesitis observed by ultrasound in spondyloarthritis compared with other rheumatic diseases that may also have ultrasound abnormalities such enthesis level. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  11. Thermal stability of thiophene biomarkers as studied by hydrous pyrolysis

    NARCIS (Netherlands)

    Sinninghe Damsté, J.S.; Koopmans, M.P.; Lewan, M.D.; Leeuw, J.W. de

    1995-01-01

    An immature (Ro = 0.25%) sulphur-rich calcareous shale from the Gessoso-solfifera Formation (Messinian) in the Vena del Gesso Basin (northern Italy) was artificially matured by hydrous pyrolysis at constant temperatures ranging from 160 to 330°C for 72 h to study the applicability of alkylthiophenes

  12. Sedentary leisure time behavior, snacking habits and cardiovascular biomarkers: the Inter99 Study

    DEFF Research Database (Denmark)

    Frydenlund, Gitte; Jørgensen, Torben; Toft, Ulla

    2011-01-01

    Aim: To explore the association between sedentary leisure time behavior (SLTB) and cardiovascular biomarkers, taking into account snacking habits, alcohol intake and physical activity level. Design: Cross-sectional. Methods: Study participants were recruited from the 5-year follow-up of a populat......Aim: To explore the association between sedentary leisure time behavior (SLTB) and cardiovascular biomarkers, taking into account snacking habits, alcohol intake and physical activity level. Design: Cross-sectional. Methods: Study participants were recruited from the 5-year follow...... non-significant in men (ß = 0.9924, [0.9839; 1.0011]) and women (ß = 0.9932, [0.8605; 1.0014]). Conclusion: SLTB appears to be an independent CVD risk factor, regardless of snacking habits and physical activity....

  13. Biomarkers for equine joint injury and osteoarthritis.

    Science.gov (United States)

    McIlwraith, C Wayne; Kawcak, Christopher E; Frisbie, David D; Little, Christopher B; Clegg, Peter D; Peffers, Mandy J; Karsdal, Morten A; Ekman, Stina; Laverty, Sheila; Slayden, Richard A; Sandell, Linda J; Lohmander, L S; Kraus, Virginia B

    2018-03-01

    We report the results of a symposium aimed at identifying validated biomarkers that can be used to complement clinical observations for diagnosis and prognosis of joint injury leading to equine osteoarthritis (OA). Biomarkers might also predict pre-fracture change that could lead to catastrophic bone failure in equine athletes. The workshop was attended by leading scientists in the fields of equine and human musculoskeletal biomarkers to enable cross-disciplinary exchange and improve knowledge in both. Detailed proceedings with strategic planning was written, added to, edited and referenced to develop this manuscript. The most recent information from work in equine and human osteoarthritic biomarkers was accumulated, including the use of personalized healthcare to stratify OA phenotypes, transcriptome analysis of anterior cruciate ligament (ACL) and meniscal injuries in the human knee. The spectrum of "wet" biomarker assays that are antibody based that have achieved usefulness in both humans and horses, imaging biomarkers and the role they can play in equine and human OA was discussed. Prediction of musculoskeletal injury in the horse remains a challenge, and the potential usefulness of spectroscopy, metabolomics, proteomics, and development of biobanks to classify biomarkers in different stages of equine and human OA were reviewed. The participants concluded that new information and studies in equine musculoskeletal biomarkers have potential translational value for humans and vice versa. OA is equally important in humans and horses, and the welfare issues associated with catastrophic musculoskeletal injury in horses add further emphasis to the need for good validated biomarkers in the horse. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:823-831, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  14. Biomarkers of acute lung injury: worth their salt?

    Directory of Open Access Journals (Sweden)

    Proudfoot Alastair G

    2011-12-01

    Full Text Available Abstract The validation of biomarkers has become a key goal of translational biomedical research. The purpose of this article is to discuss the role of biomarkers in the management of acute lung injury (ALI and related research. Biomarkers should be sensitive and specific indicators of clinically important processes and should change in a relevant timeframe to affect recruitment to trials or clinical management. We do not believe that they necessarily need to reflect pathogenic processes. We critically examined current strategies used to identify biomarkers and which, owing to expedience, have been dominated by reanalysis of blood derived markers from large multicenter Phase 3 studies. Combining new and existing validated biomarkers with physiological and other data may add predictive power and facilitate the development of important aids to research and therapy.

  15. Standardisation And Validation Study Of A New Study Skills ...

    African Journals Online (AJOL)

    Concerns have also been raised by various researchers about the latent constructs of existing western scales to assess study skills. The objective of this study was to develop, standardize and validate a culturally sensitive study skills questionnaire (SSQ). Methods: a stratified random sample of secondary school students (n ...

  16. The biomarker-based validity of a food frequency questionnaire to assess the intake status of folate, pyridoxine and cobalamin among Iranian primary breast cancer patients.

    Science.gov (United States)

    Pirouzpanah, S; Taleban, F-A; Mehdipour, P; Atri, M; Hooshyareh-rad, A; Sabour, S

    2014-03-01

    Folate, pyridoxine and cobalamin are coenzymatically essential in one-carbon methyl metabolism, and their deficiencies could explain some alterations during breast carcinogenesis. We aimed to evaluate the validity of folate, pyridoxine and cobalamin estimates from a food frequency questionnaire (FFQ) on the basis of their corresponding fasting plasma biomarkers, in breast cancer (BC) patients. In a prospective, consecutive case series, 149 women with primary BC aged between 30 and 69 years as a representative sample of Iranian women with BC were recruited. The 136-item FFQ was used for the validity assay. Fasting plasma folate and cobalamin were tested by automated electrochemiluminescence. The high-pressure liquid chromatography with fluorescence detection was used to determine the plasma levels of pyridoxal-5'-phosphate (PLP) and total homocysteine (tHcy). Area under the curve (AUC) for assessing the diagnostic accuracy of folate-related data through an FFQ was 0.74 (Pfasting plasma concentrations. Our data supported the validity of new FFQ to rank individuals by dietary intake status of folate and cobalamin.

  17. Validation of Dietary Vitamin D Intake from Two Food Frequency Questionnaires, Using Food Records and the Biomarker 25-Hydroxyvitamin D among Pregnant Women

    Directory of Open Access Journals (Sweden)

    Linnea Bärebring

    2018-06-01

    Full Text Available Our objective was to validate vitamin D intake from a short vitamin D questionnaire (VDQ and a longer online food frequency questionnaire (FFQ against a food record and 25-hydroxyvitamin D (25OHD as a biomarker of vitamin D status, among pregnant women in Sweden. The number of women included was 1125 with VDQ, FFQ and 25OHD, and of those, 64 also completed the food record. Median vitamin D intakes were 3.9 µg by VDQ (p < 0.001, and 5.3 µg by FFQ (p = 0.89, compared to 5.0 µg by food record. Correlations between vitamin D intake from food record and VDQ (rho = 0.51, p < 0.001 or FFQ (rho = 0.49, p < 0.001 were similar. The VDQ and FFQ also had a similar ability to rank the individuals according to vitamin D intake. However, only vitamin D intake from the VDQ was significantly associated with vitamin D status as assessed by 25OHD. The validation coefficient for the VDQ was 0.68 and 0.75 for the FFQ. In conclusion, assessing dietary vitamin D intake is challenging, regardless of the dietary assessment method. The VDQ, that includes only four food items, is a valid, simple and useful tool in assessing vitamin D intake of pregnant women in Sweden, while imposing a minimal burden on women and researchers.

  18. Validation of Dietary Vitamin D Intake from Two Food Frequency Questionnaires, Using Food Records and the Biomarker 25-Hydroxyvitamin D among Pregnant Women.

    Science.gov (United States)

    Bärebring, Linnea; Amberntsson, Anna; Winkvist, Anna; Augustin, Hanna

    2018-06-08

    Our objective was to validate vitamin D intake from a short vitamin D questionnaire (VDQ) and a longer online food frequency questionnaire (FFQ) against a food record and 25-hydroxyvitamin D (25OHD) as a biomarker of vitamin D status, among pregnant women in Sweden. The number of women included was 1125 with VDQ, FFQ and 25OHD, and of those, 64 also completed the food record. Median vitamin D intakes were 3.9 µg by VDQ ( p D intake from food record and VDQ (rho = 0.51, p D intake. However, only vitamin D intake from the VDQ was significantly associated with vitamin D status as assessed by 25OHD. The validation coefficient for the VDQ was 0.68 and 0.75 for the FFQ. In conclusion, assessing dietary vitamin D intake is challenging, regardless of the dietary assessment method. The VDQ, that includes only four food items, is a valid, simple and useful tool in assessing vitamin D intake of pregnant women in Sweden, while imposing a minimal burden on women and researchers.

  19. Storage Time and Urine Biomarker Levels in the ASSESS-AKI Study

    Science.gov (United States)

    Liu, Kathleen D.; Siew, Edward D.; Reeves, W. Brian; Himmelfarb, Jonathan; Go, Alan S.; Hsu, Chi-yuan; Bennett, Michael R.; Devarajan, Prasad; Ikizler, T. Alp; Kaufman, James S.; Kimmel, Paul L.; Chinchilli, Vernon M.; Parikh, Chirag R.

    2016-01-01

    Background Although stored urine samples are often used in biomarker studies focused on acute and chronic kidney disease, how storage time impacts biomarker levels is not well understood. Methods 866 subjects enrolled in the NIDDK-sponsored ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Study were included. Samples were processed under standard conditions and stored at -70°C until analyzed. Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and liver fatty acid binding protein (L-FABP) were measured in urine samples collected during the index hospitalization or an outpatient visit 3 months later. Mixed effects models were used to determine the effect of storage time on biomarker levels and stratified by visit. Results Median storage was 17.8 months (25–75% IQR 10.6–23.7) for samples from the index hospitalization and 14.6 months (IQR 7.3–20.4) for outpatient samples. In the mixed effects models, the only significant association between storage time and biomarker concentration was for KIM-1 in outpatient samples, where each month of storage was associated with a 1.7% decrease (95% CI -3% to -0.3%). There was no relationship between storage time and KIM-1 levels in samples from the index hospitalization. Conclusion There was no significant impact of storage time over a median of 18 months on urine KIM-1, NGAL, IL-18 or L-FABP in hospitalized samples; a statistically significant effect towards a decrease over time was noted for KIM-1 in outpatient samples. Additional studies are needed to determine whether longer periods of storage at -70°C systematically impact levels of these analytes. PMID:27788160

  20. Storage Time and Urine Biomarker Levels in the ASSESS-AKI Study.

    Directory of Open Access Journals (Sweden)

    Kathleen D Liu

    Full Text Available Although stored urine samples are often used in biomarker studies focused on acute and chronic kidney disease, how storage time impacts biomarker levels is not well understood.866 subjects enrolled in the NIDDK-sponsored ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI Study were included. Samples were processed under standard conditions and stored at -70°C until analyzed. Kidney injury molecule-1 (KIM-1, neutrophil gelatinase-associated lipocalin (NGAL, interleukin-18 (IL-18, and liver fatty acid binding protein (L-FABP were measured in urine samples collected during the index hospitalization or an outpatient visit 3 months later. Mixed effects models were used to determine the effect of storage time on biomarker levels and stratified by visit.Median storage was 17.8 months (25-75% IQR 10.6-23.7 for samples from the index hospitalization and 14.6 months (IQR 7.3-20.4 for outpatient samples. In the mixed effects models, the only significant association between storage time and biomarker concentration was for KIM-1 in outpatient samples, where each month of storage was associated with a 1.7% decrease (95% CI -3% to -0.3%. There was no relationship between storage time and KIM-1 levels in samples from the index hospitalization.There was no significant impact of storage time over a median of 18 months on urine KIM-1, NGAL, IL-18 or L-FABP in hospitalized samples; a statistically significant effect towards a decrease over time was noted for KIM-1 in outpatient samples. Additional studies are needed to determine whether longer periods of storage at -70°C systematically impact levels of these analytes.

  1. Imaging studies and biomarkers to detect clinically meaningful vesicoureteral reflux

    Directory of Open Access Journals (Sweden)

    Michaella Maloney Prasad

    2017-06-01

    Full Text Available The work-up of a febrile urinary tract infection is generally performed to detect vesicoureteral reflux (VUR and its possible complications. The imaging modalities most commonly used for this purpose are renal-bladder ultrasound, voiding cystourethrogram and dimercapto-succinic acid scan. These studies each contribute valuable information, but carry individual benefits and limitations that may impact their efficacy. Biochemical markers are not commonly used in pediatric urology to diagnose or differentiate high-risk disease, but this is the emerging frontier, which will hopefully change our approach to VUR in the future. As it becomes more apparent that there is tremendous clinical variation within grades of VUR, the need to distinguish clinically significant from insignificant disease grows. The unfortunate truth about VUR is that recommendations for treatment may be inconsistent. Nuances in clinical decision-making will always exist, but opinions for medical versus surgical intervention should be more standardized, based on risk of injury to the kidney.

  2. Systemic sclerosis biomarkers discovered using mass-spectrometry-based proteomics: a systematic review.

    Science.gov (United States)

    Bălănescu, Paul; Lădaru, Anca; Bălănescu, Eugenia; Băicuş, Cristian; Dan, Gheorghe Andrei

    2014-08-01

    Systemic sclerosis (SSc) is an autoimmune disease with incompletely known physiopathology. There is a great challenge to predict its course and therapeutic response using biomarkers. To critically review proteomic biomarkers discovered from biological specimens from systemic sclerosis patients using mass spectrometry technologies. Medline and Embase databases were searched in February 2014. Out of the 199 records retrieved, a total of 20 records were included, identifying 116 candidate proteomic biomarkers. Research in SSc proteomic biomarkers should focus on biomarker validation, as there are valuable mass-spectrometry proteomics studies in the literature.

  3. Identification and validation of biomarkers of IgV(H) mutation status in chronic lymphocytic leukemia using microfluidics quantitative real-time polymerase chain reaction technology.

    Science.gov (United States)

    Abruzzo, Lynne V; Barron, Lynn L; Anderson, Keith; Newman, Rachel J; Wierda, William G; O'brien, Susan; Ferrajoli, Alessandra; Luthra, Madan; Talwalkar, Sameer; Luthra, Rajyalakshmi; Jones, Dan; Keating, Michael J; Coombes, Kevin R

    2007-09-01

    To develop a model incorporating relevant prognostic biomarkers for untreated chronic lymphocytic leukemia patients, we re-analyzed the raw data from four published gene expression profiling studies. We selected 88 candidate biomarkers linked to immunoglobulin heavy-chain variable region gene (IgV(H)) mutation status and produced a reliable and reproducible microfluidics quantitative real-time polymerase chain reaction array. We applied this array to a training set of 29 purified samples from previously untreated patients. In an unsupervised analysis, the samples clustered into two groups. Using a cutoff point of 2% homology to the germline IgV(H) sequence, one group contained all 14 IgV(H)-unmutated samples; the other contained all 15 mutated samples. We confirmed the differential expression of 37 of the candidate biomarkers using two-sample t-tests. Next, we constructed 16 different models to predict IgV(H) mutation status and evaluated their performance on an independent test set of 20 new samples. Nine models correctly classified 11 of 11 IgV(H)-mutated cases and eight of nine IgV(H)-unmutated cases, with some models using three to seven genes. Thus, we can classify cases with 95% accuracy based on the expression of as few as three genes.

  4. An exploratory study of inflammatory cytokines as prognostic biomarkers in patients with ductal pancreatic adenocarcinoma.

    Science.gov (United States)

    Dima, Simona O; Tanase, Cristiana; Albulescu, Radu; Herlea, Vlad; Chivu-Economescu, Mihaela; Purnichescu-Purtan, Raluca; Dumitrascu, Traian; Duda, Dan G; Popescu, Irinel

    2012-10-01

    We measured the serum concentration of a panel of inflammatory cytokines and evaluated their association with circulating proangiogenic biomarkers and with outcome in patients with pancreatic ductal adenocarcinoma (PDAC). We collected serum samples from 36 patients with PDAC, 9 patients with chronic pancreatitis, and 22 healthy volunteers as a control. Inflammatory cytokines and proangiogenic biomarkers were measured using the multianalyte xMAP array and carcinoembryonic antigen (CEA) and carbohydrate 19-9 by immunoassay. Patients with PDAC had higher circulating levels of interleukin 6 (IL-6) than those of patients with pancreatitis or healthy individuals and higher levels of IL-10 and tumor necrosis factor α (TNF-α) compared with those of healthy individuals. In patients with PDAC, circulating IL-6, TNF-α, IL-1β, and IL-10 correlated with serum concentrations of vascular endothelial growth factor and basic fibroblast growth factor; circulating IL-6, IL-1β, and TNF-α correlated with carbohydrate 19-9; and IL-8, IL-10, and TNF-α correlated with CEA levels. Circulating IL-8, TNF-α, and CEA; tumor stage; and lymph node metastases were associated with a poor outcome. The results of this exploratory study indicate that inflammatory cytokines should be pursued as potential prognostic biomarkers as well as targets for therapy in larger studies in PDAC.

  5. Serum biomarkers for the early diagnosis of TIA: The MIND-TIA study protocol.

    Science.gov (United States)

    Dolmans, L Servaas; Rutten, Frans H; El Bartelink, Marie-Louise; Seppenwoolde, Gerdien; van Delft, Sanne; Kappelle, L Jaap; Hoes, Arno W

    2015-07-28

    A Transient Ischaemic Attack (TIA) bears a high risk of a subsequent ischaemic stroke. Adequate diagnosis of a TIA should be followed immediately by the start of appropriate preventive therapy, including antiplatelets. The diagnosis of a TIA based on symptoms and signs only is notoriously difficult and biomarkers of brain ischaemia might improve the recognition, and target management and prognosis of TIA patients. Our aim is to quantify the added diagnostic value of serum biomarkers of brain ischaemia in patients suspected of TIA. a cross-sectional diagnostic accuracy study with an additional six month follow-up period. 350 patients suspected of TIA in the primary care setting. Patients suspected of a TIA will be recruited by at least 200 general practitioners (GPs) in the catchment area of seven TIA outpatient clinics willing to participate in the study. In all patients a blood sample will be drawn as soon as possible after the patient has contacted the GP, but at least within 72 h after onset of symptoms. Participants will be referred by the GP to the regional TIA outpatient clinic for additional investigations, including brain imaging. The 'definite' diagnosis (reference standard) will be made by a panel consisting of three experienced neurologists who will use all available diagnostic information and the clinical information obtained during the outpatient clinic assessment, and a six month follow-up period. The diagnostic accuracy, and value in addition to signs and symptoms of candidate serum biomarkers will be assessed in terms of discrimination with C statistics, and calibration with plots. We aim to include 350 suspected cases, with 250 patients with indeed definite TIA (or minor stroke) according to the panel. We hope to find novel biomarkers that will enable a rapid and accurate diagnosis of TIA. This would largely improve the management and prognosis of such patients. ClinicalTrials.gov Identifier NCT01954329.

  6. Biomarkers for acute kidney injury in decompensated cirrhosis: A Prospective Study.

    Science.gov (United States)

    Jaques, David A; Spahr, Laurent; Berra, Gregory; Poffet, Vincent; Lescuyer, Pierre; Gerstel, Eric; Garin, Nicolas; Martin, Pierre-Yves; Ponte, Belen

    2018-01-25

    Acute kidney injury (AKI) is a frequent complication in cirrhotic patients. As serum creatinine is a poor marker of renal function in this population, we aimed to study the utility of several biomarkers in this context. A prospective study was conducted in hospitalized patients with decompensated cirrhosis. Serum creatinine (SCr), Cystatin C (CystC), NGAL and urinary NGAL, KIM-1, protein, albumin and sodium were measured on three separate occasions. Renal resistive index (RRI) was obtained. We analyzed the value of these biomarkers to determine the presence of AKI, its etiology [prerenal, acute tubular necrosis (ATN), or hepatorenal (HRS)], its severity and a composite clinical outcome at 30 days (death, dialysis and intensive care admission). We included 105 patients, of which 55 had AKI. SCr, CystC, NGAL (plasma and urinary), urinary sodium and RRI at inclusion were independently associated with the presence of AKI. SCr, CystC and plasma NGAL were able to predict the subsequent development of AKI. Pre-renal state showed lower levels of SCr, NGAL (plasma and urinary) and RRI. ATN patients had high levels of NGAL (plasma and urinary) as well as urinary protein and sodium. HRS patients presented an intermediate pattern. All biomarkers paralleled the severity of AKI. SCr, CystC and plasma NGAL predicted the development of the composite clinical outcome with the same performance as the MELD score. In patients with decompensated cirrhosis, early measurement of renal biomarkers provides valuable information on AKI etiology. It could also improve AKI diagnosis and prognosis. This article is protected by copyright. All rights reserved.

  7. Thrombelastography and biomarker profiles in acute coagulopathy of trauma: a prospective study

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    Larsen Claus F

    2011-10-01

    Full Text Available Abstract Background Severe injury induces an acute coagulopathy associated with increased mortality. This study compared the Thrombelastography (TEG and biomarker profiles upon admission in trauma patients. Methods Prospective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry including standard coagulation tests, hematology, transfusions, Injury Severity Score (ISS and TEG were recorded. Retrospective analysis of thawed plasma/serum for biomarkers reflecting tissue injury (histone-complexed DNA fragments, sympathoadrenal activation (adrenaline, noradrenaline, coagulation activation/inhibition and fibrinolysis (sCD40L, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer, prothrombinfragment 1+2, plasmin/α2-antiplasmin complex, thrombin/antithrombin complex, tissue factor pathway inhibitor, antithrombin, von willebrand factor, factor XIII. Comparison of patients stratified according to ISS/TEG maximum clot strength. Linear regression analysis of variables associated with clot strength. Results Trauma patients had normal (86%, hypercoagulable (11% or hypocoagulable (1% TEG clot strength; one had primary hyperfibrinolysis. Hypercoagulable patients had higher age, fibrinogen and platelet count (all p 10 red blood cells the initial 24 h. Patients with normal or hypercoagulable TEG clot strength had comparable biomarker profiles, but the few patients with hypocoagulable TEG clot strength and/or hyperfibrinolysis had very different biomarker profiles. Increasing ISS was associated with higher levels of catecholamines, histone-complexed DNA fragments, sCD40L, activated protein C and D-dimer and reduced levels of non-activated protein C, antithrombin, fibrinogen and factor XIII (all p 26. In patients with ISS > 26, adrenaline and sCD40L were independently negatively associated with clot strength. Conclusions Trauma patients displayed

  8. Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study.

    Science.gov (United States)

    Nickolas, Thomas L; Schmidt-Ott, Kai M; Canetta, Pietro; Forster, Catherine; Singer, Eugenia; Sise, Meghan; Elger, Antje; Maarouf, Omar; Sola-Del Valle, David Antonio; O'Rourke, Matthew; Sherman, Evan; Lee, Peter; Geara, Abdallah; Imus, Philip; Guddati, Achuta; Polland, Allison; Rahman, Wasiq; Elitok, Saban; Malik, Nasir; Giglio, James; El-Sayegh, Suzanne; Devarajan, Prasad; Hebbar, Sudarshan; Saggi, Subodh J; Hahn, Barry; Kettritz, Ralph; Luft, Friedrich C; Barasch, Jonathan

    2012-01-17

    This study aimed to determine the diagnostic and prognostic value of urinary biomarkers of intrinsic acute kidney injury (AKI) when patients were triaged in the emergency department. Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI. In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization. All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase-associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events. Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  9. Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study.

    Science.gov (United States)

    Daan, Nadine M P; Koster, Maria P H; de Wilde, Marlieke A; Dalmeijer, Gerdien W; Evelein, Annemieke M V; Fauser, Bart C J M; de Jager, Wilco

    2016-01-01

    To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring. Cross-sectional comparison of serum biomarkers. University Medical Center Utrecht. Hyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n = 34), non-PCOS reference population (n = 32), PCOS offspring (n = 14, age 6-8 years), and a paedriatic reference population (n = 30). Clustering profile of adipocytokines (IL-1b, IL-6, IL-13, IL-17, IL-18, TNF-α, adiponectin, adipsin, leptin, chemerin, resistin, RBP4, DPP-IV/sCD26, CCL2/MCP-1), growth factors (PIGF, VEGF, sVEGF-R1), soluble cell adhesion molecules (sICAM-1/sCD54, sVCAM-1/sCD106), and other inflammatory related proteases (MMP-9, S100A8, Cathepsin S). Differences in median biomarker concentrations between groups, and associations with the free androgen index (FAI; Testosterone/SHBG x100). The cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R2 = 0.219) and adiponectin (R2 = 0.182) showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P PCOS offspring, MMP-9 (P = 0.001) and S100A8 (P PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers (MMP-9, S100A8) were increased, suggesting that these children may exhibit increased chronic low-grade inflammation. Additional research is required to confirm results of the current exploratory investigation.

  10. Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy.

    Science.gov (United States)

    Stern, Robert A; Tripodis, Yorghos; Baugh, Christine M; Fritts, Nathan G; Martin, Brett M; Chaisson, Christine; Cantu, Robert C; Joyce, James A; Shah, Sahil; Ikezu, Tsuneya; Zhang, Jing; Gercel-Taylor, Cicek; Taylor, Douglas D

    2016-01-01

    Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers. The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

  11. Utility of CSF biomarkers in psychiatric disorders: a national multicentre prospective study.

    Science.gov (United States)

    Paquet, Claire; Magnin, Eloi; Wallon, David; Troussière, Anne-Cécile; Dumurgier, Julien; Jager, Alain; Bellivier, Frank; Bouaziz-Amar, Elodie; Blanc, Frédéric; Beaufils, Emilie; Miguet-Alfonsi, Carole; Quillard, Muriel; Schraen, Susanna; Pasquier, Florence; Hannequin, Didier; Robert, Philippe; Hugon, Jacques; Mouton-Liger, François

    2016-06-13

    Affective and psychotic disorders are mental or behavioural patterns resulting in an inability to cope with life's ordinary demands and routines. These conditions can be a prodromal event of Alzheimer's disease (AD). The prevalence of underlying AD lesions in psychiatric diseases is unknown, and it would be helpful to determine them in patients. AD cerebrospinal fluid (CSF) biomarkers (amyloid β, tau and phosphorylated tau) have high diagnostic accuracy, both for AD with dementia and to predict incipient AD (mild cognitive impairment due to AD), and they are sometimes used to discriminate psychiatric diseases from AD. Our objective in the present study was to evaluate the clinical utility of CSF biomarkers in a group of patients with psychiatric disease as the main diagnosis. In a multicentre prospective study, clinicians filled out an anonymous questionnaire about all of their patients who had undergone CSF biomarker evaluation. Before and after CSF biomarker results were obtained, clinicians provided a diagnosis with their level of confidence and information about the treatment. We included patients with a psychiatric disorder as the initial diagnosis. In a second part of the study conducted retrospectively in a followed subgroup, clinicians detailed the psychiatric history and we classified patients into three categories: (1) psychiatric symptoms associated with AD, (2) dual diagnosis and (3) cognitive decline not linked to a neurodegenerative disorder. Of 957 patients, 69 had an initial diagnosis of a psychiatric disorder. Among these 69 patients, 14 (20.2 %) had a CSF AD profile, 5 (7.2 %) presented with an intermediate CSF profile and 50 (72.4 %) had a non-AD CSF profile. Ultimately, 13 (18.8 %) patients were diagnosed with AD. We show that in the AD group psychiatric symptoms occurred later and the delay between the first psychiatric symptoms and the cognitive decline was shorter. This study revealed that about 20 % of patients with a primary

  12. Urinary proteomic biomarkers for diagnosis and risk stratification of autosomal dominant polycystic kidney disease: a multicentric study.

    Directory of Open Access Journals (Sweden)

    Andreas D Kistler

    Full Text Available Treatment options for autosomal dominant polycystic kidney disease (ADPKD will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS, we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI. The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001 with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.

  13. Searching for non-genetic molecular and imaging PTSD risk and resilience markers: Systematic review of literature and design of the German Armed Forces PTSD biomarker study.

    Science.gov (United States)

    Schmidt, Ulrike; Willmund, Gerd-Dieter; Holsboer, Florian; Wotjak, Carsten T; Gallinat, Jürgen; Kowalski, Jens T; Zimmermann, Peter

    2015-01-01

    Biomarkers allowing the identification of individuals with an above average vulnerability or resilience for posttraumatic stress disorder (PTSD) would especially serve populations at high risk for trauma exposure like firefighters, police officers and combat soldiers. Aiming to identify the most promising putative PTSD vulnerability markers, we conducted the first systematic review on potential imaging and non-genetic molecular markers for PTSD risk and resilience. Following the PRISMA guidelines, we systematically screened the PubMed database for prospective longitudinal clinical studies and twin studies reporting on pre-trauma and post-trauma PTSD risk and resilience biomarkers. Using 25 different combinations of search terms, we retrieved 8151 articles of which we finally included and evaluated 9 imaging and 27 molecular studies. In addition, we briefly illustrate the design of the ongoing prospective German Armed Forces (Bundeswehr) PTSD biomarker study (Bw-BioPTSD) which not only aims to validate these previous findings but also to identify novel and clinically applicable molecular, psychological and imaging risk, resilience and disease markers for deployment-related psychopathology in a cohort of German soldiers who served in Afghanistan. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. The Role of Epigenomics in the Study of Cancer Biomarkers and in the Development of Diagnostic Tools.

    Science.gov (United States)

    Verma, Mukesh

    2015-01-01

    Epigenetics plays a key role in cancer development. Genetics alone cannot explain sporadic cancer and cancer development in individuals with no family history or a weak family history of cancer. Epigenetics provides a mechanism to explain the development of cancer in such situations. Alterations in epigenetic profiling may provide important insights into the etiology and natural history of cancer. Because several epigenetic changes occur before histopathological changes, they can serve as biomarkers for cancer diagnosis and risk assessment. Many cancers may remain asymptomatic until relatively late stages; in managing the disease, efforts should be focused on early detection, accurate prediction of disease progression, and frequent monitoring. This chapter describes epigenetic biomarkers as they are expressed during cancer development and their potential use in cancer diagnosis and prognosis. Based on epigenomic information, biomarkers have been identified that may serve as diagnostic tools; some such biomarkers also may be useful in identifying individuals who will respond to therapy and survive longer. The importance of analytical and clinical validation of biomarkers is discussed, along with challenges and opportunities in this field.

  15. Biomarker-based classification of bacterial and fungal whole-blood infections in a genome-wide expression study

    Directory of Open Access Journals (Sweden)

    Andreas eDix

    2015-03-01

    Full Text Available Sepsis is a clinical syndrome that can be caused by bacteria or fungi. Early knowledge on the nature of the causative agent is a prerequisite for targeted anti-microbial therapy. Besides currently used detection methods like blood culture and PCR-based assays, the analysis of the transcriptional response of the host to infecting organisms holds great promise. In this study, we aim to examine the transcriptional footprint of infections caused by the bacterial pathogens Staphylococcus aureus and Escherichia coli and the fungal pathogens Candida albicans and Aspergillus fumigatus in a human whole-blood model. Moreover, we use the expression information to build a random forest classifier to classify if a sample contains a bacterial, fungal, or mock-infection. After normalizing the transcription intensities using stably expressed reference genes, we filtered the gene set for biomarkers of bacterial or fungal blood infections. This selection is based on differential expression and an additional gene relevance measure. In this way, we identified 38 biomarker genes, including IL6, SOCS3, and IRG1 which were already associated to sepsis by other studies. Using these genes, we trained the classifier and assessed its performance. It yielded a 96% accuracy (sensitivities >93%, specificities >97% for a 10-fold stratified cross-validation and a 92% accuracy (sensitivities and specificities >83% for an additional test dataset comprising Cryptococcus neoformans infections. Furthermore, the classifier is robust to Gaussian noise, indicating correct class predictions on datasets of new species. In conclusion, this genome-wide approach demonstrates an effective feature selection process in combination with the construction of a well-performing classification model. Further analyses of genes with pathogen-dependent expression patterns can provide insights into the systemic host responses, which may lead to new anti-microbial therapeutic advances.

  16. Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke

    OpenAIRE

    Hecht, S

    2004-01-01

    Objective: To review the literature on carcinogen derived biomarkers of exposure to secondhand tobacco smoke (SHS). These biomarkers are specifically related to known carcinogens in tobacco smoke and include urinary metabolites, DNA adducts, and blood protein adducts.

  17. Prognostic clinical and molecular biomarkers of renal disease in type 2 diabetes

    DEFF Research Database (Denmark)

    Pena, Michelle J; de Zeeuw, Dick; Mischak, Harald

    2015-01-01

    biomarkers address the predictive performance of novel biomarker panels in addition to the classical panel in type 2 diabetes. However, the prospective studies conducted so far have small sample sizes, are insufficiently powered and lack external validation. Adequately sized validation studies of multiple......Diabetic kidney disease occurs in ∼ 25-40% of patients with type 2 diabetes. Given the high risk of progressive renal function loss and end-stage renal disease, early identification of patients with a renal risk is important. Novel biomarkers may aid in improving renal risk stratification...... and metabolomics biomarkers. We focus on multiple biomarker panels since the molecular processes of renal disease progression in type 2 diabetes are heterogeneous, rendering it unlikely that a single biomarker significantly adds to clinical risk prediction. A limited number of prospective studies of multiple...

  18. Analysis of biomarker data a practical guide

    CERN Document Server

    Looney, Stephen W

    2015-01-01

    A "how to" guide for applying statistical methods to biomarker data analysis Presenting a solid foundation for the statistical methods that are used to analyze biomarker data, Analysis of Biomarker Data: A Practical Guide features preferred techniques for biomarker validation. The authors provide descriptions of select elementary statistical methods that are traditionally used to analyze biomarker data with a focus on the proper application of each method, including necessary assumptions, software recommendations, and proper interpretation of computer output. In addition, the book discusses

  19. Searching for new biomarkers in ovarian cancer patients: Rationale and design of a retrospective study under the Mermaid III project

    Directory of Open Access Journals (Sweden)

    Julie L. Hentze

    2017-12-01

    A thorough investigation of biomarkers in ovarian cancer, including large numbers of different markers, has never been done before. Besides from improving diagnosis and treatment, other outcomes could be markers for screening, knowledge of the molecular aspects of cancer and the discovery of new drugs. Moreover, biomarkers are a prerequisite for the development of precision medicine. This study will attack the ovarian cancer problem from several angles, thereby increasing the chance of successfully contributing to saving lives.

  20. Identification, validation, and clinical implementation of tumor-associated biomarkers to improve therapy concepts, survival, and quality of life of cancer patients: tasks of the Receptor and Biomarker Group of the European Organization for Research and Treatment of Cancer.

    NARCIS (Netherlands)

    Schmitt, M.; Harbeck, N.; Daidone, M.G.; Brynner, N.; Duffy, M.J.; Foekens, J.A.; Sweep, C.G.J.

    2004-01-01

    Guiding principles are provided and discussed on how to inform the physician scientist and cancer researcher about quality control systems to enable a consistent assessment of the clinical value of tumor-associated biomarkers. Next to cancer research itself, the Receptor and Biomarker Group of the

  1. Partial verification bias and incorporation bias affected accuracy estimates of diagnostic studies for biomarkers that were part of an existing composite gold standard.

    Science.gov (United States)

    Karch, Annika; Koch, Armin; Zapf, Antonia; Zerr, Inga; Karch, André

    2016-10-01

    To investigate how choice of gold standard biases estimates of sensitivity and specificity in studies reassessing the diagnostic accuracy of biomarkers that are already part of a lifetime composite gold standard (CGS). We performed a simulation study based on the real-life example of the biomarker "protein 14-3-3" used for diagnosing Creutzfeldt-Jakob disease. Three different types of gold standard were compared: perfect gold standard "autopsy" (available in a small fraction only; prone to partial verification bias), lifetime CGS (including the biomarker under investigation; prone to incorporation bias), and "best available" gold standard (autopsy if available, otherwise CGS). Sensitivity was unbiased when comparing 14-3-3 with autopsy but overestimated when using CGS or "best available" gold standard. Specificity of 14-3-3 was underestimated in scenarios comparing 14-3-3 with autopsy (up to 24%). In contrast, overestimation (up to 20%) was observed for specificity compared with CGS; this could be reduced to 0-10% when using the "best available" gold standard. Choice of gold standard affects considerably estimates of diagnostic accuracy. Using the "best available" gold standard (autopsy where available, otherwise CGS) leads to valid estimates of specificity, whereas sensitivity is estimated best when tested against autopsy alone. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Building a gold standard to construct search filters: a case study with biomarkers for oral cancer.

    Science.gov (United States)

    Frazier, John J; Stein, Corey D; Tseytlin, Eugene; Bekhuis, Tanja

    2015-01-01

    To support clinical researchers, librarians and informationists may need search filters for particular tasks. Development of filters typically depends on a "gold standard" dataset. This paper describes generalizable methods for creating a gold standard to support future filter development and evaluation using oral squamous cell carcinoma (OSCC) as a case study. OSCC is the most common malignancy affecting the oral cavity. Investigation of biomarkers with potential prognostic utility is an active area of research in OSCC. The methods discussed here should be useful for designing quality search filters in similar domains. The authors searched MEDLINE for prognostic studies of OSCC, developed annotation guidelines for screeners, ran three calibration trials before annotating the remaining body of citations, and measured inter-annotator agreement (IAA). We retrieved 1,818 citations. After calibration, we screened the remaining citations (n = 1,767; 97.2%); IAA was substantial (kappa = 0.76). The dataset has 497 (27.3%) citations representing OSCC studies of potential prognostic biomarkers. The gold standard dataset is likely to be high quality and useful for future development and evaluation of filters for OSCC studies of potential prognostic biomarkers. The methodology we used is generalizable to other domains requiring a reference standard to evaluate the performance of search filters. A gold standard is essential because the labels regarding relevance enable computation of diagnostic metrics, such as sensitivity and specificity. Librarians and informationists with data analysis skills could contribute to developing gold standard datasets and subsequent filters tuned for their patrons' domains of interest.

  3. Biomarkers in molecular epidemiology study of oral squamous cell carcinoma in the era of precision medicine

    Directory of Open Access Journals (Sweden)

    Qing-Hao Zhu

    2017-01-01

    Full Text Available Oral cancer, which occurs in the mouth, lips, and tongue, is a multifactorial disease whose etiology involves environment, genetic, and epigenetic factors. Tobacco use and alcohol consumption are regarded as the primary risk factors for oral squamous cell carcinoma (OSCC, and betel use, other chemicals, radiation, environmental, and genetics are reported as relevant risk factors for oral carcinogenesis. The human papillomavirus infection is an independent risk factor. Traditional epidemiology studies have revealed that environmental carcinogens are risk factors for OSCC. Molecular epidemiology studies have revealed that the susceptibility to OSCC is influenced by both environmental and genetic risk factors. However, the details and mechanisms of risk factors involved in OSCC are unclear. Advanced methods and techniques used in human genome studies provide great opportunities for researchers to explore and identify (a the details of such risk factors and (b genetic susceptibility involved in OSCC. Human genome epidemiology is a new branch of epidemiology, which leads the epidemiology study from the molecular epidemiology era into the era of genome-wide association study. In the era of precision medicine, molecular epidemiology studies should focus on biomarkers for cancer genomics and their potential utility in clinical practice. Here, we briefly reviewed several molecular epidemiology studies of OSCC, focusing on biomarkers as valuable utility in risk assessment, clinical screening, diagnosis, and prognosis prediction of OSCC in the era of precision medicine.

  4. LABORATORY BIOMARKERS FOR ANKYLOSING SPONDYLITIS

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    E. N. Aleksandrova

    2017-01-01

    Full Text Available Ankylosing spondylitis (AS is a chronic inflammatory disease from a group of spondyloarthritis (SpA, which is characterized by lesions of the sacroiliac joints and spine with the common involvement of entheses and peripheral joints in the pathological process. Advances in modern laboratory medicine have contributed to a substantial expansion of the range of pathogenetic, diagnostic, and prognostic biomarkers of AS. As of now, there are key pathogenetic biomarkers of AS (therapeutic targets, which include tumor necrosis factor-α (TNF-α, interleukin 17 (IL-17, and IL-23. Among the laboratory diagnostic and prognostic biomarkers, HLA-B27 and C-reactive protein are of the greatest value in clinical practice; the former for the early diagnosis of the disease and the latter for the assessment of disease activity, the risk of radiographic progression and the efficiency of therapy. Anti-CD74 antibodies are a new biomarker that has high sensitivity and specificity values in diagnosing axial SpA at an early stage. A number of laboratory biomarkers, including calprotectin, matrix metalloproteinase-3 (MMP-3, vascular endothelial growth factor, Dickkopf-1 (Dkk-1, and C-terminal telopeptide of type II collagen (CTX II do not well reflect disease activity, but may predict progressive structural changes in the spine and sacroiliac joints in AS. Blood calprotectin level monitoring allows the effective prediction of a response to therapy with TNF inhibitors and anti-IL-17А monoclonal antibodies. The prospects for the laboratory diagnosis of AS are associated with the clinical validation of candidate biomarkers during large-scale prospective cohort studies and with a search for new proteomic, transcriptomic and genomic markers, by using innovative molecular and cellular technologies.

  5. Relative validity of a food frequency questionnaire used in the Inter99 study

    DEFF Research Database (Denmark)

    Toft, U.; Kristoffersen, Lars; Ladelund, S.

    2008-01-01

    OBJECTIVE: To evaluate the validity of the Inter99 food frequency questionnaire (FFQ) compared with a 28-days' diet history and biomarkers. SUBJECTS: A random sample of 13 016 individuals were drawn from a general population and invited for a health screening programme. Participation rate was 52.......5%. All high-risk individuals were re-invited for assessment after 1 and 3 years and completed a 198-item FFQ at all three occasions. Participants attending for 3 years follow-up were invited to participate in the validation study, including a 28-days' diet history, a 24-h urine collection and a fasting...... blood sample. Overall, 264 subjects participated. RESULTS: Spearman's rank correlation coefficients between the two dietary methods ranged from 0.31(beta-carotene) to 0.64 (fruits) in men and from 0.31 (polyunsaturated fat and sodium) to 0.64 (fruits) for women. The proportion of individuals classified...

  6. Testing of the preliminary OMERACT validation criteria for a biomarker to be regarded as reflecting structural damage endpoints in rheumatoid arthritis clinical trials: the example of C-reactive protein

    DEFF Research Database (Denmark)

    Keeling, Stephanie O; Landewe, Robert; van der Heijde, Desiree

    2007-01-01

    OBJECTIVE: A list of 14 criteria for guiding the validation of a soluble biomarker as reflecting structural damage endpoints in rheumatoid arthritis (RA) clinical trials was drafted by an international working group after a Delphi consensus exercise. C-reactive protein (CRP), a soluble biomarker...... of individual criteria in the draft set. METHODS: A systematic literature review was conducted to elicit evidence in support of each specific criterion composing the 14-criteria draft set. A summary of the key literature findings per criterion was presented to both the working group and to participants...

  7. Biomarkers of tolerance: searching for the hidden phenotype.

    Science.gov (United States)

    Perucha, Esperanza; Rebollo-Mesa, Irene; Sagoo, Pervinder; Hernandez-Fuentes, Maria P

    2011-08-01

    Induction of transplantation tolerance remains the ideal long-term clinical and logistic solution to the current challenges facing the management of renal allograft recipients. In this review, we describe the recent studies and advances made in identifying biomarkers of renal transplant tolerance, from study inceptions, to the lessons learned and their implications for current and future studies with the same goal. With the age of biomarker discovery entering a new dimension of high-throughput technologies, here we also review the current approaches, developments, and pitfalls faced in the subsequent statistical analysis required to identify valid biomarker candidates.

  8. Discovery and Validation of Pyridoxic Acid and Homovanillic Acid as Novel Endogenous Plasma Biomarkers of Organic Anion Transporter (OAT) 1 and OAT3 in Cynomolgus Monkeys.

    Science.gov (United States)

    Shen, Hong; Nelson, David M; Oliveira, Regina V; Zhang, Yueping; Mcnaney, Colleen A; Gu, Xiaomei; Chen, Weiqi; Su, Ching; Reily, Michael D; Shipkova, Petia A; Gan, Jinping; Lai, Yurong; Marathe, Punit; Humphreys, W Griffith

    2018-02-01

    Perturbation of organic anion transporter (OAT) 1- and OAT3-mediated transport can alter the exposure, efficacy, and safety of drugs. Although there have been reports of the endogenous biomarkers for OAT1/3, none of these have all of the characteristics required for a clinical useful biomarker. Cynomolgus monkeys were treated with intravenous probenecid (PROB) at a dose of 40 mg/kg in this study. As expected, PROB increased the area under the plasma concentration-time curve (AUC) of coadministered furosemide, a known substrate of OAT1 and OAT3, by 4.1-fold, consistent with the values reported in humans (3.1- to 3.7-fold). Of the 233 plasma metabolites analyzed using a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics method, 29 metabolites, including pyridoxic acid (PDA) and homovanillic acid (HVA), were significantly increased after either 1 or 3 hours in plasma from the monkeys pretreated with PROB compared with the treated animals. The plasma of animals was then subjected to targeted LC-MS/MS analysis, which confirmed that the PDA and HVA AUCs increased by approximately 2- to 3-fold by PROB pretreatments. PROB also increased the plasma concentrations of hexadecanedioic acid (HDA) and tetradecanedioic acid (TDA), although the increases were not statistically significant. Moreover, transporter profiling assessed using stable cell lines constitutively expressing transporters demonstrated that PDA and HVA are substrates for human OAT1, OAT3, OAT2 (HVA), and OAT4 (PDA), but not OCT2, MATE1, MATE2K, OATP1B1, OATP1B3, and sodium taurocholate cotransporting polypeptide. Collectively, these findings suggest that PDA and HVA might serve as blood-based endogenous probes of cynomolgus monkey OAT1 and OAT3, and investigation of PDA and HVA as circulating endogenous biomarkers of human OAT1 and OAT3 function is warranted. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  9. A Systematic Review of Longitudinal Studies Which Measure Alzheimer's Disease Biomarkers.

    Science.gov (United States)

    Lawrence, Emma; Vegvari, Carolin; Ower, Alison; Hadjichrysanthou, Christoforos; De Wolf, Frank; Anderson, Roy M

    2017-01-01

    Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, with no effective treatment or cure. A gold standard therapy would be treatment to slow or halt disease progression; however, knowledge of causation in the early stages of AD is very limited. In order to determine effective endpoints for possible therapies, a number of quantitative surrogate markers of disease progression have been suggested, including biochemical and imaging biomarkers. The dynamics of these various surrogate markers over time, particularly in relation to disease development, are, however, not well characterized. We reviewed the literature for studies that measured cerebrospinal fluid or plasma amyloid-β and tau, or took magnetic resonance image or fluorodeoxyglucose/Pittsburgh compound B-positron electron tomography scans, in longitudinal cohort studies. We summarized the properties of the major cohort studies in various countries, commonly used diagnosis methods and study designs. We have concluded that additional studies with repeat measures over time in a representative population cohort are needed to address the gap in knowledge of AD progression. Based on our analysis, we suggest directions in which research could move in order to advance our understanding of this complex disease, including repeat biomarker measurements, standardization and increased sample sizes.

  10. A metabolomics-driven approach to predict cocoa product consumption by designing a multimetabolite biomarker model in free-living subjects from the PREDIMED study.

    Science.gov (United States)

    Garcia-Aloy, Mar; Llorach, Rafael; Urpi-Sarda, Mireia; Jáuregui, Olga; Corella, Dolores; Ruiz-Canela, Miguel; Salas-Salvadó, Jordi; Fitó, Montserrat; Ros, Emilio; Estruch, Ramon; Andres-Lacueva, Cristina

    2015-02-01

    The aim of the current study was to apply an untargeted metabolomics strategy to characterize a model of cocoa intake biomarkers in a free-living population. An untargeted HPLC-q-ToF-MS based metabolomics approach was applied to human urine from 32 consumers of cocoa or derived products (CC) and 32 matched control subjects with no consumption of cocoa products (NC). The multivariate statistical analysis (OSC-PLS-DA) showed clear differences between CC and NC groups. The discriminant biomarkers identified were mainly related to the metabolic pathways of theobromine and polyphenols, as well as to cocoa processing. Consumption of cocoa products was also associated with reduced urinary excretions of methylglutarylcarnitine, which could be related to effects of cocoa exposure on insulin resistance. To improve the prediction of cocoa consumption, a combined urinary metabolite model was constructed. ROC curves were performed to evaluate the model and individual metabolites. The AUC values (95% CI) for the model were 95.7% (89.8-100%) and 92.6% (81.9-100%) in training and validation sets, respectively, whereas the AUCs for individual metabolites were cocoa consumption in free-living subjects reveals that combining different metabolites as biomarker models improves prediction of dietary exposure to cocoa. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. The Dutch Healthy Diet index as assessed by 24 h recalls and FFQ: associations with biomarkers from a cross-sectional study.

    Science.gov (United States)

    van Lee, Linde; Feskens, Edith J M; Hooft van Huysduynen, Eveline J C; de Vries, Jeanne H M; van 't Veer, Pieter; Geelen, Anouk

    2013-01-01

    The Dutch Healthy Diet index (DHD-index) was developed using data from two 24 h recalls (24hR) and appeared useful to evaluate diet quality in Dutch adults. As many epidemiologic studies use FFQ, we now estimated the DHD-index score using FFQ data. We compared whether this score showed similar associations with participants' characteristics, micronutrient intakes, and biomarkers of intake and metabolism compared with the DHD-index using 24hR data. Data of 121 Dutch participants of the European Food Consumption Validation study were used. Dietary intake was assessed by two 24hR and a 180-item FFQ. Biomarkers measured were serum total cholesterol and carotenoids, EPA + DHA in plasma phospholipids and 24 h urinary Na. A correlation of 0·48 (95 % CI 0·33, 0·61) was observed between the DHD-index score based on 24hR data and on FFQ data. Classification of participants into the same tertiles of the DHD-index was achieved for 57 %. Women showed higher DHD-index scores. Energy intake was inversely associated with both DHD-index scores. Furthermore, age and intakes of folate, Fe, Mg, K, vitamin B6 and vitamin C were positively associated with both DHD-index scores. DHD-index scores showed acceptable correlations with the four combined biomarkers taking energy intake into account (r 24hR 0.55; r FFQ 0.51). In conclusion, the DHD-index score based on FFQ data shows similar associations with participants' characteristics, energy intake, micronutrient intake and biomarkers compared with the score based on 24hR data. Furthermore, ranking of participants was acceptable for both methods. FFQ data may therefore be used to assess diet quality using the DHD-index in Dutch populations.

  12. Urinary volatile compounds as biomarkers for lung cancer: a proof of principle study using odor signatures in mouse models of lung cancer.

    Directory of Open Access Journals (Sweden)

    Koichi Matsumura

    2010-01-01

    Full Text Available A potential strategy for diagnosing lung cancer, the leading cause of cancer-related death, is to identify metabolic signatures (biomarkers of the disease. Although data supports the hypothesis that volatile compounds can be detected in the breath of lung cancer patients by the sense of smell or through bioanalytical techniques, analysis of breath samples is cumbersome and technically challenging, thus limiting its applicability. The hypothesis explored here is that variations in small molecular weight volatile organic compounds ("odorants" in urine could be used as biomarkers for lung cancer. To demonstrate the presence and chemical structures of volatile biomarkers, we studied mouse olfactory-guided behavior and metabolomics of volatile constituents of urine. Sensor mice could be trained to discriminate between odors of mice with and without experimental tumors demonstrating that volatile odorants are sufficient to identify tumor-bearing mice. Consistent with this result, chemical analyses of urinary volatiles demonstrated that the amounts of several compounds were dramatically different between tumor and control mice. Using principal component analysis and supervised machine-learning, we accurately discriminated between tumor and control groups, a result that was cross validated with novel test groups. Although there were shared differences between experimental and control animals in the two tumor models, we also found chemical differences between these models, demonstrating tumor-based specificity. The success of these studies provides a novel proof-of-principle demonstration of lung tumor diagnosis through urinary volatile odorants. This work should provide an impetus for similar searches for volatile diagnostic biomarkers in the urine of human lung cancer patients.

  13. Italian version of Dyspnoea-12: cultural-linguistic validation, quantitative and qualitative content validity study.

    Science.gov (United States)

    Caruso, Rosario; Arrigoni, Cristina; Groppelli, Katia; Magon, Arianna; Dellafiore, Federica; Pittella, Francesco; Grugnetti, Anna Maria; Chessa, Massimo; Yorke, Janelle

    2018-01-16

    Dyspnoea-12 is a valid and reliable scale to assess dyspneic symptom, considering its severity, physical and emotional components. However, it is not available in Italian version due to it was not yet translated and validated. For this reason, the aim of this study was to develop an Italian version Dyspnoea-12, providing a cultural and linguistic validation, supported by the quantitative and qualitative content validity. This was a methodological study, divided into two phases: phase one is related to the cultural and linguistic validation, phase two is related to test the quantitative and qualitative content validity. Linguistic validation followed a standardized translation process. Quantitative content validity was assessed computing content validity ratio (CVR) and index (I-CVIs and S-CVI) from expert panellists response. Qualitative content validity was assessed by the narrative analysis on the answers of three open-ended questions to the expert panellists, aimed to investigate the clarity and the pertinence of the Italian items. The translation process found a good agreement in considering clear the items in both the six involved bilingual expert translators and among the ten voluntary involved patients. CVR, I-CVIs and S-CVI were satisfactory for all the translated items. This study has represented a pivotal step to use Dyspnoea-12 amongst Italian patients. Future researches are needed to deeply investigate the Italian version of  Dyspnoea-12 construct validity and its reliability, and to describe how dyspnoea components (i.e. physical and emotional) impact the life of patients with cardiorespiratory diseases.

  14. Lichen biomarkers upon heating: a Raman spectroscopic study with implications for extra-terrestrial exploration

    Science.gov (United States)

    Miralles, I.; Capel Ferrón, C.; Hernández, V.; López-Navarrete, J. T.; Jorge-Villar, S. E.

    2017-01-01

    Lithopanspermia Theory has suggested that life was transferred among planets by meteorites and other rocky bodies. If the planet had an atmosphere, this transfer of life had to survive drastic temperature changes in a very short time in its entry or exit. Only organisms able to endure such a temperature range could colonize a planet from outer space. Many experiments are being carried out by NASA and European Space Agency to understand which organisms were able to survive and how. Among the suite of instruments designed for extraplanetary exploration, particularly for Mars surface exploration, a Raman spectrometer was selected with the main objective of looking for life signals. Among all attributes, Raman spectroscopy is able to identify organic and inorganic compounds, either pure or in admixture, without requiring sample manipulation. In this study, we used Raman spectroscopy to examine the lichen Squamarina lentigera biomarkers. We analyse spectral signature changes after sample heating under different experimental situations, such as (a) laser, (b) analysis accumulations over the same spot and (c) environmental temperature increase. Our goal is to evaluate the capability of Raman spectroscopy to identify unambiguously life markers even if heating has induced spectral changes, reflecting biomolecular transformations. Usnic acid, chlorophyll, carotene and calcium oxalates were identified by the Raman spectra. From our experiments, we have seen that usnic acid, carotene and calcium oxalates (the last two have been suggested to be good biomarkers) respond in a different way to environmental heating. Our main conclusion is that despite their abundance in nature or their inorganic composition the resistance to heat makes some molecules more suitable than others as biomarkers.

  15. Urinary 1H Nuclear Magnetic Resonance Metabolomic Fingerprinting Reveals Biomarkers of Pulse Consumption Related to Energy-Metabolism Modulation in a Subcohort from the PREDIMED study.

    Science.gov (United States)

    Madrid-Gambin, Francisco; Llorach, Rafael; Vázquez-Fresno, Rosa; Urpi-Sarda, Mireia; Almanza-Aguilera, Enrique; Garcia-Aloy, Mar; Estruch, Ramon; Corella, Dolores; Andres-Lacueva, Cristina

    2017-04-07

    Little is known about the metabolome fingerprint of pulse consumption. The study of robust and accurate biomarkers for pulse dietary assessment has great value for nutritional epidemiology regarding health benefits and their mechanisms. To characterize the fingerprinting of dietary pulses (chickpeas, lentils, and beans), spot urine samples from a subcohort from the PREDIMED study were stratified using a validated food frequency questionnaire. Urine samples of nonpulse consumers (≤4 g/day of pulse intake) and habitual pulse consumers (≥25 g/day of pulse intake) were analyzed using a 1 H nuclear magnetic resonance (NMR) metabolomics approach combined with multi- and univariate data analysis. Pulse consumption showed differences through 16 metabolites coming from (i) choline metabolism, (ii) protein-related compounds, and (iii) energy metabolism (including lower urinary glucose). Stepwise logistic regression analysis was applied to design a combined model of pulse exposure, which resulted in glutamine, dimethylamine, and 3-methylhistidine. This model was evaluated by a receiver operating characteristic curve (AUC > 90% in both training and validation sets). The application of NMR-based metabolomics to reported pulse exposure highlighted new candidates for biomarkers of pulse consumption and the impact on energy metabolism, generating new hypotheses on energy modulation. Further intervention studies will confirm these findings.

  16. Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study.

    Directory of Open Access Journals (Sweden)

    Nadine M P Daan

    Full Text Available To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring.Cross-sectional comparison of serum biomarkers.University Medical Center Utrecht.Hyperandrogenic PCOS women (HA-PCOS, n = 34, normoandrogenic PCOS women (NA-PCOS, n = 34, non-PCOS reference population (n = 32, PCOS offspring (n = 14, age 6-8 years, and a paedriatic reference population (n = 30.Clustering profile of adipocytokines (IL-1b, IL-6, IL-13, IL-17, IL-18, TNF-α, adiponectin, adipsin, leptin, chemerin, resistin, RBP4, DPP-IV/sCD26, CCL2/MCP-1, growth factors (PIGF, VEGF, sVEGF-R1, soluble cell adhesion molecules (sICAM-1/sCD54, sVCAM-1/sCD106, and other inflammatory related proteases (MMP-9, S100A8, Cathepsin S. Differences in median biomarker concentrations between groups, and associations with the free androgen index (FAI; Testosterone/SHBG x100.The cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R2 = 0.219 and adiponectin (R2 = 0.182 showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P < 0.001, DPP-IV (P = 0.005, and adiponectin (P < 0.001. Adjusting for age, BMI and multiple testing attenuated all differences. In PCOS offspring, MMP-9 (P = 0.001 and S100A8 (P < 0.001 concentrations were significantly higher compared to a healthy matched reference population, even after correcting for age and BMI and adjustment for multiple testing.In this preliminary investigation we observed significant differences in adipocytokines between women with or without hyperandrogenic PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers

  17. A fully validated bioanalytical method using an UHPLC-MS/MS system for quantification of DNA and RNA oxidative stress biomarkers.

    Science.gov (United States)

    Cervinkova, Barbora; Krcmova, Lenka Kujovska; Sestakova, Veronika; Solichova, Dagmar; Solich, Petr

    2017-05-01

    A new, rapid and effective ultra-high-performance liquid chromatography method with mass spectrometry detection is described for the separation and quantification of 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine and creatinine in human urine. The present study uses an isotope-labelled internal standard ([ 15 N] 5 -8-hydroxy-2-deoxyguanosine), a BIO core-shell stationary phase and an isocratic elution of methanol and water. Sample preparation of human urine was performed by solid-phase extraction (SPE) on Oasis HLB cartridges with methanol/water 50:50 (v/v) elution. Extraction recoveries ranged from 98.1% to 109.2%. Biological extracts showed high short-term stability. Several aspects of this procedure make it suitable for both clinical and research purposes: a short elution time of less than 3.2 min, an intra-day precision of 2.5-8.9%, an inter-day precision of 3.4-8.7% and low limits of quantification (27.7 nM for 8-hydroxyguanosine, 6.0 nM for 8-hydroxy-2-deoxyguanosine). Finally, simultaneous analysis of DNA and RNA oxidative stress biomarkers is a useful tool for monitoring disease progression in neurodegenerative disorders and cancer. Graphical abstract UHPLC-MS/MS analysis of DNA and RNA oxidative stress biomarkers.

  18. Dried Blood Spot Collection of Health Biomarkers to Maximize Participation in Population Studies

    Science.gov (United States)

    Ostler, Michael W.; Porter, James H.; Buxton, Orfeu M.

    2014-01-01

    Biomarkers are directly-measured biological indicators of disease, health, exposures, or other biological information. In population and social sciences, biomarkers need to be easy to obtain, transport, and analyze. Dried Blood Spots meet this need, and can be collected in the field with high response rates. These elements are particularly important in longitudinal study designs including interventions where attrition is critical to avoid, and high response rates improve the interpretation of results. Dried Blood Spot sample collection is simple, quick, relatively painless, less invasive then venipuncture, and requires minimal field storage requirements (i.e. samples do not need to be immediately frozen and can be stored for a long period of time in a stable freezer environment before assay). The samples can be analyzed for a variety of different analytes, including cholesterol, C-reactive protein, glycosylated hemoglobin, numerous cytokines, and other analytes, as well as provide genetic material. DBS collection is depicted as employed in several recent studies. PMID:24513728

  19. Top-down proteomics with mass spectrometry imaging: a pilot study towards discovery of biomarkers for neurodevelopmental disorders.

    Directory of Open Access Journals (Sweden)

    Hui Ye

    Full Text Available In the developing mammalian brain, inhibition of NMDA receptor can induce widespread neuroapoptosis, inhibit neurogenesis and cause impairment of learning and memory. Although some mechanistic insights into adverse neurological actions of these NMDA receptor antagonists exist, our understanding of the full spectrum of developmental events affected by early exposure to these chemical agents in the brain is still limited. Here we attempt to gain insights into the impact of pharmacologically induced excitatory/inhibitory imbalance in infancy on the brain proteome using mass spectrometric imaging (MSI. Our goal was to study changes in protein expression in postnatal day 10 (P10 rat brains following neonatal exposure to the NMDA receptor antagonist dizocilpine (MK801. Analysis of rat brains exposed to vehicle or MK801 and comparison of their MALDI MS images revealed differential relative abundances of several proteins. We then identified these markers such as ubiquitin, purkinje cell protein 4 (PEP-19, cytochrome c oxidase subunits and calmodulin, by a combination of reversed-phase (RP HPLC fractionation and top-down tandem MS platform. More in-depth large scale study along with validation experiments will be carried out in the future. Overall, our findings indicate that a brief neonatal exposure to a compound that alters excitatory/inhibitory balance in the brain has a long term effect on protein expression patterns during subsequent development, highlighting the utility of MALDI-MSI as a discovery tool for potential biomarkers.

  20. Clinical validity of delayed recall tests as a gateway biomarker for Alzheimer's disease in the context of a structured 5-phase development framework.

    Science.gov (United States)

    Cerami, Chiara; Dubois, Bruno; Boccardi, Marina; Monsch, Andreas U; Demonet, Jean Francois; Cappa, Stefano F

    2017-04-01

    Although Alzheimer's disease criteria promote the use of biomarkers, their maturity in clinical routine still needs to be assessed. In the light of the oncology framework, we conducted a literature review on measures used to assess delayed recall impairment due to medial temporal lobe dysfunction (i.e., free and cued word list recall tests). Ample evidence is available for phases 1 (rationale for use), 2 (discriminative ability), and 3 (early detection ability) for many of the tests in routine use. Evidence about phase 4 (performance in real world) and phase 5 (quantify impact and costs) is yet to come. Administration procedures have been standardized and cutoff scores are well validated in large Alzheimer's disease and mild cognitive impaired series. Some aspects (e.g., different task formats), however, hamper the comparability of results among different populations and the reproducibility between laboratories. No definite guideline for their use can thus be proposed at the moment. Accordingly, the maturity of such markers is not yet sufficient and requires future investigation to promote the proper use of memory measures in clinical settings. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Validation of biomarkers for distinguishing Mycobacterium tuberculosis from non-tuberculous mycobacteria using gas chromatography-mass spectrometry and chemometrics.

    Directory of Open Access Journals (Sweden)

    Ngoc A Dang

    Full Text Available Tuberculosis (TB remains a major international health problem. Rapid differentiation of Mycobacterium tuberculosis complex (MTB from non-tuberculous mycobacteria (NTM is critical for decisions regarding patient management and choice of therapeutic regimen. Recently we developed a 20-compound model to distinguish between MTB and NTM. It is based on thermally assisted hydrolysis and methylation gas chromatography-mass spectrometry and partial least square discriminant analysis. Here we report the validation of this model with two independent sample sets, one consisting of 39 MTB and 17 NTM isolates from the Netherlands, the other comprising 103 isolates (91 MTB and 12 NTM from Stellenbosch, Cape Town, South Africa. All the MTB strains in the 56 Dutch samples were correctly identified and the model had a sensitivity of 100% and a specificity of 94%. For the South African samples the model had a sensitivity of 88% and specificity of 100%. Based on our model, we have developed a new decision-tree that allows the differentiation of MTB from NTM with 100% accuracy. Encouraged by these findings we will proceed with the development of a simple, rapid, affordable, high-throughput test to identify MTB directly in sputum.

  2. 'Omics' biomarkers associated with chronic low back pain: protocol of a retrospective longitudinal study.

    Science.gov (United States)

    Allegri, Massimo; De Gregori, Manuela; Minella, Cristina E; Klersy, Catherine; Wang, Wei; Sim, Moira; Gieger, Christian; Manz, Judith; Pemberton, Iain K; MacDougall, Jane; Williams, Frances Mk; Van Zundert, Jan; Buyse, Klaas; Lauc, Gordan; Gudelj, Ivan; Primorac, Dragan; Skelin, Andrea; Aulchenko, Yurii S; Karssen, Lennart C; Kapural, Leonardo; Rauck, Richard; Fanelli, Guido

    2016-10-19

    Chronic low back pain (CLBP) produces considerable direct costs as well as indirect burdens for society, industry and health systems. CLBP is characterised by heterogeneity, inclusion of several pain syndromes, different underlying molecular pathologies and interaction with psychosocial factors that leads to a range of clinical manifestations. There is still much to understand in the underlying pathological processes and the non-psychosocial factors which account for differences in outcomes. Biomarkers that may be objectively used for diagnosis and personalised, targeted and cost-effective treatment are still lacking. Therefore, any data that may be obtained at the '-omics' level (glycomics, Activomics and genome-wide association studies-GWAS) may be helpful to use as dynamic biomarkers for elucidating CLBP pathogenesis and may ultimately provide prognostic information too. By means of a retrospective, observational, case-cohort, multicentre study, we aim to investigate new promising biomarkers potentially able to solve some of the issues related to CLBP. The study follows a two-phase, 1:2 case-control model. A total of 12 000 individuals (4000 cases and 8000 controls) will be enrolled; clinical data will be registered, with particular attention to pain characteristics and outcomes of pain treatments. Blood samples will be collected to perform -omics studies. The primary objective is to recognise genetic variants associated with CLBP; secondary objectives are to study glycomics and Activomics profiles associated with CLBP. The study is part of the PainOMICS project funded by European Community in the Seventh Framework Programme. The study has been approved from competent ethical bodies and copies of approvals were provided to the European Commission before starting the study. Results of the study will be reviewed by the Scientific Board and Ethical Committee of the PainOMICS Consortium. The scientific results will be disseminated through peer-reviewed journals

  3. Mining biomarker information in biomedical literature

    Directory of Open Access Journals (Sweden)

    Younesi Erfan

    2012-12-01

    Full Text Available Abstract Background For selection and evaluation of potential biomarkers, inclusion of already published information is of utmost importance. In spite of significant advancements in text- and data-mining techniques, the vast knowledge space of biomarkers in biomedical text has remained unexplored. Existing named entity recognition approaches are not sufficiently selective for the retrieval of biomarker information from the literature. The purpose of this study was to identify textual features that enhance the effectiveness of biomarker information retrieval for different indication areas and diverse end user perspectives. Methods A biomarker terminology was created and further organized into six concept classes. Performance of this terminology was optimized towards balanced selectivity and specificity. The information retrieval performance using the biomarker terminology was evaluated based on various combinations of the terminology's six classes. Further validation of these results was performed on two independent corpora representing two different neurodegenerative diseases. Results The current state of the biomarker terminology contains 119 entity classes supported by 1890 different synonyms. The result of information retrieval shows improved retrieval rate of informative abstracts, which is achieved by including clinical management terms and evidence of gene/protein alterations (e.g. gene/protein expression status or certain polymorphisms in combination with disease and gene name recognition. When additional filtering through other classes (e.g. diagnostic or prognostic methods is applied, the typical high number of unspecific search results is significantly reduced. The evaluation results suggest that this approach enables the automated identification of biomarker information in the literature. A demo version of the search engine SCAIView, including the biomarker retrieval, is made available to the public through http

  4. Biomarker Detection in Association Studies: Modeling SNPs Simultaneously via Logistic ANOVA

    KAUST Repository

    Jung, Yoonsuh; Huang, Jianhua Z.; Hu, Jianhua

    2014-01-01

    In genome-wide association studies, the primary task is to detect biomarkers in the form of Single Nucleotide Polymorphisms (SNPs) that have nontrivial associations with a disease phenotype and some other important clinical/environmental factors. However, the extremely large number of SNPs comparing to the sample size inhibits application of classical methods such as the multiple logistic regression. Currently the most commonly used approach is still to analyze one SNP at a time. In this paper, we propose to consider the genotypes of the SNPs simultaneously via a logistic analysis of variance (ANOVA) model, which expresses the logit transformed mean of SNP genotypes as the summation of the SNP effects, effects of the disease phenotype and/or other clinical variables, and the interaction effects. We use a reduced-rank representation of the interaction-effect matrix for dimensionality reduction, and employ the L 1-penalty in a penalized likelihood framework to filter out the SNPs that have no associations. We develop a Majorization-Minimization algorithm for computational implementation. In addition, we propose a modified BIC criterion to select the penalty parameters and determine the rank number. The proposed method is applied to a Multiple Sclerosis data set and simulated data sets and shows promise in biomarker detection.

  5. Urinary metabonomics study on toxicity biomarker discovery in rats treated with Xanthii Fructus.

    Science.gov (United States)

    Lu, Fang; Cao, Min; Wu, Bin; Li, Xu-zhao; Liu, Hong-yu; Chen, Da-zhong; Liu, Shu-min

    2013-08-26

    Xanthii Fructus (XF) is commonly called "Cang-Erzi" in traditional Chinese medicine (TCM) and widely used for the treatment of sinusitis, headache, rheumatism, and skin itching. However, the clinical utilization of XF is relatively restricted owing to its toxicity. To discover the characteristic potential biomarkers in rats treated with XF by urinary metabonomics. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was applied in the study. The total ion chromatograms obtained from control and different dosage groups were distinguishable by a multivariate statistical analysis method. The greatest difference in metabolic profile was observed between high dosage group and control group, and the metabolic characters in rats treated with XF were perturbed in a dose-dependent manner. The metabolic changes in response for XF treatment were observed in urinary samples, which were revealed by orthogonal projection to latent structures discriminate analysis (OPLS-DA), and 10 metabolites could be served as the potential toxicity biomarkers. In addition, the mechanism associated with the damages of lipid per-oxidation and the metabolic disturbances of fatty acid oxidation were investigated. These results indicate that metabonomics analysis in urinary samples may be useful for predicting the toxicity induced by XF. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  6. Biomarker Detection in Association Studies: Modeling SNPs Simultaneously via Logistic ANOVA

    KAUST Repository

    Jung, Yoonsuh

    2014-10-02

    In genome-wide association studies, the primary task is to detect biomarkers in the form of Single Nucleotide Polymorphisms (SNPs) that have nontrivial associations with a disease phenotype and some other important clinical/environmental factors. However, the extremely large number of SNPs comparing to the sample size inhibits application of classical methods such as the multiple logistic regression. Currently the most commonly used approach is still to analyze one SNP at a time. In this paper, we propose to consider the genotypes of the SNPs simultaneously via a logistic analysis of variance (ANOVA) model, which expresses the logit transformed mean of SNP genotypes as the summation of the SNP effects, effects of the disease phenotype and/or other clinical variables, and the interaction effects. We use a reduced-rank representation of the interaction-effect matrix for dimensionality reduction, and employ the L 1-penalty in a penalized likelihood framework to filter out the SNPs that have no associations. We develop a Majorization-Minimization algorithm for computational implementation. In addition, we propose a modified BIC criterion to select the penalty parameters and determine the rank number. The proposed method is applied to a Multiple Sclerosis data set and simulated data sets and shows promise in biomarker detection.

  7. A study on some enzymes in rice field fish as biomarkers for pesticide exposure

    International Nuclear Information System (INIS)

    Juzu Hayati Arshad; Mazlina Muhammad; Salmijah Surif; Abdul Manan Mat Jais

    2002-01-01

    A study was carried out on three enzymes in rice field fish which can be used as possible biomarkers for pesticide exposure. The results obtained showed that the activity of the enzyme EROD (ethoxyresorufin-o-deethylase) increased between 1.5-2.2 fold in snakehead or haruan (Channa striata) sampled from the pesticide polluted areas, particularly the recycled areas and only a slight increase in EROD activity in climbing perch or puyu (Anabas testudineus). Increase in the activity of carboxylesterase was also noted. The percentage inhibition of acety1cholinesterase ranges from 18.4%-57.4% and 2.5%-34.2% for Channa striata and Anabas testudineus, respectively. Generally, a higher percentage of acety1cholinesterase inhibition was noted for those fish sampled from the recycled areas. The noted changes in the activity of these enzymes suggest exposure of rice field fish to foreign compounds, possibly pesticides, which are known to induce EROD activity and inhibit acety1cholinesterase activity. Therefore it may be possible to use these enzymes as biomarkers for pesticide exposure. (Author)

  8. Simulation of complex data structures for planning of studies with focus on biomarker comparison.

    Science.gov (United States)

    Schulz, Andreas; Zöller, Daniela; Nickels, Stefan; Beutel, Manfred E; Blettner, Maria; Wild, Philipp S; Binder, Harald

    2017-06-13

    There are a growing number of observational studies that do not only focus on single biomarkers for predicting an outcome event, but address questions in a multivariable setting. For example, when quantifying the added value of new biomarkers in addition to established risk factors, the aim might be to rank several new markers with respect to their prediction performance. This makes it important to consider the marker correlation structure for planning such a study. Because of the complexity, a simulation approach may be required to adequately assess sample size or other aspects, such as the choice of a performance measure. In a simulation study based on real data, we investigated how to generate covariates with realistic distributions and what generating model should be used for the outcome, aiming to determine the least amount of information and complexity needed to obtain realistic results. As a basis for the simulation a large epidemiological cohort study, the Gutenberg Health Study was used. The added value of markers was quantified and ranked in subsampling data sets of this population data, and simulation approaches were judged by the quality of the ranking. One of the evaluated approaches, the random forest, requires original data at the individual level. Therefore, also the effect of the size of a pilot study for random forest based simulation was investigated. We found that simple logistic regression models failed to adequately generate realistic data, even with extensions such as interaction terms or non-linear effects. The random forest approach was seen to be more appropriate for simulation of complex data structures. Pilot studies starting at about 250 observations were seen to provide a reasonable level of information for this approach. We advise to avoid oversimplified regression models for simulation, in particular when focusing on multivariable research questions. More generally, a simulation should be based on real data for adequately reflecting

  9. Ethics and data protection in human biomarker studies in environmental health.

    Science.gov (United States)

    Casteleyn, Ludwine; Dumez, Birgit; Van Damme, Karel; Anwar, Wagida A

    2013-08-01

    Human biomarker studies in environmental health are essential tools to study the relationship between health and environment. They should ultimately contribute to a better understanding of environmentally induced adverse health effects and to appropriate preventive actions. To ensure the protection of the rights and dignity of study participants a complex legal and ethical framework is applied, consisting of several international directives, conventions, and guidelines, whether or not translated in domestic laws. Main characteristics of ethics and data protection in studies using biomarkers in the field of environmental health are summarized and current discussions on related questions and bottlenecks highlighted. In the current regulatory context, dominated by the protection of the individual study participant, difficulties are reported due to the different interpretation and implementation of the regulations of concern within and across borders. Advancement of consistency and compatibility is recommended and efforts are ongoing. An increasing demand for secondary use of data and samples poses additional challenges in finding a right balance between the individual rights of the study participants on the one hand and the common interest of, and potential benefit for the public or community at large on the other. Ethics committees could play a key role in assessing problems originating from the sometimes competing needs at individual and societal level. Building trust in science amongst (potential) study participants and within the community allows the inclusion of arguments from the societal perspective. This requires increased attention for respectful communication efforts. Striving for public participation in decision making processes may promote policy relevant research and the related translation of study results into action. Copyright © 2013 Elsevier GmbH. All rights reserved.

  10. Simulation of complex data structures for planning of studies with focus on biomarker comparison

    Directory of Open Access Journals (Sweden)

    Andreas Schulz

    2017-06-01

    Full Text Available Abstract Background There are a growing number of observational studies that do not only focus on single biomarkers for predicting an outcome event, but address questions in a multivariable setting. For example, when quantifying the added value of new biomarkers in addition to established risk factors, the aim might be to rank several new markers with respect to their prediction performance. This makes it important to consider the marker correlation structure for planning such a study. Because of the complexity, a simulation approach may be required to adequately assess sample size or other aspects, such as the choice of a performance measure. Methods In a simulation study based on real data, we investigated how to generate covariates with realistic distributions and what generating model should be used for the outcome, aiming to determine the least amount of information and complexity needed to obtain realistic results. As a basis for the simulation a large epidemiological cohort study, the Gutenberg Health Study was used. The added value of markers was quantified and ranked in subsampling data sets of this population data, and simulation approaches were judged by the quality of the ranking. One of the evaluated approaches, the random forest, requires original data at the individual level. Therefore, also the effect of the size of a pilot study for random forest based simulation was investigated. Results We found that simple logistic regression models failed to adequately generate realistic data, even with extensions such as interaction terms or non-linear effects. The random forest approach was seen to be more appropriate for simulation of complex data structures. Pilot studies starting at about 250 observations were seen to provide a reasonable level of information for this approach. Conclusions We advise to avoid oversimplified regression models for simulation, in particular when focusing on multivariable research questions. More generally

  11. CFD Validation Studies for Hypersonic Flow Prediction

    Science.gov (United States)

    Gnoffo, Peter A.

    2001-01-01

    A series of experiments to measure pressure and heating for code validation involving hypersonic, laminar, separated flows was conducted at the Calspan-University at Buffalo Research Center (CUBRC) in the Large Energy National Shock (LENS) tunnel. The experimental data serves as a focus for a code validation session but are not available to the authors until the conclusion of this session. The first set of experiments considered here involve Mach 9.5 and Mach 11.3 N2 flow over a hollow cylinder-flare with 30 degree flare angle at several Reynolds numbers sustaining laminar, separated flow. Truncated and extended flare configurations are considered. The second set of experiments, at similar conditions, involves flow over a sharp, double cone with fore-cone angle of 25 degrees and aft-cone angle of 55 degrees. Both sets of experiments involve 30 degree compressions. Location of the separation point in the numerical simulation is extremely sensitive to the level of grid refinement in the numerical predictions. The numerical simulations also show a significant influence of Reynolds number on extent of separation. Flow unsteadiness was easily introduced into the double cone simulations using aggressive relaxation parameters that normally promote convergence.

  12. The study of protein biomarkers to understand the biochemical processes underlying beef color development in young bulls.

    Science.gov (United States)

    Gagaoua, Mohammed; Terlouw, E M Claudia; Picard, Brigitte

    2017-12-01

    This study investigates relationships between 21 biomarkers and meat color traits of Longissimus thoracis muscles of young Aberdeen Angus and Limousin bulls. The relationships found allowed to propose metabolic processes underlying meat color. The color coordinates were related with several biomarkers. The relationships were in some cases breed-dependent and the variability explained in the regression models varied between 31 and 56%. The correlations between biomarkers and color parameters were sometimes opposite between breeds. The PCA using the 21 biomarkers and the instrumental color coordinates showed that these variables discriminated efficiently between the two studied breeds. Results are coherent with earlier studies on other beef breeds showing that several proteins belonging to different but partly related biological pathways involved in muscle contraction, metabolism, heat stress and apoptosis are related to beef color. The results suggest that in future, biomarkers may be used to classify meat cuts sampled early post-mortem according to their forthcoming color. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Novel biomarker-based model for the prediction of sorafenib response and overall survival in advanced hepatocellular carcinoma: a prospective cohort study.

    Science.gov (United States)

    Kim, Hwi Young; Lee, Dong Hyeon; Lee, Jeong-Hoon; Cho, Young Youn; Cho, Eun Ju; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan

    2018-03-20

    Prediction of the outcome of sorafenib therapy using biomarkers is an unmet clinical need in patients with advanced hepatocellular carcinoma (HCC). The aim was to develop and validate a biomarker-based model for predicting sorafenib response and overall survival (OS). This prospective cohort study included 124 consecutive HCC patients (44 with disease control, 80 with progression) with Child-Pugh class A liver function, who received sorafenib. Potential serum biomarkers (namely, hepatocyte growth factor [HGF], fibroblast growth factor [FGF], vascular endothelial growth factor receptor-1, CD117, and angiopoietin-2) were tested. After identifying independent predictors of tumor response, a risk scoring system for predicting OS was developed and 3-fold internal validation was conducted. A risk scoring system was developed with six covariates: etiology, platelet count, Barcelona Clinic Liver Cancer stage, protein induced by vitamin K absence-II, HGF, and FGF. When patients were stratified into low-risk (score ≤ 5), intermediate-risk (score 6), and high-risk (score ≥ 7) groups, the model provided good discriminant functions on tumor response (concordance [c]-index, 0.884) and 12-month survival (area under the curve [AUC], 0.825). The median OS was 19.0, 11.2, and 6.1 months in the low-, intermediate-, and high-risk group, respectively (P functions on tumor response (c-index, 0.825) and 12-month survival (AUC, 0.803), and good calibration functions (all P > 0.05 between expected and observed values). This new model including serum FGF and HGF showed good performance in predicting the response to sorafenib and survival in patients with advanced HCC.

  14. Mitochondrial Biomarkers Reflect Semen Quality: Results from the MARCHS Study in Chongqing, China.

    Science.gov (United States)

    Zhang, Guowei; Wang, Zhi; Ling, Xi; Zou, Peng; Yang, Huan; Chen, Qing; Zhou, Niya; Sun, Lei; Gao, Jianfang; Zhou, Ziyuan; Cao, Jia; Ao, Lin

    2016-01-01

    Unexplained infertility requires that more sensitive and mechanism-based biomarkers should be developed and used independently of or in addition to conventional semen parameters for an infertility diagnosis. In the present study, semen samples were collected from young men participating in the Male Reproductive Health in Chongqing College students (MARCHS) cohort study in the follow-up stage in 2014. Conventional semen parameters were measured in all 656 participants, whereas sperm mitochondrial membrane potential (MMP), mitochondrial DNA copy number (mtDNAcn), mtDNA integrity and apoptotic parameters were measured among 627, 386, 362, and 628 participants, respectively. We found that sperm MMP was significantly positively correlated with all of conventional semen parameters including semen volume (r = 0.090, p = 0.025), sperm concentration (r = 0.301, psemen quality in a general population, and the study provides a baseline for the effects of population characteristics and lifestyles on such mitochondrial markers.

  15. Using MALDI-IMS and MRM to stablish a pipeline for discovery and validation of tumor neovasculature biomarker candidates. — EDRN Public Portal

    Science.gov (United States)

    In an effort to circumvent the limitations associated with biomarker discovery workflows involving cell lines and cell cultures, histology-directed MALDI protein profiling and imaging mass spectrometry will be used for identification of vascular endothelial biomarkers suitable for early prostate cancer detection by CEUS targeted molecular imaging

  16. Alterations in inflammatory biomarkers and energy intake in cancer cachexia: a prospective study in patients with inoperable pancreatic cancer.

    Science.gov (United States)

    Bye, Asta; Wesseltoft-Rao, Nima; Iversen, Per Ole; Skjegstad, Grete; Holven, Kirsten B; Ulven, Stine; Hjermstad, Marianne J

    2016-06-01

    Chronic systemic inflammatory response is proposed as an underlying mechanism for development of cancer cachexia. We conducted a prospective study to examine changes in inflammatory biomarkers during the disease course and the relationship between inflammatory biomarkers and cachexia in patients with inoperable pancreatic cancer. Twenty patients, median (range) age 67.5 (35-79) years, 5 females, were followed for median 5.5 (1-12) months. Cachexia was diagnosed according to the 2011 consensus-based classification system (weight loss >5 % past six months, BMI 2 %, or sarcopenia) and the modified Glasgow Prognostic score (mGPS) that combines CRP and albumin levels. Inflammatory biomarkers were measured by enzyme immunoassays. The patients had increased levels of most inflammatory biomarkers, albeit not all statistically significant, both at study entry and close to death, indicating ongoing inflammation. According to the consensus-based classification system, eleven (55 %) patients were classified as cachectic upon inclusion. They did not differ from non-cachectic patients with regard to inflammatory biomarkers or energy intake. According to the mGPS, seven (35 %) were defined as cachectic and had a higher IL-6 (p cachexia.

  17. Alterations of the Subgingival Microbiota in Pediatric Crohn's Disease Studied Longitudinally in Discovery and Validation Cohorts.

    Science.gov (United States)

    Kelsen, Judith; Bittinger, Kyle; Pauly-Hubbard, Helen; Posivak, Leah; Grunberg, Stephanie; Baldassano, Robert; Lewis, James D; Wu, Gary D; Bushman, Frederic D

    2015-12-01

    Oral manifestations are common in Crohn's disease (CD). Here we characterized the subgingival microbiota in pediatric patients with CD initiating therapy and after 8 weeks to identify microbial community features associated with CD and therapy. Pediatric patients with CD were recruited from The Children's Hospital of Pennsylvania. Healthy control subjects were recruited from primary care or orthopedics clinic. Subgingival plaque samples were collected at initiation of therapy and after 8 weeks. Treatment exposures included 5-ASAs, immunomodulators, steroids, and infliximab. The microbiota was characterized by 16S rRNA gene sequencing. The study was repeated in separate discovery (35 CD, 43 healthy) and validation cohorts (43 CD, 31 healthy). Most subjects in both cohorts demonstrated clinical response after 8 weeks of therapy (discovery cohort 88%, validation cohort 79%). At week 0, both antibiotic exposure and disease state were associated with differences in bacterial community composition. Seventeen genera were identified in the discovery cohort as candidate biomarkers, of which 11 were confirmed in the validation cohort. Capnocytophaga, Rothia, and TM7 were more abundant in CD relative to healthy controls. Other bacteria were reduced in abundance with antibiotic exposure among CD subjects. CD-associated genera were not enriched compared with healthy controls after 8 weeks of therapy. Subgingival microbial community structure differed with CD and antibiotic use. Results in the discovery cohort were replicated in a separate validation cohort. Several potentially pathogenic bacterial lineages were associated with CD but were not diminished in abundance by antibiotic treatment, suggesting targets for additional surveillance.

  18. Serum Sclerostin as a Possible Biomarker in Ankylosing Spondylitis: A Case-Control Study

    Directory of Open Access Journals (Sweden)

    Fabio Massimo Perrotta

    2018-01-01

    Full Text Available Objective. Several molecules are involved in the pathogenesis of a new bone formation in ankylosing spondylitis (AS. The aim of this study was to evaluate the serum levels of sclerostin in patients with AS as a possible biomarker and to investigate any correlations with radiographic damage, disease activity, and function. Methods. AS patients fulfilled the modified New York criteria, and healthy controls were enrolled for this study. BASDAI, ASDAS-CRP, BASMI, BASFI, patient and physician VAS, and C-reactive protein were evaluated at baseline visit. Spinal damage was assessed using the mSASSS on radiographs performed within 3 months from baseline. Serum concentrations of sclerostin were assessed at baseline and after four months of therapy in patients who started an anti-TNF. Results. Twenty healthy subjects and 40 AS patients were enrolled in the study. In our group, serum sclerostin levels (median (25th–75th percentile were significantly higher in healthy controls (18.04 (13.6–24 pg/ml than in AS patients (6.46 (4.5–11.1 pg/ml; P value < 0.01. However, no significant correlations were found between serum sclerostin levels and radiographic damage, assessed by mSASSS, and between serum sclerostin levels and clinical indices of activity and disability or with laboratory parameters. Sclerostin levels did not show significant changes after 4 months of anti-TNF therapy. Conclusions. The results of our study suggest a possible role of sclerostin in the identification of AS patients. Further studies are needed to prove the role of sclerostin as a disease activity biomarker and progression of disease in AS.

  19. Multiomics Data Triangulation for Asthma Candidate Biomarkers and Precision Medicine.

    Science.gov (United States)

    Pecak, Matija; Korošec, Peter; Kunej, Tanja

    2018-06-01

    Asthma is a common complex disorder and has been subject to intensive omics research for disease susceptibility and therapeutic innovation. Candidate biomarkers of asthma and its precision treatment demand that they stand the test of multiomics data triangulation before they can be prioritized for clinical applications. We classified the biomarkers of asthma after a search of the literature and based on whether or not a given biomarker candidate is reported in multiple omics platforms and methodologies, using PubMed and Web of Science, we identified omics studies of asthma conducted on diverse platforms using keywords, such as asthma, genomics, metabolomics, and epigenomics. We extracted data about asthma candidate biomarkers from 73 articles and developed a catalog of 190 potential asthma biomarkers (167 human, 23 animal data), comprising DNA loci, transcripts, proteins, metabolites, epimutations, and noncoding RNAs. The data were sorted according to 13 omics types: genomics, epigenomics, transcriptomics, proteomics, interactomics, metabolomics, ncRNAomics, glycomics, lipidomics, environmental omics, pharmacogenomics, phenomics, and integrative omics. Importantly, we found that 10 candidate biomarkers were apparent in at least two or more omics levels, thus promising potential for further biomarker research and development and precision medicine applications. This multiomics catalog reported herein for the first time contributes to future decision-making on prioritization of biomarkers and validation efforts for precision medicine in asthma. The findings may also facilitate meta-analyses and integrative omics studies in the future.

  20. Association of SNCA with Parkinson: replication in the Harvard NeuroDiscovery Center Biomarker Study

    Science.gov (United States)

    Ding, Hongliu; Sarokhan, Alison K.; Roderick, Sarah S.; Bakshi, Rachit; Maher, Nancy E.; Ashourian, Paymon; Kan, Caroline G.; Chang, Sunny; Santarlasci, Andrea; Swords, Kyleen E.; Ravina, Bernard M.; Hayes, Michael T.; Sohur, U. Shivraj; Wills, Anne-Marie; Flaherty, Alice W.; Unni, Vivek K.; Hung, Albert Y.; Selkoe, Dennis J.; Schwarzschild, Michael A.; Schlossmacher, Michael G.; Sudarsky, Lewis R.; Growdon, John H.; Ivinson, Adrian J.; Hyman, Bradley T.; Scherzer, Clemens R.

    2011-01-01

    Background Mutations in the α-synuclein gene (SNCA) cause autosomal dominant forms of Parkinson’s disease, but the substantial risk conferred by this locus to the common sporadic disease has only recently emerged from genome-wide association studies. Methods Here we genotyped a prioritized non-coding variant in SNCA intron-4 in 344 patients with Parkinson’s and 275 controls from the longitudinal Harvard NeuroDiscovery Center Biomarker Study. Results The common minor allele of rs2736990 was associated with elevated disease susceptibility (odds ratio = 1.40, P value = 0.0032). Conclusions This result increases confidence in the notion that in many clinically well-characterized patients genetic variation in SNCA contributes to “sporadic” disease. PMID:21953863

  1. Topic model-based mass spectrometric data analysis in cancer biomarker discovery studies.

    Science.gov (United States)

    Wang, Minkun; Tsai, Tsung-Heng; Di Poto, Cristina; Ferrarini, Alessia; Yu, Guoqiang; Ressom, Habtom W

    2016-08-18

    A fundamental challenge in quantitation of biomolecules for cancer biomarker discovery is owing to the heterogeneous nature of human biospecimens. Although this issue has been a subject of discussion in cancer genomic studies, it has not yet been rigorously investigated in mass spectrometry based proteomic and metabolomic studies. Purification of mass spectometric data is highly desired prior to subsequent analysis, e.g., quantitative comparison of the abundance of biomolecules in biological samples. We investigated topic models to computationally analyze mass spectrometric data considering both integrated peak intensities and scan-level features, i.e., extracted ion chromatograms (EICs). Probabilistic generative models enable flexible representation in data structure and infer sample-specific pure resources. Scan-level modeling helps alleviate information loss during data preprocessing. We evaluated the capability of the proposed models in capturing mixture proportions of contaminants and cancer profiles on LC-MS based serum proteomic and GC-MS based tissue metabolomic datasets acquired from patients with hepatocellular carcinoma (HCC) and liver cirrhosis as well as synthetic data we generated based on the serum proteomic data. The results we obtained by analysis of the synthetic data demonstrated that both intensity-level and scan-level purification models can accurately infer the mixture proportions and the underlying true cancerous sources with small average error ratios (data, we found more proteins and metabolites with significant changes between HCC cases and cirrhotic controls. Candidate biomarkers selected after purification yielded biologically meaningful pathway analysis results and improved disease discrimination power in terms of the area under ROC curve compared to the results found prior to purification. We investigated topic model-based inference methods to computationally address the heterogeneity issue in samples analyzed by LC/GC-MS. We observed

  2. Blood arsenic as a biomarker of arsenic exposure: Results from a prospective study

    International Nuclear Information System (INIS)

    Hall, Marni; Chen Yu; Ahsan, Habibul; Slavkovich, Vesna; Geen, Alexander van; Parvez, Faruque; Graziano, Joseph

    2006-01-01

    Exposure to arsenic (As)-contaminated drinking water affects millions of people worldwide. Arsenic exposure is associated with skin lesions, skin, lung, kidney and liver cancers, neurologic and cardiovascular effects. Past studies involving biomarkers of As exposure have typically examined urinary As (UAs) (adjusted for urinary creatinine), hair or toenail As, but not blood As (BAs) since blood concentrations are exceedingly low and are not detectable by conventional atomic absorption spectrophotometric techniques. In a case-cohort analysis of 303 newly diagnosed cases of skin lesions, and 849 subcohort members randomly selected from 8092 participants in the health effects of as longitudinal study (HEALS) in Araihazar, Bangladesh, we measured blood, urine and water As concentrations, and examined their associations with each other, and with the risk for skin lesions. BAs concentrations were highly correlated with creatinine-adjusted UAs concentrations (r = 0.85) and with water As (WAs) (r = 0.75). We observed consistent dose-response relationships between the risk of skin lesions and all the measures of As exposure. Rate ratios (RRs) for skin lesions by quintile of As exposure, adjusted for age and gender, revealed that the two highest quintiles were significantly related to an increased risk of skin lesions for each measure of exposure: BAs, UAs, WAs and a time-weighted water As variable. This prospective study confirms the increased risk of skin lesions in relation to As concentrations in blood, urine and water and also establishes that BAs is a useful biomarker of As exposure in this study population

  3. Random and correlated errors in gold standards used in nutritional epidemiology: implications for validation studies

    Science.gov (United States)

    The measurement error correction de-attenuation factor was estimated from two studies using recovery biomarkers. One study, the Observing Protein and Energy Nutrition (OPEN), was unable to adequately account for within-person variation in protein and energy intake estimated by recovery biomarkers, ...

  4. Atacama Rover Astrobiology Drilling Studies: Roving to Find Subsurface Preserved Biomarkers

    Science.gov (United States)

    Glass, B.; Davila, A.; Parro, V.; Quinn, R.; Willis, P.; Brinckerhoff, W.; DiRuggiero, J.; Williams, M.; Bergman, D.; Stoker, C.

    2016-05-01

    The ARADS project is a NASA PSTAR that will drill into a Mars analog site in search of biomarkers. Leading to a field test of an integrated rover-drill system with four prototype in-situ instruments for biomarker detection and analysis.

  5. Scrutinizing the Biomarkers for the Neglected Chagas Disease: How Remarkable!

    Science.gov (United States)

    Pinho, Rosa T; Waghabi, Mariana C; Cardillo, Fabíola; Mengel, José; Antas, Paulo R Z

    2016-01-01

    Biomarkers or biosignature profiles have become accessible over time in population-based studies for Chagas disease. Thus, the identification of consistent and reliable indicators of the diagnosis and prognosis of patients with heart failure might facilitate the prioritization of therapeutic management to those with the highest chance of contracting this disease. The purpose of this paper is to review the recent state and the upcoming trends in biomarkers for human Chagas disease. As an emerging concept, we propose a classification of biomarkers based on plasmatic-, phenotype-, antigenic-, genetic-, and management-related candidates. The available data revisited here reveal the lessons learned thus far and the existing challenges that still lie ahead to enable biomarkers to be employed consistently in risk evaluation for this disease. There is a strong need for biomarker validation, particularly for biomarkers that are specific to the clinical forms of Chagas disease. The current failure to achieve the eradication of the transmission of this disease has produced determination to solve this validation issue. Finally, it would be strategic to develop a wide variety of biomarkers and to test them in both preclinical and clinical trials.

  6. Using wound care algorithms: a content validation study.

    Science.gov (United States)

    Beitz, J M; van Rijswijk, L

    1999-09-01

    Valid and reliable heuristic devices facilitating optimal wound care are lacking. The objectives of this study were to establish content validation data for a set of wound care algorithms, to identify their associated strengths and weaknesses, and to gain insight into the wound care decision-making process. Forty-four registered nurse wound care experts were surveyed and interviewed at national and regional educational meetings. Using a cross-sectional study design and an 83-item, 4-point Likert-type scale, this purposive sample was asked to quantify the degree of validity of the algorithms' decisions and components. Participants' comments were tape-recorded, transcribed, and themes were derived. On a scale of 1 to 4, the mean score of the entire instrument was 3.47 (SD +/- 0.87), the instrument's Content Validity Index was 0.86, and the individual Content Validity Index of 34 of 44 participants was > 0.8. Item scores were lower for those related to packing deep wounds (P valid and reliable definitions. The wound care algorithms studied proved valid. However, the lack of valid and reliable wound assessment and care definitions hinders optimal use of these instruments. Further research documenting their clinical use is warranted. Research-based practice recommendations should direct the development of future valid and reliable algorithms designed to help nurses provide optimal wound care.

  7. Implementation of proteomic biomarkers: making it work.

    Science.gov (United States)

    Mischak, Harald; Ioannidis, John P A; Argiles, Angel; Attwood, Teresa K; Bongcam-Rudloff, Erik; Broenstrup, Mark; Charonis, Aristidis; Chrousos, George P; Delles, Christian; Dominiczak, Anna; Dylag, Tomasz; Ehrich, Jochen; Egido, Jesus; Findeisen, Peter; Jankowski, Joachim; Johnson, Robert W; Julien, Bruce A; Lankisch, Tim; Leung, Hing Y; Maahs, David; Magni, Fulvio; Manns, Michael P; Manolis, Efthymios; Mayer, Gert; Navis, Gerjan; Novak, Jan; Ortiz, Alberto; Persson, Frederik; Peter, Karlheinz; Riese, Hans H; Rossing, Peter; Sattar, Naveed; Spasovski, Goce; Thongboonkerd, Visith; Vanholder, Raymond; Schanstra, Joost P; Vlahou, Antonia

    2012-09-01

    While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare. © 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.

  8. Implementation of proteomic biomarkers: making it work

    Science.gov (United States)

    Mischak, Harald; Ioannidis, John PA; Argiles, Angel; Attwood, Teresa K; Bongcam-Rudloff, Erik; Broenstrup, Mark; Charonis, Aristidis; Chrousos, George P; Delles, Christian; Dominiczak, Anna; Dylag, Tomasz; Ehrich, Jochen; Egido, Jesus; Findeisen, Peter; Jankowski, Joachim; Johnson, Robert W; Julien, Bruce A; Lankisch, Tim; Leung, Hing Y; Maahs, David; Magni, Fulvio; Manns, Michael P; Manolis, Efthymios; Mayer, Gert; Navis, Gerjan; Novak, Jan; Ortiz, Alberto; Persson, Frederik; Peter, Karlheinz; Riese, Hans H; Rossing, Peter; Sattar, Naveed; Spasovski, Goce; Thongboonkerd, Visith; Vanholder, Raymond; Schanstra, Joost P; Vlahou, Antonia

    2012-01-01

    While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare. PMID:22519700

  9. Novel biomarkers of mercury-induced autoimmune dysfunction: a Cross-sectional study in Amazonian Brazil

    Science.gov (United States)

    Motts, Jonathan A.; Shirley, Devon L.; Silbergeld, Ellen K.; Nyland, Jennifer F.

    2014-01-01

    Mercury is an ubiquitous environmental contaminant, causing both neurotoxicity and immunotoxicity. Given its ability to amalgamate gold, mercury is frequently used in small-scale artisanal gold mining. We have previously reported that elevated serum titers of antinuclear autoantibodies (ANA) are associated with mercury exposures of miners in gold mining. The goal of this project was to identify novel serum biomarkers of mercury-induced immunotoxicity and autoimmune dysregulation. We conducted an analysis of serum samples from a cross-sectional epidemiological study on miners working in Amazonian Brazil. In proteomic screening analyses, samples were stratified based on mercury concentrations and ANA titer and a subset of serum samples (N=12) were profiled using Immune Response Biomarker Profiling ProtoArray protein microarray for elevated autoantibodies. Of the up-regulated autoantibodies in the mercury-exposed cohort, potential target autoantibodies were selected based on relevance to pro-inflammatory and macrophage activation pathways. ELISAs were developed to test the entire sample cohort (N=371) for serum titers to the highest of these autoantibodies (anti-glutathione S-transferase alpha, GSTA1) identified in the high mercury/high ANA group. We found positive associations between elevated mercury exposure and up-regulated serum titers of 3760 autoantibodies as identified by ProtoArray. Autoantibodies identified as potential novel biomarkers of mercury-induced immunotoxicity include antibodies to the following proteins: GSTA1, tumor necrosis factor ligand superfamily member 13, linker for activation of T cells, signal peptide peptidase like 2B, stimulated by retinoic acid 13, and interferon induced transmembrane protein. ELISA analyses confirmed that mercury-exposed gold miners had significantly higher serum titers of anti-GSTA1 autoantibody [unadjusted odds ratio = 89.6; 95% confidence interval: 27.2, 294.6] compared to emerald miners (referent population

  10. Identification of biomarkers for intake of protein from meat, dairy products and grains: A controlled dietary intervention study

    NARCIS (Netherlands)

    Altorf-van der Kuil, W.; Brink, E.J.; Boetje, M.; Siebelink, E.; Bijlsma, S.; Engberink, M.F.; Veer, P.V.'.; Tomé, D.; Bakker, S.J.L.; Baak, M.A. van; Geleijnse, J.M.

    2013-01-01

    In the present controlled, randomised, multiple cross-over dietary intervention study, we aimed to identify potential biomarkers for dietary protein from dairy products, meat and grain, which could be useful to estimate intake of these protein types in epidemiological studies. After 9 d run-in,

  11. Identification of biomarkers for intake of protein from meat, dairy products and grains : a controlled dietary intervention study

    NARCIS (Netherlands)

    Altorf-van der Kuil, Wieke; Brink, Elizabeth J.; Boetje, Martine; Siebelink, Els; Bijlsma, Sabina; Engberink, Marielle F.; van 't Veer, Pieter; Tome, Daniel; Bakker, Stephan J. L.; van Baak, Marleen A.; Geleijnse, Johanna M.

    2013-01-01

    In the present controlled, randomised, multiple cross-over dietary intervention study, we aimed to identify potential biomarkers for dietary protein from dairy products, meat and grain, which could be useful to estimate intake of these protein types in epidemiological studies. After 9 d run-in,

  12. Improved multimodal biomarkers for Alzheimer's disease and mild cognitive impairment diagnosis: data from ADNI

    Science.gov (United States)

    Martinez-Torteya, Antonio; Treviño-Alvarado, Víctor; Tamez-Peña, José

    2013-02-01

    The accurate diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) confers many clinical research and patient care benefits. Studies have shown that multimodal biomarkers provide better diagnosis accuracy of AD and MCI than unimodal biomarkers, but their construction has been based on traditional statistical approaches. The objective of this work was the creation of accurate AD and MCI diagnostic multimodal biomarkers using advanced bioinformatics tools. The biomarkers were created by exploring multimodal combinations of features using machine learning techniques. Data was obtained from the ADNI database. The baseline information (e.g. MRI analyses, PET analyses and laboratory essays) from AD, MCI and healthy control (HC) subjects with available diagnosis up to June 2012 was mined for case/controls candidates. The data mining yielded 47 HC, 83 MCI and 43 AD subjects for biomarker creation. Each subject was characterized by at least 980 ADNI features. A genetic algorithm feature selection strategy was used to obtain compact and accurate cross-validated nearest centroid biomarkers. The biomarkers achieved training classification accuracies of 0.983, 0.871 and 0.917 for HC vs. AD, HC vs. MCI and MCI vs. AD respectively. The constructed biomarkers were relatively compact: from 5 to 11 features. Those multimodal biomarkers included several widely accepted univariate biomarkers and novel image and biochemical features. Multimodal biomarkers constructed from previously and non-previously AD associated features showed improved diagnostic performance when compared to those based solely on previously AD associated features.

  13. Metabolomics as a tool in the identification of dietary biomarkers.

    Science.gov (United States)

    Gibbons, Helena; Brennan, Lorraine

    2017-02-01

    Current dietary assessment methods including FFQ, 24-h recalls and weighed food diaries are associated with many measurement errors. In an attempt to overcome some of these errors, dietary biomarkers have emerged as a complementary approach to these traditional methods. Metabolomics has developed as a key technology for the identification of new dietary biomarkers and to date, metabolomic-based approaches have led to the identification of a number of putative biomarkers. The three approaches generally employed when using metabolomics in dietary biomarker discovery are: (i) acute interventions where participants consume specific amounts of a test food, (ii) cohort studies where metabolic profiles are compared between consumers and non-consumers of a specific food and (iii) the analysis of dietary patterns and metabolic profiles to identify nutritypes and biomarkers. The present review critiques the current literature in terms of the approaches used for dietary biomarker discovery and gives a detailed overview of the currently proposed biomarkers, highlighting steps needed for their full validation. Furthermore, the present review also evaluates areas such as current databases and software tools, which are needed to advance the interpretation of results and therefore enhance the utility of dietary biomarkers in nutrition research.

  14. Biomarkers in Prodromal Parkinson Disease: a Qualitative Review.

    Science.gov (United States)

    Cooper, Christine A; Chahine, Lama M

    2016-11-01

    Over the past several years, the concept of prodromal Parkinson disease (PD) has been increasingly recognized. This term refers to individuals who do not fulfill motor diagnostic criteria for PD, but who have clinical, genetic, or biomarker characteristics suggesting risk of developing PD in the future. Clinical diagnosis of prodromal PD has low specificity, prompting the need for objective biomarkers with higher specificity. In this qualitative review, we discuss objectively defined putative biomarkers for PD and prodromal PD. We searched Pubmed and Embase for articles pertaining to objective biomarkers for PD and their application in prodromal cohorts. Articles were selected based on relevance and methodology. Objective biomarkers of demonstrated utility in prodromal PD include ligand-based imaging and transcranial sonography. Development of serum, cerebrospinal fluid, and tissue-based biomarkers is underway, but their application in prodromal PD has yet to meaningfully occur. Combining objective biomarkers with clinical or genetic prodromal features increases the sensitivity and specificity for identifying prodromal PD. Several objective biomarkers for prodromal PD show promise but require further study, including their application to and validation in prodromal cohorts followed longitudinally. Accurate identification of prodromal PD will likely require a multimodal approach. (JINS, 2016, 22, 956-967).

  15. [Tetra-saccharide glucose as a diagnostic biomarker for Pompe disease: a study with 35 patients].

    Science.gov (United States)

    Bobillo Lobato, Joaquín; Durán Parejo, Pilar; Tejero Díez, Pedro; Jiménez Jiménez, Luis M

    2013-08-04

    Pompe disease is a disorder originating from an acid alpha-glycosidase (AAG) enzyme deficiency. This disease produces an accumulation of lysosomal glycogen in different tissues, whereby the skeletal and heart muscles are especially involved. The established diagnosis is achieved through the identification of the AAG deficiency. There are also other secondary diagnostic biomarkers, such as tetra-saccharide glucose (Glc4), which shows high levels in the urine of these patients. In this study it is highlighted the usefulness of Glc4 as a diagnostic biomarker for Pompe disease in its different forms of presentation, using a high-performance liquid chromatography with ultraviolet detection (HPLC/UV) adapted to the study. A total of 75 individuals have been analyzed: 40 healthy controls and 35 patients diagnosed with Pompe disease. Twenty-four hour samples of urine were collected from all of the patients and their Glc4 levels were determined by means of HPLC/UV. The evaluation of the urinary Glc4 shows a high discrimination ability between healthy/sick individuals. In addition, the results obtained have allowed to establish the most appropriate level of decision or cut-off point for the identification of sick people. Glc4 urinary levels are found to be high in patients suffering from Pompe disease and even though increased levels are also found in other conditions, the existence of a AAG deficiency together with a compatible clinical symptoms, prove very helpful for a correct diagnosis of this serious disease. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  16. Flow Injection/Sequential Injection Analysis Systems: Potential Use as Tools for Rapid Liver Diseases Biomarker Study

    Directory of Open Access Journals (Sweden)

    Supaporn Kradtap Hartwell

    2012-01-01

    Full Text Available Flow injection/sequential injection analysis (FIA/SIA systems are suitable for carrying out automatic wet chemical/biochemical reactions with reduced volume and time consumption. Various parts of the system such as pump, valve, and reactor may be built or adapted from available materials. Therefore the systems can be at lower cost as compared to other instrumentation-based analysis systems. Their applications for determination of biomarkers for liver diseases have been demonstrated in various formats of operation but only a few and limited types of biomarkers have been used as model analytes. This paper summarizes these applications for different types of reactions as a guide for using flow-based systems in more biomarker and/or multibiomarker studies.

  17. Cerebrovascular reactivity by quantitative magnetic resonance angiography with a co2 challenge. Validation as a new imaging biomarker

    International Nuclear Information System (INIS)

    Caputi, Luigi; Ghielmetti, Francesco; Faragò, Giuseppe; Longaretti, Fabio; Lamperti, Massimo; Anzola, Gian Paolo; Carriero, Maria Rita; Charbel, Fady T.; Bruzzone, Maria Grazia; Parati, Eugenio; Ciceri, Elisa

    2014-01-01

    Assessment of cerebrovascular reactivity (CVR) is essential in cerebrovascular diseases, as exhausted CVR may enhance the risk of cerebral ischemic events. Transcranial Doppler (TCD) with a vasodilatory stimulus is currently used for CVR evaluation. Scanty data are available for Quantitative Magnetic Resonance Angiography (QMRA), which supplies higher spatial resolution and quantitative cerebral blood flow values. Aims of our pilot study were: (a) to assess safety and feasibility of CO 2 administration during QMRA, (b) evaluation of CVR under QMRA compared to TCD, and (c) quantitative evaluation of blood flow from the major intracranial arterial vessels both at rest and after CO 2 . CVR during 5% CO 2 air breathing was measured with TCD as a reference method and compared with QMRA. Fifteen healthy subjects (age 60.47 ± 2.24; male 11/15) were evaluated at rest and during CO 2 challenge. Feasibility and safety of QMRA under CO 2 were ensured in all subjects. CVR from middle cerebral artery territory was not statistically different between TCD and MRI (p > 0.05). Mean arterial pressure (MAP) and heart rate (HR) increased during QMRA and TCD (MAP p = 0.007 and p = 0.001; HR p = 0.043 and p = 0.068, respectively). Blood flow values from all intracranial vessels increased after CO 2 inhalation (p < 0.001). CO 2 administration during QMRA sessions is safe and feasible. Good correlation in terms of CVR was obtained comparing TCD and QMRA. Blood flow values significantly increased from all intracranial arterial vessels after CO 2 . Studies regarding CVR in physiopathological conditions might consider the utilization of QMRA both in routine clinical settings and in research projects

  18. Novel urinary biomarkers and their association with urinary heavy metals in chronic kidney disease of unknown aetiology in Sri Lanka: a pilot study

    Science.gov (United States)

    Wanigasuriya, K; Jayawardene, I; Amarasiriwardena, C; Wickremasinghe, R

    2017-12-26

    Chronic kidney disease of unknown etiology (CKDu) has emerged as a significant public health problem in Sri Lanka. The role of environmental exposure to cadmium and arsenic in the aetiology of CKDu is still unclear. Identification of a panel of novel urinary biomarkers would be invaluable in the study of toxin mediated damage postulated to be the aetiology of CKDu. The aims of this study were to evaluate the profile of novel urinary biomarkers in CKDu patients and identify any association with environmental exposure to heavy metals. Thirty seven randomly selected CKDu patients attending a renal clinic in the North Central Province and two control groups namely a farmer group (n=39) and a non-farmer group (n=40) from a non-endemic area were included in this comparative cross sectional study. Urine samples were analyzed for heavy metals and five urinary biomarkers. CKDu patients had significantly elevated urinary levels of fibrinogen (198.2 ng/mg creatinine pCKDu patients from normal individuals with the receiver operator areas under the curve being 0.867 and 0.853, respectively. Urinary fibrinogen and KIM-1 levels correlated positively with urinary arsenic levels. KIM-1 levels correlated positively with urinary mercury and lead levels but no correlation was seen with urinary cadmium levels. Fibrinogen and β2-microglobulin have the potential of being a screening tool for detection of CKDu and may aid the early diagnosis of toxin mediated tubular injury in CKDu. Their usefulness need to be further validated in a larger epidemiological study of patients with early stages of CKDu.

  19. Diagnostic and economic evaluation of new biomarkers for Alzheimer’s disease: the research protocol of a prospective cohort study

    Directory of Open Access Journals (Sweden)

    Handels Ron LH

    2012-08-01

    Full Text Available Abstract Background New research criteria for the diagnosis of Alzheimer’s disease (AD have recently been developed to enable an early diagnosis of AD pathophysiology by relying on emerging biomarkers. To enable efficient allocation of health care resources, evidence is needed to support decision makers on the adoption of emerging biomarkers in clinical practice. The research goals are to 1 assess the diagnostic test accuracy of current clinical diagnostic work-up and emerging biomarkers in MRI, PET and CSF, 2 perform a cost-consequence analysis and 3 assess long-term cost-effectiveness by an economic model. Methods/design In a cohort design 241 consecutive patients suspected of having a primary neurodegenerative disease are approached in four academic memory clinics and followed for two years. Clinical data and data on quality of life, costs and emerging biomarkers are gathered. Diagnostic test accuracy is determined by relating the clinical practice and new research criteria diagnoses to a reference diagnosis. The clinical practice diagnosis at baseline is reflected by a consensus procedure among experts using clinical information only (no biomarkers. The diagnosis based on the new research criteria is reflected by decision rules that combine clinical and biomarker information. The reference diagnosis is determined by a consensus procedure among experts based on clinical information on the course of symptoms over a two-year time period. A decision analytic model is built combining available evidence from different resources among which (accuracy results from the study, literature and expert opinion to assess long-term cost-effectiveness of the emerging biomarkers. Discussion Several other multi-centre trials study the relative value of new biomarkers for early evaluation of AD and related disorders. The uniqueness of this study is the assessment of resource utilization and quality of life to enable an economic evaluation. The study results

  20. Randomized clinical trial on the efficacy of hesperidin 2S on validated cardiovascular biomarkers in healthy overweight individuals.

    Science.gov (United States)

    Salden, Bouke N; Troost, Freddy J; de Groot, Eric; Stevens, Yala R; Garcés-Rimón, Marta; Possemiers, Sam; Winkens, Bjorn; Masclee, Ad A

    2016-12-01

    Endothelial dysfunction (ED) is involved in the development of atherosclerosis. Hesperidin, a citrus flavonoid with antioxidant and other biological properties, potentially exerts beneficial effects on endothelial function (EF). We investigated the effect of hesperidin 2S supplementation on EF in overweight individuals. This was a randomized, double-blind, placebo-controlled study in which 68 individuals were randomly assigned to receive hesperidin 2S (450 mg/d) or a placebo for 6 wk. At baseline and after 6 wk of intervention, flow-mediated dilation (FMD), soluble vascular adhesion molecule-1 (sVCAM-1), soluble intracellular adhesion molecule-1 (sICAM-1), soluble P-selectin (sP-selectin), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were assessed. Acute, reversible ED was induced by intake of a high-fat meal (HFM). A second FMD scan was performed 2 h postprandially, and adhesion molecules were assessed 2 and 4 h postprandially. An additional exploratory analysis was performed in subjects with baseline FMD ≥3%. No significant change in fasting or postprandial FMD was observed after 6 wk of hesperidin intake compared with placebo intake. However, there was a trend for a reduction of sVCAM-1, sICAM-1, sP-selectin, SBP, and DBP after 6 wk of hesperidin treatment. In the FMD ≥3% group, hesperidin protected individuals from postprandial ED (P = 0.050) and significantly downregulated sVCAM-1 and sICAM-1 (all P ≤ 0.030). The results reported in the current article were not adjusted for multiplicity. Six weeks of consumption of hesperidin 2S did not improve basal or postprandial FMD in our total study population. There was a tendency toward a reduction of adhesion molecules and a decrease in SBP and DBP. Further exploratory analyses revealed that, in subjects with baseline FMD ≥3%, hesperidin 2S improved ED after an HFM and reduced adhesion molecules. These results indicate the cardiovascular health benefits of hesperidin 2S in overweight and

  1. A comparative study of biological and metabolic biomarkers between healthy individuals and patients with acne vulgaris: A cross-sectional study protocol.

    Science.gov (United States)

    Kim, Kyuseok; Ha, Injin; Kim, Eunok; Kim, Kyunglee

    2017-11-01

    Acne is a multifactorial dermatosis, which is influenced not only by hormones but also by the biochemical relationship between them and the pilosebaceous unit. Inflammatory cytokines, chemokines, active oxygen, and zinc are known to be associated with the development of acne. Further, steroid metabolism is known as one of the important factors related to sebum secretion and comedone formation in acne. However, there is a lack of studies comparing these human biomarkers between healthy individuals and patients with acne. In particular, no study has investigated the relationship between human biomarkers and patterns of acne yet.The purpose of this study is to investigate diagnostic human biomarkers in acne by comparing the biological and metabolic biomarkers between healthy individuals and patients with acne and identify the relationship between human biomarkers and patterns of acne.This study is a protocol for a cross-sectional study. Forty healthy participants and 60 patients with acne will be recruited at 1 center. We will collect their blood samples and analyze the molecular biological and metabolic biomarkers (cytokines, chemokines, reactive oxygen species, corticotropin-releasing hormone, zinc, amino acid, 1-carbon metabolite, lipid metabolite, etc.). Further, we will administer questionnaires regarding their diet, sleep, stress, and other factors relating to acne and measure their skin elasticity.The study protocol was approved by the Institutional Review Board of Oriental Medical Hospital at Kyung Hee Medical Center (KOMCIRB-161118-HR-062). Written informed consent will be obtained from all the participants. The trial was registered in the Clinical Research Information Service, Republic of Korea: KCT0002212.This trial will provide evidence regarding diagnostic human biomarkers in acne and the relationship between the human biomarkers and patterns of acne.

  2. Biomarkers in Autism

    Directory of Open Access Journals (Sweden)

    Robert eHendren

    2014-08-01

    Full Text Available Autism spectrum disorders (ASD are complex, heterogeneous disorders caused by an interaction between genetic vulnerability and environmental factors. In an effort to better target the underlying roots of ASD for diagnosis and treatment, efforts to identify reliable biomarkers in genetics, neuroimaging, gene expression and measures of the body’s metabolism are growing. For this article, we review the published studies of potential biomarkers in autism and conclude that while there is increasing promise of finding biomarkers that can help us target treatment, there are none with enough evidence to support routine clinical use unless medical illness is suspected. Promising biomarkers include those for mitochondrial function, oxidative stress, and immune function. Genetic clusters are also suggesting the potential for useful biomarkers.

  3. Biomarkers in pancreatic adenocarcinoma: current perspectives.

    Science.gov (United States)

    Swords, Douglas S; Firpo, Matthew A; Scaife, Courtney L; Mulvihill, Sean J

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 7.7%. Most patients are diagnosed at an advanced stage not amenable to potentially curative resection. A substantial portion of this review is dedicated to reviewing the current literature on carbohydrate antigen (CA 19-9), which is currently the only guideline-recommended biomarker for PDAC. It provides valuable prognostic information, can predict resectability, and is useful in decision making about neoadjuvant therapy. We also discuss carcinoembryonic antigen (CEA), CA 125, serum biomarker panels, circulating tumor cells, and cell-free nucleic acids. Although many biomarkers have now been studied in relation to PDAC, significant work still needs to be done to validate their usefulness in the early detection of PDAC and management of patients with PDAC.

  4. Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study

    Directory of Open Access Journals (Sweden)

    Qin eDong

    2015-10-01

    Full Text Available Heshouwu (HSW, the dry roots of Polygonum multiflorum, a classical traditional Chinese medicine is used as a tonic for a wide range of conditions,particularly those associated with aging. However, it tends to be taken overdose or long term in these years, which has resulted in liver damage reported in many countries. In this study, the indicative roles of nine bile acids (BAs were evaluated to offer potential biomarkers for HSW induced liver injury. Nine BAs including cholic acid (CA and chenodeoxycholic acid (CDCA, taurocholic acid (TCA, glycocholic acid (GCA, glycochenodeoxycholic acid (GCDCA, deoxycholic acid (DCA, glycodeoxycholic acid (GDCA, ursodeoxycholic acid (UDCA and hyodeoxycholic acid (HDCA in rat bile and serum were detected by a developed LC-MS method after 42 days treatment. Partial least square-discriminate analysis (PLS-DA was applied to evaluate the indicative roles of the nine BAs, and metabolism of the nine BAs was summarized. Significant change was observed for the concentrations of nine BAs in treatment groups compared with normal control; In the PLS-DA plots of nine BAs in bile, normal control and raw HSW groups were separately clustered and could be clearly distinguished, GDCA was selected as the distinguished components for raw HSW overdose treatment group. In the PLS-DA plots of nine BAs in serum, the normal control and raw HSW overdose treatment group were separately clustered and could be clearly distinguished, and HDCA was selected as the distinguished components for raw HSW overdose treatment group. The results indicated the perturbation of nine BAs was associated with HSW induced liver injury; GDCA in bile, as well as HDCA in serum could be selected as potential biomarkers for HSW induced liver injury; it also laid the foundation for the further search on the mechanisms of liver injury induced by HSW .

  5. Short-Term Exposure to Air Pollution and Biomarkers of Oxidative Stress: The Framingham Heart Study.

    Science.gov (United States)

    Li, Wenyuan; Wilker, Elissa H; Dorans, Kirsten S; Rice, Mary B; Schwartz, Joel; Coull, Brent A; Koutrakis, Petros; Gold, Diane R; Keaney, John F; Lin, Honghuang; Vasan, Ramachandran S; Benjamin, Emelia J; Mittleman, Murray A

    2016-04-28

    Short-term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community-based studies have assessed this association. Two thousand thirty-five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998-2001) and urinary creatinine-indexed 8-epi-prostaglandin F2α (8-epi-PGF2α) at the seventh and eighth (2005-2008) examinations. We measured fine particulate matter (PM2.5), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1-, 2-, 3-, 5-, and 7-day moving averages of each pollutant. Measured myeloperoxidase and 8-epi-PGF2α were loge transformed. We used linear regression models and linear mixed-effects models with random intercepts for myeloperoxidase and indexed 8-epi-PGF2α, respectively. Models were adjusted for demographic variables, individual- and area-level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2- to 7-day moving averages of PM2.5 and sulfate were consistently positively associated with 8-epi-PGF2α. Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without. Our community-based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  6. Novel Stool-Based Protein Biomarkers for Improved Colorectal Cancer Screening: A Case-Control Study.

    Science.gov (United States)

    Bosch, Linda J W; de Wit, Meike; Pham, Thang V; Coupé, Veerle M H; Hiemstra, Annemieke C; Piersma, Sander R; Oudgenoeg, Gideon; Scheffer, George L; Mongera, Sandra; Sive Droste, Jochim Terhaar; Oort, Frank A; van Turenhout, Sietze T; Larbi, Ilhame Ben; Louwagie, Joost; van Criekinge, Wim; van der Hulst, Rene W M; Mulder, Chris J J; Carvalho, Beatriz; Fijneman, Remond J A; Jimenez, Connie R; Meijer, Gerrit A

    2017-12-19

    The fecal immunochemical test (FIT) for detecting hemoglobin is used widely for noninvasive colorectal cancer (CRC) screening, but its sensitivity leaves room for improvement. To identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRC and advanced adenomas. Case-control study. Colonoscopy-controlled referral population from several centers. 315 stool samples from one series of 12 patients with CRC and 10 persons without colorectal neoplasia (control samples) and a second series of 81 patients with CRC, 40 with advanced adenomas, and 43 with nonadvanced adenomas, as well as 129 persons without colorectal neoplasia (control samples); 72 FIT samples from a third independent series of 14 patients with CRC, 16 with advanced adenomas, and 18 with nonadvanced adenomas, as well as 24 persons without colorectal neoplasia (control samples). Stool samples were analyzed by mass spectrometry. Classification and regression tree (CART) analysis and logistic regression analyses were performed to identify protein combinations that differentiated CRC or advanced adenoma from control samples. Antibody-based assays for 4 selected proteins were done on FIT samples. In total, 834 human proteins were identified, 29 of which were statistically significantly enriched in CRC versus control stool samples in both series. Combinations of 4 proteins reached sensitivities of 80% and 45% for detecting CRC and advanced adenomas, respectively, at 95% specificity, which was higher than that of hemoglobin alone (P control samples (P control samples. Proof of concept that such proteins can be detected with antibody-based assays in small sample volumes indicates the potential of these biomarkers to be applied in population screening. Center for Translational Molecular Medicine, International Translational Cancer Research Dream Team, Stand Up to Cancer (American Association for Cancer Research and the Dutch Cancer Society), Dutch Digestive Foundation, and VU

  7. Prediction of fruit and vegetable intake from biomarkers using individual participant data of diet-controlled intervention studies

    NARCIS (Netherlands)

    Souverein, O.W.; Vries, J.H.M. de; Freese, R.; Watzl, B.; Bub, A.; Miller, E.R., III; Castenmiller, J.J.M.; Pasman, W.J.; Hof, K. van het; Chopra, M.; Karlsen, A.; Dragsted, L.O.; Winkels, R.; Itsiopoulos, C.; Brazionis, L.; O'Dea, K.; Loo-Bouwman, C.A. van; Naber, T.H.J.; Voet, H. van der; Boshuizen, H.C.

    2015-01-01

    Fruit and vegetable consumption produces changes in several biomarkers in blood. The present study aimed to examine the dose-response curve between fruit and vegetable consumption and carotenoid (α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein and zeaxanthin), folate and vitamin C

  8. Prediction of fruit and vegetable intake from biomarkers using individual participant data of diet-controlled intervention studies

    DEFF Research Database (Denmark)

    Souverein, Olga W; de Vries, Jeanne H M; Freese, Riitta

    2015-01-01

    concentrations. Furthermore, a prediction model of fruit and vegetable intake based on these biomarkers and subject characteristics (i.e. age, sex, BMI and smoking status) was established. Data from twelve diet-controlled intervention studies were obtained to develop a prediction model for fruit and vegetable...

  9. Evaluation of C-reactive protein as an inflammatory biomarker in rabbits for vaccine nonclinical safety studies

    NARCIS (Netherlands)

    Destexhe, E.; Prinsen, M.K.; Schöll, I. van; Kuper, C.F.; Garçon, N.; Veenstra, S.; Segal, L.

    2013-01-01

    Introduction: Inflammatory reactions are one of the potential safety concerns that are evaluated in the framework of vaccine safety testing. In nonclinical studies, the assessment of the inflammation relies notably on the measurement of biomarkers. C-reactive protein (CRP) is an acute-phase plasma

  10. Biomarkers kinetics in the assessment of ventilator-associated pneumonia response to antibiotics - results from the BioVAP study

    NARCIS (Netherlands)

    Póvoa, Pedro; Martin-Loeches, Ignacio; Ramirez, Paula; Bos, Lieuwe D.; Esperatti, Mariano; Silvestre, Joana; Gili, Gisela; Goma, Gemma; Berlanga, Eugenio; Espasa, Mateu; Gonçalves, Elsa; Torres, Antoni; Artigas, Antonio

    2017-01-01

    Purpose: Our aim was to evaluate the role of biomarker kinetics in the assessment of ventilator-associated pneumonia (VAP) response to antibiotics. Materials and methods: We performed a prospective, multicenter, observational study to evaluate in 37 microbiologically documented VAP, the kinetics of

  11. Correlation of serum MMP3 and other biomarkers with clinical outcomes in patients with ankylosing spondylitis: A pilot study

    Science.gov (United States)

    The studies aimed to assess a set of biomarkers for their correlations with disease activity/severity of patients with ankylosing spondylitis (AS). A total of 24 AS patients were treated with etanercept and prospectively followed for 12 weeks. Serum levels of TNF-alpha, IFN-gamma, TGF-beta, IL6, IL1...

  12. Biomarkers of Dairy Fatty Acids and Risk of Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis

    NARCIS (Netherlands)

    Oliveira Otto, de M.C.; Nettleton, J.A.; Lemaitre, R.N.; Steffen, L.M.; Kromhout, D.; Rich, R.L.; Tsai, M.Y.; Jacobs, D.R.; Mozaffarian, D.

    2013-01-01

    Background Evidence regarding the role of dairy fat intake in cardiovascular disease (CVD) has been mixed and inconclusive. Most earlier studies have used self-reported measures of dietary intake and focused on relatively racially homogeneous populations. Circulating biomarkers of dairy fat in a

  13. Simulation Based Studies in Software Engineering: A Matter of Validity

    Directory of Open Access Journals (Sweden)

    Breno Bernard Nicolau de França

    2015-04-01

    Full Text Available Despite the possible lack of validity when compared with other science areas, Simulation-Based Studies (SBS in Software Engineering (SE have supported the achievement of some results in the field. However, as it happens with any other sort of experimental study, it is important to identify and deal with threats to validity aiming at increasing their strength and reinforcing results confidence. OBJECTIVE: To identify potential threats to SBS validity in SE and suggest ways to mitigate them. METHOD: To apply qualitative analysis in a dataset resulted from the aggregation of data from a quasi-systematic literature review combined with ad-hoc surveyed information regarding other science areas. RESULTS: The analysis of data extracted from 15 technical papers allowed the identification and classification of 28 different threats to validity concerned with SBS in SE according Cook and Campbell’s categories. Besides, 12 verification and validation procedures applicable to SBS were also analyzed and organized due to their ability to detect these threats to validity. These results were used to make available an improved set of guidelines regarding the planning and reporting of SBS in SE. CONCLUSIONS: Simulation based studies add different threats to validity when compared with traditional studies. They are not well observed and therefore, it is not easy to identify and mitigate all of them without explicit guidance, as the one depicted in this paper.

  14. CD64 on monocytes and granulocytes in severe acute bronchiolitis: Pilot study on its usefulness as a bacterial infection biomarker.

    Science.gov (United States)

    García-Salido, Alberto; Serrano-González, Ana; Casado-Flores, Juan; Sierra-Colomina, Montserrat; de Azagra-Garde, Amelia Martínez; García-Teresa, María Ángeles; Melen, Gustavo J; Ramírez-Orellana, Manuel

    2018-02-27

    The CD64 receptor has been described as a biomarker of bacterial infection. We speculated that CD64 surface expression on monocytes and granulocytes of children with severe acute bronchiolitis (SAB) could be altered in cases of probable bacterial infection (PBI) determined using classical biomarkers (procalcitonin and C-reactive protein, leukocyte count, and radiographic findings). A prospective observational pilot study was conducted from October 2015 to February 2016 in children admitted for pediatric critical care. A blood sample was taken in the first 24 hours of admission, and CD64 was measured by flow cytometry. The values obtained were analyzed and correlated with traditional biomarkers of PBI. Thirty-two children were included; a correlation was found between CD64 expression and the PBI criteria. CD64 surface expression was higher in children with PBI (area under the receiver operating characteristic curve of 0.73; P = 0.042) and the percentage of CD64 + granulocytes was higher in children with PBI. This is the first study to describe CD64 surface expression on monocytes and granulocytes in SAB, finding CD64 values to be higher in children with PBI. Larger clinical studies are needed to elucidate the real accuracy of CD64 as a biomarker of bacterial infection. ©2018 Society for Leukocyte Biology.

  15. School Alienation: A Construct Validation Study

    Science.gov (United States)

    Morinaj, Julia; Scharf, Jan; Grecu, Alyssa; Hadjar, Andreas; Hascher, Tina; Marcin, Kaja

    2017-01-01

    Early identification of school alienation is of great importance for students' educational outcomes and successful participation in society. This study examined the psychometric characteristics of a newly developed assessment instrument, the School Alienation Scale (SALS), to measure school alienation among primary and secondary school students.…

  16. Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders

    DEFF Research Database (Denmark)

    Gnanapavan, Sharmilee; Hegen, Harald; Khalil, Michael

    2014-01-01

    , there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development. METHODS: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid...... biomarker research. A checklist of items integrating the results of other published guidances, literature, conferences, regulatory opinion, and personal expertise was created to ultimately form a structured summary guidance incorporating the key features. RESULTS: The summary guidance is comprised of a 10......-point uniform reporting format ranging from introduction, materials and methods, through to results and discussion. Each item is discussed in detail in the guidance report. CONCLUSIONS: To enhance the future development of body fluid biomarkers, it will be important to standardize the reporting...

  17. Household air pollution: a call for studies into biomarkers of exposure and predictors of respiratory disease.

    Science.gov (United States)

    Rylance, Jamie; Gordon, Stephen B; Naeher, Luke P; Patel, Archana; Balmes, John R; Adetona, Olorunfemi; Rogalsky, Derek K; Martin, William J

    2013-05-01

    Household air pollution (HAP) from indoor burning of biomass or coal is a leading global cause of morbidity and mortality, mostly due to its association with acute respiratory infection in children and chronic respiratory and cardiovascular diseases in adults. Interventions that have significantly reduced exposure to HAP improve health outcomes and may reduce mortality. However, we lack robust, specific, and field-ready biomarkers to identify populations at greatest risk and to monitor the effectiveness of interventions. New scientific approaches are urgently needed to develop biomarkers of human exposure that accurately reflect exposure or effect. In this Perspective, we describe the global need for such biomarkers, the aims of biomarker development, and the state of development of tests that have the potential for rapid transition from laboratory bench to field use.

  18. CSF biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts.

    Science.gov (United States)

    Hansson, Oskar; Seibyl, John; Stomrud, Erik; Zetterberg, Henrik; Trojanowski, John Q; Bittner, Tobias; Lifke, Valeria; Corradini, Veronika; Eichenlaub, Udo; Batrla, Richard; Buck, Katharina; Zink, Katharina; Rabe, Christina; Blennow, Kaj; Shaw, Leslie M

    2018-03-01

    We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort. Cutoffs for Elecsys amyloid-β 1-42 (Aβ), total tau/Aβ(1-42), and phosphorylated tau/Aβ(1-42) were defined against [ 18 F]flutemetamol PET in Swedish BioFINDER (n = 277) and validated against [ 18 F]florbetapir PET in Alzheimer's Disease Neuroimaging Initiative (n = 646). Clinical progression in patients with mild cognitive impairment (n = 619) was studied. CSF total tau/Aβ(1-42) and phosphorylated tau/Aβ(1-42) ratios were highly concordant with PET classification in BioFINDER (overall percent agreement: 90%; area under the curve: 94%). The CSF biomarker statuses established by predefined cutoffs were highly concordant with PET classification in Alzheimer's Disease Neuroimaging Initiative (overall percent agreement: 89%-90%; area under the curves: 96%) and predicted greater 2-year clinical decline in patients with mild cognitive impairment. Strikingly, tau/Aβ ratios were as accurate as semiquantitative PET image assessment in predicting visual read-based outcomes. Elecsys CSF biomarker assays may provide reliable alternatives to PET in Alzheimer's disease diagnosis. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  19. A prospective cohort study of biomarkers of prenatal tobacco smoke exposure: the correlation between serum and meconium and their association with infant birth weight

    Directory of Open Access Journals (Sweden)

    Braun Joe M

    2010-08-01

    Full Text Available Abstract Background The evaluation of infant meconium as a cumulative matrix of prenatal toxicant exposure requires comparison to established biomarkers of prenatal exposure. Methods We calculated the frequency of detection and concentration of tobacco smoke metabolites measured in meconium (nicotine, cotinine, and trans-3'-hydroxycotinine concentrations and three serial serum cotinine concentrations taken during the latter two-thirds of pregnancy among 337 mother-infant dyads. We estimated the duration and intensity of prenatal tobacco smoke exposure using serial serum cotinine concentrations and calculated geometric mean meconium tobacco smoke metabolite concentrations according to prenatal exposure. We also compared the estimated associations between these prenatal biomarkers and infant birth weight using linear regression. Results We detected nicotine (80%, cotinine (69%, and trans-3'-hydroxycotinine (57% in most meconium samples. Meconium tobacco smoke metabolite concentrations were positively associated with serum cotinine concentrations and increased with the number of serum cotinine measurements consistent with secondhand or active tobacco smoke exposure. Like serum cotinine, meconium tobacco smoke metabolites were inversely associated with birth weight. Conclusions Meconium is a useful biological matrix for measuring prenatal tobacco smoke exposure and could be used in epidemiological studies that enroll women and infants at birth. Meconium holds promise as a biological matrix for measuring the intensity and duration of environmental toxicant exposure and future studies should validate the utility of meconium using other environmental toxicants.

  20. Evaluation of different biomarkers to predict individual radiosensitivity in an inter-laboratory comparison--lessons for future studies.

    Directory of Open Access Journals (Sweden)

    Burkhard Greve

    Full Text Available Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs and derived lymphoblastoid cell lines (LCLs from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR-induced cell death (AnnexinV, induction and repair of DNA strand breaks (Comet assay, induction of yH2AX foci (as a result of DNA double strand breaks, and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger

  1. 29 CFR 1607.5 - General standards for validity studies.

    Science.gov (United States)

    2010-07-01

    ...) (hereinafter “A.P.A. Standards”) and standard textbooks and journals in the field of personnel selection. D... market and the job should be considered in the determination of when a validity study is outdated. ...

  2. GPM GROUND VALIDATION GCPEX SNOW MICROPHYSICS CASE STUDY V1

    Data.gov (United States)

    National Aeronautics and Space Administration — The GPM Ground Validation GCPEX Snow Microphysics Case Study characterizes the 3-D microphysical evolution and distribution of snow in context of the thermodynamic...

  3. Towards a better understanding of biomarker response in field survey: a case study in eight populations of zebra mussels.

    Science.gov (United States)

    Pain-Devin, S; Cossu-Leguille, C; Geffard, A; Giambérini, L; Jouenne, T; Minguez, L; Naudin, B; Parant, M; Rodius, F; Rousselle, P; Tarnowska, K; Daguin-Thiébaut, C; Viard, F; Devin, S

    2014-10-01

    In order to provide reliable information about responsiveness of biomarkers during environmental monitoring, there is a need to improve the understanding of inter-population differences. The present study focused on eight populations of zebra mussels and aimed to describe how variable are biomarkers in different sampling locations. Biomarkers were investigated and summarised through the Integrated Biomarker Response (IBR index). Inter-site differences in IBR index were analysed through comparisons with morphological data, proteomic profiles and genetic background of the studied populations. We found that the IBR index was a good tool to inform about the status of sites. It revealed higher stress in more polluted sites than in cleaner ones. It was neither correlated to proteomic profiles nor to genetic background, suggesting a stronger influence of environment than genes. Meanwhile, morphological traits were related to both environment and genetic background influence. Together these results attest the benefit of using biological tools to better illustrate the status of a population and highlight the need of consider inter-population difference in their baselines. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Biomarkers for severity of spinal cord injury in the cerebrospinal fluid of rats.

    Directory of Open Access Journals (Sweden)

    Joanna M Lubieniecka

    Full Text Available One of the major challenges in management of spinal cord injury (SCI is that the assessment of injury severity is often imprecise. Identification of reliable, easily quantifiable biomarkers that delineate the severity of the initial injury and that have prognostic value for the degree of functional recovery would significantly aid the clinician in the choice of potential treatments. To find such biomarkers we performed quantitative liquid chromatography-mass spectrometry (LC-MS/MS analyses of cerebrospinal fluid (CSF collected from rats 24 h after either a moderate or severe SCI. We identified a panel of 42 putative biomarkers of SCI, 10 of which represent potential biomarkers of SCI severity. Three of the candidate biomarkers, Ywhaz, Itih4, and Gpx3 were also validated by Western blot in a biological replicate of the injury. The putative biomarkers identified in this study may potentially be a valuable tool in the assessment of the extent of spinal cord damage.

  5. Biomarkers for Severity of Spinal Cord Injury in the Cerebrospinal Fluid of Rats

    Science.gov (United States)

    Lubieniecka, Joanna M.; Streijger, Femke; Lee, Jae H. T.; Stoynov, Nikolay; Liu, Jie; Mottus, Randy; Pfeifer, Tom; Kwon, Brian K.; Coorssen, Jens R.; Foster, Leonard J.; Grigliatti, Thomas A.; Tetzlaff, Wolfram

    2011-01-01

    One of the major challenges in management of spinal cord injury (SCI) is that the assessment of injury severity is often imprecise. Identification of reliable, easily quantifiable biomarkers that delineate the severity of the initial injury and that have prognostic value for the degree of functional recovery would significantly aid the clinician in the choice of potential treatments. To find such biomarkers we performed quantitative liquid chromatography-mass spectrometry (LC-MS/MS) analyses of cerebrospinal fluid (CSF) collected from rats 24 h after either a moderate or severe SCI. We identified a panel of 42 putative biomarkers of SCI, 10 of which represent potential biomarkers of SCI severity. Three of the candidate biomarkers, Ywhaz, Itih4, and Gpx3 were also validated by Western blot in a biological replicate of the injury. The putative biomarkers identified in this study may potentially be a valuable tool in the assessment of the extent of spinal cord damage. PMID:21559420

  6. Elastin: a possible genetic biomarker for more severe ligament injuries in elite soccer. A pilot study

    Science.gov (United States)

    Artells, Rosa; Pruna, Ricard; Dellal, Alexandre; Maffulli, Nicola

    2016-01-01

    Summary Background The study of new genetic biomarkers in genes related to connective tissue repair and regeneration may help to identify individuals with greater predisposition to injury, who may benefit from targeted preventive measures, and those who require longer recovery time following a muscle, ligament or tendon injury. The present study investigated whether single nucleotide polymorphisms of the Elastin gene could be related to MCL injury. Methods 60 top class football players were studied to identify single nucleotide polymorphisms for the Elastin (ELN) gene using Allelic Discrimination analysis. Each player was followed for 7 seasons, and each MCL injury was noted. Results Ligament injury rate, severity and recovery time are related to specific genotypes observed in the elastin gene, especially the ELN-AA (16 MCL) and the ELN-AG (3 MCL). Players with the ELN-GG genotype sustained no MCL injury during the 7 seasons of the study. Conclusions The identification of polymorphisms in the ELN gene may be used as a novel tool to better define an athlete’s genotype, and help to plan training and rehabilitation programmes to prevent or minimize MCL ligament injuries, and optimize the therapeutic and rehabilitation process after soft tissue injuries, and manage the workloads during trainings and matches. PMID:27900291

  7. Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies.

    Science.gov (United States)

    Sharapova, T; Devanarayan, V; LeRoy, B; Liguori, M J; Blomme, E; Buck, W; Maher, J

    2016-01-01

    MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases. © The Author(s) 2015.

  8. Use of the Method of Triads in the Validation of Sodium and Potassium Intake in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

    Science.gov (United States)

    Pereira, Taísa Sabrina Silva; Cade, Nágela Valadão; Mill, José Geraldo; Sichieri, Rosely; Molina, Maria Del Carmen Bisi

    2016-01-01

    Biomarkers are a good choice to be used in the validation of food frequency questionnaire due to the independence of their random errors. To assess the validity of the potassium and sodium intake estimated using the Food Frequency Questionnaire ELSA-Brasil. A subsample of participants in the ELSA-Brasil cohort was included in this study in 2009. Sodium and potassium intake were estimated using three methods: Semi-quantitative food frequency questionnaire, 12-hour nocturnal urinary excretion and three 24-hour food records. Correlation coefficients were calculated between the methods, and the validity coefficient was calculated using the method of triads. The 95% confidence intervals for the validity coefficient were estimated using bootstrap sampling. Exact and adjacent agreement and disagreement of the estimated sodium and potassium intake quintiles were compared among three methods. The sample consisted of 246 participants, aged 53±8 years, 52% of women. Validity coefficient for sodium were considered weak (рfood frequency questionnaire actual intake = 0.37 and рbiomarker actual intake = 0.21) and moderate (рfood records actual intake 0.56). The validity coefficient were higher for potassium (рfood frequency questionnaire actual intake = 0.60; рbiomarker actual intake = 0.42; рfood records actual intake = 0.79). Conclusions: The Food Frequency Questionnaire ELSA-Brasil showed good validity in estimating potassium intake in epidemiological studies. For sodium validity was weak, likely due to the non-quantification of the added salt to prepared food.

  9. Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

    Science.gov (United States)

    de Almeida, Sergio M; Rotta, Indianara; Ribeiro, Clea E; Oliveira, Michelli F; Chaillon, Antoine; de Pereira, Ana Paula; Cunha, Ana Paula; Zonta, Marise; Bents, Joao França; Raboni, Sonia M; Smith, Davey; Letendre, Scott; Ellis, Ronald J

    2017-06-01

    Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

  10. Do classic blood biomarkers of JSLE identify active lupus nephritis? Evidence from the UK JSLE Cohort Study.

    Science.gov (United States)

    Smith, E M D; Jorgensen, A L; Beresford, M W

    2017-10-01

    Background Lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus (JSLE) patients. The value of commonly available biomarkers, such as anti-dsDNA antibodies, complement (C3/C4), ESR and full blood count parameters in the identification of active LN remains uncertain. Methods Participants from the UK JSLE Cohort Study, aged modeling, with stepAIC function applied to select a final model. Receiver-operating curve analysis was used to assess diagnostic accuracy. Results A total of 370 patients were recruited; 191 (52%) had active LN and 179 (48%) had inactive LN. Binary logistic regression modeling demonstrated a combination of ESR, C3, white cell count, neutrophils, lymphocytes and IgG to be best for the identification of active LN (area under the curve 0.724). Conclusions At best, combining common classic blood biomarkers of lupus activity using multivariate analysis provides a 'fair' ability to identify active LN. Urine biomarkers were not included in these analyses. These results add to the concern that classic blood biomarkers are limited in monitoring discrete JSLE manifestations such as LN.

  11. Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA clinical study.

    Directory of Open Access Journals (Sweden)

    Richard S Finkel

    Full Text Available Spinal Muscular Atrophy (SMA is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1 gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets.To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches.A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2-12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS and to a number of secondary clinical measures.A total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites and 44 urine metabolites. No transcripts correlated with MHFMS.In this cross-sectional study, "BforSMA" (Biomarkers for SMA, candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm these findings, demonstrate sensitivity to change with

  12. Metabolic and inflammatory profiles of biomarkers in obesity, metabolic syndrome, and diabetes in a Mediterranean population. DARIOS Inflammatory study.

    Science.gov (United States)

    Fernández-Bergés, Daniel; Consuegra-Sánchez, Luciano; Peñafiel, Judith; Cabrera de León, Antonio; Vila, Joan; Félix-Redondo, Francisco Javier; Segura-Fragoso, Antonio; Lapetra, José; Guembe, María Jesús; Vega, Tomás; Fitó, Montse; Elosua, Roberto; Díaz, Oscar; Marrugat, Jaume

    2014-08-01

    There is a paucity of data regarding the differences in the biomarker profiles of patients with obesity, metabolic syndrome, and diabetes mellitus as compared to a healthy, normal weight population. We aimed to study the biomarker profile of the metabolic risk continuum defined by the transition from normal weight to obesity, metabolic syndrome, and diabetes mellitus. We performed a pooled analysis of data from 7 cross-sectional Spanish population-based surveys. An extensive panel comprising 20 biomarkers related to carbohydrate metabolism, lipids, inflammation, coagulation, oxidation, hemodynamics, and myocardial damage was analyzed. We employed age- and sex-adjusted multinomial logistic regression models for the identification of those biomarkers associated with the metabolic risk continuum phenotypes: obesity, metabolic syndrome, and diabetes mellitus. A total of 2851 subjects were included for analyses. The mean age was 57.4 (8.8) years, 1269 were men (44.5%), and 464 participants were obese, 443 had metabolic syndrome, 473 had diabetes mellitus, and 1471 had a normal weight (healthy individuals). High-sensitivity C-reactive protein, apolipoprotein B100, leptin, and insulin were positively associated with at least one of the phenotypes of interest. Apolipoprotein A1 and adiponectin were negatively associated. There are differences between the population with normal weight and that having metabolic syndrome or diabetes with respect to certain biomarkers related to the metabolic, inflammatory, and lipid profiles. The results of this study support the relevance of these mechanisms in the metabolic risk continuum. When metabolic syndrome and diabetes mellitus are compared, these differences are less marked. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  13. Dosimetric studies for gamma radiation validation of medical devices

    International Nuclear Information System (INIS)

    Soliman, Y.S.; Beshir, W.B.; Abdel-Fattah, A.A.; Abdel-Rehim, F.

    2013-01-01

    The delivery and validation of a specified dose to medical devices are key concerns to operators of gamma radiation facilities. The objective of the present study was to characterize the industrial gamma radiation facility and map the dose distribution inside the product-loading pattern during the validation and routine control of the sterilization process using radiochromic films. Cardboard phantoms were designed to achieve the homogeneity of absorbed doses. The uncertainty of the dose delivered during validation of the sterilization process was assessed. - Highlights: ► Using γ-rays for sterilization of hollow fiber dialyzers and blood tubing sets according to ISO 11137, 2006. ► Dosimetry studies of validations of γ-irradiation facility and sterilized medical devices. ► Places of D min and D max have been determined using FWT-60 films. ► Determining the target minimum doses required to meet the desired SAL of 10 −6 for the two products.

  14. Biomarkers of systemic lupus erythematosus identified using mass spectrometry-based proteomics: a systematic review.

    Science.gov (United States)

    Nicolaou, Orthodoxia; Kousios, Andreas; Hadjisavvas, Andreas; Lauwerys, Bernard; Sokratous, Kleitos; Kyriacou, Kyriacos

    2017-05-01

    Advances in mass spectrometry technologies have created new opportunities for discovering novel protein biomarkers in systemic lupus erythematosus (SLE). We performed a systematic review of published reports on proteomic biomarkers identified in SLE patients using mass spectrometry-based proteomics and highlight their potential disease association and clinical utility. Two electronic databases, MEDLINE and EMBASE, were systematically searched up to July 2015. The methodological quality of studies included in the review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Twenty-five studies were included in the review, identifying 241 SLE candidate proteomic biomarkers related to various aspects of the disease including disease diagnosis and activity or pinpointing specific organ involvement. Furthermore, 13 of the 25 studies validated their results for a selected number of biomarkers in an independent cohort, resulting in the validation of 28 candidate biomarkers. It is noteworthy that 11 candidate biomarkers were identified in more than one study. A significant number of potential proteomic biomarkers that are related to a number of aspects of SLE have been identified using mass spectrometry proteomic approaches. However, further studies are required to assess the utility of these biomarkers in routine clinical practice. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  15. Zinc Status Biomarkers and Cardiometabolic Risk Factors in Metabolic Syndrome: A Case Control Study

    Directory of Open Access Journals (Sweden)

    Erika P. S. Freitas

    2017-02-01

    Full Text Available Metabolic syndrome (MS involves pathophysiological alterations that might compromise zinc status. The aim of this study was to evaluate zinc status biomarkers and their associations with cardiometabolic factors in patients with MS. Our case control study included 88 patients with MS and 37 controls. We performed clinical and anthropometric assessments and obtained lipid, glycemic, and inflammatory profiles. We also evaluated zinc intake, plasma zinc, erythrocyte zinc, and 24-h urinary zinc excretion. The average zinc intake was significantly lower in the MS group (p < 0.001. Regression models indicated no significant differences in plasma zinc concentration (all p > 0.05 between the two groups. We found significantly higher erythrocyte zinc concentration in the MS group (p < 0.001 independent from co-variable adjustments. Twenty-four hour urinary zinc excretion was significantly higher in the MS group (p = 0.008, and adjustments for age and sex explained 21% of the difference (R2 = 0.21, p < 0.001. There were significant associations between zincuria and fasting blood glucose concentration (r = 0.479, waist circumference (r = 0.253, triglyceride concentration (r = 0.360, glycated hemoglobin concentration (r = 0.250, homeostatic model assessment—insulin resistance (r = 0.223, and high-sensitivity C-reactive protein concentration (r = 0.427 (all p < 0.05 in the MS group. Patients with MS had alterations in zinc metabolism mainly characterized by an increase in erythrocyte zinc and higher zincuria.

  16. Sensitivity analysis for publication bias in meta-analysis of diagnostic studies for a continuous biomarker.

    Science.gov (United States)

    Hattori, Satoshi; Zhou, Xiao-Hua

    2018-02-10

    Publication bias is one of the most important issues in meta-analysis. For standard meta-analyses to examine intervention effects, the funnel plot and the trim-and-fill method are simple and widely used techniques for assessing and adjusting for the influence of publication bias, respectively. However, their use may be subjective and can then produce misleading insights. To make a more objective inference for publication bias, various sensitivity analysis methods have been proposed, including the Copas selection model. For meta-analysis of diagnostic studies evaluating a continuous biomarker, the summary receiver operating characteristic (sROC) curve is a very useful method in the presence of heterogeneous cutoff values. To our best knowledge, no methods are available for evaluation of influence of publication bias on estimation of the sROC curve. In this paper, we introduce a Copas-type selection model for meta-analysis of diagnostic studies and propose a sensitivity analysis method for publication bias. Our method enables us to assess the influence of publication bias on the estimation of the sROC curve and then judge whether the result of the meta-analysis is sufficiently confident or should be interpreted with much caution. We illustrate our proposed method with real data. Copyright © 2017 John Wiley & Sons, Ltd.

  17. The use of genotoxicity biomarkers in molecular epidemiology: applications in environmental, occupational and dietary studies

    Directory of Open Access Journals (Sweden)

    Carina Ladeira

    2017-08-01

    Full Text Available Molecular epidemiology is an approach increasingly used in the establishment of associations between exposure to hazardous substances and development of disease, including the possible modulation by genetic susceptibility factors. Environmental chemicals and contaminants from anthropogenic pollution of air, water and soil, but also originating specifically in occupational contexts, are potential sources of risk of development of disease. Also, diet presents an important role in this process, with some well characterized associations existing between nutrition and some types of cancer. Genotoxicity biomarkers allow the detection of early effects that result from the interaction between the individual and the environment; they are therefore important tools in cancer epidemiology and are extensively used in human biomonitoring studies. This work intends to give an overview of the potential for genotoxic effects assessment, specifically with the cytokinesis blocked micronucleus assay and comet assay in environmental and occupational scenarios, including diet. The plasticity of these techniques allows their inclusion in human biomonitoring studies, adding important information with the ultimate aim of disease prevention, in particular cancer, and so it is important that they be included as genotoxicity assays in molecular epidemiology.

  18. Lipid biomarkers for bacterial ecosystems: studies of cultured organisms, hydrothermal environments and ancient sediments

    Science.gov (United States)

    Summons, R. E.; Jahnke, L. L.; Simoneit, B. R.

    1996-01-01

    This paper forms part of our long-term goal of using molecular structure and carbon isotopic signals preserved as hydrocarbons in ancient sediments to improve understanding of the early evolution of Earth's surface environment. We are particularly concerned with biomarkers which are informative about aerobiosis. Here, we combine bacterial biochemistry with the organic geochemistry of contemporary and ancient hydrothermal ecosystems to construct models for the nature, behaviour and preservation potential of primitive microbial communities. We use a combined molecular and isotopic approach to characterize lipids produced by cultured bacteria and test a variety of culture conditions which affect their biosynthesis. This information is then compared with lipid mixtures isolated from contemporary hot springs and evaluated for the kinds of chemical change that would accompany burial and incorporation into the sedimentary record. In this study we have shown that growth temperature does not appear to alter isotopic fractionation within the lipid classes produced by a methanotropic bacterium. We also found that cultured cyanobacteria biosynthesize diagnostic methylalkanes and dimethylalkanes with the latter only made when growing under low pCO2. In an examination of a microbial mat sample from Octopus Spring, Yellowstone National Park (USA), we could readily identify chemical structures with 13C contents which were diagnostic for the phototrophic organisms such as cyanobacteria and Chloroflexus. We could not, however, find molecular evidence for operation of a methane cycle in the particular mat samples we studied.

  19. Test of Creative Imagination: Validity and Reliability Study

    Science.gov (United States)

    Gundogan, Aysun; Ari, Meziyet; Gonen, Mubeccel

    2013-01-01

    The purpose of this study was to investigate validity and reliability of the test of creative imagination. This study was conducted with the participation of 1000 children, aged between 9-14 and were studying in six primary schools in the city center of Denizli Province, chosen by cluster ratio sampling. In the study, it was revealed that the…

  20. Prognostic Biomarkers Used for Localised Prostate Cancer Management: A Systematic Review.

    Science.gov (United States)

    Lamy, Pierre-Jean; Allory, Yves; Gauchez, Anne-Sophie; Asselain, Bernard; Beuzeboc, Philippe; de Cremoux, Patricia; Fontugne, Jacqueline; Georges, Agnès; Hennequin, Christophe; Lehmann-Che, Jacqueline; Massard, Christophe; Millet, Ingrid; Murez, Thibaut; Schlageter, Marie-Hélène; Rouvière, Olivier; Kassab-Chahmi, Diana; Rozet, François; Descotes, Jean-Luc; Rébillard, Xavier

    2017-03-07

    Prostate cancer stratification is based on tumour size, pretreatment PSA level, and Gleason score, but it remains imperfect. Current research focuses on the discovery and validation of novel prognostic biomarkers to improve the identification of patients at risk of aggressive cancer or of tumour relapse. This systematic review by the Intergroupe Coopérateur Francophone de Recherche en Onco-urologie (ICFuro) analysed new evidence on the analytical validity and clinical validity and utility of six prognostic biomarkers (PHI, 4Kscore, MiPS, GPS, Prolaris, Decipher). All available data for the six biomarkers published between January 2002 and April 2015 were systematically searched and reviewed. The main endpoints were aggressive prostate cancer prediction, additional value compared to classical prognostic parameters, and clinical benefit for patients with localised prostate cancer. The preanalytical and analytical validations were heterogeneous for all tests and often not adequate for the molecular signatures. Each biomarker was studied for specific indications (candidates for a first or second biopsy, and potential candidates for active surveillance, radical prostatectomy, or adjuvant treatment) for which the level of evidence (LOE) was variable. PHI and 4Kscore were the biomarkers with the highest LOE for discriminating aggressive and indolent tumours in different indications. Blood biomarkers (PHI and 4Kscore) have the highest LOE for the prediction of more aggressive prostate cancer and could help clinicians to manage patients with localised prostate cancer. The other biomarkers show a potential prognostic value; however, they should be evaluated in additional studies to confirm their clinical validity. We reviewed studies assessing the value of six prognostic biomarkers for prostate cancer. On the basis of the available evidence, some biomarkers could help in discriminating between aggressive and non-aggressive tumours with an additional value compared to the

  1. [A surveillance study on CRISPR/Cas molecular biomarker in Escherichia coli].

    Science.gov (United States)

    Liang, W J; Zhang, R G; Duan, G C; Hong, L J; Zhang, B; Xi, Y L; Yang, H Y; Chen, S Y; Lou, T Y; Zhao, Y X

    2016-08-10

    A new method related to molecular biomarker with CRISPR/Cas (clustered regularly interspaced short palindromic repeats-cas) in Escherichia (E.) coli was developed and used for surveillance programs. CRISPR/Cas sequence that containing 135 strains with complete sequence and 203 strains with whole genome shotgun sequence of E. coli in GenBank by BLAST and 361 strains of E. coli (including 38 strains of E. coli O157∶H7) in laboratory were identified by PCR and analyzed with the CRISPR Finder. Spacers were compared with DANMAN and the phylogenetic trees of cas gene were constructed under Clustal Ⅹ and Mega 5.1. With new perspective, a descriptive method was developed targeting on the position of CRISPR/cas in E. coli. The CRISPR1 was detected in 77.04%, 100.00% and 75.62% and the CRISPR2 was detected in 74.81%, 100.00% and 92.24% and the CRISPR3 and CRISPR4 were detected in 11.85%, 0 and 1.39% for 135 strains with complete sequence, 203 strains with whole genome shotgun sequence and 361 strains in the laboratory, respectively. One strain downloaded in GenBank with whole genome sequencing and 2 strains in the our laboratory were identified that containing four CRISPR locus. The other E. coli strain was with insertion sequence in downstream of the non-cas CRISPR1. The unique CRISPR was found in 8 strains of O55∶H7, in 180 strains of O157∶H7, in 8 strains of O157∶HNM, in 40 strains of O104∶H4, in 4 strains of O145∶H28, in all the 699 E. coli strains. The phylogenetic tree could be divided into two groups-cas with type I-E or type I-F. CRISPR/Cas might be used as a valuable molecular biomarker in epidemiological surveillance studies to identify the high virulent strains or new strains of E. coli. Phage night be related to the missing or obtaining of spacers.

  2. Biomarkers-a potential route for improved diagnosis and management of ongoing renal damage.

    Science.gov (United States)

    Oberbauer, R

    2008-12-01

    Currently, the identification and validation of biomarkers of kidney injury is among the top priorities of many diagnostic biotechnology companies as well as academic research institutes. Specifically, in renal transplantation, validated biomarkers of tissue injury with good discriminatory power between the various renal compartments and the underlying pathophysiology are desired, because sequential allograft biopsies are limited in number and cannot be used as a screening tool. Given the high demands on these markers, it is not surprising that none of those currently under evaluation has been thoroughly validated for a specific entity. Published biomarker candidates for early tubular damage include neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, soluble CD30, perforin, and granzyme B. Recently, C4d flow panel reactive antibodies were evaluated as biomarkers for humoral alloimmune responses. Additional biomarkers such as FOXP3 and kidney injury molecule 1 have been studied in the maintenance phase of renal transplantation. Given the complex prerequisites, it is not surprising that no biomarker panel has been sufficiently validated for clinical use. However, in the near future a biomarker for use as an indicator of renal tubule cell injury will be available. Troponin T or transaminase of the kidney may then at least be used to differentiate between functional renal failure (equivalent to a rise in creatinine) and intrinsic kidney injury.

  3. MiRNA-155 and miRNA-132 as potential diagnostic biomarkers for pulmonary tuberculosis: A preliminary study.

    Science.gov (United States)

    Zheng, Meng-Li; Zhou, Nai-Kang; Luo, Cheng-Hua

    2016-11-01

    In our study, we aimed to profile a panel microRNAs (miRNAs) as potential biomarkers for the early diagnosis of pulmonary tuberculosis (PTB) and to illuminate the molecular mechanisms in the development of PTB. Firstly, gene expression profile of E-GEOD-49951 was downloaded from ArrayExpress database, and quantile-adjusted conditional maximum likelihood method was utilized to identify statistical difference between miRNAs of Mycobacterium tuberculosis (MTB)-infected individuals and healthy subjects. Furthermore, in order to assess the performance of our methodology, random forest (RF) classification model was utilized to identify the top 10 miRNAs with better Area Under The Curve (AUC) using 10-fold cross-validation method. Additionally, Monte Carlo Cross-Validation was repeated 50 times to explore the best miRNAs. In order to learn more about the differentially-expressed miRNAs, the target genes of differentially-expressed miRNAs were retrieved from TargetScan database and Ingenuity Pathways Analysis (IPA) was used to screen out biological pathways where target genes were involved. After normalization, a total of 478 miRNAs with higher than 0.25-fold quantile average across all samples were required. Based on the differential expression analysis, 38 differentially expressed miRNAs were identified when the significance was set as false discovery rate (FDR) < 0.01. Among the top 10 differentially expressed miRNAs, miRNA-155 obtained a highest AUC value 0.976, showing a good performance between PTB and control groups. Similarly, miRNA-449a, miRNA-212 and miRNA-132 revealed also a good performance with AUC values 0.947, 0.931 and 0.930, respectively. Moreover, miRNA-155, miRNA-449a, miRNA-29b-1* and miRNA-132 appeared in 50, 49, 49 and 48 bootstraps. Thus, miRNA-155 and miRNA-132 might be important in the progression of PTB and thereby, might present potential signatures for diagnosis of PTB. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Plasma levels of the MMP-9:TIMP-1 complex as prognostic biomarker in breast cancer: a retrospective study

    International Nuclear Information System (INIS)

    Thorsen, Stine B; Møller, Susanne; Brünner, Nils; Schrohl, Anne-Sofie; Stenvang, Jan; Christensen, Sarah LT; Würtz, Sidse Ø; Lundberg, Martin; Nielsen, Birgitte S; Vinther, Lena; Knowles, Mick; Gee, Nick; Fredriksson, Simon

    2013-01-01

    Worldwide more than one million women are annually diagnosed with breast cancer. A considerable fraction of these women receive systemic adjuvant therapy; however, some are cured by primary surgery and radiotherapy alone. Prognostic biomarkers guide stratification of patients into different risk groups and hence improve management of breast cancer patients. Plasma levels of Matrix Metalloproteinase-9 (MMP-9) and its natural inhibitor Tissue inhibitor of metalloproteinase-1 (TIMP-1) have previously been associated with poor patient outcome and resistance to certain forms of chemotherapy. To pursue additional prognostic information from MMP-9 and TIMP-1, the level of the MMP-9 and TIMP-1 complex (MMP-9:TIMP-1) was investigated in plasma from breast cancer patients. Detection of protein:protein complexes in plasma was performed using a commercially available ELISA kit and, for the first time, the highly sensitive in-solution proximity ligation assay (PLA). We screened plasma from 465 patients with primary breast cancer for prognostic value of the MMP-9:TIMP-1 complex. Both assays were validated and applied for quantification of MMP-9:TIMP-1 concentration. In this retrospective study, we analyzed the association between the concentration of the MMP-9:TIMP-1 complex and clinicopathological data and disease free survival (DFS) in univariate and multivariate survival analyses. Following successful validation both assays were applied for MMP-9:TIMP-1 measurements. Of the clinicopathological parameters, only menopausal status demonstrated significant association with the MMP-9:TIMP-1 complex; P = 0.03 and P = 0.028 for the ELISA and PLA measurements, respectively. We found no correlation between the MMP-9:TIMP-1 protein complex and DFS neither in univariate nor in multivariate survival analyses. Despite earlier reports linking MMP-9 and TIMP-1 with prognosis in breast cancer patients, we here demonstrate that plasma levels of the MMP-9:TIMP-1 protein complex hold no

  5. Diagnostic accuracy for apical and chronic periodontitis biomarkers in gingival crevicular fluid: an exploratory study.

    Science.gov (United States)

    Baeza, Mauricio; Garrido, Mauricio; Hernández-Ríos, Patricia; Dezerega, Andrea; García-Sesnich, Jocelyn; Strauss, Franz; Aitken, Juan Pablo; Lesaffre, Emmanuel; Vanbelle, Sophie; Gamonal, Jorge; Brignardello-Petersen, Romina; Tervahartiala, Taina; Sorsa, Timo; Hernández, Marcela

    2016-01-01

    The aim of this study was to assess the levels and diagnostic accuracy of a set of potential biomarkers of periodontal tissue metabolism in gingival crevicular fluid (GCF) from patients with chronic periodontitis (CP) and asymptomatic apical periodontitis ( AAP). Thirty one GCF samples from 11 CP patients, 44 GCF samples from 38 AAP patients and 31 GCF samples from 13 healthy volunteers were obtained (N = 106). Matrix metalloproteinases (MMPs) -2 and -9 were determined by zymography; levels of MMP-8 by ELISA and IFMA and MPO by ELISA. IL-1, IL-6, TNFα, DKK-1, Osteonectin, Periostin, TRAP-5 and OPG were determined by a multiplex quantitative panel. Statistical analysis was performed using linear mixed-effects models. The MMP-9 and MMP-8 were higher in CP, followed by AAP, versus healthy individuals (p 0.97) in CP, and for the active form of MMP-9 and MMP-8 (AUC > 0.90) in AAP. Gingival crevicular fluid composition is modified by CP and AAP. MMP-9 and MMP-8 show diagnostic potential for CP and AAP, whereas MMP-2 and TRAP-5 are useful only for CP. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. A New Serum Biomarker for Lung Cancer - Transthyretin

    Directory of Open Access Journals (Sweden)

    Liyun LIU

    2009-04-01

    Full Text Available Background and objective Lung cancer is the leading cause of cancer death worldwide and very few specific biomarkers could be used in clinical diagnosis at present. The aim of this study is to find novel potential serum biomarkers for lung cancer using Surface Enhanced Laser Desorption/Ionization (SELDI technique. Methods Serumsample of 227 cases including 146 lung cancer, 13 pneumonia, 28 tuberculous pleurisy and 40 normal individuals were analyzed by CM10 chips. The candidate biomarkers were identified by ESI/MS-MS and database searching, and further confirmed by immunoprecipitation. The same sets of serum sample from all groups were re-measured by ELISA assay. Results Three protein peaks with the molecular weight 13.78 kDa, 13.90 kDa and 14.07 kDa were found significantlydecreased in lung cancer serum compared to the other groups and were all automatically selected as specific biomarkers by Biomarker Wizard software. The candidate biomarkers obtained from 1-D SDS gel bands by matching the molecular weight with peaks on CM10 chips were identified by Mass spectrometry as the native transthyretin (nativeTTR, cysTTR and glutTTR, and the identity was further validated by immunoprecipitation using commercial TTR antibodies. Downregulated of TTR was found in both ELISA and SELDI analysis. Conclusion TTRs acted as the potentially useful biomarkers for lung cancer by SELDI technique.

  7. Overlap of proteomics biomarkers between women with pre-eclampsia and PCOS: a systematic review and biomarker database integration.

    Science.gov (United States)

    Khan, Gulafshana Hafeez; Galazis, Nicolas; Docheva, Nikolina; Layfield, Robert; Atiomo, William

    2015-01-01

    Do any proteomic biomarkers previously identified for pre-eclampsia (PE) overlap with those identified in women with polycystic ovary syndrome (PCOS). Five previously identified proteomic biomarkers were found to be common in women with PE and PCOS when compared with controls. Various studies have indicated an association between PCOS and PE; however, the pathophysiological mechanisms supporting this association are not known. A systematic review and update of our PCOS proteomic biomarker database was performed, along with a parallel review of PE biomarkers. The study included papers from 1980 to December 2013. In all the studies analysed, there were a total of 1423 patients and controls. The number of proteomic biomarkers that were catalogued for PE was 192. Five proteomic biomarkers were shown to be differentially expressed in women with PE and PCOS when compared with controls: transferrin, fibrinogen α, β and γ chain variants, kininogen-1, annexin 2 and peroxiredoxin 2. In PE, the biomarkers were identified in serum, plasma and placenta and in PCOS, the biomarkers were identified in serum, follicular fluid, and ovarian and omental biopsies. The techniques employed to detect proteomics have limited ability in identifying proteins that are of low abundance, some of which may have a diagnostic potential. The sample sizes and number of biomarkers identified from these studies do not exclude the risk of false positives, a limitation of all biomarker studies. The biomarkers common to PE and PCOS were identified from proteomic analyses of different tissues. This data amalgamation of the proteomic studies in PE and in PCOS, for the first time, discovered a panel of five biomarkers for PE which are common to women with PCOS, including transferrin, fibrinogen α, β and γ chain variants, kininogen-1, annexin 2 and peroxiredoxin 2. If validated, these biomarkers could provide a useful framework for the knowledge infrastructure in this area. To accomplish this goal, a

  8. Cancer predictive value of cytogenetic markers used in occupational health surveillance programs. A report from an ongoing study by the European Study Group on Cytogenetic Biomarkers and Health

    Energy Technology Data Exchange (ETDEWEB)

    Hagmar, Lars; Stroemberg, Ulf; Mikoczy, Zoli; Tinnerberg, Hakan; Skerfving, Staffan [Department of Occupational and Environmental Medicine, Lund University, S-221 85 Lund (Sweden); Bonassi, Stefano; Lando, Cecilia [Department of Environmental Epidemiology, Istituto Nazionale per la Ricerca sul Cancro, Viale Benedetto XV, I-1016132 Genoa (Italy); Hansteen, Inger-Lise [Department of Occupational Medicine, Telemark Central Hospital, N-3710 Skien (Norway); Montagud, Alicia Huici [Centro Nacional de Condiciones de Trabajo, Instituto Nacional de Seguridad e Higiene en el Trabajo, Dulcet 2-10, ES-08034 Barcelona (Spain); Knudsen, Lisbeth [National Institute of Occupational Health, Lersoe Parkalle 105, DK-2100 Copenhagen (Denmark); Norppa, Hannu [Finnish Institute of Occupational Health, Topeliuksekatu 41 aA, FIN-00250 Helsinki (Finland); Reuterwall, Christina [National Institute of Work Life, S-171 84 Solna (Sweden); Broegger, Anton [Norwegian Radium Hospital, Oslo (Norway); Forni, Alessandra [Istituto di Medicina del Lavoro Clinica del Lavoro `L. Devoto`, Milan (Italy); Hoegstedt, Benkt [Department of Occupational Medicine, Central Hospital, Halmstad (Sweden); Lambert, Bo [Department of Environmental Medicine, Centre for Nutrition and Toxicology, Karolinska Institute, Stockholm (Sweden); Mitelman, Felix [Department of Clinical Genetics, Lund University, Lund (Sweden); Nordenson, Ingrid [National Institute of Work Life, Umea (Sweden); Salomaa, Sisko [Finnish Center for Radiation and Nuclear Safety, Helsinki (Finland)

    1998-09-20

    The cytogenetic endpoints in peripheral blood lymphocytes: chromosomal aberrations (CA), sister chromatid exchange (SCE) and micronuclei (MN) are established biomarkers of exposure for mutagens or carcinogens in the work environment. However, it is not clear whether these biomarkers also may serve as biomarkers for genotoxic effects which will result in an enhanced cancer risk. In order to assess this problem, Nordic and Italian cohorts were established, and preliminary results from these two studies indicated a predictive value of CA frequency for cancer risk, whereas no such associations were observed for SCE or MN. A collaborative study between the Nordic and Italian research groups, will enable a more thorough evaluation of the cancer predictivity of the cytogenetic endpoints. We here report on the establishment of a joint data base comprising 5271 subjects, examined 1965-1988 for at least one cytogenetic biomarker. Totally, 3540 subjects had been examined for CA, 2702 for SCE and 1496 for MN. These cohorts have been followed-up with respect to subsequent cancer mortality or cancer incidence, and the expected values have been calculated from rates derived from the general populations in each country. Stratified cohort analyses will be performed with respect to the levels of the cytogenetic biomarkers. The importance of potential effect modifiers such as gender, age at test, and time since test, will be evaluated using Poisson regression models. The remaining two potential effect modifiers, occupational exposures and smoking, will be assessed in a case-referent study within the study base

  9. Cancer predictive value of cytogenetic markers used in occupational health surveillance programs. A report from an ongoing study by the European Study Group on Cytogenetic Biomarkers and Health

    International Nuclear Information System (INIS)

    Hagmar, Lars; Stroemberg, Ulf; Mikoczy, Zoli; Tinnerberg, Hakan; Skerfving, Staffan; Bonassi, Stefano; Lando, Cecilia; Hansteen, Inger-Lise; Montagud, Alicia Huici; Knudsen, Lisbeth; Norppa, Hannu; Reuterwall, Christina; Broegger, Anton; Forni, Alessandra; Hoegstedt, Benkt; Lambert, Bo; Mitelman, Felix; Nordenson, Ingrid; Salomaa, Sisko

    1998-01-01

    The cytogenetic endpoints in peripheral blood lymphocytes: chromosomal aberrations (CA), sister chromatid exchange (SCE) and micronuclei (MN) are established biomarkers of exposure for mutagens or carcinogens in the work environment. However, it is not clear whether these biomarkers also may serve as biomarkers for genotoxic effects which will result in an enhanced cancer risk. In order to assess this problem, Nordic and Italian cohorts were established, and preliminary results from these two studies indicated a predictive value of CA frequency for cancer risk, whereas no such associations were observed for SCE or MN. A collaborative study between the Nordic and Italian research groups, will enable a more thorough evaluation of the cancer predictivity of the cytogenetic endpoints. We here report on the establishment of a joint data base comprising 5271 subjects, examined 1965-1988 for at least one cytogenetic biomarker. Totally, 3540 subjects had been examined for CA, 2702 for SCE and 1496 for MN. These cohorts have been followed-up with respect to subsequent cancer mortality or cancer incidence, and the expected values have been calculated from rates derived from the general populations in each country. Stratified cohort analyses will be performed with respect to the levels of the cytogenetic biomarkers. The importance of potential effect modifiers such as gender, age at test, and time since test, will be evaluated using Poisson regression models. The remaining two potential effect modifiers, occupational exposures and smoking, will be assessed in a case-referent study within the study base

  10. Metabolites as Biomarkers of Adverse Reactions Following Vaccination: A Pilot Study using Nuclear Magnetic Resonance Metabolomics

    Science.gov (United States)

    McClenathan, Bruce M.; Stewart, Delisha A.; Spooner, Christina E.; Pathmasiri, Wimal W.; Burgess, Jason P.; McRitchie, Susan L.; Choi, Y. Sammy; Sumner, Susan C.J.

    2017-01-01

    An Adverse Event Following Immunization (AEFI) is an adverse reaction to a vaccination that goes above and beyond the usual side effects associated with vaccinations. One serious AEFI related to the smallpox vaccine is myopericarditis. Metabolomics involves the study of the low molecular weight metabolite profile of cells, tissues, and biological fluids, and provides a functional readout of the phenotype. Metabolomics may help identify a particular metabolic signature in serum of subjects who are predisposed to developing AEFIs. The goal of this study was to identify metabolic markers that may predict the development of adverse events following smallpox vaccination. Serum samples were collected from military personnel prior to and following receipt of smallpox vaccine. The study population included five subjects who were clinically diagnosed with myopericarditis, 30 subjects with asymptomatic elevation of troponins, and 31 subjects with systemic symptoms following immunization, and 34 subjects with no AEFI, serving as controls. Two-hundred pre- and post-smallpox vaccination sera were analyzed by untargeted metabolomics using 1H nuclear magnetic resonance (NMR) spectroscopy. Baseline (pre-) and post-vaccination samples from individuals who experienced clinically verified myocarditis or asymptomatic elevation of troponins were more metabolically distinguishable pre- and post-vaccination compared to individuals who only experienced systemic symptoms, or controls. Metabolomics profiles pre- and post-receipt of vaccine differed substantially when an AEFI resulted. This study is the first to describe pre- and post-vaccination metabolic profiles of subjects who developed an adverse event following immunization. The study demonstrates the promise of metabolites for determining mechanisms associated with subjects who develop AEFI and the potential to develop predictive biomarkers. PMID:28169076

  11. Urinary Proteomics Pilot Study for Biomarker Discovery and Diagnosis in Heart Failure with Reduced Ejection Fraction

    DEFF Research Database (Denmark)

    Rossing, Kasper; Bosselmann, Helle Skovmand; Gustafsson, Finn

    2016-01-01

    and Results Urine samples were analyzed by on-line capillary electrophoresis coupled to electrospray ionization micro time-of-flight mass spectrometry (CE-MS) to generate individual urinary proteome profiles. In an initial biomarker discovery cohort, analysis of urinary proteome profiles from 33 HFr......Background Biomarker discovery and new insights into the pathophysiology of heart failure with reduced ejection fraction (HFrEF) may emerge from recent advances in high-throughput urinary proteomics. This could lead to improved diagnosis, risk stratification and management of HFrEF. Methods.......6%) in individuals with diastolic left ventricular dysfunction (N = 176). The HFrEF-related peptide biomarkers mainly included fragments of fibrillar type I and III collagen but also, e.g., of fibrinogen beta and alpha-1-antitrypsin. Conclusion CE-MS based urine proteome analysis served as a sensitive tool...

  12. Protein biomarkers on tissue as imaged via MALDI mass spectrometry: A systematic approach to study the limits of detection.

    Science.gov (United States)

    van de Ven, Stephanie M W Y; Bemis, Kyle D; Lau, Kenneth; Adusumilli, Ravali; Kota, Uma; Stolowitz, Mark; Vitek, Olga; Mallick, Parag; Gambhir, Sanjiv S

    2016-06-01

    MALDI mass spectrometry imaging (MSI) is emerging as a tool for protein and peptide imaging across tissue sections. Despite extensive study, there does not yet exist a baseline study evaluating the potential capabilities for this technique to detect diverse proteins in tissue sections. In this study, we developed a systematic approach for characterizing MALDI-MSI workflows in terms of limits of detection, coefficients of variation, spatial resolution, and the identification of endogenous tissue proteins. Our goal was to quantify these figures of merit for a number of different proteins and peptides, in order to gain more insight in the feasibility of protein biomarker discovery efforts using this technique. Control proteins and peptides were deposited in serial dilutions on thinly sectioned mouse xenograft tissue. Using our experimental setup, coefficients of variation were biomarkers and a new benchmarking strategy that can be used for comparing diverse MALDI-MSI workflows. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. The validity of the 4-Skills Scan: A double validation study.

    Science.gov (United States)

    van Kernebeek, W G; de Kroon, M L A; Savelsbergh, G J P; Toussaint, H M

    2018-06-01

    Adequate gross motor skills are an essential aspect of a child's healthy development. Where physical education (PE) is part of the primary school curriculum, a strong curriculum-based emphasis on evaluation and support of motor skill development in PE is apparent. Monitoring motor development is then a task for the PE teacher. In order to fulfil this task, teachers need adequate tools. The 4-Skills Scan is a quick and easily manageable gross motor skill instrument; however, its validity has never been assessed. Therefore, the purpose of this study is to assess the construct and concurrent validity of both 4-Skills Scans (version 2007 and version 2015). A total of 212 primary school children (6 - 12 years old), was requested to participate in both versions of the 4-Skills Scan. For assessing construct validity, children covered an obstacle course with video recordings for observation by an expert panel. For concurrent validity, a comparison was made with the MABC-2, by calculating Pearson correlations. Multivariable linear regression analyses were performed to determine the contribution of each subscale to the construct of gross motor skills, according to the MABC-2 and the expert panel. Correlations between the 4-Skills Scans and expert valuations were moderate, with coefficients of .47 (version 2007) and .46 (version 2015). Correlations between the 4-Skills Scans and the MABC-2 (gross) were moderate (.56) for version 2007 and high (.64) for version 2015. It is concluded that both versions of the 4-Skills Scans are satisfactory valid instruments for assessing gross motor skills during PE lessons. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  14. The Australian biomarker, imaging and lifestyle study: phase 1 amyloid imaging results

    International Nuclear Information System (INIS)

    Rowe, C. C.; Pike, K.; Villemagne, V. L.; Morandeau, L.; Masters, C. L.; Ames, D.

    2009-01-01

    Full text:Background: Phase 1 of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing, a three-year prospective longitudinal study recruiting 1,112 volunteers from a cross-section of Australia's elderly population, concluded with more than a quarter of the participants undergoing PiB-PET. Methods: 287 participants received PiB PET scans: 177 Healthy controls (HC); 57 Mild Cognitive Impairment (MCI) subjects; and 53 mild Alzheimer's disease (AD) patients. HC were further classified according to their subjective memory complaints and genetic predisposition. All participants underwent a comprehensive neuropsychological examination, a 3D T1 MP-RAGE and T2 FSE MR, and a PiB-PET scan. Regional and global cortical SUVR were calculated using the cerebellar cortex as reference region. A SUVR cut-off of 1.40 was used to define PiB scans as normal or abnormal. Results: Cortical PIB binding was markedly elevated in all AD patients except one. MCI subjects presented either an AD-like (63%) or normal pattern. Cortical PiB retention was abnormal in 34% of HC and the prevalence increased with age. HC with subjective memory complaints carrying an ApoE4 allele had significantly higher A burdens than non ApoE4 carriers. Conclusions: Phase 1 of the AIBL study has set the foundations for the longitudinal assessment of A burden in HC, MCI and AD. This wil assist the development of techniques for early detection of AD providing a cohort suitable for targeted early intervention studies.

  15. Considerations on development, validation, application, and quality control of immuno(metric) biomarker assays in clinical cancer research: an EORTC-NCI working group report.

    NARCIS (Netherlands)

    Sweep, C.G.J.; Fritsche, H.A.; Gion, M.; Klee, G.G.; Schmitt, M.

    2003-01-01

    A major dilemma associated with immuno(metric) assays for biomarkers is that various kits employing antibodies with differing specificities and binding affinities may generate non-equivalent test results. Also, variation in sample processing and the use of different standards (reference material)

  16. Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker Study.

    Science.gov (United States)

    Ding, Hongliu; Dhima, Kaltra; Lockhart, Kaitlin C; Locascio, Joseph J; Hoesing, Ashley N; Duong, Karen; Trisini-Lipsanopoulos, Ana; Hayes, Michael T; Sohur, U Shivraj; Wills, Anne-Marie; Mollenhauer, Brit; Flaherty, Alice W; Hung, Albert Y; Mejia, Nicte; Khurana, Vikram; Gomperts, Stephen N; Selkoe, Dennis J; Schwarzschild, Michael A; Schlossmacher, Michael G; Hyman, Bradley T; Sudarsky, Lewis R; Growdon, John H; Scherzer, Clemens R

    2013-10-22

    To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD). We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study. Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson's Disease Rating Scale scores at baseline and during follow-up. Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D-deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

  17. The Biomarkers of Exposure and Effect in Agriculture (BEEA) Study: Rationale, Design, Methods, and Participant Characteristics.

    Science.gov (United States)

    Hofmann, Jonathan N; Beane Freeman, Laura E; Lynch, Charles F; Andreotti, Gabriella; Thomas, Kent W; Sandler, Dale P; Savage, Sharon A; Alavanja, Michael C

    2015-01-01

    Agricultural exposures including pesticides, endotoxin, and allergens have been associated with risk of various cancers and other chronic diseases, although the biological mechanisms underlying these associations are generally unclear. To facilitate future molecular epidemiologic investigations, in 2010 the study of Biomarkers of Exposure and Effect in Agriculture (BEEA) was initiated within the Agricultural Health Study, a large prospective cohort in Iowa and North Carolina. Here the design and methodology of BEEA are described and preliminary frequencies for participant characteristics and current agricultural exposures are reported. At least 1,600 male farmers over 50 years of age will be enrolled in the BEEA study. During a home visit, participants are asked to complete a detailed interview about recent agricultural exposures and provide samples of blood, urine, and (since 2013) house dust. As of mid-September 2014, in total, 1,233 participants have enrolled. Most of these participants (83%) were still farming at the time of interview. Among those still farming, the most commonly reported crops were corn (81%) and soybeans (74%), and the most frequently noted animals were beef cattle (35%) and hogs (13%). There were 861 (70%) participants who reported occupational pesticide use in the 12 months prior to interview; among these participants, the most frequently noted herbicides were glyphosate (83%) and 2,4-D (72%), and most commonly reported insecticides were malathion (21%), cyfluthrin (13%), and permethrin (12%). Molecular epidemiologic investigations within BEEA have the potential to yield important new insights into the biological mechanisms through which these or other agricultural exposures influence disease risk.

  18. Brain tissues atrophy is not always the best structural biomarker of physiological aging: A multimodal cross-sectional study.

    Science.gov (United States)

    Cherubini, Andrea; Caligiuri, Maria Eugenia; Péran, Patrice; Sabatini, Umberto; Cosentino, Carlo; Amato, Francesco

    2015-01-01

    This study presents a voxel-based multiple regression analysis of different magnetic resonance image modalities, including anatomical T1-weighted, T2* relaxometry, and diffusion tensor imaging. Quantitative parameters sensitive to complementary brain tissue alterations, including morphometric atrophy, mineralization, microstructural damage, and anisotropy loss, were compared in a linear physiological aging model in 140 healthy subjects (range 20-74 years). The performance of different predictors and the identification of the best biomarker of age-induced structural variation were compared without a priori anatomical knowledge. The best quantitative predictors in several brain regions were iron deposition and microstructural damage, rather than macroscopic tissue atrophy. Age variations were best resolved with a combination of markers, suggesting that multiple predictors better capture age-induced tissue alterations. These findings highlight the importance of a combined evaluation of multimodal biomarkers for the study of aging and point to a number of novel applications for the method described.

  19. Data on serologic inflammatory biomarkers assessed using multiplex assays and host characteristics in the Multicenter AIDS Cohort Study (MACS

    Directory of Open Access Journals (Sweden)

    Heather S. McKay

    2016-12-01

    Full Text Available This article contains data on the associations between fixed and modifiable host characteristics and twenty-three biomarkers of inflammation and immune activation measured longitudinally in a cohort of 250 HIV-uninfected men from the Multicenter AIDS Cohort Study (1984–2009 after adjusting for age, study site, and blood draw time of day using generalized gamma regression. This article also presents associations between each biomarker and each host characteristic in a sample restricted to 2001–2009. These data are supplemental to our original research article entitled “Host factors associated with serologic inflammatory markers assessed using multiplex assays” (McKay, S. Heather, Bream, H. Jay, Margolick, B. Joseph, Martínez-Maza, Otoniel, Phair, P. John, Rinaldo, R. Charles, Abraham, G. Alison, L.P. Jacobson, 2016 [1].

  20. The Jackson Career Explorer: Two Further Validity Studies

    Science.gov (United States)

    Schermer, Julie Aitken

    2012-01-01

    The present report consists of two further validity studies using the Jackson Career Explorer (JCE), a short form and continuous version of the Jackson Vocational Interest Survey, measuring 34 interests. The first study examined the relationships between the JCE and five personality factors, from a sample of 528 individuals. The correlations found…

  1. Basic School Skills Inventory-3: Validity and Reliability Study

    Science.gov (United States)

    Yildiz, F. Ülkü; Çagdas, Aysel; Kayili, Gökhan

    2017-01-01

    The purpose of this study is to perform the validity-reliability analysis of the three subtests of Basic School Skills Inventory 3--Mathematics, Classroom Behavior and Daily Life skills--and do its adaptation for four to six year-old Turkish children. The sample of the study included 595 four to six year-old Turkish children attending public and…

  2. A Validation Study of the Adolescent Dissociative Experiences Scale

    Science.gov (United States)

    Keck Seeley, Susan. M.; Perosa, Sandra, L.; Perosa, Linda, M.

    2004-01-01

    Objective: The purpose of this study was to further the validation process of the Adolescent Dissociative Experiences Scale (A-DES). In this study, a 6-item Likert response format with descriptors was used when responding to the A-DES rather than the 11-item response format used in the original A-DES. Method: The internal reliability and construct…

  3. Pilot study of the pharmacokinetics of betel nut and betel quid biomarkers in saliva, urine, and hair of betel consumers.

    Science.gov (United States)

    Franke, Adrian A; Li, Xingnan; Lai, Jennifer F

    2016-10-01

    Approximately 600 million people worldwide practise the carcinogenic habit of betel nut/quid chewing. Carcinogenic N-nitroso compounds have been identified in saliva or urine of betel chewers and the betel alkaloid arecoline in hair from habitual betel quid chewers. However, the pharmacokinetic parameters of these compounds have been little explored. Assessment of betel use by biomarkers is urgently needed to evaluate the effectiveness of cessation programmes aimed at reducing betel consumption to decrease the burden of cancers in regions of high betel consumption. In the search for biomarkers of betel consumption, we measured by liquid chromatography-mass spectrometry (LC-MS) the appearance and disappearance of betel alkaloids (characteristic for betel nuts), N-nitroso compounds, and chavibetol (characteristic for Piper Betle leaves) in saliva (n=4), hair (n=2), and urine (n=1) of occasional betel nut/quid chewers. The betel alkaloids arecoline, guvacoline, guvacine, and arecaidine were detected in saliva of all four participants and peaked within the first 2 h post-chewing before returning to baseline levels after 8 h. Salivary chavibetol was detected in participants consuming Piper Betle leaves in their quid and peaked ~1 h post-chewing. Urinary arecoline, guvacoline, and arecaidine excretion paralleled saliva almost exactly while chavibetol glucuronide excretion paralleled salivary chavibetol. No betel nut related compounds were detected in the tested hair samples using various extraction methods. From these preliminary results, we conclude that betel exposure can only be followed on a short-term basis (≤8 h post-chewing) using the applied biomarkers from urine and saliva while the feasibility of using hair has yet to be validated. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  4. California Diploma Project Technical Report III: Validity Study--Validity Study of the Health Sciences and Medical Technology Standards

    Science.gov (United States)

    McGaughy, Charis; Bryck, Rick; de Gonzalez, Alicia

    2012-01-01

    This study is a validity study of the recently revised version of the Health Science Standards. The purpose of this study is to understand how the Health Science Standards relate to college and career readiness, as represented by survey ratings submitted by entry-level college instructors of health science courses and industry representatives. For…

  5. Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia.

    Directory of Open Access Journals (Sweden)

    Gregory A Light

    Full Text Available Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1 associated with schizophrenia, 2 stable over time, independent of state-related changes, and 3 free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ and nonpsychiatric comparison subjects (NCS. Stability of clinical and functional measures was also assessed.Participants (SZ n = 341; NCS n = 205 completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade, neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II. In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF. 223 subjects (SZ n = 163; NCS n = 58 returned for retesting after 1 year.Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria.The majority of neurophysiological and neurocognitive measures exhibited deficits in

  6. Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia.

    Science.gov (United States)

    Light, Gregory A; Swerdlow, Neal R; Rissling, Anthony J; Radant, Allen; Sugar, Catherine A; Sprock, Joyce; Pela, Marlena; Geyer, Mark A; Braff, David L

    2012-01-01

    Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed. Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year. Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria. The majority of neurophysiological and neurocognitive measures exhibited deficits in patients

  7. Cooperative learning benefits scale: construction and validation studies

    Directory of Open Access Journals (Sweden)

    José Lopes

    2014-07-01

    Full Text Available The aim of this study was to develop and validate a scale of benefits of the Cooperative Learning (SBCL given the exiguity of instruments that evaluate these outputs of the method. The study resorted to a convenience sample comprised of 162 students, males and females, aged between 11 and 18 years. The final instrument has 23 items in a two-dimensional factor structure: psychological and academic benefits and social benefits. The results indicate that the SBCL present good psychometric properties (construct and discriminant validity and reliability. The results are discussed in light of the model of cooperative learning.

  8. Chasing the Effects of Pre-Analytical Confounders - A Multicenter Study on CSF-AD Biomarkers

    DEFF Research Database (Denmark)

    Leitão, Maria João; Baldeiras, Inês; Herukka, Sanna-Kaisa

    2015-01-01

    INTRODUCTION: Core cerebrospinal fluid (CSF) biomarkers - Aβ42, Tau, and phosphorylated Tau (pTau) - have been recently incorporated in the revised criteria for Alzheimer's disease (AD). However, their widespread clinical application lacks standardization. Pre-analytical sample handling and storage...

  9. Long-interval intracortical inhibition as biomarker for epilepsy : a transcranial magnetic stimulation study

    NARCIS (Netherlands)

    Bauer, Prisca R.; de Goede, Annika A.; Stern, William M.; Pawley, Adam D.; Chowdhury, Fahmida A.; Helling, Robert M.; Bouet, Romain; Kalitzin, Stiliyan N.; Visser, Gerhard H.; Sisodiya, Sanjay M.; Rothwell, John C.; Richardson, Mark P.; van Putten, Michel J.A.M.; Sander, Josemir W.

    2018-01-01

    Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95),

  10. Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers

    International Nuclear Information System (INIS)

    Matheis, Katja A.; Com, Emmanuelle; Gautier, Jean-Charles; Guerreiro, Nelson; Brandenburg, Arnd; Gmuender, Hans; Sposny, Alexandra; Hewitt, Philip; Amberg, Alexander; Boernsen, Olaf; Riefke, Bjoern; Hoffmann, Dana; Mally, Angela; Kalkuhl, Arno; Suter, Laura; Dieterle, Frank; Staedtler, Frank

    2011-01-01

    The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with 'omics' data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.

  11. Discomfort Intolerance Scale: A Study of Reliability and Validity

    Directory of Open Access Journals (Sweden)

    Kadir ÖZDEL

    2012-03-01

    Full Text Available Objective: Discomfort Intolerance Scale was developed by Norman B. Schmidt et al. to assess the individual differences of capacity to withstand physical perturbations or uncomfortable bodily states (2006. The aim of this study is to investigate the validity and reliability of Discomfort Intolerance Scale-Turkish Version (RDÖ. Method: From two different universities, total of 225 students (male=167, female=58 were participated in this study. In order to determine the criterion validity, Beck Anxiety Inventory (BAI and State-Trait Anxiety Inventory (STAI were used. Construct validity was evaluated by factor analysis after the Kaiser-Meyer-Olkin (KMO and Barlett test had been performed. To assess the test-retest reliability the scale was re-applied to 54 participants 6 weeks later. Results: To assess construct validity of DIS, factor analyses were performed using varimax principal components analysis with varimax rotation. The factor analysis resulted in two factors named “discomfort (in tolerance” and “discomfort avoidance”. The Cronbach’s alpha coefficient for the entire scale, discomfort-(intolerance subscale, discomfortavoidance subscale were, .592, .670, .600 respectively. Correlations between two factors of DIS, discomfort intolerance and discomfort avoidance, and Trait Anxiety Inventory of STAI (State-Trait Anxiety Inventory were statistically significant at the level of 0.05. Test-retest reliability was statistically significant at the level of 0.01. Conclusion: Analysis demonstrated that DIS had a satisfactory level of reliability and validity in Turkish university students.

  12. A pilot randomized study of a gratitude journaling intervention on HRV and inflammatory biomarkers in Stage B heart failure patients

    Science.gov (United States)

    Redwine, Laura; Henry, Brook L.; Pung, Meredith A.; Wilson, Kathleen; Chinh, Kelly; Knight, Brian; Jain, Shamini; Rutledge, Thomas; Greenberg, Barry; Maisel, Alan; Mills, Paul J

    2016-01-01

    Objective Stage B, asymptomatic heart failure (HF) presents a therapeutic window for attenuating disease progression and development of HF symptoms, and improving quality of life. Gratitude, the practice of appreciating positive life features, is highly related to quality of life, leading to development of promising clinical interventions. However, few gratitude studies have investigated objective measures of physical health; most relied on self-report measures. We conducted a pilot study in Stage B HF patients to examine whether gratitude journaling improved biomarkers related to HF prognosis. Methods Patients (N = 70; mean age = 66.2 years, SD = 7.6) were randomized to an 8-week gratitude journaling intervention or treatment as usual (TAU). Baseline (T1) assessments included 6-item Gratitude Questionnaire (GQ-6), resting heart rate variability (HRV), and an inflammatory biomarker index. At T2 (mid-intervention) GQ6 was measured. At T3 (post-intervention), T1 measures were repeated but also included a gratitude journaling task. Results The gratitude intervention was associated with improved trait gratitude scores (F = 6.0, p = .017, η2 = .10), reduced inflammatory biomarker index score over time (F = 9.7, p = .004, η2 = .21) and increased parasympathetic HRV responses during the gratitude journaling task (F = 4.2, p = .036, η2 = .15), compared with TAU. However, there were no resting pre- to post-intervention group differences in HRV (p's > .10). Conclusions Gratitude journaling may improve biomarkers related to HF morbidity, such as reduced inflammation; large-scale studies with active control conditions are needed to confirm these findings. PMID:27187845

  13. Pleural effusion biomarkers and computed tomography findings in diagnosing malignant pleural mesothelioma: A retrospective study in a single center

    Science.gov (United States)

    Kataoka, Yuki; Ikegaki, Shunkichi; Saito, Emiko; Matsumoto, Hirotaka; Kaku, Sawako; Shimada, Masatoshi; Hirabayashi, Masataka

    2017-01-01

    In this study, we aimed to examine the clinical value of the pleural effusion (PE) biomarkers, soluble mesothelin-related peptide (SMRP), cytokeratin 19 fragment (CYFRA 21–1) and carcinoembryonic antigen (CEA), and the utility of combining chest computed tomography (CT) findings with these biomarkers, in diagnosing malignant pleural mesothelioma (MPM). We conducted a retrospective cohort study in a single center. Consecutive patients with undiagnosed pleural effusions who underwent PE analysis between September 2014 and August 2016 were reviewed. This study included 240 patients (32 with MPM and 208 non-MPM). SMRP and the CYFRA 21-1/CEA ratio had a sensitivity and specificity for diagnosing MPM of 56.3% and 86.5%, and 87.5% and 74.0%, respectively. Using receiver operating characteristics (ROC) curve analysis of the ability of these markers to distinguish MPM from all other PE causes, the area under the ROC curve (AUC) for SMRP and the CYFRA 21-1/CEA ratio was 0.804 and 0.874, respectively. The sensitivity and specificity of SMRP combined with the CYFRA 21-1/CEA ratio were 93.8% and 64.9%, respectively. The sensitivity of the combination of SMRP, the CYFRA 21-1/CEA ratio, and the presence of Leung’s criteria (a chest CT finding that is suggestive of malignant pleural disease) was 93.8%. In conclusion, the combined PE biomarkers had a high sensitivity for diagnosing MPM, although the addition of chest CT findings did not improve the sensitivity of SMRP combined with the CYFRA 21-1/CEA ratio. Combination of these biomarkers helped to rule out MPM effectively among patients at high risk of suffering MPM and would be valuable especially for old frail patients who have difficulty in undergoing invasive procedures such as thoracoscopy. PMID:28968445

  14. Applications of biological tools or biomarkers in aquatic biota: A case study of the Tamar estuary, South West England.

    Science.gov (United States)

    Dallas, Lorna J; Jha, Awadhesh N

    2015-06-30

    Biological systems are the ultimate recipients of pollutant-induced damage. Consequently, our traditional reliance on analytical tools is not enough to assess ecosystem health. Biological responses or biomarkers are therefore also considered to be important tools for environmental hazard and risk assessments. Due to historical mining, other anthropogenic activities, and its conservational importance (e.g. NATURA sites, SACs), the Tamar estuary in South West England is an ideal environment in which to examine applications of such biological tools. This review presents a thorough and critical evaluation of the different biological tools used in the Tamar estuary thus far, while also discussing future perspectives for biomarker studies from a global perspective. In particular, we focus on the challenges which hinder applications of biological tools from being more readily incorporated into regulatory frameworks, with the aim of enabling both policymakers and primary stakeholders to maximise the environmental relevance and regulatory usefulness of such tools. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. A pilot study to evaluate the application of a generic protein standard panel for quality control of biomarker detection technologies

    Directory of Open Access Journals (Sweden)

    Valdivia Hernan J

    2011-08-01

    Full Text Available Abstract Background Protein biomarker studies are currently hampered by a lack of measurement standards to demonstrate quality, reliability and comparability across multiple assay platforms. This is especially pertinent for immunoassays where multiple formats for detecting target analytes are commonly used. Findings In this pilot study a generic panel of six non-human protein standards (50 - 10^7 pg/mL of varying abundance was prepared as a quality control (QC material. Simulated "normal" and "diseased" panels of proteins were prepared in pooled human plasma and incorporated into immunoassays using the Meso Scale Discovery® (MSD® platform to illustrate reliable detection of the component proteins. The protein panel was also evaluated as a spike-in material for a model immunoassay involving detection of ovarian cancer biomarkers within individual human plasma samples. Our selected platform could discriminate between two panels of the proteins exhibiting small differences in abundance. Across distinct experiments, all component proteins exhibited reproducible signal outputs in pooled human plasma. When individual donor samples were used, half the proteins produced signals independent of matrix effects. These proteins may serve as a generic indicator of platform reliability. Each of the remaining proteins exhibit differential signals across the distinct samples, indicative of sample matrix effects, with the three proteins following the same trend. This subset of proteins may be useful for characterising the degree of matrix effects associated with the sample which may impact on the reliability of quantifying target diagnostic biomarkers. Conclusions We have demonstrated the potential utility of this panel of standards to act as a generic QC tool for evaluating the reproducibility of the platform for protein biomarker detection independent of serum matrix effects.

  16. High levels of biomarkers of collagen remodeling are associated with increased mortality in COPD – results from the ECLIPSE study

    DEFF Research Database (Denmark)

    Sand, Jannie M B; Leeming, Diana J; Byrjalsen, Inger

    2016-01-01

    with mortality in COPD and measured neo-epitopes originating from ECM proteins associated with lung tissue remodeling. METHODS: Biomarkers of ECM remodeling were assessed in a subpopulation (n = 1000) of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. Validated......BACKGROUND: There is a need to identify individuals with COPD at risk for disease progression and mortality. Lung tissue remodeling is associated with the release of extracellular matrix (ECM) fragments into the peripheral circulation. We hypothesized that ECM remodeling was associated...... immunoassays measuring serological neo-epitopes produced by proteolytic cleavage associated with degradation of collagen type I, III, IV, and VI, elastin, and biglycan, and formation of collagen type VI as well as fibrinogen and C-reactive protein were used. Multivariate models were used to assess...

  17. Cancer predictive value of cytogenetic markers used in occupational health surveillance programs: a report from an ongoing study by the European Study Group on Cytogenetic Biomarkers and Health

    DEFF Research Database (Denmark)

    Hagmar, L; Bonassi, S; Strömberg, U

    1998-01-01

    cytogenetic biomarker. Totally, 3540 subjects had been examined for CA, 2702 for SCE and 1496 for MN. These cohorts have been followed-up with respect to subsequent cancer mortality or cancer incidence, and the expected values have been calculated from rates derived from the general populations in each...... as biomarkers for genotoxic effects which will result in an enhanced cancer risk. In order to assess this problem, Nordic and Italian cohorts were established, and preliminary results from these two studies indicated a predictive value of CA frequency for cancer risk, whereas no such associations were observed...... country. Stratified cohort analyses will be performed with respect to the levels of the cytogenetic biomarkers. The importance of potential effect modifiers such as gender, age at test, and time since test, will be evaluated using Poisson regression models. The remaining two potential effect modifiers...

  18. Development and validation of stability indicating studies of ...

    African Journals Online (AJOL)

    Development and validation of stability indicating studies of paliperidone ... A simple and sensitive stability indicating HPLC method is developed for the ... The developed method was proved adequate for quantitative determination of ... Browse By Country · List All Titles · Free To Read Titles This Journal is Open Access.

  19. Teachers' Engagement at Work: An International Validation Study

    Science.gov (United States)

    Klassen, Robert M.; Aldhafri, Said; Mansfield, Caroline F.; Purwanto, Edy; Siu, Angela F. Y.; Wong, Marina W.; Woods-McConney, Amanda

    2012-01-01

    This study explored the validity of the Utrecht Work Engagement Scale in a sample of 853 practicing teachers from Australia, Canada, China (Hong Kong), Indonesia, and Oman. The authors used multigroup confirmatory factor analysis to test the factor structure and measurement invariance across settings, after which they examined the relationships…

  20. 29 CFR 1607.14 - Technical standards for validity studies.

    Science.gov (United States)

    2010-07-01

    ..., if the behavior results in work product(s), an analysis of the work product(s). Any job analysis.... This job analysis should show the work behavior(s) required for successful performance of the job, or... 29 Labor 4 2010-07-01 2010-07-01 false Technical standards for validity studies. 1607.14 Section...

  1. Validation Study of the Abbreviated Math Anxiety Scale: Spanish Adaptation

    Science.gov (United States)

    Brown, Jennifer L.; Sifuentes, Lucía Macías

    2016-01-01

    With growing numbers of Hispanic students enrolling in post-secondary school, there is a need to increase retention and graduation rates. The purpose of this study was to validate the Spanish adaptation of the Abbreviated Math Anxiety Scale (AMAS). The AMAS was translated and administered to 804 freshman students at a post-secondary institution in…

  2. A Validation Study of Maslow's Hierarchy of Needs Theory.

    Science.gov (United States)

    Clay, Rex J.

    A study was conducted to expand the body of research that tests the validity of Abraham Maslow's hierarchy of needs theory in a work context where it often serves as a guide for the supervisor's relationships with his subordinates. Data was gathered by questionnaire which tested for a hierarchy of needs among instructors at four community colleges…

  3. A validation study of the Brief Irrational Thoughts Inventory

    NARCIS (Netherlands)

    Hoogsteder, L.M.; Wissink, I.B.; Stams, G.J.J.M.; van Horn, J.E.; Hendriks, J.

    2014-01-01

    This study examines the reliability and validity of the "Brief Irrational Thoughts Inventory" (BITI) in a sample of 256 justice-involved youths. The BITI is a questionnaire used to determine the nature and severity of irrational thoughts related to aggressive (externalizing), sub-assertive

  4. Model validation studies of solar systems, Phase III. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Lantz, L.J.; Winn, C.B.

    1978-12-01

    Results obtained from a validation study of the TRNSYS, SIMSHAC, and SOLCOST solar system simulation and design are presented. Also included are comparisons between the FCHART and SOLCOST solar system design programs and some changes that were made to the SOLCOST program. Finally, results obtained from the analysis of several solar radiation models are presented. Separate abstracts were prepared for ten papers.

  5. A Validity Study of the Self-Esteem Inventory.

    Science.gov (United States)

    Landis, H. John

    Results of this validation study of a slightly modified version of the Coppersmith Self-Esteem Inventory substantiate its use with seventh graders to assess Goal I (concerning self-understanding and appreciation of self-worth) of the Educational Quality Assessment Program in Pennsylvania. Appendixes include the definition and rationale for Goal I,…

  6. Turkish Metalinguistic Awareness Scale: A Validity and Reliability Study

    Science.gov (United States)

    Varisoglu, Behice

    2018-01-01

    The aim of this study is to develop a useful, valid and reliable measurement tool that will help teacher candidates determine their Turkish metalinguistic awareness. During the development of the scale, a pool of items was created by scanning the relevant literature and examining other awareness scales. The materials prepared were re-examined…

  7. A Validation Study of the Student Oral Proficiency Assessment (SOPA).

    Science.gov (United States)

    Thompson, Lynn E.; Kenyon, Dorry M.; Rhodes, Nancy C.

    This study validated the Student Oral Proficiency Assessment (SOPA), an oral proficiency instrument designed for students in elementary foreign language programs. Elementary students who were tested with the SOPA were also administered other instruments designed to measure proficiency. These instruments included the Stanford Foreign Language Oral…

  8. Assessing validity of observational intervention studies - the Benchmarking Controlled Trials.

    Science.gov (United States)

    Malmivaara, Antti

    2016-09-01

    Benchmarking Controlled Trial (BCT) is a concept which covers all observational studies aiming to assess impact of interventions or health care system features to patients and populations. To create and pilot test a checklist for appraising methodological validity of a BCT. The checklist was created by extracting the most essential elements from the comprehensive set of criteria in the previous paper on BCTs. Also checklists and scientific papers on observational studies and respective systematic reviews were utilized. Ten BCTs published in the Lancet and in the New England Journal of Medicine were used to assess feasibility of the created checklist. The appraised studies seem to have several methodological limitations, some of which could be avoided in planning, conducting and reporting phases of the studies. The checklist can be used for planning, conducting, reporting, reviewing, and critical reading of observational intervention studies. However, the piloted checklist should be validated in further studies. Key messages Benchmarking Controlled Trial (BCT) is a concept which covers all observational studies aiming to assess impact of interventions or health care system features to patients and populations. This paper presents a checklist for appraising methodological validity of BCTs and pilot-tests the checklist with ten BCTs published in leading medical journals. The appraised studies seem to have several methodological limitations, some of which could be avoided in planning, conducting and reporting phases of the studies. The checklist can be used for planning, conducting, reporting, reviewing, and critical reading of observational intervention studies.

  9. Reliability and validity of the foot and ankle outcome score: a validation study from Iran.

    Science.gov (United States)

    Negahban, Hossein; Mazaheri, Masood; Salavati, Mahyar; Sohani, Soheil Mansour; Askari, Marjan; Fanian, Hossein; Parnianpour, Mohamad

    2010-05-01

    The aims of this study were to culturally adapt and validate the Persian version of Foot and Ankle Outcome Score (FAOS) and present data on its psychometric properties for patients with different foot and ankle problems. The Persian version of FAOS was developed after a standard forward-backward translation and cultural adaptation process. The sample included 93 patients with foot and ankle disorders who were asked to complete two questionnaires: FAOS and Short-Form 36 Health Survey (SF-36). To determine test-retest reliability, 60 randomly chosen patients completed the FAOS again 2 to 6 days after the first administration. Test-retest reliability and internal consistency were assessed using intraclass correlation coefficient (ICC) and Cronbach's alpha, respectively. To evaluate convergent and divergent validity of FAOS compared to similar and dissimilar concepts of SF-36, the Spearman's rank correlation was used. Dimensionality was determined by assessing item-subscale correlation corrected for overlap. The results of test-retest reliability show that all the FAOS subscales have a very high ICC, ranging from 0.92 to 0.96. The minimum Cronbach's alpha level of 0.70 was exceeded by most subscales. The Spearman's correlation coefficient for convergent construct validity fell within 0.32 to 0.58 for the main hypotheses presented a priori between FAOS and SF-36 subscales. For dimensionality, the minimum Spearman's correlation coefficient of 0.40 was exceeded by most items. In conclusion, the results of our study show that the Persian version of FAOS seems to be suitable for Iranian patients with various foot and ankle problems especially lateral ankle sprain. Future studies are needed to establish stronger psychometric properties for patients with different foot and ankle problems.

  10. Developing biomarkers in mood disorders research through the use of rapid-acting antidepressants.

    Science.gov (United States)

    Niciu, Mark J; Mathews, Daniel C; Nugent, Allison C; Ionescu, Dawn F; Furey, Maura L; Richards, Erica M; Machado-Vieira, Rodrigo; Zarate, Carlos A

    2014-04-01

    An impediment to progress in mood disorders research is the lack of analytically valid and qualified diagnostic and treatment biomarkers. Consistent with the National Institute of Mental Health (NIMH)'s Research Domain Criteria (RDoC) initiative, the lack of diagnostic biomarkers has precluded us from moving away from a purely subjective (symptom-based) toward a more objective diagnostic system. In addition, treatment response biomarkers in mood disorders would facilitate drug development and move beyond trial-and-error toward more personalized treatments. As such, biomarkers identified early in the pathophysiological process are proximal biomarkers (target engagement), while those occurring later in the disease process are distal (disease pathway components). One strategy to achieve this goal in biomarker development is to increase efforts at the initial phases of biomarker development (i.e. exploration and validation) at single sites with the capability of integrating multimodal approaches across a biological systems level. Subsequently, resultant putative biomarkers could then undergo characterization and surrogacy as these latter phases require multisite collaborative efforts. We have used multimodal approaches - genetics, proteomics/metabolomics, peripheral measures, multimodal neuroimaging, neuropsychopharmacological challenge paradigms and clinical predictors - to explore potential predictor and mediator/moderator biomarkers of the rapid-acting antidepressants ketamine and scopolamine. These exploratory biomarkers may then be used for a priori stratification in larger multisite controlled studies during the validation and characterization phases with the ultimate goal of surrogacy. In sum, the combination of target engagement and well-qualified disease-related measures are crucial to improve our pathophysiological understanding, personalize treatment selection, and expand our armamentarium of novel therapeutics. © 2013 Wiley Periodicals, Inc.

  11. Vitamins and iron blood biomarkers are associated with blood pressure levels in European adolescents. The HELENA study.

    Science.gov (United States)

    de Moraes, Augusto César Ferreira; Gracia-Marco, Luis; Iglesia, Iris; González-Gross, Marcela; Breidenassel, Christina; Ferrari, Marika; Molnar, Dénes; Gómez-Martínez, Sonia; Androutsos, Odysseas; Kafatos, Anthony; Cuenca-García, Magdalena; Sjöström, Michael; Gottrand, Frederic; Widhalm, Kurt; Carvalho, Heráclito Barbosa; Moreno, Luis A

    2014-01-01

    Previous research showed that low concentration of biomarkers in the blood during adolescence (i.e., iron status; retinol; and vitamins B6, B12, C, and D) may be involved in the early stages of development of many chronic diseases, such as hypertension. The aim was to evaluate if iron biomarkers and vitamins in the blood are associated with blood pressure in European adolescents. Participants from the Healthy Lifestyle in Europe by Nutrition in Adolescence cross-sectional study (N = 1089; 12.5-17.5 y; 580 girls) were selected by complex sampling. Multilevel linear regression models examined the associations between iron biomarkers and vitamins in the blood and blood pressure; the analyses were stratified by sex and adjusted for contextual and individual potential confounders. A positive association was found in girls between RBC folate concentration and systolic blood pressure (SBP) (β = 3.19; 95% confidence interval [CI], 0.61-5.77), although no association between the vitamin serum biomarkers concentrations and diastolic blood pressure (DBP) was found. In boys, retinol was positively associated with DBP (β = 3.84; 95% CI, 0.51-7.17) and vitamin B6 was positively associated with SBP (β = 3.82; 95% CI, 1.46-6.18). In contrast, holotranscobalamin was inversely associated with SBP (β = -3.74; 95% CI, -7.28 to -0.21). Levels of RBC folate and vitamin B6 in blood may affect BP in adolescents. In this context, programs aimed at avoiding high BP levels should promote healthy eating behavior by focusing on the promotion of vegetable proteins and foods rich in vitamin B12 (i.e., white meat and eggs), which may help to achieve BP blood control in adolescents. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Intercorrelation between immunological biomarkers and job stress indicators among female nurses: A nine-month longitudinal study

    Directory of Open Access Journals (Sweden)

    Hyung-Suk eYoon

    2014-10-01

    Full Text Available Some immunological biomarkers have been reported to be associated with job stress. This study was conducted to explore an intercorrelation between the psychological components of job stress and various immunological biomarkers among female nurses. To assess monthly and weekly job stress, 41 nurses had repeatedly completed the questionnaires such as the GJSQ, the POMS and the CES-D. Using flow cytometry and radioimmunoassay, the number of white blood cells, lymphocytic proliferation to mitogens, and toxoid were measured. Moreover, the levels of hydrocortisol, IL-b, INF-r, and TNF-a and salivary IgA were eveluated by enzyme-linked immunosorbent assay. When the Pearson correlation coefficients between job stress and immunological biomarkers were estimated after adjusting for age and smoking status, Clashes: conflict at work was significantly related to the number of CD4 cells (r = 0.36, p-value < 0.05, CD4 to CD8 ratio (0.35; < 0.05, response to concanavalin A (0.42; < 0.05, and phytohemagglutinin (0.35; < 0.05. Additionally, the level of hydrocortisol was significantly related to seven psychosocial measures; i.e., role conflict (-0.47; < 0.01, role ambiguity (-0.39; < 0.05, clashes at work (-0.38; < 0.05, control & influence at work (0.53; < 0.01, task control (0.55; < 0.001, resources at work (0.35; < 0.05, and skill underutilization (0.43; < 0.05. The results indicate that 1 the psychological job stress is associated with the levels of some immunological biomarkers in nurses; and 2 especially, hydrocortisol shows a remarkable relationship with diverse job stress indicators.

  13. Development, validation and application of a micro-liquid chromatography-tandem mass spectrometry based method for simultaneous quantification of selected protein biomarkers of endothelial dysfunction in murine plasma.

    Science.gov (United States)

    Suraj, Joanna; Kurpińska, Anna; Olkowicz, Mariola; Niedzielska-Andres, Ewa; Smolik, Magdalena; Zakrzewska, Agnieszka; Jasztal, Agnieszka; Sitek, Barbara; Chlopicki, Stefan; Walczak, Maria

    2018-02-05

    The objective of this study was to develop and validate the method based on micro-liquid chromatography-tandem mass spectrometry (microLC/MS-MRM) for simultaneous determination of adiponectin (ADN), von Willebrand factor (vWF), soluble form of vascular cell adhesion molecule 1 (sVCAM-1), soluble form of intercellular adhesion molecule 1 (sICAM-1) and syndecan-1 (SDC-1) in mouse plasma. The calibration range was established from 2.5pmol/mL to 5000pmol/mL for ADN; 5pmol/mL to 5000pmol/mL for vWF; 0.375pmol/mL to 250pmol/mL for sVCAM-1 and sICAM-1; and 0.25pmol/mL to 250pmol/mL for SDC-1. The method was applied to measure the plasma concentration of selected proteins in mice fed high-fat diet (HFD), and revealed the pro-thrombotic status by increased concentration of vWF (1.31±0.17 nmol/mL (Control) vs 1.98±0.09 nmol/mL (HFD), p <0.05) and the dysregulation of adipose tissue metabolism by decreased concentration of ADN (0.62±0.08 nmol/mL (Control) vs 0.37±0.06 nmol/mL (HFD), p <0.05). In conclusion, the microLC/MS-MRM-based method allows for reliable measurements of selected protein biomarkers of endothelial dysfunction in mouse plasma. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Linking stress and immunity: Immunoglobulin A as a non-invasive physiological biomarker in animal welfare studies.

    Science.gov (United States)

    Staley, Molly; Conners, Melinda G; Hall, Katie; Miller, Lance J

    2018-04-26

    As the animal welfare community strives to empirically assess how care and management practices can help maintain or even enhance welfare, the development of tools for non-invasively measuring physiological biomarkers is essential. Of the suite of physiological biomarkers, Immunoglobulin A (IgA), particularly the secretory form (Secretory IgA or SIgA), is at the forefront because of its crucial role in mucosal immunity and links to physical health, stress, and overall psychological well-being. While interpretation of SIgA values on short time scales is complex, long-term SIgA patterns are consistent: conditions that create chronic stress lead to suppression of SIgA. In contrast, when welfare is enhanced, SIgA concentrations are predicted to stabilize at higher concentrations. In this review, we examine how SIgA concentrations are reflective of both physiological stress and immune function. We then review the literature associating SIgA concentrations with various metrics of animal welfare and provide detailed methodological considerations for SIgA monitoring. Overall, our aim is to provide an in-depth discussion regarding the value of SIgA as physiological biomarker to studies aiming to understand the links between stress and immunity. Copyright © 2017. Published by Elsevier Inc.

  15. Fatty acid biomarkers: validation of food web and trophic markers using C-13-labelled fatty acids in juvenile sandeel ( Ammodytes tobianus )

    DEFF Research Database (Denmark)

    Dalsgaard, Anne Johanne Tang; St. John, Michael

    2004-01-01

    A key issue in marine science is parameterizing trophic interactions in marine food webs, thereby developing an understanding of the importance of top-down and bottom-up controls on populations of key trophic players. This study validates the utility of fatty acid food web and trophic markers usi......), respectively. Lack of temporal trends in nonlabelled fatty acids confirmed the conservative incorporation of labelled fatty acids by the fish.......A key issue in marine science is parameterizing trophic interactions in marine food webs, thereby developing an understanding of the importance of top-down and bottom-up controls on populations of key trophic players. This study validates the utility of fatty acid food web and trophic markers using...... C-13-labelled fatty acids to verify the conservative incorporation of fatty acid tracers by juvenile sandeel (Ammodytes tobianus) and assess their uptake, clearance, and metabolic turnover rates. Juvenile sandeel were fed for 16 days in the laboratory on a formulated diet enriched in (13)C16...

  16. Development and validation study of the Smartphone Overuse Screening Questionnaire.

    Science.gov (United States)

    Lee, Han-Kyeong; Kim, Ji-Hae; Fava, Maurizio; Mischoulon, David; Park, Jae-Hyun; Shim, Eun-Jung; Lee, Eun-Ho; Lee, Ji Hyeon; Jeon, Hong Jin

    2017-11-01

    The aim of this study was to develop a screening questionnaire that could distinguish individuals at high risk of smartphone overuse from casual users. The reliability, validity, and diagnostic ability of the Smartphone Overuse Screening Questionnaire (SOS-Q) were evaluated. Preliminary items were assessed by 50 addiction experts on-line, and 28 questions were selected. A total of 158 subjects recruited from six community centers for internet addiction participated in this study. The SOS-Q, Young's internet addiction scale, Korean scale for internet addiction, and Smartphone Scale for Smartphone Addiction (S-Scale) were used to assess the concurrent validity. Construct validity was supported by a six-factor model using an exploratory factor analysis. The internal consistency and the item-total correlations were favorable (α = 0.95, r = 0.35-0.81). The test-retest reliability was moderate (r = 0.70). The SOS-Q showed superior concurrent validity with the highest correlation between the S-Scale (r = 0.76). Receiver operating characteristic curve analysis revealed an area under the curve of 0.877. A cut-off point of 49 effectively categorized addiction high-risk group with a sensitivity of 0.81 and specificity of 0.86. Overall, the current study supports the use of SOS-Q as both a primary and supplementary measurement tool in a variety of settings. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Molecular Elucidation of Disease Biomarkers at the Interface of Chemistry and Biology.

    Science.gov (United States)

    Zhang, Liqin; Wan, Shuo; Jiang, Ying; Wang, Yanyue; Fu, Ting; Liu, Qiaoling; Cao, Zhijuan; Qiu, Liping; Tan, Weihong

    2017-02-22

    Disease-related biomarkers are objectively measurable molecular signatures of physiological status that can serve as disease indicators or drug targets in clinical diagnosis and therapy, thus acting as a tool in support of personalized medicine. For example, the prostate-specific antigen (PSA) biomarker is now widely used to screen patients for prostate cancer. However, few such biomarkers are currently available, and the process of biomarker identification and validation is prolonged and complicated by inefficient methods of discovery and few reliable analytical platforms. Therefore, in this Perspective, we look at the advanced chemistry of aptamer molecules and their significant role as molecular probes in biomarker studies. As a special class of functional nucleic acids evolved from an iterative technology termed Systematic Evolution of Ligands by Exponential Enrichment (SELEX), these single-stranded oligonucleotides can recognize their respective targets with selectivity and affinity comparable to those of protein antibodies. Because of their fast turnaround time and exceptional chemical properties, aptamer probes can serve as novel molecular tools for biomarker investigations, particularly in assisting identification of new disease-related biomarkers. More importantly, aptamers are able to recognize biomarkers from complex biological environments such as blood serum and cell surfaces, which can provide direct evidence for further clinical applications. This Perspective highlights several major advancements of aptamer-based biomarker discovery strategies and their potential contribution to the practice of precision medicine.

  18. Biomarkers of inflammation, coagulation and microbial translocation in HIV/HCV co-infected patients in the SMART study

    DEFF Research Database (Denmark)

    Peters, Lars; Neuhaus, Jacqueline; Duprez, Daniel

    2014-01-01

    BACKGROUND: Previous results from the SMART study showed that HIV/viral hepatitis co-infected persons with impaired liver function are at increased risk of death following interruption of antiretroviral therapy (ART). OBJECTIVES: To investigate the influence of fibrosis and ART interruption...... on levels of biomarkers of inflammation, coagulation and microbial translocation in HIV/HCV co-infected persons in the SMART study. STUDY DESIGN: All HIV/HCV co-infected persons with stored plasma at study entry and at six months of follow-up were included (N=362). D-dimer, IL-6, sCD14 and hepatic...

  19. Urine Metabonomics Reveals Early Biomarkers in Diabetic Cognitive Dysfunction.

    Science.gov (United States)

    Song, Lili; Zhuang, Pengwei; Lin, Mengya; Kang, Mingqin; Liu, Hongyue; Zhang, Yuping; Yang, Zhen; Chen, Yunlong; Zhang, Yanjun

    2017-09-01

    Recently, increasing attention has been paid to diabetic encephalopathy, which is a frequent diabetic complication and affects nearly 30% of diabetics. Because cognitive dysfunction from diabetic encephalopathy might develop into irreversible dementia, early diagnosis and detection of this disease is of great significance for its prevention and treatment. This study is to investigate the early specific metabolites biomarkers in urine prior to the onset of diabetic cognitive dysfunction (DCD) by using metabolomics technology. An ultra-high performance liquid-chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q/TOF-MS) platform was used to analyze the urine samples from diabetic mice that were associated with mild cognitive impairment (MCI) and nonassociated with MCI in the stage of diabetes (prior to the onset of DCD). We then screened and validated the early biomarkers using OPLS-DA model and support vector machine (SVM) method. Following multivariate statistical and integration analysis, we found that seven metabolites could be accepted as early biomarkers of DCD, and the SVM results showed that the prediction accuracy is as high as 91.66%. The identities of four biomarkers were determined by mass spectrometry. The identified biomarkers were largely involved in nicotinate and nicotinamide metabolism, glutathione metabolism, tryptophan metabolism, and sphingolipid metabolism. The present study first revealed reliable biomarkers for early diagnosis of DCD. It provides new insight and strategy for the early diagnosis and treatment of DCD.

  20. Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy.

    Science.gov (United States)

    Forker, L J; Choudhury, A; Kiltie, A E

    2015-10-01

    Radiotherapy is an essential component of treatment for more than half of newly diagnosed cancer patients. The response to radiotherapy varies widely between individuals and although advances in technology have allowed the adaptation of radiotherapy fields to tumour anatomy, it is still not possible to tailor radiotherapy based on tumour biology. A biomarker of intrinsic radiosensitivity would be extremely valuable for individual dosing, aiding decision making between radical treatment options and avoiding toxicity of neoadjuvant or adjuvant radiotherapy in those unlikely to benefit. This systematic review summarises the current evidence for biomarkers under investigation as predictors of radiotherapy benefit. Only 10 biomarkers were identified as having been evaluated for their radiotherapy-specific predictive value in over 100 patients in a clinical setting, highlighting that despite a rich literature there were few high-quality studies for inclusion. The most extensively studied radiotherapy predictive biomarkers were the radiosensitivity index and MRE11; however, neither has been evaluated in a randomised controlled trial. Although these biomarkers show promise, there is not enough evidence to justify their use in routine practice. Further validation is needed before biomarkers can fulfil their potential and predict treatment outcomes for large numbers of patients. Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

  1. Plasma Soluble Prion Protein, a Potential Biomarker for Sport-Related Concussions: A Pilot Study

    OpenAIRE

    Pham, Nam; Akonasu, Hungbo; Shishkin, Rhonda; Taghibiglou, Changiz

    2015-01-01

    Sport-related mild traumatic brain injury (mTBI) or concussion is a significant health concern to athletes with potential long-term consequences. The diagnosis of sport concussion and return to sport decision making is one of the greatest challenges facing health care clinicians working in sports. Blood biomarkers have recently demonstrated their potential in assisting the detection of brain injury particularly, in those cases with no obvious physical injury. We have recently discovered plasm...

  2. Online crowdsourcing for efficient rating of speech: a validation study.

    Science.gov (United States)

    McAllister Byun, Tara; Halpin, Peter F; Szeredi, Daniel

    2015-01-01

    Blinded listener ratings are essential for valid assessment of interventions for speech disorders, but collecting these ratings can be time-intensive and costly. This study evaluated the validity of speech ratings obtained through online crowdsourcing, a potentially more efficient approach. 100 words from children with /r/ misarticulation were electronically presented for binary rating by 35 phonetically trained listeners and 205 naïve listeners recruited through the Amazon Mechanical Turk (AMT) crowdsourcing platform. Bootstrapping was used to compare different-sized samples of AMT listeners against a "gold standard" (mode across all trained listeners) and an "industry standard" (mode across bootstrapped samples of three trained listeners). There was strong overall agreement between trained and AMT listeners. The "industry standard" level of performance was matched by bootstrapped samples with n = 9 AMT listeners. These results support the hypothesis that valid ratings of speech data can be obtained in an efficient manner through AMT. Researchers in communication disorders could benefit from increased awareness of this method. Readers will be able to (a) discuss advantages and disadvantages of data collection through the crowdsourcing platform Amazon Mechanical Turk (AMT), (b) describe the results of a validity study comparing samples of AMT listeners versus phonetically trained listeners in a speech-rating task. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. A multiplex quantitative proteomics strategy for protein biomarker studies in urinary exosomes.

    Science.gov (United States)

    Raj, Delfin A A; Fiume, Immacolata; Capasso, Giovambattista; Pocsfalvi, Gabriella

    2012-06-01

    Urinary exosomes have received considerable attention as a potential biomarker source for the diagnosis of renal diseases. Notwithstanding, their use in protein biomarker research is hampered by the lack of efficient methods for vesicle isolation, lysis, and protein quantification. Here we report an improved ultracentrifugation-based method that facilitates the solubilization and removal of major impurities associated with urinary exosomes. A double-cushion sucrose/D(2)O centrifugation step was used after a two-step differential centrifugation to separate exosomes from the heavier vesicles. After the removal of uromodulin, 378 and 79 unique proteins were identified, respectively, in low- and high-density fractions. Comparison of our data with two previously published data sets helped to define proteins commonly found in urinary exosomes. Lysis, protein extraction, and in-solution digestion of exosomes were then optimized for MudPIT application. More than a hundred exosomal proteins were quantified by four-plex iTRAQ analysis of single and pooled samples from two different age groups. For healthy men, six proteins (TSN1, PODXL, IDHC, PPAP, ACBP, and ANXA5) showed significant expression differences between exosome pools of those aged 25-50 and 50-70 years old. Thus, exosomes isolated by our method provide the basis for the development of robust quantitative methods for protein biomarker research.

  4. Paleoenvironmental assessment of recent environmental changes in Florida Bay, USA: a biomarker based study

    Science.gov (United States)

    Xu, Y.; Holmes, C.W.; Jaffe, R.

    2007-01-01

    The extractable lipid compositions in four Florida Bay cores were determined in order to understand environmental changes over the last 160 years. The most significant environmental change was recorded by oscillations in the amplitude and frequency of biomarkers during the 20th century. Two seagrass molecular proxies (Paq and the C25/C27n-alkan-2-one ratio) reached a maximum post 1900, suggesting that abundant seagrass communities existed during the 20th century. A sharp drop in the Paq value from 0.65 to 0.48 in the central Bay at about 1987 seems to reflect seagrass die-off. The concentrations of microbial biomarkers (C20 HBIs, C25 HBIs and dinosterol) substantially increased after 1950 in the TC, BA and NB cores, reflecting an increase in algal (planktonic organism) primary productivity. However, the RB core presented the highest abundance of C25 HBIs and dinosterol during the period of 1880–1940, suggesting historically large inputs from diatoms and dinoflagellates. A substantial rise in abundance of taraxerol (a specific biomarker of mangroves) from 20 μg/g TOC in the 1830s to 279 μg/g TOC in the l980s is likely a result of increased mangrove primary productivity along the shore of the NE Bay. These changes are most likely the result of hydrological alterations in South Florida.

  5. Biomarkers in pancreatic adenocarcinoma: current perspectives

    Directory of Open Access Journals (Sweden)

    Swords DS

    2016-12-01

    Full Text Available Douglas S Swords, Matthew A Firpo, Courtney L Scaife, Sean J Mulvihill Department of Surgery, University of Utah Health Sciences, Salt Lake City, UT, USA Abstract: Pancreatic ductal adenocarcinoma (PDAC has a poor prognosis, with a 5-year survival rate of 7.7%. Most patients are diagnosed at an advanced stage not amenable to potentially curative resection. A substantial portion of this review is dedicated to reviewing the current literature on carbohydrate antigen (CA 19-9, which is currently the only guideline-recommended biomarker for PDAC. It provides valuable prognostic information, can predict resectability, and is useful in decision making about neoadjuvant therapy. We also discuss carcinoembryonic antigen (CEA, CA 125, serum biomarker panels, circulating tumor cells, and cell-free nucleic acids. Although many biomarkers have now been studied in relation to PDAC, significant work still needs to be done to validate their usefulness in the early detection of PDAC and management of patients with PDAC. Keywords: pancreatic cancer, biomarkers, screening, CA 19-9, CEA

  6. Functional MRI and CT biomarkers in oncology

    Energy Technology Data Exchange (ETDEWEB)

    Winfield, J.M. [Institute of Cancer Research and Royal Marsden NHS Foundation Trust, CRUK Imaging Centre at the Institute of Cancer Research, Sutton (United Kingdom); Institute of Cancer Research and Royal Marsden Hospital, MRI Unit, Sutton (United Kingdom); Payne, G.S.; DeSouza, N.M. [Institute of Cancer Research and Royal Marsden NHS Foundation Trust, CRUK Imaging Centre at the Institute of Cancer Research, Sutton (United Kingdom)

    2015-04-01

    Imaging biomarkers derived from MRI or CT describe functional properties of tumours and normal tissues. They are finding increasing numbers of applications in diagnosis, monitoring of response to treatment and assessment of progression or recurrence. Imaging biomarkers also provide scope for assessment of heterogeneity within and between lesions. A wide variety of functional parameters have been investigated for use as biomarkers in oncology. Some imaging techniques are used routinely in clinical applications while others are currently restricted to clinical trials or preclinical studies. Apparent diffusion coefficient, magnetization transfer ratio and native T{sub 1} relaxation time provide information about structure and organization of tissues. Vascular properties may be described using parameters derived from dynamic contrast-enhanced MRI, dynamic contrast-enhanced CT, transverse relaxation rate (R{sub 2}*), vessel size index and relative blood volume, while magnetic resonance spectroscopy may be used to probe the metabolic profile of tumours. This review describes the mechanisms of contrast underpinning each technique and the technical requirements for robust and reproducible imaging. The current status of each biomarker is described in terms of its validation, qualification and clinical applications, followed by a discussion of the current limitations and future perspectives. (orig.)

  7. External validity of post-stroke interventional gait rehabilitation studies.

    Science.gov (United States)

    Kafri, Michal; Dickstein, Ruth

    2017-01-01

    Gait rehabilitation is a major component of stroke rehabilitation, and is supported by extensive research. The objective of this review was to examine the external validity of intervention studies aimed at improving gait in individuals post-stroke. To that end, two aspects of these studies were assessed: subjects' exclusion criteria and the ecological validity of the intervention, as manifested by the intervention's technological complexity and delivery setting. Additionally, we examined whether the target population as inferred from the titles/abstracts is broader than the population actually represented by the reported samples. We systematically researched PubMed for intervention studies to improve gait post-stroke, working backwards from the beginning of 2014. Exclusion criteria, the technological complexity of the intervention (defined as either elaborate or simple), setting, and description of the target population in the titles/abstracts were recorded. Fifty-two studies were reviewed. The samples were exclusive, with recurrent stroke, co-morbidities, cognitive status, walking level, and residency being major reasons for exclusion. In one half of the studies, the intervention was elaborate. Descriptions of participants in the title/abstract in almost one half of the studies included only the diagnosis (stroke or comparable terms) and its stage (acute, subacute, and chronic). The external validity of a substantial number of intervention studies about rehabilitation of gait post-stroke appears to be limited by exclusivity of the samples as well as by deficiencies in ecological validity of the interventions. These limitations are not accurately reflected in the titles or abstracts of the studies.

  8. Distress Tolerance Scale: A Study of Reliability and Validity

    Directory of Open Access Journals (Sweden)

    Ahmet Emre SARGIN

    2012-11-01

    Full Text Available Objective: Distress Tolerance Scale (DTS is developed by Simons and Gaher in order to measure individual differences in the capacity of distress tolerance.The aim of this study is to assess the reliability and validity of the Turkish version of DTS. Method: One hundred and sixty seven university students (male=66, female=101 participated in this study. Beck Anxiety Inventory (BAI, State-trait Anxiety Inventory (STAI and Discomfort Intolerance Scale (DIS were used to determine the criterion validity. Construct validity was evaluated with factor analysis after the Kaiser-Meyer-Olkin (KMO and Barlett test had been performed. To assess the test-retest reliability, the scale was re-applied to 79 participants six weeks later. Results: To assess construct validity, factor analyses were performed using varimax principal components analysis with varimax rotation. While there were factors in the original study, our factor analysis resulted in three factors. Cronbach’s alpha coefficients for the entire scale and tolerance, regulation, self-efficacy subscales were .89, .90, .80 and .64 respectively. There were correlations at the level of 0.01 between the Trait Anxiety Inventory of STAI and BAI, and all the subscales of DTS and also between the State Anxiety Inventory and regulation subscale. Both of the subscales of DIS were correlated with the entire subscale and all the subscales except regulation at the level of 0.05.Test-retest reliability was statistically significant at the level of 0.01. Conclusion: Analysis demonstrated that DTS had a satisfactory level of reliability and validity in Turkish university students.

  9. Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility

    Directory of Open Access Journals (Sweden)

    Ashok Agarwal

    2016-01-01

    Full Text Available To study the major differences in the distribution of spermatozoa proteins in infertile men with varicocele by comparative proteomics and validation of their level of expression. The study-specific estimates for each varicocele outcome were combined to identify the proteins involved in varicocele-associated infertility in men irrespective of stage and laterality of their clinical varicocele. Expression levels of 5 key proteins (PKAR1A, AK7, CCT6B, HSPA2, and ODF2 involved in stress response and sperm function including molecular chaperones were validated by Western blotting. Ninety-nine proteins were differentially expressed in the varicocele group. Over 87% of the DEP involved in major energy metabolism and key sperm functions were underexpressed in the varicocele group. Key protein functions affected in the varicocele group were spermatogenesis, sperm motility, and mitochondrial dysfunction, which were further validated by Western blotting, corroborating the proteomics analysis. Varicocele is essentially a state of energy deprivation, hypoxia, and hyperthermia due to impaired blood supply, which is corroborated by down-regulation of lipid metabolism, mitochondrial electron transport chain, and Krebs cycle enzymes. To corroborate the proteomic analysis, expression of the 5 identified proteins of interest was validated by Western blotting. This study contributes toward establishing a biomarker "fingerprint" to assess sperm quality on the basis of molecular parameters.

  10. The role of novel biomarkers in predicting diabetic nephropathy: a review

    Directory of Open Access Journals (Sweden)

    Uwaezuoke SN

    2017-08-01

    Full Text Available Samuel N Uwaezuoke Pediatric Nephrology Firm, Department of Pediatrics, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria Abstract: Diabetic nephropathy (DN is one of the microvascular complications of the kidney arising commonly from type 1 diabetes mellitus (T1DM, and occasionally from type 2 diabetes mellitus (T2DM. Microalbuminuria serves as an early indicator of DN risk and a predictor of its progression as well as cardiovascular disease risk in both T1DM and T2DM. Although microalbuminuria remains the gold standard for early detection of DN, it is not a sufficiently accurate predictor of DN risk due to some limitations. Thus, there is a paradigm shift to novel biomarkers which would help to predict DN risk early enough and possibly prevent the occurrence of end-stage kidney disease. These new biomarkers have been broadly classified into glomerular biomarkers, tubular biomarkers, biomarkers of inflammation, biomarkers of oxidative stress, and miscellaneous biomarkers which also include podocyte biomarkers, some of which are also considered as tubular and glomerular biomarkers. Although they are potentially useful for the evaluation of DN, current data still preclude the routine clinical use of majority of them. However, their validation using high-quality and large longitudinal studies is of paramount importance, as well as the subsequent development of a biomarker panel which can reliably predict and evaluate this renal microvascular disease. This paper aims to review the predictive role of these biomarkers in the evaluation of DN. Keywords: type 1 diabetes mellitus, renal microvascular complication, microalbuminuria, end-stage kidney disease, biomarker panel

  11. Biomarkers in Prostate Cancer Epidemiology

    Directory of Open Access Journals (Sweden)

    Mudit Verma

    2011-09-01

    Full Text Available Understanding the etiology of a disease such as prostate cancer may help in identifying populations at high risk, timely intervention of the disease, and proper treatment. Biomarkers, along with exposure history and clinical data, are useful tools to achieve these goals. Individual risk and population incidence of prostate cancer result from the intervention of genetic susceptibility and exposure. Biochemical, epigenetic, genetic, and imaging biomarkers are used to identify people at high risk for developing prostate cancer. In cancer epidemiology, epigenetic biomarkers offer advantages over other types of biomarkers because they are expressed against a person’s genetic background and environmental exposure, and because abnormal events occur early in cancer development, which includes several epigenetic alterations in cancer cells. This article describes different biomarkers that have potential use in studying the epidemiology of prostate cancer. We also discuss the characteristics of an ideal biomarker for prostate cancer, and technologies utilized for biomarker assays. Among epigenetic biomarkers, most reports indicate GSTP1 hypermethylation as the diagnostic marker for prostate cancer; however, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS, and NSE1 also have been reported to be regulated by methylation mechanisms in prostate cancer. Current challenges in utilization of biomarkers in prostate cancer diagnosis and epidemiologic studies and potential solutions also are discussed.

  12. Quantitative redox imaging biomarkers for studying tissue metabolic state and its heterogeneity

    Directory of Open Access Journals (Sweden)

    He N. Xu

    2014-03-01

    Full Text Available NAD+/NADH redox state has been implicated in many diseases such as cancer and diabetes as well as in the regulation of embryonic development and aging. To fluorimetrically assess the mitochondrial redox state, Dr. Chance and co-workers measured the fluorescence of NADH and oxidized flavoproteins (Fp including flavin–adenine–dinucleotide (FAD and demonstrated their ratio (i.e. the redox ratio is a sensitive indicator of the mitochondrial redox states. The Chance redox scanner was built to simultaneously measure NADH and Fp in tissue at submillimeter scale in 3D using the freeze-trap protocol. This paper summarizes our recent research experience, development and new applications of the redox scanning technique in collaboration with Dr. Chance beginning in 2005. Dr. Chance initiated or actively involved in many of the projects during the last several years of his life. We advanced the redox scanning technique by measuring the nominal concentrations (in reference to the frozen solution standards of the endogenous fluorescent analytes, i.e., [NADH] and [Fp] to quantify the redox ratios in various biological tissues. The advancement has enabled us to identify an array of the redox indices as quantitative imaging biomarkers (including [NADH], [Fp], [Fp]/([NADH]+[Fp], [NADH]/[Fp], and their standard deviations for studying some important biological questions on cancer and normal tissue metabolism. We found that the redox indices were associated or changed with (1 tumorigenesis (cancer versus non-cancer of human breast tissue biopsies; (2 tumor metastatic potential; (3 tumor glucose uptake; (4 tumor p53 status; (5 PI3K pathway activation in pre-malignant tissue; (6 therapeutic effects on tumors; (7 embryonic stem cell differentiation; (8 the heart under fasting. Together, our work demonstrated that the tissue redox indices obtained from the redox scanning technique may provide useful information about tissue metabolism and physiology status in normal

  13. Flavonoids as fruit and vegetable intake biomarkers

    DEFF Research Database (Denmark)

    Krogholm, Kirstine Suszkiewicz

    calculation of the bivariate correlation coefficients is the common approach when using only one reference method. Back in 2002, a strictly controlled dietary intervention study indicated that the sum of 7 different flavonoid aglycones excreted in 24h urine samples potentially could be used as a biomarker...... and cohort studies. The Ph.D. thesis contains four scientific papers. Paper I provides evidence that the sum of 7 flavonoids in 24h urine respond in a linear and sensitive manner to moderate increases in the intake of fruits and vegetables, and thus consolidates that the flavonoids are a valid biomarker...... of fruit and vegetable intakes. In Paper I, the urinary recovery of the 7 flavonoids in morning spot urine (i.e. all urine voids from midnight including the first morning void) was also found to respond to moderate increases in the intake of fruits and vegetables. However, the association was somewhat...

  14. A Study on Guide Sign Validity in Driving Simulator

    Directory of Open Access Journals (Sweden)

    Wei Zhonghua

    2011-12-01

    Full Text Available The role of guide sign to inform road user about the information of network is important. How to design and locate guide sign to increase traffic operation efficiency is a key point for traffic engineers. Driving simulator is useful devised to study guide sign in the process and system control. For the purpose of studying guide signs using the tool of driving simulator, guide sign's validity in driving simulator was studied. Results of this experiment are the foundation of further study on guide sign. Simulator calibration procedure for guide sign was set up in this study. Legibility distance as measure of performance was used to evaluate the validity of guide sign in driving simulator. Thirty two participants were recruited. Results indicated legibility distance and speed were inversely related with the method of data mining. Legibility distance and text height of guide sign were positive related. When speed is 20km/h, 30km/h, 40km/h, magnifying power of text height is 4.3, 4.1, 3.8, while guide signs are absolute validity in driving simulator.

  15. Some aspects of cancer biomarkers and their clinical application in solid tumors – revisited

    Directory of Open Access Journals (Sweden)

    Isaac D

    2017-07-01

    Full Text Available Cancer biomarkers can be used for a variety of purposes related to screening, prediction, stratification, detection, diagnosis, prognosis, treatment design, and monitoring of a therapeutic response. One of the most important characteristics of a given biomarker includes ease of collection allowing for a non-invasive approach and frequent sampling. Such samples may be obtained from serum or plasma, sputum, bronchoalveolar lavage, saliva, nipple discharge, pleural, or peritoneal effusions. Validation of different biomarkers is considered a mandatory method for useful evaluation. In this review, we highlight the clinical applicability of some cancer biomarkers, as well as future approaches for their development and collection, which may help guide clinicians and researchers. The role of liquid biopsies will also be summarized. Further studies using liquid biopsies are needed to elucidate the significance of various sources of biomarkers suitable for clinical application.

  16. Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study

    DEFF Research Database (Denmark)

    Molnos, Sophie; Wahl, Simone; Haid, Mark

    2018-01-01

    ) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes. Methods: We measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families......Aims/hypothesis: Circulating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1...... (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case–control studies of prevalent (n = 4925) and incident (n = 4277...

  17. Biomarkers of the Dementia

    Directory of Open Access Journals (Sweden)

    Mikio Shoji

    2011-01-01

    Full Text Available Recent advances in biomarker studies on dementia are summarized here. CSF Aβ40, Aβ42, total tau, and phosphorylated tau are the most sensitive biomarkers for diagnosis of Alzheimer's disease (AD and prediction of onset of AD from mild cognitive impairment (MCI. Based on this progress, new diagnostic criteria for AD, MCI, and preclinical AD were proposed by National Institute of Aging (NIA and Alzheimer's Association in August 2010. In these new criteria, progress in biomarker identification and amyloid imaging studies in the past 10 years have added critical information. Huge contributions of basic and clinical studies have established clinical evidence supporting these markers. Based on this progress, essential therapy for cure of AD is urgently expected.

  18. Relating biomarkers to whole-organism effects using species sensitivity distributions : A pilot study for marine species exposed to oil

    NARCIS (Netherlands)

    Smit, M.G.D.; Bechmann, R.K.; Hendriks, A.J.; Skadsheim, A.; Larsen, B.K.; Baussant, T.; Bamber, S.; Sannei, S.

    2009-01-01

    Biomarkers are widely used to measure environmental impacts on marine species. For many biomarkers, it is not clear how the signal levels relate to effects on the whole organism. This paper shows how species sensitivity distributions (SSDs) can be applied to evaluate multiple biomarker responses in

  19. Urinary sugars biomarker relates better to extrinsic than to intrinsic sugars intake in a metabolic study with volunteers consuming their normal diet.

    Science.gov (United States)

    Tasevska, N; Runswick, S A; Welch, A A; McTaggart, A; Bingham, S A

    2009-05-01

    Sugars in diet are very difficult to measure because of the unreliability of self-reported dietary intake. Sucrose and fructose excreted in urine have been recently suggested as a biomarker for total sugars intake. To further characterize the use of this biomarker, we investigated whether urinary sugars correlated better to extrinsic compared to intrinsic sugars in the diet. Seven male and six female healthy participants were living for 30 days in a metabolic suite under strictly controlled conditions consuming their usual diet as assessed beforehand from four consecutive 7-day food diaries kept at home. During the 30-day study, all 24 h urine specimens were collected, validated for their completeness and analysed for sucrose and fructose. The mean total sugars intake in the group was 202+/-69 g day(-1). Daily intake of extrinsic, intrinsic and milk sugars contributed 60.1, 34.4 and 5.5%, to the total sugars intake, respectively. The individuals' 30-day mean sugars excretion levels were significantly correlated with the 30-day means of extrinsic sugars (r=0.84; Psugars intake (r=0.43; P=0.144). In the regression, only extrinsic sugars intake explained a significant proportion of the variability in sugars excretion (adjusted R(2)=0.64; P=0.001); daily excretion of 100 mg sucrose and fructose in urine predicted 124 g of extrinsic total sugars in the diet. Using fewer urinary and dietary measurements in the analysis did not change the overall trend of the findings. In this group of volunteers, sucrose and fructose in urine better correlated to extrinsic than to intrinsic sugars intake.

  20. The validity of vignettes in cross country health studies

    DEFF Research Database (Denmark)

    Pozzoli, Dario; Gupta, Nabanita Datta; Kristensen, Nicolai

    Cross-country comparisons of subjective assessments may be ham-pered by sub-population speci.c response style. To correct for this, the use of vignettes has become increasingly popular - notably within cross-country health studies. However, the validity of vignettes as a means to re-scale across ...... that the assumption of RC is not innocous and that our extended model improves the fit and significantly changes the cross-country rankings of health vis-á-vis the standard Chopit model.......Cross-country comparisons of subjective assessments may be ham-pered by sub-population speci.c response style. To correct for this, the use of vignettes has become increasingly popular - notably within cross-country health studies. However, the validity of vignettes as a means to re-scale across...

  1. Biomarkers of nanomaterial exposure and effect: current status

    Science.gov (United States)

    Iavicoli, Ivo; Leso, Veruscka; Manno, Maurizio; Schulte, Paul A.

    2014-03-01

    Recent advances in nanotechnology have induced a widespread production and application of nanomaterials. As a consequence, an increasing number of workers are expected to undergo exposure to these xenobiotics, while the possible hazards to their health remain not being completely understood. In this context, biological monitoring may play a key role not only to identify potential hazards from and to evaluate occupational exposure to nanomaterials, but also to detect their early biological effects to better assess and manage risks of exposure in respect of the health of workers. Therefore, the aim of this review is to provide a critical evaluation of potential biomarkers of nanomaterial exposure and effect investigated in human and animal studies. Concerning exposure biomarkers, internal dose of metallic or metal oxide nanoparticle exposure may be assessed measuring the elemental metallic content in blood or urine or other biological materials, whereas specific molecules may be carefully evaluated in target tissues as possible biomarkers of biologically effective dose. Oxidative stress biomarkers, such as 8-hydroxy-deoxy-guanosine, genotoxicity biomarkers, and inflammatory response indicators may also be useful, although not specific, as biomarkers of nanomaterial early adverse health effects. Finally, potential biomarkers from "omic" technologies appear to be quite innovative and greatly relevant, although mechanistic, ethical, and practical issues should all be resolved before their routine application in occupational settings could be implemented. Although all these findings are interesting, they point out the need for further research to identify and possibly validate sensitive and specific biomarkers of exposure and effect, suitable for future use in occupational biomonitoring programs. A valuable contribution may derive from the studies investigating the biological behavior of nanomaterials and the factors influencing their toxicokinetics and reactivity. In

  2. Opportunities and Challenges of Proteomics in Pediatric Patients: Circulating Biomarkers After Hematopoietic Stem Cell Transplantation As a Successful Example

    Science.gov (United States)

    Paczesny, Sophie; Duncan, Christine; Jacobsohn, David; Krance, Robert; Leung, Kathryn; Carpenter, Paul; Bollard, Catherine; Renbarger, Jamie; Cooke, Kenneth

    2015-01-01

    Biomarkers have the potential to improve diagnosis and prognosis, facilitate targeted treatment, and reduce health care costs. Thus, there is great hope that biomarkers will be integrated in all clinical decisions in the near future. A decade ago, the biomarker field was launched with great enthusiasm because mass spectrometry revealed that blood contains a rich library of candidate biomarkers. However, biomarker research has not yet delivered on its promise due to several limitations: (i) improper sample handling and tracking as well as limited sample availability in the pediatric population, (ii) omission of appropriate controls in original study designs, (iii) lability and low abundance of interesting biomarkers in blood, and (iv) the inability to mechanistically tie biomarker presence to disease biology. These limitations as well as successful strategies to overcome them are discussed in this review. Several advances in biomarker discovery and validation have been made in hematopoietic stem cell transplantation, the current most effective tumor immunotherapy, and these could serve as examples for other conditions. This review provides fresh optimism that biomarkers clinically relevant in pediatrics are closer to being realized based on: (i) a uniform protocol for low-volume blood collection and preservation, (ii) inclusion of well-controlled independent cohorts, (iii) novel technologies and instrumentation with low analytical sensitivity, and (iv) integrated animal models for exploring potential biomarkers and targeted therapies. PMID:25196024

  3. Artificial neural network inference (ANNI: a study on gene-gene interaction for biomarkers in childhood sarcomas.

    Directory of Open Access Journals (Sweden)

    Dong Ling Tong

    Full Text Available OBJECTIVE: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI. METHOD: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model. RESULTS: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS; FCGRT and OLFM1 in Ewing's sarcoma (EWS suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. CONCLUSIONS: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas.

  4. The birth satisfaction scale: Turkish adaptation, validation and reliability study

    Science.gov (United States)

    Cetin, Fatma Cosar; Sezer, Ayse; Merih, Yeliz Dogan

    2015-01-01

    OBJECTIVE: The objective of this study is to investigate the validity and the reliability of Birth Satisfaction Scale (BSS) and to adapt it into the Turkish language. This scale is used for measuring maternal satisfaction with birth in order to evaluate women’s birth perceptions. METHODS: In this study there were 150 women who attended to inpatient postpartum clinic. The participants filled in an information form and the BSS questionnaire forms. The properties of the scale were tested by conducting reliability and validation analyses. RESULTS: BSS entails 30 Likert-type questions. It was developed by Hollins Martin and Fleming. Total scale scores ranged between 30–150 points. Higher scores from the scale mean increases in birth satisfaction. Three overarching themes were identified in Scale: service provision (home assessment, birth environment, support, relationships with health care professionals); personal attributes (ability to cope during labour, feeling in control, childbirth preparation, relationship with baby); and stress experienced during labour (distress, obstetric injuries, receiving sufficient medical care, obstetric intervention, pain, prolonged labour and baby’s health). Cronbach’s alfa coefficient was 0.62. CONCLUSION: According to the present study, BSS entails 30 Likert-type questions and evaluates women’s birth perceptions. The Turkish version of BSS has been proven to be a valid and a reliable scale. PMID:28058355

  5. Videoconference-based mini mental state examination: a validation study.

    Science.gov (United States)

    Timpano, Francesca; Pirrotta, Fabio; Bonanno, Lilla; Marino, Silvia; Marra, Angela; Bramanti, Placido; Lanzafame, Pietro

    2013-12-01

    Neuropsychological testing is a prime criterion of good practice to document cognitive deficits in a rapidly aging population. Telecommunication technologies may overcome limitations related to test administration. We compared performance of the Italian videoconference-based version of the Mini Mental State Examination (VMMSE) with performance of the standard MMSE administered face-to-face (F2F), to validate the Italian version of the 28-item VMMSE. To validate the Italian version of the VMMSE, we compared its performance with standard F2F. The sample (n=342) was administered three VMMSEs within 6 weeks after F2F testing. We identified the optimal cutoff through the receiver operating characteristic curve, as well as the VMMSE consistency through inter- and intrarater reliability (Inter/RR and Intra/RR) analysis. We found high levels of sensitivity and specificity for the optimal VMMSE cutoff identification and an accuracy of 0.96 (95% confidence interval 0.94-0.98). Intra/RR and inter/RR were highly significant. This study demonstrates that VMMSE is a valid instrument in clinical and research screening and monitoring of subjects affected by cognitive disorders. This study shows a significant correlation between videoconference assessment and the F2F one, providing an important impetus to expand studies and the knowledge about the usefulness of tele-assistance services. Our findings have important implications for both longitudinal assistance and clinical care of demented patients.

  6. Diagnostic and Prognostic MicroRNA Biomarkers for Prostate Cancer in Cell-free Urine

    DEFF Research Database (Denmark)

    Fredsøe, Jacob Christian; Rasmussen, Anne Karin; Thomsen, Anni Rønfeldt

    2017-01-01

    Background: Widespread use of prostate-specific antigen (PSA) testing for prostate cancer (PC) detection has led to extensive overdiagnosis and overtreatment. Urine-based microRNA (miRNA) biomarkers could be useful in PC diagnosis and prognosis. Objective: To train and validate urine-based micro......RNA (miRNA) biomarkers that may assist in PC diagnosis and prognosis. Design, setting, and participants: We profiled the expression levels of 92 miRNAs via reverse transcriptase–poymerase chain reaction in cell-free urine samples from 29 patients with benign prostatic hyperplasia (BPH) and 215 patients...... could help in primary diagnosis of PC and guide treatment decisions. Further validation studies are warranted. Patient summary: Using two large patient cohorts, we searched for novel prostate cancer biomarkers in urine. We found two new sets of microRNA biomarkers in urine that could accurately predict...

  7. Biomarkers of adverse drug reactions.

    Science.gov (United States)

    Carr, Daniel F; Pirmohamed, Munir

    2018-02-01

    and represent a significant burden to patients, healthcare providers, and the pharmaceutical industry. • This review details the current state of the art in biomarkers of ADRs (both genetic and circulating). There is still significant variability in patient response which cannot be explained by current knowledge of genetic risk factors for ADRs; however, we discussed how specific advances in genomics have the potential to yield better and more predictive models. • Many current clinically utilized circulating biomarkers of tissue injury are valid biomarkers for a number of ADRs. However, they often give little insight into the specific cell or tissue subtype which may be affected. Emerging circulating biomarkers with potential to provide greater information on the etiology/pathophysiology of ADRs are described.

  8. Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies.

    Science.gov (United States)

    Fernandes, Brisa S; Molendijk, Marc L; Köhler, Cristiano A; Soares, Jair C; Leite, Cláudio Manuel G S; Machado-Vieira, Rodrigo; Ribeiro, Thamara L; Silva, Jéssica C; Sales, Paulo M G; Quevedo, João; Oertel-Knöchel, Viola; Vieta, Eduard; González-Pinto, Ana; Berk, Michael; Carvalho, André F

    2015-11-30

    The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels. We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder. Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = -0.57, P = 0.010) and depressive (Hedges' g = -0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one. In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD.

  9. Methylated genes as new cancer biomarkers.

    LENUS (Irish Health Repository)

    Duffy, M J

    2012-02-01

    Aberrant hypermethylation of promoter regions in specific genes is a key event in the formation and progression of cancer. In at least some situations, these aberrant alterations occur early in the formation of malignancy and appear to be tumour specific. Multiple reports have suggested that measurement of the methylation status of the promoter regions of specific genes can aid early detection of cancer, determine prognosis and predict therapy responses. Promising DNA methylation biomarkers include the use of methylated GSTP1 for aiding the early diagnosis of prostate cancer, methylated PITX2 for predicting outcome in lymph node-negative breast cancer patients and methylated MGMT in predicting benefit from alkylating agents in patients with glioblastomas. However, prior to clinical utilisation, these findings require validation in prospective clinical studies. Furthermore, assays for measuring gene methylation need to be standardised, simplified and evaluated in external quality assurance programmes. It is concluded that methylated genes have the potential to provide a new generation of cancer biomarkers.

  10. Intent inferencing by an intelligent operator's associate - A validation study

    Science.gov (United States)

    Jones, Patricia M.

    1988-01-01

    In the supervisory control of a complex, dynamic system, one potential form of aiding for the human operator is a computer-based operator's associate. The design philosophy of the operator's associate is that of 'amplifying' rather than automating human skills. In particular, the associate possesses understanding and control properties. Understanding allows it to infer operator intentions and thus form the basis for context-dependent advice and reminders; control properties allow the human operator to dynamically delegate individual tasks or subfunctions to the associate. This paper focuses on the design, implementation, and validation of the intent inferencing function. Two validation studies are described which empirically demonstrate the viability of the proposed approach to intent inferencing.

  11. Robustness study in SSNTD method validation: indoor radon quality

    International Nuclear Information System (INIS)

    Dias, D.C.S.; Silva, N.C.; Bonifácio, R.L.

    2017-01-01

    Quality control practices are indispensable to organizations aiming to reach analytical excellence. Method validation is an essential component to quality systems in laboratories, serving as a powerful tool for standardization and reliability of outcomes. This paper presents a study of robustness conducted over a SSNTD technique validation process, with the goal of developing indoor radon measurements at the highest level of quality. This quality parameter indicates how well a technique is able to provide reliable results in face of unexpected variations along the measurement. In this robustness study, based on the Youden method, 7 analytical conditions pertaining to different phases of the SSNTD technique (with focus on detector etching) were selected. Based on the ideal values for each condition as reference, extreme levels regarded as high and low were prescribed to each condition. A partial factorial design of 8 unique etching procedures was defined, where each presented their own set of high and low condition values. The Youden test provided 8 indoor radon concentration results, which allowed percentage estimations that indicate the potential influence of each analytical condition on the SSNTD technique. As expected, detector etching factors such as etching solution concentration, temperature and immersion time were identified as the most critical parameters to the technique. Detector etching is a critical step in the SSNTD method – one that must be carefully designed during validation and meticulously controlled throughout the entire process. (author)

  12. Robustness study in SSNTD method validation: indoor radon quality

    Energy Technology Data Exchange (ETDEWEB)

    Dias, D.C.S.; Silva, N.C.; Bonifácio, R.L., E-mail: danilacdias@gmail.com [Comissao Nacional de Energia Nuclear (LAPOC/CNEN), Pocos de Caldas, MG (Brazil). Laboratorio de Pocos de Caldas

    2017-07-01

    Quality control practices are indispensable to organizations aiming to reach analytical excellence. Method validation is an essential component to quality systems in laboratories, serving as a powerful tool for standardization and reliability of outcomes. This paper presents a study of robustness conducted over a SSNTD technique validation process, with the goal of developing indoor radon measurements at the highest level of quality. This quality parameter indicates how well a technique is able to provide reliable results in face of unexpected variations along the measurement. In this robustness study, based on the Youden method, 7 analytical conditions pertaining to different phases of the SSNTD technique (with focus on detector etching) were selected. Based on the ideal values for each condition as reference, extreme levels regarded as high and low were prescribed to each condition. A partial factorial design of 8 unique etching procedures was defined, where each presented their own set of high and low condition values. The Youden test provided 8 indoor radon concentration results, which allowed percentage estimations that indicate the potential influence of each analytical condition on the SSNTD technique. As expected, detector etching factors such as etching solution concentration, temperature and immersion time were identified as the most critical parameters to the technique. Detector etching is a critical step in the SSNTD method – one that must be carefully designed during validation and meticulously controlled throughout the entire process. (author)

  13. Analysis of Plasma Albumin, Vitamin D, and Apolipoproteins A and B as Predictive Coronary Risk Biomarkers in the REGICOR Study.

    Science.gov (United States)

    Vázquez-Oliva, Gabriel; Zamora, Alberto; Ramos, Rafel; Subirana, Isaac; Grau, María; Dégano, Irene R; Muñoz, Daniel; Fitó, Montserrat; Elosua, Roberto; Marrugat, Jaume

    2018-05-12

    New biomarkers could improve the predictive capacity of classic risk functions. The aims of this study were to determine the association between circulating levels of apolipoprotein A1 (apoA1), apolipoprotein B (apoB), albumin, and 25-OH-vitamin D and coronary events and to analyze whether these biomarkers improve the predictive capacity of the Framingham-REGICOR risk function. A case-cohort study was designed. From an initial cohort of 5404 individuals aged 35 to 74 years with a 5-year follow-up, all the participants who had a coronary event (n = 117) and a random group of the cohort (subcohort; n = 667) were selected. Finally, 105 cases and 651 individuals representative of the cohort with an available biological sample were included. The events of interest were angina, fatal and nonfatal myocardial infarction and coronary deaths. Case participants were older, had a higher proportion of men and cardiovascular risk factors, and showed higher levels of apoB and lower levels of apoA1, apoA1/apoB ratio, 25-OH-vitamin D and albumin than the subcohort. In multivariate analyses, plasma albumin concentration was the only biomarker independently associated with coronary events (HR, 0.73; P = .002). The inclusion of albumin in the risk function properly reclassified a significant proportion of individuals, especially in the intermediate risk group (net reclassification improvement, 32.3; P = .048). Plasma albumin levels are inversely associated with coronary risk and improve the predictive capacity of classic risk functions. Copyright © 2018 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  14. Exploratory Studies on Biomarkers: An Example Study on Brown Adipose Tissue

    Science.gov (United States)

    Watanabe, Masahiro; Yamazaki, Naoshi; Kataoka, Masatoshi; Shinohara, Yasuo

    In mammals, two kinds of adipose tissue are known to exist, i.e., white (WAT) and brown (BAT) adipose tissue. The physiological role of WAT is storage of excess energy as fat, whereas that of BAT is the expenditure of excess energy as heat. The uncoupling protein UCP1, which is specifically expressed in brown fat mitochondria, dissipates the proton electrochemical potential across the inner mitochondrial membrane, known as a driving force of ATP synthesis, and thus it dissipates excess energy in a form of heat. Because deficiency in effective expenditure of excess energy causes accumulation of this energy in the form of fat (i.e., obesity), it is very important to understand the energy metabolism in this tissue for the development of anti-obesity drugs. In this article, in addition to providing a brief introduction to the functional properties of BAT and UCP1, the results of our exploratory studies on protein components involved in the energy-dissipating function in BAT.

  15. Cell Electrical Impedance as a Novel Approach for Studies on Senescence Not Based on Biomarkers

    Directory of Open Access Journals (Sweden)

    Jung-Joon Cha

    2016-01-01

    Full Text Available Senescence of cardiac myocytes is frequently associated with heart diseases. To analyze senescence in cardiac myocytes, a number of biomarkers have been isolated. However, due to the complex nature of senescence, multiple markers are required for a single assay to accurately depict complex physiological changes associated with senescence. In single cells, changes in both cytoplasm and cell membrane during senescence can affect the changes in electrical impedance. Based on this phenomenon, we developed MEDoS, a novel microelectrochemical impedance spectroscopy for diagnosis of senescence, which allows us to precisely measure quantitative changes in electrical properties of aging cells. Using cardiac myocytes isolated from 3-, 6-, and 18-month-old isogenic zebrafish, we examined the efficacy of MEDoS and showed that MEDoS can identify discernible changes in electrical impedance. Taken together, our data demonstrated that electrical impedance in cells at different ages is distinct with quantitative values; these results were comparable with previously reported ones. Therefore, we propose that MEDoS be used as a new biomarker-independent methodology to obtain quantitative data on the biological senescence status of individual cells.

  16. NMR studies of preimplantation embryo metabolism in human assisted reproductive techniques: a new biomarker for assessment of embryo implantation potential.

    Science.gov (United States)

    Pudakalakatti, Shivanand M; Uppangala, Shubhashree; D'Souza, Fiona; Kalthur, Guruprasad; Kumar, Pratap; Adiga, Satish Kumar; Atreya, Hanudatta S

    2013-01-01

    There has been growing interest in understanding energy metabolism in human embryos generated using assisted reproductive techniques (ART) for improving the overall success rate of the method. Using NMR spectroscopy as a noninvasive tool, we studied human embryo metabolism to identify specific biomarkers to assess the quality of embryos for their implantation potential. The study was based on estimation of pyruvate, lactate and alanine levels in the growth medium, ISM1, used in the culture of embryos. An NMR study involving 127 embryos from 48 couples revealed that embryos transferred on Day 3 (after 72 h in vitro culture) with successful implantation (pregnancy) exhibited significantly (p < 10(-5) ) lower pyruvate/alanine ratios compared to those that failed to implant. Lactate levels in media were similar for all embryos. This implies that in addition to lactate production, successfully implanted embryos use pyruvate to produce alanine and other cellular functions. While pyruvate and alanine individually have been used as biomarkers, the present study highlights the potential of combining them to provide a single parameter that correlates strongly with implantation potential. Copyright © 2012 John Wiley & Sons, Ltd.

  17. A practical platform for blood biomarker study by using global gene expression profiling of peripheral whole blood.

    Directory of Open Access Journals (Sweden)

    Ze Tian

    Full Text Available Although microarray technology has become the most common method for studying global gene expression, a plethora of technical factors across the experiment contribute to the variable of genome gene expression profiling using peripheral whole blood. A practical platform needs to be established in order to obtain reliable and reproducible data to meet clinical requirements for biomarker study.We applied peripheral whole blood samples with globin reduction and performed genome-wide transcriptome analysis using Illumina BeadChips. Real-time PCR was subsequently used to evaluate the quality of array data and elucidate the mode in which hemoglobin interferes in gene expression profiling. We demonstrated that, when applied in the context of standard microarray processing procedures, globin reduction results in a consistent and significant increase in the quality of beadarray data. When compared to their pre-globin reduction counterparts, post-globin reduction samples show improved detection statistics, lowered variance and increased sensitivity. More importantly, gender gene separation is remarkably clearer in post-globin reduction samples than in pre-globin reduction samples. Our study suggests that the poor data obtained from pre-globin reduction samples is the result of the high concentration of hemoglobin derived from red blood cells either interfering with target mRNA binding or giving the pseudo binding background signal.We therefore recommend the combination of performing globin mRNA reduction in peripheral whole blood samples and hybridizing on Illumina BeadChips as the practical approach for biomarker study.

  18. Epigenome-Wide Association Study Identifies Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure.

    Science.gov (United States)

    Meder, Benjamin; Haas, Jan; Sedaghat-Hamedani, Farbod; Kayvanpour, Elham; Frese, Karen; Lai, Alan; Nietsch, Rouven; Scheiner, Christina; Mester, Stefan; Bordalo, Diana Martins; Amr, Ali; Dietrich, Carsten; Pils, Dietmar; Siede, Dominik; Hund, Hauke; Bauer, Andrea; Holzer, Daniel Benjamin; Ruhparwar, Arjang; Mueller-Hennessen, Matthias; Weichenhan, Dieter; Plass, Christoph; Weis, Tanja; Backs, Johannes; Wuerstle, Maximilian; Keller, Andreas; Katus, Hugo A; Posch, Andreas E

    2017-10-17

    Biochemical DNA modification resembles a crucial regulatory layer among genetic information, environmental factors, and the transcriptome. To identify epigenetic susceptibility regions and novel biomarkers linked to myocardial dysfunction and heart failure, we performed the first multi-omics study in myocardial tissue and blood of patients with dilated cardiomyopathy and controls. Infinium human methylation 450 was used for high-density epigenome-wide mapping of DNA methylation in left-ventricular biopsies and whole peripheral blood of living probands. RNA deep sequencing was performed on the same samples in parallel. Whole-genome sequencing of all patients allowed exclusion of promiscuous genotype-induced methylation calls. In the screening stage, we detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy (false discovery corrected P ≤0.05), with 3 of them reaching epigenome-wide significance at P ≤5×10 -8 . Twenty-seven (46%) of these loci could be replicated in independent cohorts, underlining the role of epigenetic regulation of key cardiac transcription regulators. Using a staged multi-omics study design, we link a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression. Furthermore, we identified distinct epigenetic methylation patterns that are conserved across tissues, rendering these CpGs novel epigenetic biomarkers for heart failure. The present study provides to our knowledge the first epigenome-wide association study in living patients with heart failure using a multi-omics approach. © 2017 American Heart Association, Inc.

  19. Emmprin Expression Predicts Response and Survival following Cisplatin Containing Chemotherapy for Bladder Cancer: A Validation Study.

    Science.gov (United States)

    Hemdan, Tammer; Malmström, Per-Uno; Jahnson, Staffan; Segersten, Ulrika

    2015-12-01

    Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response. Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry. Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, pemmprin expression was not associated with overall survival (46% vs 35%, p=0.23) or cancer specific survival (55% vs 51%, p=0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5-9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials. Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  20. DEVELOPING VISUAL PRESENTATION ATTITUDE RUBRIC: VALIDITY AND RELIABILITY STUDY

    OpenAIRE

    ATEŞ, Hatice KADIOĞLU; ADA, Sefer; BAYSAL, Z. Nurdan

    2015-01-01

    Abstract The aim of this study is to develop visual presentation attitude rubric which is valid and reliable for the 4th grade students. 218 students took part in this study from Engin Can Güre which located in Istanbul, Esenler. While preparing this assessment tool with 34 criterias , 6 university lecturers view have been taken who are experts in their field. The answer key sheet has 4 (likert )type options. The rubric has been first tested by Kaiser-Meyer Olkin and Bartletts tests an...