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Sample records for surrogate endpoint biomarker

  1. CFTR biomarkers : Time for promotion to surrogate end-point?

    NARCIS (Netherlands)

    De Boeck, K.; Kent, L.; Davies, J.; Derichs, N.; Amaral, M.; Rowe, S. M.; Middleton, P.; de Jonge, Hendrik; Bronsveld, I.; Wilschanski, M.; Melotti, P.; Danner-Boucher, I.; Boerner, S.; Fajac, I.; Southern, K.; de Nooijer, R. A.; Bot, A.; de Rijke, Y.; de Wachter, E.; Leal, T.; Vermeulen, F.; Hug, M. J.; Rault, G.; Nguyen-Khoa, T.; Barreto, C.; Proesmans, M.; Sermet-Gaudelus, I.

    2013-01-01

    In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809

  2. CFTR biomarkers: Time for promotion to surrogate end-point?

    NARCIS (Netherlands)

    K. de Boeck; L. Kent; J. Davies (J.); N. Derichs; M.D. Amaral (Margarida); S.M. Rowe (S.); P. Middleton (P.); H.R. de Jonge (Hugo); I. Bronsveld (Inez); M. Wilschanski (Michael); P. Melotti; I. Danner-Boucher (I.); S. Boerner (S.); I. Fajac; K. Southern; R.A. de Nooijer; A.G. Bot (Alice); Y.B. de Rijke (Yolanda); E. de Wachter (E.); T. Leal (Teresinha); F. Vermeulen; M. Hug; G. Rault (G.); T. Nguyen-Khoa (T.); C. Barreto (C.); W. Proesmans (Willem); I. Sermet-Gaudelus (I.)

    2013-01-01

    textabstractIn patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-

  3. CFTR biomarkers: Time for promotion to surrogate end-point?

    NARCIS (Netherlands)

    K. de Boeck; L. Kent; J. Davies (J.); N. Derichs; M.D. Amaral (Margarida); S.M. Rowe (S.); P. Middleton (P.); H.R. de Jonge (Hugo); I. Bronsveld (Inez); M. Wilschanski (Michael); P. Melotti; I. Danner-Boucher (I.); S. Boerner (S.); I. Fajac; K. Southern; R.A. de Nooijer; A.G. Bot (Alice); Y.B. de Rijke (Yolanda); E. de Wachter (E.); T. Leal (Teresinha); F. Vermeulen; M. Hug; G. Rault (G.); T. Nguyen-Khoa (T.); C. Barreto (C.); W. Proesmans (Willem); I. Sermet-Gaudelus (I.)

    2013-01-01

    textabstractIn patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-

  4. CFTR biomarkers : Time for promotion to surrogate end-point?

    NARCIS (Netherlands)

    De Boeck, K.; Kent, L.; Davies, J.; Derichs, N.; Amaral, M.; Rowe, S. M.; Middleton, P.; de Jonge, Hendrik; Bronsveld, I.; Wilschanski, M.; Melotti, P.; Danner-Boucher, I.; Boerner, S.; Fajac, I.; Southern, K.; de Nooijer, R. A.; Bot, A.; de Rijke, Y.; de Wachter, E.; Leal, T.; Vermeulen, F.; Hug, M. J.; Rault, G.; Nguyen-Khoa, T.; Barreto, C.; Proesmans, M.; Sermet-Gaudelus, I.

    2013-01-01

    In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809

  5. 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

    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...... 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...

  6. 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

    to develop a hierarchical schema that systematically evaluates and ranks the surrogacy status of biomarkers and surrogates; and to obtain feedback from stakeholders. METHODS: 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. 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...

  7. 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

    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 d...

  8. Biomarkers and surrogate endpoints for normal-tissue effects of radiation therapy: the importance of dose-volume effects

    Science.gov (United States)

    Bentzen, Søren M.; Parliament, Matthew; Deasy, Joseph O.; Dicker, Adam; Curran, Walter J.; Williams, Jacqueline P.; Rosenstein, Barry S.

    2012-01-01

    Biomarkers are of interest for predicting or monitoring normal tissue toxicity of radiation therapy. Advances in molecular radiobiology provide novel leads in the search for normal tissue biomarkers with sufficient sensitivity and specificity to become clinically useful. This paper reviews examples of studies of biomarkers as predictive markers, as response markers or as surrogate endpoints for radiation side-effects. Single nucleotide polymorphisms (SNPs) are briefly discussed in the context of candidate gene and genome wide association studies. The importance of adjusting for radiation dose distribution in normal tissue biomarker studies is underlined. Finally, research priorities in this field are identified and discussed. PMID:20171510

  9. Surrogate endpoints and emerging surrogate endpoints for risk reduction of cardiovascular disease.

    Science.gov (United States)

    Rasnake, Crystal M; Trumbo, Paula R; Heinonen, Therese M

    2008-02-01

    This article reviews surrogate endpoints and emerging biomarkers that were discussed at the annual "Cardiovascular Biomarkers and Surrogate Endpoints" symposium cosponsored by the US Food and Drug Administration (FDA) and the Montreal Heart Institute. The FDA's Center for Food Safety and Applied Nutrition (CFSAN) uses surrogate endpoints in its scientific review of a substance/disease relationship for a health claim. CFSAN currently recognizes three validated surrogate endpoints: blood pressure, blood total cholesterol, and blood low-density lipoprotein (LDL) concentration in its review of a health claim for cardiovascular disease (CVD). Numerous potential surrogate endpoints of CVD are being evaluated as the pathophysiology of heart disease is becoming better understood. However, these emerging biomarkers need to be validated as surrogate endpoints before they are used by CFSAN in the evaluation of a CVD health claim.

  10. Surrogate Endpoints in Suicide Research

    Science.gov (United States)

    Wortzel, Hal S.; Gutierrez, Peter M.; Homaifar, Beeta Y.; Breshears, Ryan E.; Harwood, Jeri E.

    2010-01-01

    Surrogate endpoints frequently substitute for rare outcomes in research. The ability to learn about completed suicides by investigating more readily available and proximate outcomes, such as suicide attempts, has obvious appeal. However, concerns with surrogates from the statistical science perspective exist, and mounting evidence from…

  11. Biomarkers and Surrogate Endpoints in Uveitis: The Impact of Quantitative Imaging.

    Science.gov (United States)

    Denniston, Alastair K; Keane, Pearse A; Srivastava, Sunil K

    2017-05-01

    Uveitis is a major cause of sight loss across the world. The reliable assessment of intraocular inflammation in uveitis ('disease activity') is essential in order to score disease severity and response to treatment. In this review, we describe how 'quantitative imaging', the approach of using automated analysis and measurement algorithms across both standard and emerging imaging modalities, can develop objective instrument-based measures of disease activity. This is a narrative review based on searches of the current world literature using terms related to quantitative imaging techniques in uveitis, supplemented by clinical trial registry data, and expert knowledge of surrogate endpoints and outcome measures in ophthalmology. Current measures of disease activity are largely based on subjective clinical estimation, and are relatively insensitive, with poor discrimination and reliability. The development of quantitative imaging in uveitis is most established in the use of optical coherence tomographic (OCT) measurement of central macular thickness (CMT) to measure severity of macular edema (ME). The transformative effect of CMT in clinical assessment of patients with ME provides a paradigm for the development and impact of other forms of quantitative imaging. Quantitative imaging approaches are now being developed and validated for other key inflammatory parameters such as anterior chamber cells, vitreous haze, retinovascular leakage, and chorioretinal infiltrates. As new forms of quantitative imaging in uveitis are proposed, the uveitis community will need to evaluate these tools against the current subjective clinical estimates and reach a new consensus for how disease activity in uveitis should be measured. The development, validation, and adoption of sensitive and discriminatory measures of disease activity is an unmet need that has the potential to transform both drug development and routine clinical care for the patient with uveitis.

  12. Biomarkers and Surrogate Endpoints: How and When might They Impact Drug Development?

    Directory of Open Access Journals (Sweden)

    Chetan D. Lathia

    2002-01-01

    Full Text Available As the pharmaceutical industry starts developing novel molecules developed based on molecular biology principles and a better understanding of the human genome, it becomes increasingly important to develop early indicators of activity and/or toxicity. Biomarkers are measurements based on molecular pharmacology and/or pathophysiology of the disease being evaluated that may assist with decision-making in various phases of drug development. The utility of biomarkers in the development of drugs is described in this review. Additionally, the utility of pharmacokinetic data in drug development is described. Development of biomarkers may help reduce the cost of drug development by allowing key decisions earlier in the drug development process. Additionally, biomarkers may be used to select patients who have a high likelihood of benefit or they could be used by clinicians to evaluate the potential for efficacy after start of treatment.

  13. Biomarkers and Surrogate Endpoints: How and When might They Impact Drug Development?

    OpenAIRE

    Chetan D. Lathia

    2002-01-01

    As the pharmaceutical industry starts developing novel molecules developed based on molecular biology principles and a better understanding of the human genome, it becomes increasingly important to develop early indicators of activity and/or toxicity. Biomarkers are measurements based on molecular pharmacology and/or pathophysiology of the disease being evaluated that may assist with decision-making in various phases of drug development. The utility of biomarkers in the development of drugs i...

  14. The use of surrogate endpoints in regulating medicines for cardio-renal disease: opinions of stakeholders.

    Directory of Open Access Journals (Sweden)

    Bauke Schievink

    Full Text Available AIM: There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. METHODS: We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations and medical specialties (cardiology or nephrology vs. other. Participants were enrolled through purposeful sampling. We inquired for conditions under which surrogate endpoints can be used, the validity of various cardio-renal biomarkers and new approaches for biomarker use. RESULTS: Participants agreed that surrogate endpoints can be used when the surrogate is scientifically valid (5-point Likert response format, mean score: 4.3, SD: 0.9 or when there is an unmet clinical need (mean score: 3.8, SD: 1.2. Industry participants agreed to a greater extent than regulators and academics. However, out of four proposed surrogates (blood pressure (BP, HbA1c, albuminuria, CRP for cardiovascular outcomes or end-stage renal disease, only use of BP for cardiovascular outcomes was deemed moderately accurate (mean: 3.6, SD: 1.1. Specialists in cardiology or nephrology tended to be more positive about the use of surrogate endpoints. CONCLUSION: Stakeholders in drug development do not oppose to the use of surrogate endpoints in drug marketing authorization, but most surrogates are not considered valid. To solve this impasse, increased efforts are required to validate surrogate endpoints and to explore alternative ways to use them.

  15. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE)

    DEFF Research Database (Denmark)

    Vestbo, J; Anderson, W; Coxson, H O

    2008-01-01

    computed tomography, biomarker measurement (in blood, sputum, urine and exhaled breath condensate), health outcomes, body impedance, resting oxygen saturation and 6-min walking distance. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points is the largest study attempting to better...

  16. Biomarkers of intermediate endpoints in environmental and occupational health

    DEFF Research Database (Denmark)

    Knudsen, Lisbeth E; Hansen, Ase M

    2007-01-01

    The use of biomarkers in environmental and occupational health is increasing due to increasing demands on information about health risks from unfavourable exposures. Biomarkers provide information about individual loads. Biomarkers of intermediate endpoints benefit in comparison with biomarkers...... of exposure from the fact that they are closer to the adverse outcome in the pathway from exposure to health effects and may provide powerful information for intervention. Some biomarkers are specific, e.g., DNA and protein adducts, while others are unspecific like the cytogenetic biomarkers of chromosomal...... health effect from the result of the measurement has been performed for the cytogenetic biomarkers showing a predictive value of high levels of CA and increased risk of cancer. The use of CA in future studies is, however, limited by the laborious and sensitive procedure of the test and lack of trained...

  17. A causal framework for surrogate endpoints with semi-competing risks data.

    Science.gov (United States)

    Ghosh, Debashis

    2012-10-01

    In this note, we address the problem of surrogacy using a causal modelling framework that differs substantially from the potential outcomes model that pervades the biostatistical literature. The framework comes from econometrics and conceptualizes direct effects of the surrogate endpoint on the true endpoint. While this framework can incorporate the so-called semi-competing risks data structure, we also derive a fundamental non-identifiability result. Relationships to existing causal modelling frameworks are also discussed.

  18. Surrogate endpoints for EDSS worsening in multiple sclerosis. A meta-analytic approach.

    Science.gov (United States)

    Sormani, M P; Bonzano, L; Roccatagliata, L; Mancardi, G L; Uccelli, A; Bruzzi, P

    2010-07-27

    To evaluate whether the effects on potential surrogate endpoints, such as MRI markers and relapses, observed in trials of experimental treatments are able to predict the effects of these treatments on disability progression as defined in relapsing-remitting multiple sclerosis (RRMS) trials. We used a pooled analysis of all the published randomized controlled clinical trials in RRMS reporting data on Expanded Disability Status Scale (EDSS) worsening and relapses or MRI lesions or both. We extracted data on relapses, MRI lesions, and the proportion of progressing patients. A regression analysis weighted on trial size and duration was performed to study the relationship between the treatment effect observed in each trial on relapses and MRI lesions and the observed treatment effect on EDSS worsening. A set of 19 randomized double-blind controlled trials in RRMS were identified, for a total of 44 arms, 25 contrasts, and 10,009 patients. A significant correlation was found between the effect of treatments on relapses and the effect of treatments on EDSS worsening: the adjusted R(2) value of the weighted regression was 0.71. The correlation between the treatment effect on MRI lesions and EDSS worsening was slightly weaker (R(2) = 0.57) but significant. These findings support the use of commonly used surrogate markers of EDSS worsening as endpoints in multiple sclerosis clinical trials. Further research is warranted to validate surrogate endpoints at the individual level rather than at the trial level, to draw important conclusions in the management of the individual patient.

  19. An evaluation of culture results during treatment for tuberculosis as surrogate endpoints for treatment failure and relapse.

    Directory of Open Access Journals (Sweden)

    Patrick P J Phillips

    Full Text Available It is widely acknowledged that new regimens are urgently needed for the treatment of tuberculosis. The primary endpoint in the Phase III trials is a composite outcome of failure at the end of treatment or relapse after stopping treatment. Such trials are usually both long and expensive. Valid surrogate endpoints measured during or at the end of treatment could dramatically reduce both the time and cost of assessing the effectiveness of new regimens. The objective of this study was to evaluate sputum culture results on solid media during treatment as surrogate endpoints for poor outcome. Data were obtained from twelve randomised controlled trials conducted by the British Medical Research Council in the 1970s and 80s in East Africa and East Asia, consisting of 6974 participants and 49 different treatment regimens. The month two culture result was shown to be a poor surrogate in East Africa but a good surrogate in Hong Kong. In contrast, the month three culture was a good surrogate in trials conducted in East Africa but not in Hong Kong. As well as differences in location, ethnicity and probable strain of Mycobacteria tuberculosis, Hong Kong trials more often evaluated regimens with rifampicin throughout and intermittent regimens, and patients in East African trials more often presented with extensive cavitation and were slower to convert to culture negative during treatment. An endpoint that is a summary measure of the longitudinal profile of culture results over time or that is able to detect the presence of M. tuberculosis later in treatment is more likely to be a better endpoint for a phase II trial than a culture result at a single time point and may prove to be an acceptable surrogate. More data are needed before any endpoint can be used as a surrogate in a confirmatory phase III trial.

  20. Imaging readouts as biomarkers or surrogate parameters for the assessment of therapeutic interventions

    Energy Technology Data Exchange (ETDEWEB)

    Rudin, Markus [University of Zuerich/ETH Zuerich, Institute for Biomedical Engineering, Zuerich (Switzerland); University of Zuerich, Institute for Pharmacology and Toxicology, Zuerich (Switzerland)

    2007-10-15

    Surrogate markers and biomarkers based on imaging readouts providing predictive information on clinical outcome are of increasing importance in the preclinical and clinical evaluation of novel therapies. They are primarily used in studies designed to establish evidence that the therapeutic principle is valid in a representative patient population or in an individual. A critical step in the development of (imaging) surrogates is validation: correlation with established clinical endpoints must be demonstrated. Biomarkers must not fulfill such stringent validation criteria; however, they should provide insight into mechanistic aspects of the therapeutic intervention (proof-of-mechanism) or document therapy efficacy with prognostic quality with regard to the long-term clinical outcome (proof of concept). Currently used imaging biomarkers provide structural, physiological and metabolic information. Novel imaging approaches annotate structure with molecular signatures that are tightly linked to the pathophysiology or to the therapeutic principle. These cellular and molecular imaging methods yield information on drug biodistribution, receptor expression and occupancy, and/or intra- and intercellular signaling. The design of novel target-specific imaging probes is closely related to the development of the therapeutic agents and should be considered early in the discovery phase. Significant technical and regulatory hurdles have to be overcome to foster the use of imaging biomarkers for clinical drug evaluation. (orig.)

  1. On the relationship between the causal-inference and meta-analytic paradigms for the validation of surrogate endpoints.

    Science.gov (United States)

    Alonso, Ariel; Van der Elst, Wim; Molenberghs, Geert; Buyse, Marc; Burzykowski, Tomasz

    2015-03-01

    The increasing cost of drug development has raised the demand for surrogate endpoints when evaluating new drugs in clinical trials. However, over the years, it has become clear that surrogate endpoints need to be statistically evaluated and deemed valid, before they can be used as substitutes of "true" endpoints in clinical studies. Nowadays, two paradigms, based on causal-inference and meta-analysis, dominate the scene. Nonetheless, although the literature emanating from these paradigms is wide, till now the relationship between them has largely been left unexplored. In the present work, we discuss the conceptual framework underlying both approaches and study the relationship between them using theoretical elements and the analysis of a real case study. Furthermore, we show that the meta-analytic approach can be embedded within a causal-inference framework on the one hand and that it can be heuristically justified why surrogate endpoints successfully evaluated using this approach will often be appealing from a causal-inference perspective as well, on the other. A newly developed and user friendly R package Surrogate is provided to carry out the evaluation exercise.

  2. Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints.

    Science.gov (United States)

    Kakkis, Emil D; O'Donovan, Mary; Cox, Gerald; Hayes, Mark; Goodsaid, Federico; Tandon, P K; Furlong, Pat; Boynton, Susan; Bozic, Mladen; Orfali, May; Thornton, Mark

    2015-02-10

    For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV.In 2012, the AA provisions were amended to enhance the application of the AA pathway to expedite the development of drugs for rare disorders under the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA, among many provisions, requires the development of a more relevant FDA guidance on the types of evidence that may be acceptable in support of using a novel surrogate endpoint. The application of AA to rare diseases requires more predictability to drive greater access to appropriate use of AA for more rare disease treatments that might not be developed otherwise.This white paper proposes a scientific framework for assessing biomarker endpoints to enhance the development of novel therapeutics for rare and devastating diseases currently without adequate treatment and is based on the opinions of experts in drug development and rare disease patient groups. Specific recommendations include: 1) Establishing regulatory rationale for increased AA access in rare disease programs; 2) Implementing a Biomarker Qualification Request Process to provide the opportunity for an early determination of biomarker acceptance; and 3) A proposed scientific framework for qualifying biomarkers as primary endpoints. The paper's final section highlights case studies of successful examples that have incorporated biomarker endpoints into

  3. Early Proctoscopy is a Surrogate Endpoint of Late Rectal Toxicity in Prostate Cancer Treated With Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Ippolito, Edy; Massaccesi, Mariangela; Digesu, Cinzia; Deodato, Francesco [Radiotherapy Unit, Fondazione di Ricerca e Cura Giovanni Paolo II, Universita Cattolica del S. Cuore, Campobasso (Italy); Macchia, Gabriella, E-mail: gmacchia@rm.unicatt.it [Radiotherapy Unit, Fondazione di Ricerca e Cura Giovanni Paolo II, Universita Cattolica del S. Cuore, Campobasso (Italy); Pirozzi, Giuseppe Antonio [Endoscopy Unit, Fondazione di Ricerca e Cura Giovanni Paolo II, Universita Cattolica del S. Cuore, Campobasso (Italy); Cilla, Savino [Medical Physics Unit, Fondazione di Ricerca e Cura Giovanni Paolo II, Universita Cattolica del S. Cuore, Campobasso (Italy); Cuscuna, Daniele; Di Lallo, Alessandra [Urology Unit, General Hospital A. Cardarelli, Campobasso (Italy); Mattiucci, Gian Carlo; Mantini, Giovanna [Department of Radiotherapy, Policlinico Universitario Agostino Gemelli, Universita Cattolica del S. Cuore, Rome (Italy); Pacelli, Fabio [Surgery Unit, Fondazione di Ricerca e Cura Giovanni Paolo II, Universita Cattolica del S. Cuore, Campobasso (Italy); Valentini, Vincenzo; Cellini, Numa [Department of Radiotherapy, Policlinico Universitario Agostino Gemelli, Universita Cattolica del S. Cuore, Rome (Italy); Ingrosso, Marcello [Endoscopy Unit, Fondazione di Ricerca e Cura Giovanni Paolo II, Universita Cattolica del S. Cuore, Campobasso (Italy); Morganti, Alessio Giuseppe [Radiotherapy Unit, Fondazione di Ricerca e Cura Giovanni Paolo II, Universita Cattolica del S. Cuore, Campobasso (Italy); Department of Radiotherapy, Policlinico Universitario Agostino Gemelli, Universita Cattolica del S. Cuore, Rome (Italy)

    2012-06-01

    Purpose: To predict the grade and incidence of late clinical rectal toxicity through short-term (1 year) mucosal alterations. Methods and Materials: Patients with prostate adenocarcinoma treated with curative or adjuvant radiotherapy underwent proctoscopy a year after the course of radiotherapy. Mucosal changes were classified by the Vienna Rectoscopy Score (VRS). Late toxicity data were analyzed according to the Kaplan-Meier method. Comparison between prognosis groups was performed by log-rank analysis. Results: After a median follow-up time of 45 months (range, 18-99), the 3-year incidence of grade {>=}2 rectal late toxicity according to the criteria of the European Organization for Research and Treatment of Cancer and the Radiation Therapy Oncology Group was 24%, with all patients (24/24; 100%) experiencing rectal bleeding. The occurrence of grade {>=}2 clinical rectal late toxicity was higher in patients with grade {>=}2 (32% vs. 15 %, p = 0.02) or grade {>=}3 VRS telangiectasia (47% vs. 17%, p {<=} 0.01) and an overall VRS score of {>=}2 (31% vs. 16 %, p = 0.04) or {>=}3 (48% vs. 17%, p = 0.01) at the 1-year proctoscopy. Conclusions: Early proctoscopy (1 year) predicts late rectal bleeding and therefore can be used as a surrogate endpoint for late rectal toxicity in studies aimed at reducing this frequent complication.

  4. Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

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    Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B.; George, Kerry A.; Cucinotta, Francis A.

    2016-01-01

    The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed. PMID:27111667

  5. Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints.

    Directory of Open Access Journals (Sweden)

    Eliedonna Cacao

    Full Text Available The biological effects of high charge and energy (HZE particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE's using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE's are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (10 are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE's against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed.

  6. Exploring the relationship between the causal-inference and meta-analytic paradigms for the evaluation of surrogate endpoints.

    Science.gov (United States)

    Van der Elst, Wim; Molenberghs, Geert; Alonso, Ariel

    2016-04-15

    Nowadays, two main frameworks for the evaluation of surrogate endpoints, based on causal-inference and meta-analysis, dominate the scene. Earlier work showed that the metrics of surrogacy introduced in both paradigms are related, although in a complex way that is difficult to study analytically. In the present work, this relationship is further examined using simulations and the analysis of a case study. The results indicate that the extent to which both paradigms lead to similar conclusions regarding the validity of the surrogate, depends on a complex interplay between multiple factors like the ratio of the between and within trial variability and the unidentifiable correlations between the potential outcomes. All the analyses were carried out using the newly developed R package Surrogate, which is freely available via CRAN.

  7. Early Change in Proteinuria as a Surrogate Endpoint for Kidney Disease Progression: An Individual Patient Meta-analysis

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    Inker, Lesley A.; Levey, Andrew S.; Pandya, Kruti; Stoycheff, Nicholas; Okparavero, Aghogho; Greene, Tom

    2014-01-01

    Background It is controversial whether proteinuria is a valid surrogate endpoint for randomized trials in chronic kidney disease. Study Design Meta-analysis of individual patient level data. Setting & Population Individual patient data on 9008 patients from 32 randomized trials evaluating five intervention types. Selection Criteria for Studies Randomized controlled trials of kidney disease progression until 2007 with measurements of proteinuria both at baseline and during the first year of follow-up, with at least one further year of follow-up for the clinical outcome. Predictor Early change in proteinuria. Outcomes Doubling of serum creatinine, end stage renal disease or death. Results Early decline in proteinuria was associated with a lower risk of the clinical outcome (pooled HR, 0.74 per 50% reduction in proteinuria); this association was stronger at higher levels of baseline proteinuria. Pooled estimates for the proportion of treatment effect on the clinical outcome explained by early decline in proteinuria ranged from −7.0% (95% CI, −40.6% to 26.7%) to 43.9% (95% CI, 25.3% to 62.6%) across five intervention types. The direction of the pooled treatment effects on early change in proteinuria agreed with the direction of the treatment effect on the clinical outcome for all 5 intervention types, with the magnitudes of the pooled treatment effects on the two endpoints agreeing for 4 of the 5 intervention types. The pooled treatment effects on both endpoints were simultaneously stronger at higher levels of proteinuria. However, statistical power was insufficient to determine if differences in treatment effects on the clinical outcome corresponded to differences in treatment effects on proteinuria between individual studies. Limitations Limited variety of interventions tested and low statistical power for many chronic kidney disease clinical trials. Conclusions These results provide new evidence supporting the use of an early reduction in proteinuria as a

  8. Biomarkers of Host Response Predict Primary End-Point Radiological Pneumonia in Tanzanian Children with Clinical Pneumonia: A Prospective Cohort Study.

    Directory of Open Access Journals (Sweden)

    Laura K Erdman

    Full Text Available Diagnosing pediatric pneumonia is challenging in low-resource settings. The World Health Organization (WHO has defined primary end-point radiological pneumonia for use in epidemiological and vaccine studies. However, radiography requires expertise and is often inaccessible. We hypothesized that plasma biomarkers of inflammation and endothelial activation may be useful surrogates for end-point pneumonia, and may provide insight into its biological significance.We studied children with WHO-defined clinical pneumonia (n = 155 within a prospective cohort of 1,005 consecutive febrile children presenting to Tanzanian outpatient clinics. Based on x-ray findings, participants were categorized as primary end-point pneumonia (n = 30, other infiltrates (n = 31, or normal chest x-ray (n = 94. Plasma levels of 7 host response biomarkers at presentation were measured by ELISA. Associations between biomarker levels and radiological findings were assessed by Kruskal-Wallis test and multivariable logistic regression. Biomarker ability to predict radiological findings was evaluated using receiver operating characteristic curve analysis and Classification and Regression Tree analysis.Compared to children with normal x-ray, children with end-point pneumonia had significantly higher C-reactive protein, procalcitonin and Chitinase 3-like-1, while those with other infiltrates had elevated procalcitonin and von Willebrand Factor and decreased soluble Tie-2 and endoglin. Clinical variables were not predictive of radiological findings. Classification and Regression Tree analysis generated multi-marker models with improved performance over single markers for discriminating between groups. A model based on C-reactive protein and Chitinase 3-like-1 discriminated between end-point pneumonia and non-end-point pneumonia with 93.3% sensitivity (95% confidence interval 76.5-98.8, 80.8% specificity (72.6-87.1, positive likelihood ratio 4.9 (3.4-7.1, negative likelihood ratio 0

  9. Biomarker report from the phase II lamotrigine trial in secondary progressive MS - neurofilament as a surrogate of disease progression.

    Directory of Open Access Journals (Sweden)

    Sharmilee Gnanapavan

    Full Text Available OBJECTIVE: Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH and other biomarkers in predicting prognosis and/or response to treatment. METHODS: SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored. RESULTS: Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p=0.043, Nfh 0-24 months p=0.023. Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand, PASAT, z-score, MSIS-29 (psychological and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin. CONCLUSIONS: The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.

  10. Emerging treatments in management of prostate cancer: biomarker validation and endpoints for immunotherapy clinical trial design

    Directory of Open Access Journals (Sweden)

    Slovin SF

    2013-12-01

    Full Text Available Susan F SlovinGenitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: The rapidly emerging field of immunotherapy and the development of novel immunologic agents that have been approved in melanoma and successfully studied in lung cancer, kidney cancer, and prostate cancer have mandated that there be uniformity in clinical trial analysis beyond conventional survival endpoints and imaging. This includes some measure of determining whether the immunologic target is hit and how the treatment has impacted on the immune system in toto. While melanoma is leading the field towards these ends, there is some doubt that not all of the recent successes with immune therapies, for example, checkpoint inhibitors, will be effective for every cancer, and that the toxicities may also be different depending on the malignancy. This review serves to elucidate the current issues facing clinical investigators who perform immunologic trials targeted at patients with prostate cancer and discusses the challenges in assessing the right immunologic endpoints to demonstrate biologic/immunologic targeting leading to clinical benefit.Keywords: sipuleucel-T, prostate-specific antigen, prostate cancer, biomarkers, monoclonal antibodies, vaccines, cellular therapy

  11. Automated Device for Asynchronous Extraction of RNA, DNA, or Protein Biomarkers from Surrogate Patient Samples.

    Science.gov (United States)

    Bitting, Anna L; Bordelon, Hali; Baglia, Mark L; Davis, Keersten M; Creecy, Amy E; Short, Philip A; Albert, Laura E; Karhade, Aditya V; Wright, David W; Haselton, Frederick R; Adams, Nicholas M

    2016-12-01

    Many biomarker-based diagnostic methods are inhibited by nontarget molecules in patient samples, necessitating biomarker extraction before detection. We have developed a simple device that purifies RNA, DNA, or protein biomarkers from complex biological samples without robotics or fluid pumping. The device design is based on functionalized magnetic beads, which capture biomarkers and remove background biomolecules by magnetically transferring the beads through processing solutions arrayed within small-diameter tubing. The process was automated by wrapping the tubing around a disc-like cassette and rotating it past a magnet using a programmable motor. This device recovered biomarkers at ~80% of the operator-dependent extraction method published previously. The device was validated by extracting biomarkers from a panel of surrogate patient samples containing clinically relevant concentrations of (1) influenza A RNA in nasal swabs, (2) Escherichia coli DNA in urine, (3) Mycobacterium tuberculosis DNA in sputum, and (4) Plasmodium falciparum protein and DNA in blood. The device successfully extracted each biomarker type from samples representing low levels of clinically relevant infectivity (i.e., 7.3 copies/µL of influenza A RNA, 405 copies/µL of E. coli DNA, 0.22 copies/µL of TB DNA, 167 copies/µL of malaria parasite DNA, and 2.7 pM of malaria parasite protein). © 2015 Society for Laboratory Automation and Screening.

  12. Cadmium phytotoxicity: Quantitative sensitivity relationships between classical endpoints and antioxidative enzyme biomarkers

    Energy Technology Data Exchange (ETDEWEB)

    Rosa Correa, Albertina Xavier da [Centro de Ciencias Tecnologicas da Terra e do Mar, Universidade do Vale do Itajai, Rua Uruguai, 458, 88302-202 Itajai SC (Brazil); Roerig, Leonardo Rubi [Centro de Ciencias Tecnologicas da Terra e do Mar, Universidade do Vale do Itajai, Rua Uruguai, 458, 88302-202 Itajai SC (Brazil); Verdinelli, Miguel A. [Centro de Ciencias Tecnologicas da Terra e do Mar, Universidade do Vale do Itajai, Rua Uruguai, 458, 88302-202 Itajai SC (Brazil); Cotelle, Sylvie [Centre des Sciences de l' Environnement, Universite de Metz, 57000 Metz (France); Ferard, Jean-Francois [Centre des Sciences de l' Environnement, Universite de Metz, 57000 Metz (France); Radetski, Claudemir Marcos [Centro de Ciencias Tecnologicas da Terra e do Mar, Universidade do Vale do Itajai, Rua Uruguai, 458, 88302-202 Itajai SC (Brazil)]. E-mail: radetski@univali.br

    2006-03-15

    In this work, cadmium phytotoxicity and quantitative sensitivity relationships between different hierarchical endpoints in plants cultivated in a contaminated soil were studied. Thus, germination rate, biomass growth and antioxidative enzyme activity (i.e. superoxide dismutase, peroxidase, catalase and glutathione reductase) in three terrestrial plants (Avena sativa L., Brassica campestris L. cv. Chinensis, Lactuca sativa L. cv. hanson) were analyzed. Plant growth tests were carried out according to an International Standard Organization method and the results were analyzed by ANOVA followed by Williams' test. The concentration of Cd{sup 2+} that had the smallest observed significant negative effect (LOEC) on plant biomass was 6.25, 12.5 and 50 mg Cd/kg dry soil for lettuce, oat and Chinese cabbage, respectively. Activity of all enzymes studied increased significantly compared to enzyme activity in plant controls. For lettuce, LOEC values (mg Cd/kg dry soil) for enzymic activity ranged from 0.05 (glutathione reductase) to 0.39 (catalase). For oat, LOEC values (mg Cd/kg dry soil) ranged from 0.19 (for superoxide dismutase and glutathione reductase) to 0.39 (for catalase and peroxidase). For Chinese cabbage, LOEC values (mg Cd/kg dry soil) ranged from 0.19 (peroxidase, catalase and glutathione reductase) to 0.39 (superoxide dismutase). Classical (i.e. germination and biomass) and biochemical (i.e. enzyme activity) endpoints were compared to establish a sensitivity ranking, which was: enzyme activity > biomass > germination rate. For cadmium-soil contamination, the determination of quantitative sensitivity relationships (QSR) between classical and antioxidative enzyme biomarkers showed that the most sensitive plant species have, generally, the lowest QSR values.

  13. Pathologic complete response and disease-free survival are not surrogate endpoints for 5-year survival in rectal cancer: an analysis of 22 randomized trials

    Science.gov (United States)

    Borgonovo, Karen; Cabiddu, Mary; Ghilardi, Mara; Lonati, Veronica; Barni, Sandro

    2017-01-01

    Background We performed a literature-based analysis of randomized clinical trials to assess the pathologic complete response (pCR) (ypT0N0 after neoadjuvant therapy) and 3-year disease-free survival (DFS) as potential surrogate endpoints for 5-year overall survival (OS) in rectal cancer treated with neoadjuvant (chemo)radiotherapy (CT)RT. Methods A systematic literature search of PubMed, EMBASE, the Web of Science, SCOPUS, CINAHL, and the Cochrane Library was performed. Treatment effects on 3-year DFS and 5-year OS were expressed as rates of patients alive (%), and those on pCR as differences in pCR rates (∆pCR%). A weighted regression analysis was performed at individual- and trial-level to test the association between treatment effects on surrogate (∆pCR% and ∆3yDFS) and the main clinical outcome (∆5yOS). Results Twenty-two trials involving 10,050 patients, were included in the analysis. The individual level surrogacy showed that the pCR% and 3-year DFS were poorly correlated with 5-year OS (R=0.52; 95% CI, 0.31–0.91; P=0.002; and R=0.60; 95% CI, 0.36–1; P=0.002). The trial-level surrogacy analysis confirmed that the two treatment effects on surrogates (∆pCR% and ∆3yDFS) are not strong surrogates for treatment effects on 5-year OS % (R=0.2; 95% CI, −0.29–0.78; P=0.5 and R=0.64; 95% CI, 0.29–1; P=0.06). These findings were confirmed in neoadjuvant CTRT studies but not in phase III trials were 3-year DFS could still represent a valid surrogate. Conclusions This analysis does not support the use of pCR and 3-year DFS% as appropriate surrogate endpoints for 5-year OS% in patients with rectal cancer treated with neoadjuvant therapy.

  14. Importance of glomerular filtration rate change as surrogate endpoint for the future incidence of end-stage renal disease in general Japanese population: community-based cohort study.

    Science.gov (United States)

    Kanda, Eiichiro; Usui, Tomoko; Kashihara, Naoki; Iseki, Chiho; Iseki, Kunitoshi; Nangaku, Masaomi

    2017-09-07

    Because of the necessity for extended period and large costs until the event occurs, surrogate endpoints are indispensable for implementation of clinical studies to improve chronic kidney disease (CKD) patients' prognosis. Subjects with serum creatinine level for a baseline period over 1-3 years were enrolled (n = 69,238) in this community-based prospective cohort study in Okinawa, Japan, and followed up for 15 years. The endpoint was end-stage renal disease (ESRD). The percent of estimated glomerular filtration rate (%eGFR) change was calculated on the basis of the baseline period. Subjects had a mean ± SD age, 55.59 ± 14.69 years; eGFR, 80.15 ± 21.15 ml/min/1.73 m(2). Among the subjects recruited, 15.81% had a low eGFR (changes over 2 or 3 years in the high- and low-eGFR groups. The specificities and positive predictive values for ESRD based on a cutoff value of %eGFR change of less than -30% over 2 or 3 years were high in the high- and low-eGFR groups. %eGFR change tends to be associated with the risk of ESRD. %eGFR change of less than -30% over 2 or 3 years can be a candidate surrogate endpoint for ESRD in the general Japanese population.

  15. Plasma matrix metalloproteinase 9 as an early surrogate biomarker of advanced colorectal neoplasia.

    Science.gov (United States)

    Gimeno-García, Antonio Z; Triñanes, Javier; Quintero, Enrique; Salido, Eduardo; Nicolás-Pérez, David; Adrián-de-Ganzo, Zaida; Alarcón-Fernández, Onofre; Abrante, Beatriz; Romero, Rafael; Carrillo, Marta; Ramos, Laura; Alonso, Inmaculada; Ortega, Juan; Jiménez, Alejandro

    2016-01-01

    Matrix metalloproteinases (MMPs) are overexpressed at different stages of colorectal carcinogenesis and could serve as early surrogate biomarkers of colorectal neoplasia. To assess the utility of plasma MMP2 and MMP9 levels in the detection of advanced colorectal neoplasia and their correlation with tissue levels. We analysed blood and tissue samples from patients with non-advanced adenomas (n=25), advanced adenomas (n=25), colorectal cancer (n=25) and healthy controls (n=75). Plasma and tissue gelatinase levels were determined by Luminex XMAP technology and gelatin zymography. Receiver operating characteristic (ROC) curve analysis was used to calculate the optimum cut-off for the detection of advanced colorectal neoplasia. Plasma MMP2 levels were similar between groups whatever the type of lesion. Plasma MMP9 levels were significantly higher in patients with neoplastic lesions than in healthy controls (median 292.3ng/ml vs. 139.08ng/ml, P<0.001). MMP9 levels were also higher in colorectal cancer than in non-advanced adenomas (median 314.6ng/ml vs. 274.3ng/ml, P=0.03). There was a significant correlation between plasma and tissue levels of MMP9 (r=0.5, P<0.001). The plasma MMP9 cut-off range with the highest diagnostic accuracy was between 173ng/ml and 204ng/ml (AUC=0.80 [95% CI: 0.72-0.86], P<0.001; sensitivity, 80-86% and specificity, 57-67%). Plasma MMP9 could be a surrogate biomarker for the early detection of advanced colorectal neoplasia, although its diagnostic performance could be increased by combination with other biomarkers. Copyright © 2015 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

  16. Aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research.

    Science.gov (United States)

    Leiser, Steven C; Dunlop, John; Bowlby, Mark R; Devilbiss, David M

    2011-06-15

    Electroencephalography (EEG) and related methodologies offer the promise of predicting the likelihood that novel therapies and compounds will exhibit clinical efficacy early in preclinical development. These analyses, including quantitative EEG (e.g. brain mapping) and evoked/event-related potentials (EP/ERP), can provide a physiological endpoint that may be used to facilitate drug discovery, optimize lead or candidate compound selection, as well as afford patient stratification and Go/No-Go decisions in clinical trials. Currently, the degree to which these different methodologies hold promise for translatability between preclinical models and the clinic have not been well summarized. To address this need, we review well-established and emerging EEG analytic approaches that are currently being integrated into drug discovery programs throughout preclinical development and clinical research. Furthermore, we present the use of EEG in the drug development process in the context of a number of major central nervous system disorders including Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder, and pain. Lastly, we discuss the requirements necessary to consider EEG technologies as a biomarker. Many of these analyses show considerable translatability between species and are used to predict clinical efficacy from preclinical data. Nonetheless, the next challenge faced is the selection and validation of EEG endpoints that provide a set of robust and translatable biomarkers bridging preclinical and clinical programs.

  17. Acetylcholinesterase from Human Erythrocytes as a Surrogate Biomarker of Lead Induced Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Vivek Kumar Gupta

    2015-01-01

    Full Text Available Lead induced neurotoxicity in the people engaged in different occupations has received wide attention but very little studies have been carried out to monitor occupational neurotoxicity directly due to lead exposure using biochemical methods. In the present paper an endeavour has been made in order to assess the lead mediated neurotoxicity by in vitro assay of the activity of acetylcholinesterase (AChE from human erythrocytes in presence of different concentrations of lead. The results suggested that the activity of this enzyme was localized in membrane bound fraction and it was found to be highly stable up to 30 days when stored at −20°C in phosphate buffer (50 mM, pH 7.4 containing 0.2% Triton X-100. The erythrocyte’s AChE exhibited Km for acetylcholinesterase to be 0.1 mM. Lead caused sharp inhibition of the enzyme and its IC50 value was computed to be 1.34 mM. The inhibition of the enzyme by lead was found to be of uncompetitive type (Ki value, 3.6 mM which negatively influenced both the Vmax and the enzyme-substrate binding affinity. Taken together, these results indicate that AChE from human erythrocytes could be exploited as a surrogate biomarker of lead induced neurotoxicity particularly in the people occupationally exposed to lead.

  18. Biomarkers in chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Sin, Don D; Vestbo, Jørgen

    2009-01-01

    Currently, with exception of lung function tests, there are no well validated biomarkers or surrogate endpoints that can be used to establish efficacy of novel drugs for chronic obstructive pulmonary disease (COPD). However, the lung function test is not an ideal surrogate for short-term drug...

  19. Proposal for levels of evidence schema for validation of a soluble biomarker reflecting damage endpoints in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, and recommendations for study design

    DEFF Research Database (Denmark)

    Maksymowych, Walter P; Fitzgerald, Oliver; Wells, George A

    2009-01-01

    arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We also aimed to generate consensus on minimum standards for the design of longitudinal studies aimed at validating biomarkers. METHODS: Before the meeting, the Soluble Biomarker Working Group prepared a preliminary framework...... and discussed various models for association and prediction related to the statistical strength domain. In addition, 3 Delphi exercises addressing longitudinal study design for RA, PsA, and AS were conducted within the working group and members of the Assessments in SpondyloArthritis International Society (ASAS...... Biomarker Group has successfully formulated a levels of evidence scheme and a study design template that will provide guidance to conduct validation studies in the setting of soluble biomarkers proposed to replace the measurement of damage endpoints in RA, PsA, and AS....

  20. 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...

  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

    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......-based survey. RESULTS: Minimal data were extracted from the literature pertaining to those criteria listed under the category of truth. Ratings for strength of evidence were moderate to low (

  2. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the Screening for Pregnancy Endpoints (SCOPE) international cohort study.

    Science.gov (United States)

    Kenny, Louise C; Black, Michael A; Poston, Lucilla; Taylor, Rennae; Myers, Jenny E; Baker, Philip N; McCowan, Lesley M; Simpson, Nigel A B; Dekker, Gus A; Roberts, Claire T; Rodems, Kelline; Noland, Brian; Raymundo, Michael; Walker, James J; North, Robyn A

    2014-09-01

    More than half of all cases of preeclampsia occur in healthy first-time pregnant women. Our aim was to develop a method to predict those at risk by combining clinical factors and measurements of biomarkers in women recruited to the Screening for Pregnancy Endpoints (SCOPE) study of low-risk nulliparous women. Forty-seven biomarkers identified on the basis of (1) association with preeclampsia, (2) a biological role in placentation, or (3) a role in cellular mechanisms involved in the pathogenesis of preeclampsia were measured in plasma sampled at 14 to 16 weeks' gestation from 5623 women. The cohort was randomly divided into training (n=3747) and validation (n=1876) cohorts. Preeclampsia developed in 278 (4.9%) women, of whom 28 (0.5%) developed early-onset preeclampsia. The final model for the prediction of preeclampsia included placental growth factor, mean arterial pressure, and body mass index at 14 to 16 weeks' gestation, the consumption of ≥3 pieces of fruit per day, and mean uterine artery resistance index. The area under the receiver operator curve (95% confidence interval) for this model in training and validation cohorts was 0.73 (0.70-0.77) and 0.68 (0.63-0.74), respectively. A predictive model of early-onset preeclampsia included angiogenin/placental growth factor as a ratio, mean arterial pressure, any pregnancy loss preeclampsia in populations of mixed parity and risk. In nulliparous women, combining multiple biomarkers and clinical data provided modest prediction of preeclampsia. © 2014 American Heart Association, Inc.

  3. The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation

    DEFF Research Database (Denmark)

    Vlachopoulos, Charalambos; Xaplanteris, Panagiotis; Aboyans, Victor

    2015-01-01

    While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a s...

  4. Use of Surrogate end points in HTA

    Directory of Open Access Journals (Sweden)

    Mangiapane, Sandra

    2009-08-01

    Full Text Available The different actors involved in health system decision-making and regulation have to deal with the question which are valid parameters to assess the health value of health technologies.So called surrogate endpoints represent in the best case preliminary steps in the casual chain leading to the relevant outcome (e. g. mortality, morbidity and are not usually directly perceptible by patients. Surrogate endpoints are not only used in trials of pharmaceuticals but also in studies of other technologies. Their use in the assessment of the benefit of a health technology is however problematic. In this report we intend to answer the following research questions: Which criteria need to be fulfilled for a surrogate parameter to be considered a valid endpoint? Which methods have been described in the literature for the assessment of the validity of surrogate endpoints? Which methodological recommendations concerning the use of surrogate endpoints have been made by international HTA agencies? Which place has been given to surrogate endpoints in international and German HTA reports? For this purpose, we choose three different approaches. Firstly, we conduct a review of the methodological literature dealing with the issue of surrogate endpoints and their validation. Secondly, we analyse current methodological guidelines of HTA agencies members of the International network of agencies for Health Technology Assessment (INAHTA as well as of agencies concerned with assessments for reimbursement purposes. Finally, we analyse the outcome parameter used in a sample of HTA reports available for the public. The analysis of methodological guidelines shows a very cautious position of HTA institutions regarding the use of surrogate endpoints in technology assessment. Surrogate endpoints have not been prominently used in HTA reports. None of the analysed reports based its conclusions solely on the results of surrogate endpoints. The analysis of German HTA reports shows a

  5. Circulating Biomarkers for Duchenne Muscular Dystrophy

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Spitali, Pietro

    2015-01-01

    Abstract Duchenne muscular dystrophy is the most common form of muscular dystrophy. Genetic and biochemical research over the years has characterized the cause, pathophysiology and development of the disease providing several potential therapeutic targets and/or biomarkers. High throughput – omic technologies have provided a comprehensive understanding of the changes occurring in dystrophic muscles. Murine and canine animal models have been a valuable source to profile muscles and body fluids, thus providing candidate biomarkers that can be evaluated in patients. This review will illustrate known circulating biomarkers that could track disease progression and response to therapy in patients affected by Duchenne muscular dystrophy. We present an overview of the transcriptomic, proteomic, metabolomics and lipidomic biomarkers described in literature. We show how studies in muscle tissue have led to the identification of serum and urine biomarkers and we highlight the importance of evaluating biomarkers as possible surrogate endpoints to facilitate regulatory processes for new medicinal products. PMID:27858763

  6. Screening for chronic kidney disease of uncertain aetiology in Sri Lanka: usability of surrogate biomarkers over dipstick proteinuria

    OpenAIRE

    Ratnayake, Samantha; Badurdeen, Zeid; Nanayakkara, Nishantha; Abeysekara, Tilak; Ratnatunga, Neelakanthi; Kumarasiri, Ranjith

    2017-01-01

    Background The use of dipstick proteinuria to screen Chronic Kidney Disease of uncertain aetiology (CKDu) in Sri Lanka is a recently debated matter of dispute. The aim of this study was to assess the suitability of biomarkers: serum creatinine, cystatin C and urine albumin to creatinine ratio (ACR) for screening CKDu in Sri Lanka. Methods Forty-four male CKDu patients and 49 healthy males from a CKDu-endemic region were selected. Meanwhile, 25 healthy males from a non-endemic region were sele...

  7. Evaluation of Circulating Tumor Cells and Related Events as Prognostic Factors and Surrogate Biomarkers in Advanced NSCLC Patients Receiving First-Line Systemic Treatment

    Directory of Open Access Journals (Sweden)

    Laura Muinelo-Romay

    2014-01-01

    Full Text Available In the present study we investigated the prognostic value of Circulating Tumour Cells (CTC and their utility for therapy monitoring in non-small cell lung cancer (NSCLC. A total of 43 patients newly diagnosed with NSCLC were prospectively enrolled. Blood samples were obtained before the 1st, 2nd and 5th cycles of chemotherapy and analyzed using CellSearch technology. Both CTC and CTC-related objects (not morphological standard or broken epithelial cells were counted. At baseline 18 (41.9% patients were positive for intact CTC count and 10 (23.2% of them had ≥5 CTC, while CK positive events were found in 79.1% of patients. The group of patients with CTC ³5 at baseline presented worse PFS and OS than those with <5 CTC (p = 0.034 and p = 0.008, respectively. Additionally, high levels of total CK positive events were associated with poor prognosis in the group of patients with <5 CTC. Regarding therapy monitoring, patients presenting increased levels of CTC during the treatment demonstrated lower OS and PFS rates. All these data supported the value of CTC as a prognostic biomarker and as a surrogate indicator of chemotherapy effectiveness in advanced NSCLC patients, with the additional value of analyzing other “objects” such as apoptotic CTC or CK fragments to guide the clinical management of these patients.

  8. Evaluation of Circulating Tumor Cells and Related Events as Prognostic Factors and Surrogate Biomarkers in Advanced NSCLC Patients Receiving First-Line Systemic Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Muinelo-Romay, Laura; Vieito, Maria; Abalo, Alicia; Alonso Nocelo, Marta; Barón, Francisco; Anido, Urbano; Brozos, Elena; Vázquez, Francisca; Aguín, Santiago; Abal, Miguel; López López, Rafael, E-mail: rafael.lopez.lopez@sergas.es [Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela (Spain)

    2014-01-21

    In the present study we investigated the prognostic value of Circulating Tumour Cells (CTC) and their utility for therapy monitoring in non-small cell lung cancer (NSCLC). A total of 43 patients newly diagnosed with NSCLC were prospectively enrolled. Blood samples were obtained before the 1st, 2nd and 5th cycles of chemotherapy and analyzed using CellSearch technology. Both CTC and CTC-related objects (not morphological standard or broken epithelial cells) were counted. At baseline 18 (41.9%) patients were positive for intact CTC count and 10 (23.2%) of them had ≥5 CTC, while CK positive events were found in 79.1% of patients. The group of patients with CTC ≥5 at baseline presented worse PFS and OS than those with <5 CTC (p = 0.034 and p = 0.008, respectively). Additionally, high levels of total CK positive events were associated with poor prognosis in the group of patients with <5 CTC. Regarding therapy monitoring, patients presenting increased levels of CTC during the treatment demonstrated lower OS and PFS rates. All these data supported the value of CTC as a prognostic biomarker and as a surrogate indicator of chemotherapy effectiveness in advanced NSCLC patients, with the additional value of analyzing other “objects” such as apoptotic CTC or CK fragments to guide the clinical management of these patients.

  9. Screening for chronic kidney disease of uncertain aetiology in Sri Lanka: usability of surrogate biomarkers over dipstick proteinuria.

    Science.gov (United States)

    Ratnayake, Samantha; Badurdeen, Zeid; Nanayakkara, Nishantha; Abeysekara, Tilak; Ratnatunga, Neelakanthi; Kumarasiri, Ranjith

    2017-06-19

    The use of dipstick proteinuria to screen Chronic Kidney Disease of uncertain aetiology (CKDu) in Sri Lanka is a recently debated matter of dispute. The aim of this study was to assess the suitability of biomarkers: serum creatinine, cystatin C and urine albumin to creatinine ratio (ACR) for screening CKDu in Sri Lanka. Forty-four male CKDu patients and 49 healthy males from a CKDu-endemic region were selected. Meanwhile, 25 healthy males from a non-endemic region were selected as an absolute control. The diagnostic accuracy of each marker was compared using the above three study groups. In receiver operating characteristics (ROC) plots for creatinine, cystatin C and ACR, values of area under the curve (AUC) were 0.926, 0.920 and 0.737 respectively when CKDu was compared to non-endemic control. When CKDu was compared to endemic control, AUCs of above three analytes were distinctly lower as 0.718, 0.808 and 0.678 respectively. Cystatin C exhibited the highest sensitivity for CKDu when analyzed against both control groups where respective sensitivities were 0.75 against endemic control and 0.89 against non-endemic control. ROC-optimal cutoff limits of creatinine, cystatin C and ACR in CKDu vs non-endemic control were 89.0 μmol/L, 1.01 mg/L and 6.06 mg/g-Cr respectively, whereas in CKDu vs endemic control the respective values were 111.5 μmol/L, 1.22 mg/L and 12.66 mg/g-Cr. Amongst the three biomarkers evaluated in this study, our data suggest that Cystatin C is the most accurate functional marker in detecting CKDu in endemic regions, yet the high cost hinders its usability on general population. Creatinine is favorable over dipstick proteinuria owing to its apparent accuracy and cost efficiency, while having the ability to complement the kidney damage marker (ACR) in screening. ACR may not be favorable as a standalone screening marker in place of dipstick proteinuria due to its significant decline in sensitivity against the CKDu-endemic population. However

  10. 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......-based survey. RESULTS: Minimal data were extracted from the literature pertaining to those criteria listed under the category of truth. Ratings for strength of evidence were moderate to low (

  11. Biomarkers and sustainable innovation in cardiovascular drug development: lessons from near and far afield.

    Science.gov (United States)

    Medford, Russell M; Dagi, T Forcht; Rosenson, Robert S; Offermann, Margaret K

    2013-05-01

    Future innovative therapies targeting cardiovascular disease (CVD) have the potential to improve health outcomes and to contain rising healthcare costs. Unsustainable increases in the size, cost and duration of clinical trial programs necessary for regulatory approval, however, threaten the entire innovation enterprise. Rising costs for clinical trials are due in large part to increasing demands for hard cardiovascular clinical endpoints as measures of therapeutic efficacy. The development and validation of predictive and surrogate biomarkers, as laboratory or other objective measures predictive or reflective of clinical endpoints, are an important part of the solution to this challenge. This review will discuss insights applicable to CVD derived from the use of predictive biomarkers in oncologic drug development, the evolving role of high density lipoprotein (HDL) in CVD drug development and the impact biomarkers and surrogates have on the continued investment from multiple societal sources critical for innovative CVD drug discovery and development.

  12. Biomarker method validation in anticancer drug development.

    Science.gov (United States)

    Cummings, J; Ward, T H; Greystoke, A; Ranson, M; Dive, C

    2008-02-01

    Over recent years the role of biomarkers in anticancer drug development has expanded across a spectrum of applications ranging from research tool during early discovery to surrogate endpoint in the clinic. However, in Europe when biomarker measurements are performed on samples collected from subjects entered into clinical trials of new investigational agents, laboratories conducting these analyses become subject to the Clinical Trials Regulations. While these regulations are not specific in their requirements of research laboratories, quality assurance and in particular assay validation are essential. This review, therefore, focuses on a discussion of current thinking in biomarker assay validation. Five categories define the majority of biomarker assays from 'absolute quantitation' to 'categorical'. Validation must therefore take account of both the position of the biomarker in the spectrum towards clinical end point and the level of quantitation inherent in the methodology. Biomarker assay validation should be performed ideally in stages on 'a fit for purpose' basis avoiding unnecessarily dogmatic adherence to rigid guidelines but with careful monitoring of progress at the end of each stage. These principles are illustrated with two specific examples: (a) absolute quantitation of protein biomarkers by mass spectrometry and (b) the M30 and M65 ELISA assays as surrogate end points of cell death.

  13. Proposal for levels of evidence schema for validation of a soluble biomarker reflecting damage endpoints in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, and recommendations for study design

    DEFF Research Database (Denmark)

    Maksymowych, W.P.; Fitzgerald, O.; Wells, G.A.

    2009-01-01

    arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We also aimed to generate consensus on minimum standards for the design of longitudinal studies aimed at validating biomarkers. METHODS: Before the meeting, the Soluble Biomarker Working Group prepared a preliminary framework...... and discussed various models for association and prediction related to the statistical strength domain. In addition, 3 Delphi exercises addressing longitudinal study design for RA, PsA, and AS were conducted within the working group and members of the Assessments in SpondyloArthritis International Society (ASAS...

  14. BACE-1, PS-1 and sAPPβ Levels Are Increased in Plasma from Sporadic Inclusion Body Myositis Patients: Surrogate Biomarkers among Inflammatory Myopathies

    Science.gov (United States)

    Catalán-García, Marc; Garrabou, Glòria; Morén, Constanza; Guitart-Mampel, Mariona; Gonzalez-Casacuberta, Ingrid; Hernando, Adriana; Gallego-Escuredo, Jose Miquel; Yubero, Dèlia; Villarroya, Francesc; Montero, Raquel; O-Callaghan, Albert Selva; Cardellach, Francesc; Grau, Josep Maria

    2015-01-01

    Sporadic inclusion body myositis (sIBM) is a rare disease that is difficult to diagnose. Muscle biopsy provides three prominent pathological findings: inflammation, mitochondrial abnormalities and fibber degeneration, represented by the accumulation of protein depots constituted by β-amyloid peptide, among others. We aim to perform a screening in plasma of circulating molecules related to the putative etiopathogenesis of sIBM to determine potential surrogate biomarkers for diagnosis. Plasma from 21 sIBM patients and 20 age- and gender-paired healthy controls were collected and stored at −80°C. An additional population of patients with non-sIBM inflammatory myopathies was also included (nine patients with dermatomyositis and five with polymyositis). Circulating levels of inflammatory cytokines (interleukin [IL]-6 and tumor necrosis factor [TNF]-α), mitochondrial-related molecules (free plasmatic mitochondrial DNA [mtDNA], fibroblast growth factor-21 [FGF-21] and coenzyme-Q10 [CoQ]) and amyloidogenic-related molecules (beta-secretase-1 [BACE-1], presenilin-1 [PS-1], and soluble Aβ precursor protein [sAPPβ]) were assessed with magnetic bead–based assays, real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA) and high-pressure liquid chromatography (HPLC). Despite remarkable trends toward altered plasmatic expression of inflammatory and mitochondrial molecules (increased IL-6, TNF-α, circulating mtDNA and FGF-21 levels and decreased content in CoQ), only amyloidogenic degenerative markers including BACE-1, PS-1 and sAPPβ levels were significantly increased in plasma from sIBM patients compared with controls and other patients with non-sIBM inflammatory myopathies (p < 0.05). Inflammatory, mitochondrial and amyloidogenic degeneration markers are altered in plasma of sIBM patients confirming their etiopathological implication in the disease. Sensitivity and specificity analysis show that BACE-1, PS-1 and sAPPβ represent a good

  15. The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: Endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society.

    Science.gov (United States)

    Vlachopoulos, Charalambos; Xaplanteris, Panagiotis; Aboyans, Victor; Brodmann, Marianne; Cífková, Renata; Cosentino, Francesco; De Carlo, Marco; Gallino, Augusto; Landmesser, Ulf; Laurent, Stéphane; Lekakis, John; Mikhailidis, Dimitri P; Naka, Katerina K; Protogerou, Athanasios D; Rizzoni, Damiano; Schmidt-Trucksäss, Arno; Van Bortel, Luc; Weber, Thomas; Yamashina, Akira; Zimlichman, Reuven; Boutouyrie, Pierre; Cockcroft, John; O'Rourke, Michael; Park, Jeong Bae; Schillaci, Giuseppe; Sillesen, Henrik; Townsend, Raymond R

    2015-08-01

    While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  16. Breast Cancer Survival Defined by the ER/PR/HER2 Subtypes and a Surrogate Classification according to Tumor Grade and Immunohistochemical Biomarkers

    Directory of Open Access Journals (Sweden)

    Carol A. Parise

    2014-01-01

    Full Text Available Introduction. ER, PR, and HER2 are routinely available in breast cancer specimens. The purpose of this study is to contrast breast cancer-specific survival for the eight ER/PR/HER2 subtypes with survival of an immunohistochemical surrogate for the molecular subtype based on the ER/PR/HER2 subtypes and tumor grade. Methods. We identified 123,780 cases of stages 1–3 primary female invasive breast cancer from California Cancer Registry. The surrogate classification was derived using ER/PR/HER2 and tumor grade. Kaplan-Meier survival analysis and Cox proportional hazards modeling were used to assess differences in survival and risk of mortality for the ER/PR/HER2 subtypes and surrogate classification within each stage. Results. The luminal B/HER2− surrogate classification had a higher risk of mortality than the luminal B/HER2+ for all stages of disease. There was no difference in risk of mortality between the ER+/PR+/HER2− and ER+/PR+/HER2+ in stage 3. With one exception in stage 3, the ER-negative subtypes all had an increased risk of mortality when compared with the ER-positive subtypes. Conclusions. Assessment of survival using ER/PR/HER2 illustrates the heterogeneity of HER2+ subtypes. The surrogate classification provides clear separation in survival and adjusted mortality but underestimates the wide variability within the subtypes that make up the classification.

  17. In vivo evaluation of battery-operated light-emitting diode-based photodynamic therapy efficacy using tumor volume and biomarker expression as endpoints

    Science.gov (United States)

    Mallidi, Srivalleesha; Mai, Zhiming; Rizvi, Imran; Hempstead, Joshua; Arnason, Stephen; Celli, Jonathan; Hasan, Tayyaba

    2015-01-01

    Abstract. In view of the increase in cancer-related mortality rates in low- to middle-income countries (LMIC), there is an urgent need to develop economical therapies that can be utilized at minimal infrastructure institutions. Photodynamic therapy (PDT), a photochemistry-based treatment modality, offers such a possibility provided that low-cost light sources and photosensitizers are available. In this proof-of-principle study, we focus on adapting the PDT light source to a low-resource setting and compare an inexpensive, portable, battery-powered light-emitting diode (LED) light source with a standard, high-cost laser source. The comparison studies were performed in vivo in a xenograft murine model of human squamous cell carcinoma subjected to 5-aminolevulinic acid-induced protoporphyrin IX PDT. We observed virtually identical control of the tumor burden by both the LED source and the standard laser source. Further insights into the biological response were evaluated by biomarker analysis of necrosis, microvessel density, and hypoxia [carbonic anhydrase IX (CAIX) expression] among groups of control, LED-PDT, and laser-PDT treated mice. There is no significant difference in the percent necrotic volume and CAIX expression in tumors that were treated with the two different light sources. These encouraging preliminary results merit further investigations in orthotopic animal models of cancers prevalent in LMICs. PMID:25909707

  18. In vivo evaluation of battery-operated light-emitting diode-based photodynamic therapy efficacy using tumor volume and biomarker expression as endpoints.

    Science.gov (United States)

    Mallidi, Srivalleesha; Mai, Zhiming; Rizvi, Imran; Hempstead, Joshua; Arnason, Stephen; Celli, Jonathan; Hasan, Tayyaba

    2015-04-01

    In view of the increase in cancer-related mortality rates in low- to middle-income countries (LMIC), there is an urgent need to develop economical therapies that can be utilized at minimal infrastructure institutions. Photodynamic therapy (PDT), a photochemistry-based treatment modality, offers such a possibility provided that low-cost light sources and photosensitizers are available. In this proof-of-principle study, we focus on adapting the PDT light source to a low-resource setting and compare an inexpensive, portable, battery-powered light-emitting diode (LED) light source with a standard, high-cost laser source. The comparison studies were performed in vivo in a xenograft murine model of human squamous cell carcinoma subjected to 5-aminolevulinic acid-induced protoporphyrin IX PDT. We observed virtually identical control of the tumor burden by both the LED source and the standard laser source. Further insights into the biological response were evaluated by biomarker analysis of necrosis, microvessel density, and hypoxia [carbonic anhydrase IX (CAIX) expression] among groups of control, LED-PDT, and laser-PDT treated mice. There is no significant difference in the percent necrotic volume and CAIX expression in tumors that were treated with the two different light sources. These encouraging preliminary results merit further investigations in orthotopic animal models of cancers prevalent in LMICs.

  19. Permutation criteria to evaluate multiple clinical endpoints in a proof-of-concept study : lessons from Pre-RELAX-AHF

    NARCIS (Netherlands)

    Davison, Beth A.; Cotter, Gad; Sun, Hengrui; Chen, Li; Teerlink, John R.; Metra, Marco; Felker, G. Michael; Voors, Adriaan A.; Ponikowski, Piotr; Filippatos, Gerasimos; Greenberg, Barry; Teichman, Sam L.; Unemori, Elaine; Koch, Gary G.

    2011-01-01

    Clinically relevant endpoints cannot be routinely targeted with reasonable power in a small study. Hence, proof-of-concept studies are often powered to a primary surrogate endpoint. However, in acute heart failure (AHF) effects on surrogates have not translated into clinical benefit in confirmatory

  20. Molecular pathology endpoints useful for aging studies.

    Science.gov (United States)

    Niedernhofer, L J; Kirkland, J L; Ladiges, W

    2017-05-01

    The first clinical trial aimed at targeting fundamental processes of aging will soon be launched (TAME: Targeting Aging with Metformin). In its wake is a robust pipeline of therapeutic interventions that have been demonstrated to extend lifespan or healthspan of preclinical models, including rapalogs, antioxidants, anti-inflammatory agents, and senolytics. This ensures that if the TAME trial is successful, numerous additional clinical trials are apt to follow. But a significant impediment to these trials remains the question of what endpoints should be measured? The design of the TAME trial very cleverly skirts around this based on the fact that there are decades of data on metformin in humans, providing unequaled clarity of what endpoints are most likely to yield a positive outcome. But for a new chemical entity, knowing what endpoints to measure remains a formidable challenge. For economy's sake, and to achieve results in a reasonable time frame, surrogate markers of lifespan and healthy aging are desperately needed. This review provides a comprehensive analysis of molecular endpoints that are currently being used as indices of age-related phenomena (e.g., morbidity, frailty, mortality) and proposes an approach for validating and prioritizing these endpoints. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Biomarkers in Barrett's esophagus.

    Science.gov (United States)

    Reid, Brian J; Blount, Patricia L; Rabinovitch, Peter S

    2003-04-01

    future. Biopsy repositories are now readily available for phase 3 studies that can evaluate and compare biomarkers. There are initiatives for multi-institutional Barrett's Centers of Excellence that could provide rapid progress in biomarker evaluation. In addition to new candidate biomarkers, the human genome project has provided high-throughput methodologies and methods for computer analysis of data, which can provide the volume and quality control required for clinically useful biomarkers. Currently, 17p (p53) LOH has progressed the furthest among molecular biomarkers. The authors do not recommend its routine clinical use at the present time, however. Finally, it is likely that clinicians will want to follow the results of clinical treatment-response studies and epidemiologic studies that evaluate relationship between clinical interventions or environmental risk and protective factors and surrogate endpoints, especially if the endpoints are progessing well along the phases of biomarker validation. These studies are likely to be of clinical interest because they may becoming the basis for randomized clinical trials to prevent cancer in BE.

  2. Lessons from ECLIPSE: a review of COPD biomarkers.

    Science.gov (United States)

    Faner, Rosa; Tal-Singer, Ruth; Riley, John H; Celli, Bartolomé; Vestbo, Jørgen; MacNee, William; Bakke, Per; Calverley, Peter M A; Coxson, Harvey; Crim, Courtney; Edwards, Lisa D; Locantore, Nick; Lomas, David A; Miller, Bruce E; Rennard, Stephen I; Wouters, Emiel F M; Yates, Julie C; Silverman, Edwin K; Agusti, Alvar

    2014-07-01

    The Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study was a large 3-year observational controlled multicentre international study aimed at defining clinically relevant subtypes of chronic obstructive pulmonary disease (COPD) and identifying novel biomarkers and genetic factors. So far, the ECLIPSE study has produced more than 50 original publications and 75 communications to international meetings, many of which have significantly influenced our understanding of COPD. However, because there is not one paper reporting the biomarker results of the ECLIPSE study that may serve as a reference for practising clinicians, researchers and healthcare providers from academia, industry and government agencies interested in COPD, we decided to write a review summarising the main biomarker findings in ECLIPSE.

  3. Choosing the best endpoint

    DEFF Research Database (Denmark)

    Christensen, Erik

    2008-01-01

    Design and endpoints of clinical trials in hepatocellular carcinoma. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ; for the Panel of Experts in HCC-Design Clinical Trials. The design of clinical trials in hepatocellular c...

  4. Biomarker-based adaptive trials for patients with glioblastoma--lessons from I-SPY 2.

    Science.gov (United States)

    Alexander, Brian M; Wen, Patrick Y; Trippa, Lorenzo; Reardon, David A; Yung, Wai-Kwan Alfred; Parmigiani, Giovanni; Berry, Donald A

    2013-08-01

    The traditional clinical trials infrastructure may not be ideally suited to evaluate the numerous therapeutic hypotheses that result from the increasing number of available targeted agents combined with the various methodologies to molecularly subclassify patients with glioblastoma. Additionally, results from smaller screening studies are rarely translated to successful larger confirmatory studies, potentially related to a lack of efficient control arms or the use of unvalidated surrogate endpoints. Streamlining clinical trials and providing a flexible infrastructure for biomarker development is clearly needed for patients with glioblastoma. The experience developing and implementing the I-SPY studies in breast cancer may serve as a guide to developing such trials in neuro-oncology.

  5. High levels of biomarkers of collagen remodeling are associated with increased mortality in COPD

    DEFF Research Database (Denmark)

    Sand, Jannie M B; Leeming, Diana J; Byrjalsen, Inger

    2016-01-01

    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...... 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...... the prognostic value of these biomarkers. RESULTS: Thirty subjects (3.0 %) died during follow-up. Non-survivors were older, had reduced exercise capacity, increased dyspnea score, and included fewer current smokers. All collagen biomarkers were significantly elevated in non-survivors compared to survivors...

  6. Alzheimer's Disease Cerebrospinal Fluid and Neuroimaging Biomarkers: Diagnostic Accuracy and Relationship to Drug Efficacy.

    Science.gov (United States)

    Khan, Tapan K; Alkon, Daniel L

    2015-01-01

    Widely researched Alzheimer's disease (AD) biomarkers include in vivo brain imaging with PET and MRI, imaging of amyloid plaques, and biochemical assays of Aβ 1 - 42, total tau, and phosphorylated tau (p-tau-181) in cerebrospinal fluid (CSF). In this review, we critically evaluate these biomarkers and discuss their clinical utility for the differential diagnosis of AD. Current AD biomarker tests are either highly invasive (requiring CSF collection) or expensive and labor-intensive (neuroimaging), making them unsuitable for use in the primary care, clinical office-based setting, or to assess drug efficacy in clinical trials. In addition, CSF and neuroimaging biomarkers continue to face challenges in achieving required sensitivity and specificity and minimizing center-to-center variability (for CSF-Aβ 1 - 42 biomarkers CV = 26.5% ; http://www.alzforum.org/news/conference-coverage/paris-standardization-hurdle-spinal-fluid-imaging-markers). Although potentially useful for selecting patient populations for inclusion in AD clinical trials, the utility of CSF biomarkers and neuroimaging techniques as surrogate endpoints of drug efficacy needs to be validated. Recent trials of β- and γ-secretase inhibitors and Aβ immunization-based therapies in AD showed no significant cognitive improvements, despite changes in CSF and neuroimaging biomarkers. As we learn more about the dysfunctional cellular and molecular signaling processes that occur in AD, and how these processes are manifested in tissues outside of the brain, new peripheral biomarkers may also be validated as non-invasive tests to diagnose preclinical and clinical AD.

  7. Biomarkers-A General Review.

    Science.gov (United States)

    Aronson, Jeffrey K; Ferner, Robin E

    2017-03-17

    A biomarker is a biological observation that substitutes for and ideally predicts a clinically relevant endpoint or intermediate outcome that is more difficult to observe. The use of clinical biomarkers is easier and less expensive than direct measurement of the final clinical endpoint, and biomarkers are usually measured over a shorter time span. They can be used in disease screening, diagnosis, characterization, and monitoring; as prognostic indicators; for developing individualized therapeutic interventions; for predicting and treating adverse drug reactions; for identifying cell types; and for pharmacodynamic and dose-response studies. To understand the value of a biomarker, it is necessary to know the pathophysiological relationship between the biomarker and the relevant clinical endpoint. Good biomarkers should be measurable with little or no variability, should have a sizeable signal to noise ratio, and should change promptly and reliably in response to changes in the condition or its therapy. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  8. Modulation of biologic endpoints by topical difluoromethylornithine (DFMO), in subjects at high-risk for nonmelanoma skin cancer.

    Science.gov (United States)

    Einspahr, Janine G; Nelson, Mark A; Saboda, Kathylynn; Warneke, James; Bowden, G Timothy; Alberts, David S

    2002-01-01

    More than one million new skin cancers are diagnosed yearly in the United States creating the need for effective primary and chemopreventive strategies to reduce the incidence, morbidity, and mortality associated with skin cancer. Skin chemoprevention trials often focus on subjects at high risk of nonmelanoma skin cancers and include biological endpoints like number of actinic keratoses (AK) and measures of cell proliferation, apoptosis, and p53 expression and/or mutation. Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, suppresses increased polyamine synthesis and inhibits tumors in models of skin carcinogenesis. Thus, DFMO is a good candidate chemopreventive agent in humans at increased risk of NMSC. We reported previously results of a randomized, placebo-controlled trial of topical DFMO in 48 participants with AK. In this study there was a significant reduction in the number of AK (23.5%; P = 0.001) and the polyamine, spermidine (26%, P = 0.04; Alberts, D. S. et al. Cancer Epidemiol. Biomark. Prev., 9: 1281-2186, 2000). In skin biopsies from the same study, we demonstrate that topical DFMO significantly reduces the percentage of p53-positive cells (22%; P = 0.04); however, there were no significant changes in proliferating cell nuclear antigen or apoptotic indices, or in the frequency of p53 mutations (25% at baseline, 21% after placebo, and 26% after DFMO). We conclude that inhibition of the premalignant AK lesions as well as a reduction in the expression of p53 and in spermidine concentrations may serve as surrogate endpoint biomarkers of DFMO and possibly other topically administered skin cancer chemopreventive agents.

  9. Birds as biodiversity surrogates

    DEFF Research Database (Denmark)

    Larsen, Frank Wugt; Bladt, Jesper Stentoft; Balmford, Andrew

    2012-01-01

    1. Most biodiversity is still unknown, and therefore, priority areas for conservation typically are identified based on the presence of surrogates, or indicator groups. Birds are commonly used as surrogates of biodiversity owing to the wide availability of relevant data and their broad popular...... appeal. However, some studies have found birds to perform relatively poorly as indicators. We therefore ask how the effectiveness of this approach can be improved by supplementing data on birds with information on other taxa. 2. Here, we explore two strategies using (i) species data for other taxa...... areas identified on the basis of birds alone performed well in representing overall species diversity where birds were relatively speciose compared to the other taxa in the data sets. Adding species data for one taxon increased surrogate effectiveness better than adding genus- and family-level data...

  10. Plutonium radiation surrogate

    Science.gov (United States)

    Frank, Michael I [Dublin, CA

    2010-02-02

    A self-contained source of gamma-ray and neutron radiation suitable for use as a radiation surrogate for weapons-grade plutonium is described. The source generates a radiation spectrum similar to that of weapons-grade plutonium at 5% energy resolution between 59 and 2614 keV, but contains no special nuclear material and emits little .alpha.-particle radiation. The weapons-grade plutonium radiation surrogate also emits neutrons having fluxes commensurate with the gamma-radiation intensities employed.

  11. Systemic, local and imaging biomarkers of brain injury: more needed, and better use of those already established?

    Directory of Open Access Journals (Sweden)

    Keri Linda Carpenter

    2015-02-01

    Full Text Available Much progress has been made over the past two decades in the treatment of severe acute brain injury, including traumatic brain injury and subarachnoid haemorrhage, resulting in a higher proportion of patients surviving with better outcomes. This has arisen from a combination of factors. These include improvements in procedures at the scene (pre-hospital and in the hospital emergency department, advances in neuromonitoring in the intensive care unit, both continuously at the bedside and intermittently in scans, evolution and refinement of protocol-driven therapy for better management of patients, and advances in surgical procedures and rehabilitation. Nevertheless, many patients still experience varying degrees of long-term disabilities post-injury with consequent demands on carers and resources, and there is room for improvement. Biomarkers are a key aspect of neuromonitoring. A broad definition of a biomarker is any observable feature that can be used to inform on the state of the patient, e.g. a molecular species, a feature on a scan, or a monitoring characteristic e.g. cerebrovascular pressure reactivity index. Biomarkers are usually quantitative measures, which can be utilised in diagnosis and monitoring of response to treatment. They are thus crucial to the development of therapies and may be utilised as surrogate endpoints in Phase II clinical trials. To date, there is no specific drug treatment for acute brain injury, and many seemingly promising agents emerging from pre-clinical animal models have failed in clinical trials. Large Phase III studies of clinical outcomes are costly, consuming time and resources. It is therefore important that adequate Phase II clinical studies with informative surrogate endpoints are performed employing appropriate biomarkers. In this article we review some of the available systemic, local and imaging biomarkers and technologies relevant in acute brain injury patients, and highlight gaps in the current

  12. Correlation between the genotoxicity endpoints measured by two different genotoxicity assays: comet assay and CBMN assay

    OpenAIRE

    Carina Ladeira; Susana Viegas; Manuel C. Gomes

    2015-01-01

    The cytokinesis-block micronucleus cytome (CBMN) assay is a comprehensive system for measuring DNA damage; cytostasis and cytotoxicity-DNA damage events are scored specifically in once-divided binucleated cells. The endpoints possible to be measured are micronuclei (MN), a biomarker of chromosome breakage and/or whole chromosome loss, nucleoplasmic bridges (NPB), a biomarker of DNA misrepair and/or telomere end-fusions, and nuclear buds (NBUD), a biomarker of elimination of amplified DNA and/...

  13. Surrogate Markers of Abdominal Aortic Aneurysm Progression.

    Science.gov (United States)

    Wanhainen, Anders; Mani, Kevin; Golledge, Jonathan

    2016-02-01

    The natural course of many abdominal aortic aneurysms (AAA) is to gradually expand and eventually rupture and monitoring the disease progression is essential to their management. In this publication, we review surrogate markers of AAA progression. AAA diameter remains the most widely used and important marker of AAA growth. Standardized reporting of reproducible methods of measuring AAA diameter is essential. Newer imaging assessments, such as volume measurements, biomechanical analyses, and functional and molecular imaging, as well as circulating biomarkers, have potential to add important information about AAA progression. Currently, however, there is insufficient evidence to recommend their routine use in clinical practice.

  14. Endpoints in pediatric pain studies

    NARCIS (Netherlands)

    M. van Dijk (Monique); I. Ceelie (Ilse); D. Tibboel (Dick)

    2010-01-01

    textabstractAssessing pain intensity in (preverbal) children is more difficult than in adults. Tools to measure pain are being used as primary endpoints [e.g., pain intensity, time to first (rescue) analgesia, total analgesic consumption, adverse effects, and long-term effects] in studies on the eff

  15. Receiver Operating Characteristic (ROC to Determine Cut-Off Points of Biomarkers in Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Heidi L. Weiss

    2004-01-01

    Full Text Available The role of biomarkers in disease prognosis continues to be an important investigation in many cancer studies. In order for these biomarkers to have practical application in clinical decision making regarding patient treatment and follow-up, it is common to dichotomize patients into those with low vs. high expression levels. In this study, receiver operating characteristic (ROC curves, area under the curve (AUC of the ROC, sensitivity, specificity, as well as likelihood ratios were calculated to determine levels of growth factor biomarkers that best differentiate lung cancer cases versus control subjects. Selected cut-off points for p185erbB-2 and EGFR membrane appear to have good discriminating power to differentiate control tissues versus uninvolved tissues from patients with lung cancer (AUC = 89% and 90%, respectively; while AUC increased to at least 90% for selected cut-off points for p185erbB-2 membrane, EGFR membrane, and FASE when comparing between control versus carcinoma tissues from lung cancer cases. Using data from control subjects compared to patients with lung cancer, we presented a simple and intuitive approach to determine dichotomized levels of biomarkers and validated the value of these biomarkers as surrogate endpoints for cancer outcome.

  16. Developments in Surrogating Methods

    Directory of Open Access Journals (Sweden)

    Hans van Dormolen

    2005-11-01

    Full Text Available In this paper, I would like to talk about the developments in surrogating methods for preservation. My main focus will be on the technical aspects of preservation surrogates. This means that I will tell you something about my job as Quality Manager Microfilming for the Netherlands’ national preservation program, Metamorfoze, which is coordinated by the National Library. I am responsible for the quality of the preservation microfilms, which are produced for Metamorfoze. Firstly, I will elaborate on developments in preservation methods in relation to the following subjects: · Preservation microfilms · Scanning of preservation microfilms · Preservation scanning · Computer Output Microfilm. In the closing paragraphs of this paper, I would like to tell you something about the methylene blue test. This is an important test for long-term storage of preservation microfilms. Also, I will give you a brief report on the Cellulose Acetate Microfilm Conference that was held in the British Library in London, May 2005.

  17. Establishing a group of endpoints to support collective operations without specifying unique identifiers for any endpoints

    Energy Technology Data Exchange (ETDEWEB)

    Archer, Charles J.; Blocksom, Michael A.; Ratterman, Joseph D.; Smith, Brian E.; Xue, Hanghon

    2016-02-02

    A parallel computer executes a number of tasks, each task includes a number of endpoints and the endpoints are configured to support collective operations. In such a parallel computer, establishing a group of endpoints receiving a user specification of a set of endpoints included in a global collection of endpoints, where the user specification defines the set in accordance with a predefined virtual representation of the endpoints, the predefined virtual representation is a data structure setting forth an organization of tasks and endpoints included in the global collection of endpoints and the user specification defines the set of endpoints without a user specification of a particular endpoint; and defining a group of endpoints in dependence upon the predefined virtual representation of the endpoints and the user specification.

  18. Biomarkers in Airway Diseases

    Directory of Open Access Journals (Sweden)

    Janice M Leung

    2013-01-01

    Full Text Available The inherent limitations of spirometry and clinical history have prompted clinicians and scientists to search for surrogate markers of airway diseases. Although few biomarkers have been widely accepted into the clinical armamentarium, the authors explore three sources of biomarkers that have shown promise as indicators of disease severity and treatment response. In asthma, exhaled nitric oxide measurements can predict steroid responsiveness and sputum eosinophil counts have been used to titrate anti-inflammatory therapies. In chronic obstructive pulmonary disease, inflammatory plasma biomarkers, such as fibrinogen, club cell secretory protein-16 and surfactant protein D, can denote greater severity and predict the risk of exacerbations. While the multitude of disease phenotypes in respiratory medicine make biomarker development especially challenging, these three may soon play key roles in the diagnosis and management of airway diseases.

  19. Objective biomarkers of balance and gait for Parkinson's disease using body-worn sensors.

    Science.gov (United States)

    Horak, Fay B; Mancini, Martina

    2013-09-15

    Balance and gait impairments characterize the progression of Parkinson's disease (PD), predict the risk of falling, and are important contributors to reduced quality of life. Advances in technology of small, body-worn, inertial sensors have made it possible to develop quick, objective measures of balance and gait impairments in the clinic for research trials and clinical practice. Objective balance and gait metrics may eventually provide useful biomarkers for PD. In fact, objective balance and gait measures are already being used as surrogate endpoints for demonstrating clinical efficacy of new treatments, in place of counting falls from diaries, using stop-watch measures of gait speed, or clinical balance rating scales. This review summarizes the types of objective measures available from body-worn sensors. The metrics are organized based on the neural control system for mobility affected by PD: postural stability in stance, postural responses, gait initiation, gait (temporal-spatial lower and upper body coordination and dynamic equilibrium), postural transitions, and freezing of gait. However, the explosion of metrics derived by wearable sensors during prescribed balance and gait tasks, which are abnormal in individuals with PD, do not yet qualify as behavioral biomarkers, because many balance and gait impairments observed in PD are not specific to the disease, nor have they been related to specific pathophysiologic biomarkers. In the future, the most useful balance and gait biomarkers for PD will be those that are sensitive and specific for early PD and are related to the underlying disease process.

  20. Differences in surrogate threshold effect estimates between original and simplified correlation-based validation approaches.

    Science.gov (United States)

    Schürmann, Christoph; Sieben, Wiebke

    2016-03-30

    Surrogate endpoint validation has been well established by the meta-analytical correlation-based approach as outlined in the seminal work of Buyse et al. (Biostatistics, 2000). Surrogacy can be assumed if strong associations on individual and study levels can be demonstrated. Alternatively, if an effect on a true endpoint is to be predicted from a surrogate endpoint in a new study, the surrogate threshold effect (STE, Burzykowski and Buyse, Pharmaceutical Statistics, 2006) can be used. In practice, as individual patient data (IPD) are hard to obtain, some authors use only aggregate data and perform simplified regression analyses. We are interested in to what extent such simplified analyses are biased compared with the ones from a full model with IPD. To this end, we conduct a simulation study with IPD and compute STEs from full and simplified analyses for varying data situations in terms of number of studies, correlations, variances and so on. In the scenarios considered, we show that, for normally distributed patient data, STEs derived from ordinary (weighted) linear regression generally underestimate STEs derived from the original model, whereas meta-regression often results in overestimation. Therefore, if individual data cannot be obtained, STEs from meta-regression may be used as conservative alternatives, but ordinary (weighted) linear regression should not be used for surrogate endpoint validation. Copyright © 2015 John Wiley & Sons, Ltd.

  1. Surrogate Modeling for Geometry Optimization

    DEFF Research Database (Denmark)

    Rojas Larrazabal, Marielba de la Caridad; Abraham, Yonas; Holzwarth, Natalie;

    2009-01-01

    A new approach for optimizing the nuclear geometry of an atomic system is described. Instead of the original expensive objective function (energy functional), a small number of simpler surrogates is used.......A new approach for optimizing the nuclear geometry of an atomic system is described. Instead of the original expensive objective function (energy functional), a small number of simpler surrogates is used....

  2. Behavioral endpoints for radiation injury

    Science.gov (United States)

    Rabin, B. M.; Joseph, J. A.; Hunt, W. A.; Dalton, T. B.; Kandasamy, S. B.; Harris, A. H.; Ludewig, B.

    1994-10-01

    The relative behavioral effectiveness of heavy particles was evaluated. Using the taste aversion paradigm in rats, the behavioral toxicity of most types of radiation (including 20Ne and 40Ar) was similar to that of 60Co photons. Only 56Fe and 93Nb particles and fission neutrons were significantly more effective. Using emesis in ferrets as the behavioral endpoint, 56Fe particles and neutrons were again the most effective; however, 60Co photons were significantly more effective than 18 MeV electrons. These results suggest that LET does not completely predict behavioral effectiveness. Additionally, exposing rats to 10 cGy of 56Fe particles attenuated amphetamine-induced taste aversion learning. This behavior is one of a broad class of behaviors which depends on the integrity of the dopaminergic system and suggests the possibility of alterations in these behaviors following exposure to heavy particles in a space radiation environment.

  3. Reduction of adverse effects by a mushroom product, active hexose correlated compound (AHCC) in patients with advanced cancer during chemotherapy--the significance of the levels of HHV-6 DNA in saliva as a surrogate biomarker during chemotherapy.

    Science.gov (United States)

    Ito, Toshinori; Urushima, Hayato; Sakaue, Miki; Yukawa, Sayoko; Honda, Hatsumi; Hirai, Kei; Igura, Takumi; Hayashi, Noriyuki; Maeda, Kazuhisa; Kitagawa, Toru; Kondo, Kazuhiro

    2014-01-01

    Chemotherapy improves the outcome of cancer treatment, but patients are sometimes forced to discontinue chemotherapy or drop out of a clinical trial due to adverse effects, such as gastrointestinal disturbances and suppression of bone marrow function. The objective of this study was to evaluate the safety and effectiveness of a mushroom product, active hexose correlated compound (AHCC), on chemotherapy-induced adverse effects and quality of life (QOL) in patients with cancer. Twenty-four patients with cancer received their first cycle of chemotherapy without AHCC and then received their second cycle with AHCC. During chemotherapy, we weekly evaluated adverse effects and QOL via a blood test, EORTC QLQ-C30 questionnaire, and DNA levels of herpes virus type 6 (HHV-6) in saliva. The DNA levels of HHV-6 were significantly increased after chemotherapy. Interestingly, administration of AHCC significantly decreased the levels of HHV-6 in saliva during chemotherapy and improved not only QOL scores in the EORTC QLQ-C30 questionnaire but also hematotoxicity and hepatotoxicity. These findings suggest that salivary HHV-6 levels may be a good biomarker of QOL in patients during chemotherapy, and that AHCC may have a beneficial effect on chemotherapy-associated adverse effects and QOL in patients with cancer undergoing chemotherapy.

  4. Carotid intimal-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors

    Directory of Open Access Journals (Sweden)

    Morgan Timothy

    2005-03-01

    Full Text Available Abstract Background Surrogate measures for cardiovascular disease events have the potential to increase greatly the efficiency of clinical trials. A leading candidate for such a surrogate is the progression of intima-media thickness (IMT of the carotid artery; much experience has been gained with this endpoint in trials of HMG-CoA reductase inhibitors (statins. Methods and Results We examine two separate systems of criteria that have been proposed to define surrogate endpoints, based on clinical and statistical arguments. We use published results and a formal meta-analysis to evaluate whether progression of carotid IMT meets these criteria for HMG-CoA reductase inhibitors (statins. IMT meets clinical-based criteria to serve as a surrogate endpoint for cardiovascular events in statin trials, based on relative efficiency, linkage to endpoints, and congruency of effects. Results from a meta-analysis and post-trial follow-up from a single published study suggest that IMT meets established statistical criteria by accounting for intervention effects in regression models. Conclusion Carotid IMT progression meets accepted definitions of a surrogate for cardiovascular disease endpoints in statin trials. This does not, however, establish that it may serve universally as a surrogate marker in trials of other agents.

  5. ENDPOINT PROTECTION SECURITY SYSTEM FOR AN ENTERPRISE

    OpenAIRE

    Ruotsalainen, Petri

    2013-01-01

    The thesis subscriber was Metso Shared Services Ltd. The objective was to find out if Microsoft Forefront Endpoint Protection 2010 (FEP) would be secure and cost-effective enough system to fulfill the requirements of the company’s endpoint protection security system. Microsoft FEP was compared and benchmarked with some other most significant endpoint protection products based on the requirements and definitions of the subscriber. The comparison and evaluation were based on investigation a...

  6. Biological surrogate end-points in cancer trials: potential uses, benefits and pitfalls.

    NARCIS (Netherlands)

    Cooper, R.; Kaanders, J.H.A.M.

    2005-01-01

    New technologies have led to the development of an increasing number of targeted therapies and interest in combining these with conventional therapy to provide individualised patient treatments. New drug or treatment regimens must, however, undergo rigorous testing under strictly controlled conditio

  7. COPD association and repeatability of blood biomarkers in the ECLIPSE cohort

    Directory of Open Access Journals (Sweden)

    Dickens Jennifer A

    2011-11-01

    Full Text Available Abstract Background There is a need for biomarkers to better characterise individuals with COPD and to aid with the development of therapeutic interventions. A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE cohort. Methods Thirty-four blood biomarkers were assessed in 201 subjects with COPD, 37 ex-smoker controls with normal lung function and 37 healthy non-smokers selected from the ECLIPSE cohort. Biomarker repeatability was assessed using baseline and 3-month samples. Intergroup comparisons were made using analysis of variance, repeatability was assessed through Bland-Altman plots, and correlations between biomarkers and clinical characteristics were assessed using Spearman correlation coefficients. Results Fifteen biomarkers were significantly different in individuals with COPD when compared to former or non-smoker controls. Some biomarkers, including tumor necrosis factor-α and interferon-γ, were measurable in only a minority of subjects whilst others such as C-reactive protein showed wide variability over the 3-month replication period. Fibrinogen was the most repeatable biomarker and exhibited a weak correlation with 6-minute walk distance, exacerbation rate, BODE index and MRC dyspnoea score in COPD subjects. 33% (66/201 of the COPD subjects reported at least 1 exacerbation over the 3 month study with 18% (36/201 reporting the exacerbation within 30 days of the 3-month visit. CRP, fibrinogen interleukin-6 and surfactant protein-D were significantly elevated in those COPD subjects with exacerbations within 30 days of the 3-month visit compared with those individuals that did not exacerbate or whose exacerbations had resolved. Conclusions Only a few of the biomarkers assessed may be useful in diagnosis or management of COPD where the diagnosis is based on airflow obstruction (GOLD. Further analysis of more promising biomarkers may reveal

  8. A proposed panel of biomarkers of healthy ageing.

    Science.gov (United States)

    Lara, Jose; Cooper, Rachel; Nissan, Jack; Ginty, Annie T; Khaw, Kay-Tee; Deary, Ian J; Lord, Janet M; Kuh, Diana; Mathers, John C

    2015-09-15

    studies of human ageing, in health surveys of older people and as outcomes in intervention studies that aim to promote healthy ageing. Further, the inclusion of the same common panel of measures of healthy ageing in diverse study designs and populations may enhance the value of those studies by allowing the harmonisation of surrogate endpoints or outcome measures, thus facilitating less equivocal comparisons between studies and the pooling of data across studies.

  9. Trends in Qualifying Biomarkers in Drug Safety. Consensus of the 2011 Meeting of the Spanish Society of Clinical Pharmacology

    Science.gov (United States)

    Agúndez, José A. G.; del Barrio, Jaime; Padró, Teresa; Stephens, Camilla; Farré, Magí; Andrade, Raúl J.; Badimon, Lina; García-Martín, Elena; Vilahur, Gemma; Lucena, M. Isabel

    2012-01-01

    In this paper we discuss the consensus view on the use of qualifying biomarkers in drug safety, raised within the frame of the XXIV meeting of the Spanish Society of Clinical Pharmacology held in Málaga (Spain) in October, 2011. The widespread use of biomarkers as surrogate endpoints is a goal that scientists have long been pursuing. Thirty years ago, when molecular pharmacogenomics evolved, we anticipated that these genetic biomarkers would soon obviate the routine use of drug therapies in a way that patients should adapt to the therapy rather than the opposite. This expected revolution in routine clinical practice never took place as quickly nor with the intensity as initially expected. The concerted action of operating multicenter networks holds great promise for future studies to identify biomarkers related to drug toxicity and to provide better insight into the underlying pathogenesis. Today some pharmacogenomic advances are already widely accepted, but pharmacogenomics still needs further development to elaborate more precise algorithms and many barriers to implementing individualized medicine exist. We briefly discuss our view about these barriers and we provide suggestions and areas of focus to advance in the field. PMID:22294980

  10. Blood-based biomarkers for Parkinson's disease.

    Science.gov (United States)

    Chahine, Lama M; Stern, Matthew B; Chen-Plotkin, Alice

    2014-01-01

    There is a pressing need for biomarkers to diagnose Parkinson's disease (PD), assess disease severity, and prognosticate course. Various types of biologic specimens are potential candidates for identifying biomarkers--defined here as surrogate indicators of physiological or pathophysiological states--but blood has the advantage of being minimally invasive to obtain. There are, however, several challenges to identifying biomarkers in blood. Several candidate biomarkers identified in other diseases or in other types of biological fluids are being pursued as blood-based biomarkers in PD. In addition, unbiased discovery is underway using techniques including metabolomics, proteomics, and gene expression profiling. In this review, we summarize these techniques and discuss the challenges and successes of blood-based biomarker discovery in PD. Blood-based biomarkers that are discussed include α-synuclein, DJ-1, uric acid, epidermal growth factor, apolipoprotein-A1, and peripheral inflammatory markers.

  11. Compton scattering in the Endpoint Model

    CERN Document Server

    Dagaonkar, Sumeet

    2016-01-01

    We use the Endpoint model for exclusive hadronic processes to study Compton scattering of the proton. The parameters of the Endpoint model are fixed using the data for $F_1$ and the ratio of Pauli and Dirac form factors ($F_2/F_1$) and then used to get numerical predictions for the differential scattering cross section. We studied the Compton scattering at fixed $\\theta_{CM}$ in the $s \\sim t \\gg \\Lambda_{QCD}$ limit and at fixed $s$ much larger than $t$ limit. We observed that the calculations in the Endpoint Model give a good fit with experimental data in both regions.

  12. Speech endpoint detection in real noise environments

    Institute of Scientific and Technical Information of China (English)

    GUO Yanmeng; FU Qiang; YAN Yonghong

    2007-01-01

    A method of speech endpoint detection in environments of complicated additive noise is presented. Based on the analysis of noise, an adaptive model of stationary noise is proposed to detect the section where the signal is nonstationary. Then the voice is detected in this section by its harmonic structure, and the accurate endpoint is searched using energy.Compared with the typical algorithms, this algorithm operates reliably in most real noise environments.

  13. Critical endpoint behavior: A Wang Landau study

    Science.gov (United States)

    Landau, D. P.; Wang, Fugao; Tsai, Shan-Ho

    2008-07-01

    We study the critical endpoint behavior using an asymmetric Ising model with two- and three-body interactions on a triangular lattice, in the presence of an external field. The simulation method we use is Wang-Landau sampling in a two-dimensional parameter space. We observe a clear divergence of the curvature of the spectator phase boundary and of the magnetization coexistence diameter derivative at the critical endpoint, and the exponents for both divergences agree well with previous theoretical predictions.

  14. Revisiting algorithms for generating surrogate time series

    CERN Document Server

    Raeth, C; Papadakis, I E; Brinkmann, W

    2011-01-01

    The method of surrogates is one of the key concepts of nonlinear data analysis. Here, we demonstrate that commonly used algorithms for generating surrogates often fail to generate truly linear time series. Rather, they create surrogate realizations with Fourier phase correlations leading to non-detections of nonlinearities. We argue that reliable surrogates can only be generated, if one tests separately for static and dynamic nonlinearities.

  15. Establishing a group of endpoints in a parallel computer

    Energy Technology Data Exchange (ETDEWEB)

    Archer, Charles J.; Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.; Xue, Hanhong

    2016-02-02

    A parallel computer executes a number of tasks, each task includes a number of endpoints and the endpoints are configured to support collective operations. In such a parallel computer, establishing a group of endpoints receiving a user specification of a set of endpoints included in a global collection of endpoints, where the user specification defines the set in accordance with a predefined virtual representation of the endpoints, the predefined virtual representation is a data structure setting forth an organization of tasks and endpoints included in the global collection of endpoints and the user specification defines the set of endpoints without a user specification of a particular endpoint; and defining a group of endpoints in dependence upon the predefined virtual representation of the endpoints and the user specification.

  16. Novel biomarkers for cancer detection and prognostication

    NARCIS (Netherlands)

    Mehra, N.

    2007-01-01

    In this thesis we used a variety of approaches for biomarker discovery; in Part I we assessed whether we could identify a non-invasive surrogate markers of angiogenesis, as new vessel formation plays critical roles in the growth and metastatic spread of tumors. Moreover, many agents targeting the va

  17. Forecasting interest rates with shifting endpoints

    DEFF Research Database (Denmark)

    Van Dijk, Dick; Koopman, Siem Jan; Wel, Michel van der

    2014-01-01

    We consider forecasting the term structure of interest rates with the assumption that factors driving the yield curve are stationary around a slowly time-varying mean or ‘shifting endpoint’. The shifting endpoints are captured using either (i) time series methods (exponential smoothing) or (ii......) long-range survey forecasts of either interest rates or inflation and output growth, or (iii) exponentially smoothed realizations of these macro variables. Allowing for shifting endpoints in yield curve factors provides substantial and significant gains in out-of-sample predictive accuracy, relative...... to stationary and random walk benchmarks. Forecast improvements are largest for long-maturity interest rates and for long-horizon forecasts....

  18. Polymorphic Endpoint Types for Copyless Message Passing

    Directory of Open Access Journals (Sweden)

    Viviana Bono

    2011-07-01

    Full Text Available We present PolySing#, a calculus that models process interaction based on copyless message passing, in the style of Singularity OS. We equip the calculus with a type system that accommodates polymorphic endpoint types, which are a variant of polymorphic session types, and we show that well-typed processes are free from faults, leaks, and communication errors. The type system is essentially linear, although linearity alone may leave room for scenarios where well-typed processes leak memory. We identify a condition on endpoint types that prevents these leaks from occurring.

  19. Quantum Endpoint Detection Based on QRDA

    Science.gov (United States)

    Wang, Jian; Wang, Han; Song, Yan

    2017-08-01

    Speech recognition technology is widely used in many applications for man - machine interaction. To face more and more speech data, the computation of speech processing needs new approaches. The quantum computation is one of emerging computation technology and has been seen as useful computation model. So we focus on the basic operation of speech recognition processing, the voice activity detection, to present quantum endpoint detection algorithm. In order to achieve this algorithm, the n-bits quantum comparator circuit is given firstly. Then based on QRDA(Quantum Representation of Digital Audio), a quantum endpoint detection algorithm is presented. These quantum circuits could efficient process the audio data in quantum computer.

  20. Quantum Endpoint Detection Based on QRDA

    Science.gov (United States)

    Wang, Jian; Wang, Han; Song, Yan

    2017-10-01

    Speech recognition technology is widely used in many applications for man - machine interaction. To face more and more speech data, the computation of speech processing needs new approaches. The quantum computation is one of emerging computation technology and has been seen as useful computation model. So we focus on the basic operation of speech recognition processing, the voice activity detection, to present quantum endpoint detection algorithm. In order to achieve this algorithm, the n-bits quantum comparator circuit is given firstly. Then based on QRDA(Quantum Representation of Digital Audio), a quantum endpoint detection algorithm is presented. These quantum circuits could efficient process the audio data in quantum computer.

  1. Use of nutrigenomics endpoints in dietary interventions

    NARCIS (Netherlands)

    Hendriks, H.F.J.

    2013-01-01

    In this paper, the nutrigenomics approach is discussed as a research tool to study the physiological effects of nutrition and consequently how nutrition affects health and disease (endpoints). Nutrigenomics is the study of the effects of foods and food constituents on gene expression; the analyses i

  2. Shift endpoint trace selection algorithm and wavelet analysis to detect the endpoint using optical emission spectroscopy

    Science.gov (United States)

    Ben Zakour, Sihem; Taleb, Hassen

    2016-06-01

    Endpoint detection (EPD) is very important undertaking on the side of getting a good understanding and figuring out if a plasma etching process is done on the right way. It is truly a crucial part of supplying repeatable effects in every single wafer. When the film to be etched has been completely erased, the endpoint is reached. In order to ensure the desired device performance on the produced integrated circuit, many sensors are used to detect the endpoint, such as the optical, electrical, acoustical/vibrational, thermal, and frictional. But, except the optical sensor, the other ones show their weaknesses due to the environmental conditions which affect the exactness of reaching endpoint. Unfortunately, some exposed area to the film to be etched is very low (signal and showing the incapacity of the traditional endpoint detection method to determine the wind-up of the etch process. This work has provided a means to improve the endpoint detection sensitivity by collecting a huge numbers of full spectral data containing 1201 spectra for each run, then a new unsophisticated algorithm is proposed to select the important endpoint traces named shift endpoint trace selection (SETS). Then, a sensitivity analysis of linear methods named principal component analysis (PCA) and factor analysis (FA), and the nonlinear method called wavelet analysis (WA) for both approximation and details will be studied to compare performances of the methods mentioned above. The signal to noise ratio (SNR) is not only computed based on the main etch (ME) period but also the over etch (OE) period. Moreover, a new unused statistic for EPD, coefficient of variation (CV), is proposed to reach the endpoint in plasma etches process.

  3. Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials).

    Science.gov (United States)

    Bonnetain, Franck; Bonsing, Bert; Conroy, Thierry; Dousseau, Adelaide; Glimelius, Bengt; Haustermans, Karin; Lacaine, François; Van Laethem, Jean Luc; Aparicio, Thomas; Aust, Daniela; Bassi, Claudio; Berger, Virginie; Chamorey, Emmanuel; Chibaudel, Benoist; Dahan, Laeticia; De Gramont, Aimery; Delpero, Jean Robert; Dervenis, Christos; Ducreux, Michel; Gal, Jocelyn; Gerber, Erich; Ghaneh, Paula; Hammel, Pascal; Hendlisz, Alain; Jooste, Valérie; Labianca, Roberto; Latouche, Aurelien; Lutz, Manfred; Macarulla, Teresa; Malka, David; Mauer, Muriel; Mitry, Emmanuel; Neoptolemos, John; Pessaux, Patrick; Sauvanet, Alain; Tabernero, Josep; Taieb, Julien; van Tienhoven, Geertjan; Gourgou-Bourgade, Sophie; Bellera, Carine; Mathoulin-Pélissier, Simone; Collette, Laurence

    2014-11-01

    Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Embryotoxicity assessment of developmental neurotoxicants using a neuronal endpoint in the embryonic stem cell test.

    Science.gov (United States)

    Baek, Dae Hyun; Kim, Tae Gyun; Lim, Hwa Kyung; Kang, Jin Wook; Seong, Su Kyoung; Choi, Seung Eun; Lim, So Yun; Park, Sung Hee; Nam, Bong-hyun; Kim, Eun Hee; Kim, Mun Sin; Park, Kui Lea

    2012-08-01

    The embryonic stem cell test (EST) is a validated in vitro embryotoxicity test; however, as the inhibition of cardiac differentiation alone is used as a differentiation endpoint in the EST, it may not be a useful test to screen embryotoxic chemicals that affect the differentiation of noncardiac tissues. Previously, methylmercury (MeHg), cadmium and arsenic compounds, which are heavy metals that induce developmental neurotoxicity in vivo, were misclassified as nonembryotoxic with the EST. The aim of this study was to improve the EST to correctly screen such developmental neurotoxicants. We developed a neuronal endpoint (Tuj-1 ID₅₀) using flow cytometry analysis of Tuj-1-positive cells to screen developmental neurotoxicants (MeHg, valproic acid, sodium arsenate and sodium arsenite) correctly using an adherent monoculture differentiation method. Using Tuj-1 ID₅₀ in the EST instead of cardiac ID₅₀, all of the tested chemicals were classified as embryotoxic, while the negative controls were correctly classified as nonembryotoxic. To support the validity of Tuj-1 ID₅₀) , we compared the results from two experimenters who independently tested MeHg using our modified EST. An additional neuronal endpoint (MAP2 ID₅₀), obtained by analyzing the relative quantity of MAP2 mRNA, was used to classify the same chemicals. There were no significant differences in the three endpoint values of the two experimenters or in the classification results, except for isoniazid. In conclusion, our results indicate that Tuj-1 ID₅₀ can be used as a surrogate endpoint of the traditional EST to screen developmental neurotoxicants correctly and it can also be applied to other chemicals.

  5. Fluid biomarkers in multiple system atrophy

    DEFF Research Database (Denmark)

    Laurens, Brice; Constantinescu, Radu; Freeman, Roy

    2015-01-01

    Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target...... engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood...... and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results...

  6. Scaling for interfacial tensions near critical endpoints.

    Science.gov (United States)

    Zinn, Shun-Yong; Fisher, Michael E

    2005-01-01

    Parametric scaling representations are obtained and studied for the asymptotic behavior of interfacial tensions in the full neighborhood of a fluid (or Ising-type) critical endpoint, i.e., as a function both of temperature and of density/order parameter or chemical potential/ordering field. Accurate nonclassical critical exponents and reliable estimates for the universal amplitude ratios are included naturally on the basis of the "extended de Gennes-Fisher" local-functional theory. Serious defects in previous scaling treatments are rectified and complete wetting behavior is represented; however, quantitatively small, but unphysical residual nonanalyticities on the wetting side of the critical isotherm are smoothed out "manually." Comparisons with the limited available observations are presented elsewhere but the theory invites new, searching experiments and simulations, e.g., for the vapor-liquid interfacial tension on the two sides of the critical endpoint isotherm for which an amplitude ratio -3.25+/-0.05 is predicted.

  7. Surrogate Analysis and Index Developer (SAID) tool

    Science.gov (United States)

    Domanski, Marian M.; Straub, Timothy D.; Landers, Mark N.

    2015-10-01

    The use of acoustic and other parameters as surrogates for suspended-sediment concentrations (SSC) in rivers has been successful in multiple applications across the Nation. Tools to process and evaluate the data are critical to advancing the operational use of surrogates along with the subsequent development of regression models from which real-time sediment concentrations can be made available to the public. Recent developments in both areas are having an immediate impact on surrogate research and on surrogate monitoring sites currently (2015) in operation.

  8. The Timing of Endpoints in Movement

    Science.gov (United States)

    1981-11-01

    order of keys- troke initiation can differ in repeated typings of the same word (Gentner, Grudin, & Conway, 1980). In piano playing, the music itself... theories of timing is discussed. A A U0@eIsion FIor TS UP A& f StUNICLASSIFIEDNO NSPOri.. a.Etd [The Timing of Endpoints in Movement IMichael I. Jordan...formal lessons or playing professionally. Four of these subjects were drummers and one was a piano player. Apparatus. The metronome beeps were

  9. Precision mass measurements utilizing beta endpoints

    CERN Document Server

    Moltz, D M; Kern, B D; Noma, H; Ritchie, B G; Toth, K S

    1981-01-01

    A technique for precise determination of beta endpoints with an intrinsic germanium detector has been developed. The energy calibration is derived from gamma -ray photopeak measurements. This analysis procedure has been checked with a /sup 27/Si source produced in a (p, n) reaction on a /sup 27/Al target and subsequently applied to mass separated samples of /sup 76/Rb, /sup 77/Rb and /sup 78/Rb. Results indicate errors <50 keV are obtainable. (29 refs).

  10. A generic operational strategy to qualify translational safety biomarkers.

    Science.gov (United States)

    Matheis, Katja; Laurie, David; Andriamandroso, Christiane; Arber, Nadir; Badimon, Lina; Benain, Xavier; Bendjama, Kaïdre; Clavier, Isabelle; Colman, Peter; Firat, Hüseyin; Goepfert, Jens; Hall, Steve; Joos, Thomas; Kraus, Sarah; Kretschmer, Axel; Merz, Michael; Padro, Teresa; Planatscher, Hannes; Rossi, Annamaria; Schneiderhan-Marra, Nicole; Schuppe-Koistinen, Ina; Thomann, Peter; Vidal, Jean-Marc; Molac, Béatrice

    2011-07-01

    The importance of using translational safety biomarkers that can predict, detect and monitor drug-induced toxicity during human trials is becoming increasingly recognized. However, suitable processes to qualify biomarkers in clinical studies have not yet been established. There is a need to define clear scientific guidelines to link biomarkers to clinical processes and clinical endpoints. To help define the operational approach for the qualification of safety biomarkers the IMI SAFE-T consortium has established a generic qualification strategy for new translational safety biomarkers that will allow early identification, assessment and management of drug-induced injuries throughout R&D. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Filament eruption with apparent reshuffle of endpoints

    CERN Document Server

    Filippov, Boris

    2014-01-01

    Filament eruption on 30 April - 1 May 2010, which shows the reconnection of one filament leg with a region far away from its initial position, is analyzed. Observations from three viewpoints are used for as precise as possible measurements of endpoint coordinates. The northern leg of the erupting prominence loop 'jumps' laterally to the latitude lower than the latitude of the originally southern endpoint. Thus, the endpoints reshuffled their positions in the limb view. Although this behaviour could be interpreted as the asymmetric zipping-like eruption, it does not look very likely. It seems more likely to be reconnection of the flux-rope field lines in its northern leg with ambient coronal magnetic field lines rooted in a quiet region far from the filament. From calculations of coronal potential magnetic field, we found that the filament before the eruption was stable for vertical displacements, but was liable to violation of the horizontal equilibrium. This is unusual initiation of an eruption with combinat...

  12. Imaging Seeker Surrogate for IRCM evaluation

    NARCIS (Netherlands)

    Schleijpen, H.M.A.; Carpenter, S.R.; Mellier, B.; Dimmeler, A.

    2007-01-01

    NATO-SCI-139 and its predecessor groups have more than a decade of history in the evaluation and recommendation of EO and IR Countermeasures against anti-aircraft missiles. Surrogate Seekers have proven to be a valuable tool for this work. The use of surrogate seekers in international co-operations

  13. 77 FR 34788 - Surrogate Foreign Corporations

    Science.gov (United States)

    2012-06-12

    ... Internal Revenue Service 26 CFR Part 1 RIN 1545-BF47 Surrogate Foreign Corporations AGENCY: Internal... regulations regarding whether a foreign corporation is treated as a surrogate foreign corporation. The final ] regulations affect certain domestic corporations and partnerships (and certain parties related thereto),...

  14. Surrogate Guderley Test Problem Definition

    Energy Technology Data Exchange (ETDEWEB)

    Ramsey, Scott D. [Los Alamos National Laboratory; Shashkov, Mikhail J. [Los Alamos National Laboratory

    2012-07-06

    The surrogate Guderley problem (SGP) is a 'spherical shock tube' (or 'spherical driven implosion') designed to ease the notoriously subtle initialization of the true Guderley problem, while still maintaining a high degree of fidelity. In this problem (similar to the Guderley problem), an infinitely strong shock wave forms and converges in one-dimensional (1D) cylindrical or spherical symmetry through a polytropic gas with arbitrary adiabatic index {gamma}, uniform density {rho}{sub 0}, zero velocity, and negligible pre-shock pressure and specific internal energy (SIE). This shock proceeds to focus on the point or axis of symmetry at r = 0 (resulting in ostensibly infinite pressure, velocity, etc.) and reflect back out into the incoming perturbed gas.

  15. On Using Surrogates with Genetic Programming.

    Science.gov (United States)

    Hildebrandt, Torsten; Branke, Jürgen

    2015-01-01

    One way to accelerate evolutionary algorithms with expensive fitness evaluations is to combine them with surrogate models. Surrogate models are efficiently computable approximations of the fitness function, derived by means of statistical or machine learning techniques from samples of fully evaluated solutions. But these models usually require a numerical representation, and therefore cannot be used with the tree representation of genetic programming (GP). In this paper, we present a new way to use surrogate models with GP. Rather than using the genotype directly as input to the surrogate model, we propose using a phenotypic characterization. This phenotypic characterization can be computed efficiently and allows us to define approximate measures of equivalence and similarity. Using a stochastic, dynamic job shop scenario as an example of simulation-based GP with an expensive fitness evaluation, we show how these ideas can be used to construct surrogate models and improve the convergence speed and solution quality of GP.

  16. Endpoint of the hot electroweak phase transition

    CERN Document Server

    Csikor, Ferenc; Heitger, J

    1999-01-01

    We give the nonperturbative phase diagram of the four-dimensional hot electroweak phase transition. The Monte-Carlo analysis is done on lattices with different lattice spacings ($a$). A systematic extrapolation $a \\to 0$ is done. Our results show that the finite temperature SU(2)-Higgs phase transition is of first order for Higgs-boson masses $m_H<66.5 \\pm 1.4$ GeV. At this endpoint the phase transition is of second order, whereas above it only a rapid cross-over can be seen. The full four-dimensional result agrees completely with that of the dimensional reduction approximation. This fact is of particular importance, because it indicates that the fermionic sector of the Standard Model can be included perturbatively. We obtain that the Higgs-boson endpoint mass in the Standard Model is $72.4 \\pm 1.7$ GeV. Taking into account the LEP Higgs-boson mass lower bound excludes any electroweak phase transition in the Standard Model.

  17. Parents and children: "surrogate" paradigm of modernity.

    Science.gov (United States)

    Adam, Archimandrite; Akhaladze, Vakhtang

    2011-06-01

    The article provides an overview of surrogate motherhood--one of many currently available forms of Assisted Reproductive Technologies for couples who find themselves unable to conceive a child on their own. Within the years of its existence surrogate motherhood managed to accumulate lots of bioethical problems, paradoxes, dilemmas and collisions. Author represents some of them. Also the legal, moral and religious implications of surrogacy are addressed. The religious perspective from the Orthodox Christian, Catholic, Jewish, Hinduism, and Islamic points of view are provided. The author concludes that surrogate motherhood is not only the answer to childlessness but it supports metamorphosis of traditional attitude towards such human value as it is a family.

  18. Extracting gluino endpoints with event topology patterns

    Energy Technology Data Exchange (ETDEWEB)

    Pietsch, N. [Hamburg Univ. (Germany). Inst. fuer Experimentalphysik; Reuter, J.; Sakurai, K.; Wiesler, D. [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

    2012-06-15

    In this paper we study the gluino dijet mass edge measurement at the LHC in a realistic situation including both SUSY and combinatorical backgrounds together with effects of initial and final state radiation as well as a finite detector resolution. Three benchmark scenarios are examined in which the dominant SUSY production process and also the decay modes are different. Several new kinematical variables are proposed to minimize the impact of SUSY and combinatorial backgrounds in the measurement. By selecting events with a particular number of jets and leptons, we attempt to measure two distinct gluino dijet mass edges originating from wino g {yields} jjW and bino g {yields}jjB decay modes, separately. We determine the endpoints of distributions of proposed and existing variables and show that those two edges can be disentangled and measured within good accuracy, irrespective of the presence of ISR, FSR, and detector effects.

  19. Surrogate mothers: whose baby is it?

    Science.gov (United States)

    Cohen, B

    1984-01-01

    Advances in medical technology offer infertile couples who wish to raise children alternatives to adoption. The increasing number of surrogate mother contracts creates a myriad of legal issues surrounding the rights of the natural mother, the natural father and the child that is produced. In this Article, the Author discusses the legal issues and rights of the parties under the Constitution, the surrogate contract and family law principles. The Author proposes that courts should consider a surrogate contract as a revocable prebirth agreement which allows the natural mother to keep the child if she chooses. In addition, the Author advocates an interpretation of the statutes forbidding baby selling that would prohibit surrogate contracts in which the mother is paid a fee for the child.

  20. Neutron capture cross sections from Surrogate measurements

    Directory of Open Access Journals (Sweden)

    Scielzo N.D.

    2010-03-01

    Full Text Available The prospects for determining cross sections for compound-nuclear neutron-capture reactions from Surrogate measurements are investigated. Calculations as well as experimental results are presented that test the Weisskopf-Ewing approximation, which is employed in most analyses of Surrogate data. It is concluded that, in general, one has to go beyond this approximation in order to obtain (n,γ cross sections of sufficient accuracy for most astrophysical and nuclear-energy applications.

  1. Cancer Biomarkers

    OpenAIRE

    Kamel, Hala Fawzy Mohamed; Al-Amodi, Hiba Saeed Bagader

    2016-01-01

    Biomarkers have many potential applications in oncology, including risk assessment, screening, differential diagnosis, determination of prognosis, prediction of response to treatment, and monitoring of progression of disease. Because of the critical role that biomarkers play at all stages of disease, it is important that they undergo rigorous evaluation, including analytical validation, clinical validation, and assessment of clinical utility, prior to incorporation into routine clinical care....

  2. Optimal allocation of resources in a biomarker setting.

    Science.gov (United States)

    Rosner, Bernard; Hendrickson, Sara; Willett, Walter

    2015-01-30

    Nutrient intake is often measured with substantial error both in commonly used surrogate instruments such as a food frequency questionnaire (FFQ) and in gold standard-type instruments such as a diet record (DR). If there is a correlated error between the FFQ and DR, then standard measurement error correction methods based on regression calibration can produce biased estimates of the regression coefficient (λ) of true intake on surrogate intake. However, if a biomarker exists and the error in the biomarker is independent of the error in the FFQ and DR, then the method of triads can be used to obtain unbiased estimates of λ, provided that there are replicate biomarker data on at least a subsample of validation study subjects. Because biomarker measurements are expensive, for a fixed budget, one can use a either design where a large number of subjects have one biomarker measure and only a small subsample is replicated or a design that has a smaller number of subjects and has most or all subjects validated. The purpose of this paper is to optimize the proportion of subjects with replicated biomarker measures, where optimization is with respect to minimizing the variance of ln(λ̂). The methodology is illustrated using vitamin C intake data from the European Prospective Investigation into Cancer and Nutrition study where plasma vitamin C is the biomarker. In this example, the optimal validation study design is to have 21% of subjects with replicated biomarker measures.

  3. Population-scale assessment endpoints in ecological risk assessment part II: selection of assessment endpoint attributes.

    Science.gov (United States)

    Landis, Wayne G; Kaminski, Laurel A

    2007-07-01

    Because ecological services often are tied to specific species, the risk to populations is a critical endpoint and important feature of ecological risk assessments. In Part 1 of this series it was demonstrated that population scale assessment endpoints are important expressions of the valued components of ecological structures. This commentary reviews several of the characteristics of populations that can be evaluated and used in population scale risk assessments. Two attributes are evaluated as promising. The 1st attribute is the change in potential productivity of the population over a specified time period. The 2nd attribute is the change in the age structure of a population, expressed graphically or as a normalized effects vector (NEV). The NEV is a description of the change in age structure due to a toxicant or other stressor and appears to be characteristic of specific stressor effects.

  4. Development of biomarkers for Huntington's disease.

    Science.gov (United States)

    Weir, David W; Sturrock, Aaron; Leavitt, Blair R

    2011-06-01

    Huntington's disease is an autosomal dominant, progressive neurodegenerative disorder, for which there is no disease-modifying treatment. By use of predictive genetic testing, it is possible to identify individuals who carry the gene defect before the onset of symptoms, providing a window of opportunity for intervention aimed at preventing or delaying disease onset. However, without robust and practical measures of disease progression (ie, biomarkers), the efficacy of therapeutic interventions in this premanifest Huntington's disease population cannot be readily assessed. Current progress in the development of biomarkers might enable evaluation of disease progression in individuals at the premanifest stage of the disease; these biomarkers could be useful in defining endpoints in clinical trials in this population. Clinical, cognitive, neuroimaging, and biochemical biomarkers are being investigated for their potential in clinical use and their value in the development of future treatments for patients with Huntington's disease.

  5. Ecosystem services as assessment endpoints for ecological risk assessment.

    Science.gov (United States)

    Munns, Wayne R; Rea, Anne W; Suter, Glenn W; Martin, Lawrence; Blake-Hedges, Lynne; Crk, Tanja; Davis, Christine; Ferreira, Gina; Jordan, Steve; Mahoney, Michele; Barron, Mace G

    2016-07-01

    Ecosystem services are defined as the outputs of ecological processes that contribute to human welfare or have the potential to do so in the future. Those outputs include food and drinking water, clean air and water, and pollinated crops. The need to protect the services provided by natural systems has been recognized previously, but ecosystem services have not been formally incorporated into ecological risk assessment practice in a general way in the United States. Endpoints used conventionally in ecological risk assessment, derived directly from the state of the ecosystem (e.g., biophysical structure and processes), and endpoints based on ecosystem services serve different purposes. Conventional endpoints are ecologically important and susceptible entities and attributes that are protected under US laws and regulations. Ecosystem service endpoints are a conceptual and analytical step beyond conventional endpoints and are intended to complement conventional endpoints by linking and extending endpoints to goods and services with more obvious benefit to humans. Conventional endpoints can be related to ecosystem services even when the latter are not considered explicitly during problem formulation. To advance the use of ecosystem service endpoints in ecological risk assessment, the US Environmental Protection Agency's Risk Assessment Forum has added generic endpoints based on ecosystem services (ES-GEAE) to the original 2003 set of generic ecological assessment endpoints (GEAEs). Like conventional GEAEs, ES-GEAEs are defined by an entity and an attribute. Also like conventional GEAEs, ES-GEAEs are broadly described and will need to be made specific when applied to individual assessments. Adoption of ecosystem services as a type of assessment endpoint is intended to improve the value of risk assessment to environmental decision making, linking ecological risk to human well-being, and providing an improved means of communicating those risks. Integr Environ Assess Manag

  6. Microvascular structure as a prognostically relevant endpoint.

    Science.gov (United States)

    Agabiti-Rosei, Enrico; Rizzoni, Damiano

    2017-05-01

    Remodelling of subcutaneous small resistance arteries, as indicated by an increased media-to-lumen ratio, is frequently present in hypertensive, obese, or diabetic patients. The increased media-to-lumen ratio may impair organ flow reserve. This may be important in the maintenance and, probably, also in the progressive worsening of hypertensive disease. The presence of structural alterations represents a prognostically relevant factor, in terms of development of target organ damage or cardiovascular events, thus allowing us a prediction of complications in hypertension. In fact, media-to-lumen ratio of small arteries at baseline, and possibly their changes during treatment may have a strong prognostic significance. However, new, non-invasive techniques are needed before suggesting extensive application of the evaluation of remodelling of small arteries for the cardiovascular risk stratification in hypertensive patients. Some new techniques for the evaluation of microvascular morphology in the retina, currently under clinical investigation, seem to represent a promising and interesting future perspective. The evaluation of microvascular structure is progressively moving from bench to bedside, and it could represent, in the near future, an evaluation to be performed in all hypertensive patients, to obtain a better stratification of cardiovascular risk, and, possibly, it might be considered as an intermediate endpoint in the evaluation of the effects of antihypertensive therapy, provided that a demonstration of a prognostic value of non-invasive measures of microvascular structure is made available.

  7. Ordered Kinematic Endpoints for 5-body Cascade Decays

    CERN Document Server

    Klimek, Matthew D

    2016-01-01

    We present expressions for the kinematic endpoints of 5-body cascade decay chains proceeding through all possible combinations of 2-body and 3-body decays, with one stable invisible particle in the final decay stage. When an invariant mass can be formed in multiple ways by choosing different final state particles from a common vertex, we introduce techniques for finding the sub-leading endpoints for all indistinguishable versions of the invariant mass. In contrast to short decay chains, where sub-leading endpoints are linearly related to the leading endpoints, we find that in 5-body decays, they provide additional independent constraints on the mass spectrum.

  8. Surrogates for herbicide removal in stormwater biofilters.

    Science.gov (United States)

    Zhang, Kefeng; Deletic, Ana; Page, Declan; McCarthy, David T

    2015-09-15

    Real time monitoring of suitable surrogate parameters are critical to the validation of any water treatment processes, and is of particularly high importance for validation of natural stormwater treatment systems. In this study, potential surrogates for herbicide removal in stormwater biofilters (also known as stormwater bio-retention or rain-gardens) were assessed using field challenge tests and matched laboratory column experiments. Differential UV absorbance at 254mn (ΔUVA254), total phosphorus (ΔTP), dissolved phosphorus (ΔDP), total nitrogen (ΔTN), ammonia (ΔNH3), nitrate and nitrite (ΔNO3+NO2), dissolved organic carbon (ΔDOC) and total suspended solids (ΔTSS) were compared with glyphosate, atrazine, simazine and prometryn removal rates. The influence of different challenge conditions on the performance of each surrogate was studied. Differential TP was significantly and linearly related to glyphosate reduction (R(2) = 0.75-0.98, P herbicides were reliable under normal and challenge dry conditions, but weaker correlations were observed under challenge wet conditions. Of those tested, ΔTP is the most promising surrogate for glyphosate removal and ΔUVA254 is a suitable surrogate for triazines removal in stormwater biofilters. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Systems biology and biomarker discovery

    Energy Technology Data Exchange (ETDEWEB)

    Rodland, Karin D.

    2010-12-01

    Medical practitioners have always relied on surrogate markers of inaccessible biological processes to make their diagnosis, whether it was the pallor of shock, the flush of inflammation, or the jaundice of liver failure. Obviously, the current implementation of biomarkers for disease is far more sophisticated, relying on highly reproducible, quantitative measurements of molecules that are often mechanistically associated with the disease in question, as in glycated hemoglobin for the diagnosis of diabetes [1] or the presence of cardiac troponins in the blood for confirmation of myocardial infarcts [2]. In cancer, where the initial symptoms are often subtle and the consequences of delayed diagnosis often drastic for disease management, the impetus to discover readily accessible, reliable, and accurate biomarkers for early detection is compelling. Yet despite years of intense activity, the stable of clinically validated, cost-effective biomarkers for early detection of cancer is pathetically small and still dominated by a handful of markers (CA-125, CEA, PSA) first discovered decades ago. It is time, one could argue, for a fresh approach to the discovery and validation of disease biomarkers, one that takes full advantage of the revolution in genomic technologies and in the development of computational tools for the analysis of large complex datasets. This issue of Disease Markers is dedicated to one such new approach, loosely termed the 'Systems Biology of Biomarkers'. What sets the Systems Biology approach apart from other, more traditional approaches, is both the types of data used, and the tools used for data analysis - and both reflect the revolution in high throughput analytical methods and high throughput computing that has characterized the start of the twenty first century.

  10. Imaging Biomarkers or Biomarker Imaging?

    Directory of Open Access Journals (Sweden)

    Markus Mitterhauser

    2014-06-01

    Full Text Available Since biomarker imaging is traditionally understood as imaging of molecular probes, we highly recommend to avoid any confusion with the previously defined term “imaging biomarkers” and, therefore, only use “molecular probe imaging (MPI” in that context. Molecular probes (MPs comprise all kinds of molecules administered to an organism which inherently carry a signalling moiety. This review highlights the basic concepts and differences of molecular probe imaging using specific biomarkers. In particular, PET radiopharmaceuticals are discussed in more detail. Specific radiochemical and radiopharmacological aspects as well as some legal issues are presented.

  11. Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED)

    Science.gov (United States)

    A study to comprehensively assess biomarkers of risk for progressive cervical neoplasia, and thus develop a new set of biomarkers that can distinguish those at highest risk of cervical cancer from those with benign infection

  12. Nitrate Salt Surrogate Blending Scoping Test Plan

    Energy Technology Data Exchange (ETDEWEB)

    Anast, Kurt Roy [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-11-13

    Test blending equipment identified in the “Engineering Options Assessment Report: Nitrate Salt Waste Stream Processing”. Determine if the equipment will provide adequate mixing of zeolite and surrogate salt/Swheat stream; optimize equipment type and operational sequencing; impact of baffles and inserts on mixing performance; and means of validating mixing performance

  13. Videotrees: Improving video surrogate presentation using hierarchy

    NARCIS (Netherlands)

    Jansen, Michel; Heeren, Willemijn; Dijk, van Betsy

    2008-01-01

    As the amount of available video content increases, so does the need for better ways of browsing all this material. Because the nature of video makes it hard to process, the need arises for adequate surrogates for video that can readily be skimmed and browsed. In this paper, the effects of the use o

  14. Fluid biomarkers in multiple system atrophy: A review of the MSA Biomarker Initiative.

    Science.gov (United States)

    Laurens, Brice; Constantinescu, Radu; Freeman, Roy; Gerhard, Alexander; Jellinger, Kurt; Jeromin, Andreas; Krismer, Florian; Mollenhauer, Brit; Schlossmacher, Michael G; Shaw, Leslie M; Verbeek, Marcel M; Wenning, Gregor K; Winge, Kristian; Zhang, Jing; Meissner, Wassilios G

    2015-08-01

    Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results suggest that combining several CSF fluid biomarkers may be more successful than using single markers, at least for the diagnosis. Currently, the clinically most useful markers may comprise a combination of the light chain of neurofilament (which is consistently elevated in MSA compared to controls and Parkinson's disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success.

  15. Combustion Kinetic Studies of Gasolines and Surrogates

    KAUST Repository

    Javed, Tamour

    2016-11-01

    Future thrusts for gasoline engine development can be broadly summarized into two categories: (i) efficiency improvements in conventional spark ignition engines, and (ii) development of advance compression ignition (ACI) concepts. Efficiency improvements in conventional spark ignition engines requires downsizing (and turbocharging) which may be achieved by using high octane gasolines, whereas, low octane gasolines fuels are anticipated for ACI concepts. The current work provides the essential combustion kinetic data, targeting both thrusts, that is needed to develop high fidelity gasoline surrogate mechanisms and surrogate complexity guidelines. Ignition delay times of a wide range of certified gasolines and surrogates are reported here. These measurements were performed in shock tubes and rapid compression machines over a wide range of experimental conditions (650 – 1250 K, 10 – 40 bar) relevant to internal combustion engines. Using the measured the data and chemical kinetic analyses, the surrogate complexity requirements for these gasolines in homogeneous environments are specified. For the discussions presented here, gasolines are classified into three categories: (i)\\tLow octane gasolines including Saudi Aramco’s light naphtha fuel (anti-knock index, AKI = (RON + MON)/2 = 64; Sensitivity (S) = RON – MON = 1), certified FACE (Fuels for Advanced Combustion Engines) gasoline I and J (AKI ~ 70, S = 0.7 and 3 respectively), and their Primary Reference Fuels (PRF, mixtures of n-heptane and iso-octane) and multi-component surrogates. (ii)\\t Mid octane gasolines including FACE A and C (AKI ~ 84, S ~ 0 and 1 respectively) and their PRF surrogates. Laser absorption measurements of intermediate and product species formed during gasoline/surrogate oxidation are also reported. (iii)\\t A wide range of n-heptane/iso-octane/toluene (TPRF) blends to adequately represent the octane and sensitivity requirements of high octane gasolines including FACE gasoline F and G

  16. A novel surrogate index for hepatic insulin resistance.

    LENUS (Irish Health Repository)

    Vangipurapu, J

    2011-03-01

    In epidemiological and genetic studies surrogate indices are needed to investigate insulin resistance in different insulin-sensitive tissues. Our objective was to develop a surrogate index for hepatic insulin resistance.

  17. Use of endpoint adjudication to improve the quality and validity of endpoint assessment for medical device development and post marketing evaluation: Rationale and best practices. A report from the cardiac safety research consortium.

    Science.gov (United States)

    Seltzer, Jonathan H; Heise, Ted; Carson, Peter; Canos, Daniel; Hiatt, Jo Carol; Vranckx, Pascal; Christen, Thomas; Cutlip, Donald E

    2017-08-01

    This white paper provides a summary of presentations, discussions and conclusions of a Thinktank entitled "The Role of Endpoint Adjudication in Medical Device Clinical Trials". The think tank was cosponsored by the Cardiac Safety Research Committee, MDEpiNet and the US Food and Drug Administration (FDA) and was convened at the FDA's White Oak headquarters on March 11, 2016. Attention was focused on tailoring best practices for evaluation of endpoints in medical device clinical trials, practical issues in endpoint adjudication of therapeutic, diagnostic, biomarker and drug-device combinations, and the role of adjudication in regulatory and reimbursement issues throughout the device lifecycle. Attendees included representatives from medical device companies, the FDA, Centers for Medicare and Medicaid Services (CMS), end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding (1) rationale for when adjudication is appropriate, (2) best practices establishment and operation of a medical device adjudication committee and (3) the role of endpoint adjudication for post market evaluation in the emerging era of real world evidence. Copyright © 2017. Published by Elsevier Inc.

  18. Time to Review the Role of Surrogate End Points in Health Policy: State of the Art and the Way Forward.

    Science.gov (United States)

    Ciani, Oriana; Buyse, Marc; Drummond, Michael; Rasi, Guido; Saad, Everardo D; Taylor, Rod S

    2017-03-01

    The efficacy of medicines, medical devices, and other health technologies should be proved in trials that assess final patient-relevant outcomes such as survival or morbidity. Market access and coverage decisions are, however, often based on surrogate end points, biomarkers, or intermediate end points, which aim to substitute and predict patient-relevant outcomes that are unavailable because of methodological, financial, or practical constraints. We provide a summary of the present use of surrogate end points in health care policy, discussing the case for and against their adoption and reviewing validation methods. We introduce a three-step framework for policymakers to handle surrogates, which involves establishing the level of evidence, assessing the strength of the association, and quantifying relations between surrogates and final outcomes. Although the use of surrogates can be problematic, they can, when selected and validated appropriately, offer important opportunities for more efficient clinical trials and faster access to new health technologies that benefit patients and health care systems. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  19. Quality of Documentation as a Surrogate Marker for Awareness and Training Effectiveness of PHTLS-Courses. Part of the Prospective Longitudinal Mixed-Methods EPPTC-Trial

    OpenAIRE

    Häske, David; Beckers, Stefan K; Hofmann, Marzellus; Lefering, Rolf; Gliwitzky, Bernhard; Wölfl, Christoph C.; Grützner, Paul; Stöckle, Ulrich; Dieroff, Marc; Münzberg, Matthias

    2017-01-01

    Objective Care for severely injured patients requires multidisciplinary teamwork. A decrease in the number of accident victims ultimately affects the routine and skills. PHTLS (“Pre-Hospital Trauma Life Support”) courses are established two-day courses for medical and non-medical rescue service personnel, aimed at improving the pre-hospital care of trauma patients worldwide. The study aims the examination of the quality of documentation before and after PHTLS courses as a surrogate endpoint o...

  20. A qualitative investigation of selecting surrogate decision-makers

    NARCIS (Netherlands)

    Edwards, S.J.L.; Brown, P.; Twyman, M.A.; Christie, D.; Rakow, T.

    2011-01-01

    Background Empirical studies of surrogate decision-making tend to assume that surrogates should make only a 'substituted judgement'—that is, judge what the patient would want if they were mentally competent. Objectives To explore what people want in a surrogate decision-maker whom they themselves se

  1. System Reliability Analysis Capability and Surrogate Model Application in RAVEN

    Energy Technology Data Exchange (ETDEWEB)

    Rabiti, Cristian; Alfonsi, Andrea; Huang, Dongli; Gleicher, Frederick; Wang, Bei; Adbel-Khalik, Hany S.; Pascucci, Valerio; Smith, Curtis L.

    2015-11-01

    This report collect the effort performed to improve the reliability analysis capabilities of the RAVEN code and explore new opportunity in the usage of surrogate model by extending the current RAVEN capabilities to multi physics surrogate models and construction of surrogate models for high dimensionality fields.

  2. Biomarkers for intracellular pathogens: establishing tools as vaccine and therapeutic endpoints for visceral leishmaniasis.

    Science.gov (United States)

    Vallur, A C; Duthie, M S; Reinhart, C; Tutterrow, Y; Hamano, S; Bhaskar, K R H; Coler, R N; Mondal, D; Reed, S G

    2014-06-01

    Visceral leishmaniasis in South Asia is a serious disease affecting children and adults. Acute visceral leishmaniasis develops in only a fraction of those infected individuals, the majority being asymptomatic with the potential to transmit infection and develop disease. We followed 56 individuals characterized as being asymptomatic by seropositivity with rk39 rapid diagnostic test in a hyperendemic district of Bangladesh to define the utility of Leishmania-specific antibodies and DNA in identifying infection. At baseline, 54 of the individuals were seropositive with one or more quantitative antibody assays and antibody levels persisted at follow up. Most seropositive individuals (47/54) tested positive by quantitative PCR at baseline, but only 16 tested positive at follow up. The discrepancies among the different tests may shed light on the dynamics of asymptomatic infections of Leishmania donovani, as well as underscore the need for standard diagnostic tools for active surveillance as well as assessing the effectiveness of prophylactic and therapeutic interventions. ©2013 Infectious Disease Research Institute Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

  3. Biomarkers in T cell therapy clinical trials

    Directory of Open Access Journals (Sweden)

    Kalos Michael

    2011-08-01

    Full Text Available Abstract T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity. This review will focus on biomarker studies as they relate to T cell therapy trials, and more specifically: i. An overview and description of categories and classes of biomarkers that are specifically relevant to T cell therapy trials, and ii. Insights into future directions and challenges for the appropriate development of biomarkers to evaluate both product bioactivity and treatment efficacy of T cell therapy trials.

  4. Accurate measurement method for tube's endpoints based on machine vision

    Science.gov (United States)

    Liu, Shaoli; Jin, Peng; Liu, Jianhua; Wang, Xiao; Sun, Peng

    2017-01-01

    Tubes are used widely in aerospace vehicles, and their accurate assembly can directly affect the assembling reliability and the quality of products. It is important to measure the processed tube's endpoints and then fix any geometric errors correspondingly. However, the traditional tube inspection method is time-consuming and complex operations. Therefore, a new measurement method for a tube's endpoints based on machine vision is proposed. First, reflected light on tube's surface can be removed by using photometric linearization. Then, based on the optimization model for the tube's endpoint measurements and the principle of stereo matching, the global coordinates and the relative distance of the tube's endpoint are obtained. To confirm the feasibility, 11 tubes are processed to remove the reflected light and then the endpoint's positions of tubes are measured. The experiment results show that the measurement repeatability accuracy is 0.167 mm, and the absolute accuracy is 0.328 mm. The measurement takes less than 1 min. The proposed method based on machine vision can measure the tube's endpoints without any surface treatment or any tools and can realize on line measurement.

  5. Accurate Measurement Method for Tube's Endpoints Based on Machine Vision

    Institute of Scientific and Technical Information of China (English)

    LIU Shaoli; JIN Peng; LIU Jianhua; WANG Xiao; SUN Peng

    2017-01-01

    Tubes are used widely in aerospace vehicles,and their accurate assembly can directly affect the assembling reliability and the quality of products.It is important to measure the processed tube's endpoints and then fix any geometric errors correspondingly.However,the traditional tube inspection method is time-consuming and complex operations.Therefore,a new measurement method for a tube's endpoints based on machine vision is proposed.First,reflected light on tube's surface can be removed by using photometric linearization.Then,based on the optimization model for the tube's endpoint measurements and the principle of stereo matching,the global coordinates and the relative distance of the tube's endpoint are obtained.To confirm the feasibility,11 tubes are processed to remove the reflected light and then the endpoint's positions of tubes are measured.The experiment results show that the measurement repeatability accuracy is 0.167 mm,and the absolute accuracy is 0.328 mm.The measurement takes less than 1 min.The proposed method based on machine vision can measure the tube's endpoints without any surface treatment or any tools and can realize on line measurement.

  6. Accurate measurement method for tube's endpoints based on machine vision

    Science.gov (United States)

    Liu, Shaoli; Jin, Peng; Liu, Jianhua; Wang, Xiao; Sun, Peng

    2016-08-01

    Tubes are used widely in aerospace vehicles, and their accurate assembly can directly affect the assembling reliability and the quality of products. It is important to measure the processed tube's endpoints and then fix any geometric errors correspondingly. However, the traditional tube inspection method is time-consuming and complex operations. Therefore, a new measurement method for a tube's endpoints based on machine vision is proposed. First, reflected light on tube's surface can be removed by using photometric linearization. Then, based on the optimization model for the tube's endpoint measurements and the principle of stereo matching, the global coordinates and the relative distance of the tube's endpoint are obtained. To confirm the feasibility, 11 tubes are processed to remove the reflected light and then the endpoint's positions of tubes are measured. The experiment results show that the measurement repeatability accuracy is 0.167 mm, and the absolute accuracy is 0.328 mm. The measurement takes less than 1 min. The proposed method based on machine vision can measure the tube's endpoints without any surface treatment or any tools and can realize on line measurement.

  7. Surrogate decision making and intellectual virtue.

    Science.gov (United States)

    Bock, Gregory L

    2014-01-01

    Patients can be harmed by a religiously motivated surrogate decision maker whose decisions are contrary to the standard of care; therefore, surrogate decision making should be held to a high standard. Stewart Eskew and Christopher Meyers proposed a two-part rule for deciding which religiously based decisions to honor: (1) a secular reason condition and (2) a rationality condition. The second condition is based on a coherence theory of rationality, which they claim is accessible, generous, and culturally sensitive. In this article, I will propose strengthening the rationality condition by grounding it in a theory of intellectual virtue, which is both rigorous and culturally sensitive. Copyright 2014 The Journal of Clinical Ethics. All rights reserved.

  8. Biomarkers in the Management of Difficult Asthma.

    Science.gov (United States)

    Schleich, Florence; Demarche, Sophie; Louis, Renaud

    2016-01-01

    Difficult asthma is a heterogeneous disease of the airways including various types of bronchial inflammation and various degrees of airway remodeling. Therapeutic response of severe asthmatics can be predicted by the use of biomarkers of Type2-high or Type2-low inflammation. Based on sputum cell analysis, four inflammatory phenotypes have been described. As induced sputum is timeconsuming and expensive technique, surrogate biomarkers are useful in clinical practice. Eosinophilic phenotype is likely to reflect ongoing adaptive immunity in response to allergen. Several biomarkers of eosinophilic asthma are easily available in clinical practice (blood eosinophils, serum IgE, exhaled nitric oxyde, serum periostin). Neutrophilic asthma is thought to reflect innate immune system activation in response to pollutants or infectious agents while paucigranulocytic asthma is thought to be not inflammatory and characterized by smooth muscle dysfunction. We currently lack of user-friendly biomarkers of neutrophilic asthma and airway remodeling. In this review, we summarize the biomarkers available for the management of difficult asthma.

  9. The Surrogate Method: Past, Present and Future

    Energy Technology Data Exchange (ETDEWEB)

    Lesher, S R; Bernstein, L A; Burke, J T; Lyles, B F; Clark, R M; Fallon, P; Phair, L

    2008-01-09

    The STARS/LiBerACE collaboration has been exploring the surrogate technique with success in the actinide region. This method uses a direct reaction to measure the decay probability of the same compound nucleus produced via a neutron-induced channel. This paper serves as an overview of these activities. Using the STARS array at 88-inch Cyclotron at Lawrence Berkeley National Laboratory we have explored the following surrogate reactions: {sup 234}U({alpha}, {alpha}{prime}f), {sup 235}U({sup 3}He, {alpha}f), {sup 236}U({alpha}, {alpha}{prime}f), {sup 238}U ({alpha},{alpha}{prime}f), {sup 238}U({sup 3}He,{alpha}f), {sup 238}U({sup 3}He, tf) surrogates for {sup 233}U(n,f), {sup 233}U(n,f), {sup 235}U(n,f), {sup 237}U(n,f), {sup 236}U(n,f), and {sup 237}Np(n,f), respectively.

  10. [Biomedical Perspective of the Surrogate Motherhood].

    Science.gov (United States)

    Jouve de la Barreda, Nicolás

    2017-01-01

    The subrogated motherhood takes place when an embryo created by in vitro fertilization (IVF) technology is implanted in a surrogate, sometimes called a gestational mother, by means a contract with her. It can imply to natural families (woman and man) with or without infertility problems, or to monoparental or biparental families of the same sex. Concerning the origin of the gametes used in the IVF emerges different implications on the genetic relationship of the resulting child with the surrogate and the future parents. The subrogated motherhood was initially considered an option to solve infertility problems. Nevertheless this practice has become a possible and attractive option as a source of economic resources for poor women. The cases of benefit of a pregnancy without mediating a contract are exceptional and they are not properly cases of ″subrogated maternity″ but of ″altruistic maternity″ and must be considered as heterologous in vitro fertilization. In this article are analyzed the medical, genetic and bioethics aspects of this new derivation of the fertilization in vitro. As points of special attention are considered the following questions: Is it the surrogate motherhood used preferably to solve infertility problems? Is not this actually a new form of exploitation of the woman? Does not suppose an attack to the natural family? Does not suppose in addition an attack to the dignity of the human being?

  11. Surrogate formulations for thermal treatment of low-level mixed waste. Part 1: Radiological surrogates

    Energy Technology Data Exchange (ETDEWEB)

    Stockdale, J.A.D.; Bostick, W.D.; Hoffmann, D.P. [Martin Marietta Energy Systems, Inc., Oak Ridge, TN (United States); Lee, H.T. [Oak Ridge Associated Universities, TN (United States)

    1994-01-01

    The evaluation and comparison of proposed thermal treatment systems for mixed wastes can be expedited by tests in which the radioactive components of the wastes are replaced by surrogate materials chosen to mimic, as far as is possible, the chemical and physical properties of the radioactive materials of concern. In this work, sponsored by the Mixed Waste Integrated Project of the US Department of Energy, the authors have examined reported experience with such surrogates and suggest a simplified standard list of materials for use in tests of thermal treatment systems. The chief radioactive nuclides of concern in the treatment of mixed wastes are {sup 239}Pu, {sup 238}U, {sup 235}U, {sup 137}Cs, {sup 103}Ru, {sup 99}Tc, and {sup 90}Sr. These nuclides are largely by-products of uranium enrichment, reactor fuel reprocessing, and weapons program activities. Cs, Ru, and Sr all have stable isotopes that can be used as perfect surrogates for the radioactive forms. Technetium exists only in radioactive form, as do plutonium and uranium. If one wishes to preclude radioactive contamination of the thermal treatment system under trial burn, surrogate elements must be chosen for these three. For technetium, the authors suggest the use of natural ruthenium, and for both plutonium and uranium, they recommend cerium. The seven radionuclides listed can therefore be simulated by a surrogate package containing stable isotopes of ruthenium, strontium, cesium, and cerium.

  12. Comparative endpoint sensitivity of in vitro estrogen agonist assays.

    Science.gov (United States)

    Dreier, David A; Connors, Kristin A; Brooks, Bryan W

    2015-07-01

    Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less

  13. Urinary Sugars--A Biomarker of Total Sugars Intake.

    Science.gov (United States)

    Tasevska, Natasha

    2015-07-01

    Measurement error in self-reported sugars intake may explain the lack of consistency in the epidemiologic evidence on the association between sugars and disease risk. This review describes the development and applications of a biomarker of sugars intake, informs its future use and recommends directions for future research. Recently, 24 h urinary sucrose and fructose were suggested as a predictive biomarker for total sugars intake, based on findings from three highly controlled feeding studies conducted in the United Kingdom. From this work, a calibration equation for the biomarker that provides an unbiased measure of sugars intake was generated that has since been used in two US-based studies with free-living individuals to assess measurement error in dietary self-reports and to develop regression calibration equations that could be used in future diet-disease analyses. Further applications of the biomarker include its use as a surrogate measure of intake in diet-disease association studies. Although this biomarker has great potential and exhibits favorable characteristics, available data come from a few controlled studies with limited sample sizes conducted in the UK. Larger feeding studies conducted in different populations are needed to further explore biomarker characteristics and stability of its biases, compare its performance, and generate a unique, or population-specific biomarker calibration equations to be applied in future studies. A validated sugars biomarker is critical for informed interpretation of sugars-disease association studies.

  14. Sample size determination in clinical trials with multiple endpoints

    CERN Document Server

    Sozu, Takashi; Hamasaki, Toshimitsu; Evans, Scott R

    2015-01-01

    This book integrates recent methodological developments for calculating the sample size and power in trials with more than one endpoint considered as multiple primary or co-primary, offering an important reference work for statisticians working in this area. The determination of sample size and the evaluation of power are fundamental and critical elements in the design of clinical trials. If the sample size is too small, important effects may go unnoticed; if the sample size is too large, it represents a waste of resources and unethically puts more participants at risk than necessary. Recently many clinical trials have been designed with more than one endpoint considered as multiple primary or co-primary, creating a need for new approaches to the design and analysis of these clinical trials. The book focuses on the evaluation of power and sample size determination when comparing the effects of two interventions in superiority clinical trials with multiple endpoints. Methods for sample size calculation in clin...

  15. Recent Experimental Progress on Surrogate Reactions

    Science.gov (United States)

    Beausang, Cornelius

    2014-09-01

    Reactions on unstable nuclei are important in a wide variety of nuclear physics scenarios. Cross sections for neutron (or light charged particle) induced reactions on target nuclei spanning the chart of the nuclei are important for nuclear astrophysics (r-process, s-process rp- and p-processes etc.), for nuclear energy generation and for national security applications. Many such reactions occur on short-lived unstable nuclei. Even with the present generation of radioactive beam facilities, many such reactions are difficult, if not impossible, to measure directly. For these reactions, often the surrogate reaction technique provides the only option to provide some experimental guidance for the calculations. The experimental and theoretical techniques required are described in some detail in the recent review article by Escher et al.. Originally introduced in the 1970's the last decade has seen a resurgence of interest in the surrogate technique. Various ratio techniques, external, internal and hybrid, have been developed to minimize the effect of target contamination. In the actinide region, a large number of surrogate (n,f) cross sections have been measured. In general, these show agreement to within 5--10%, with directly measured (n,f) data where these data exist (benchmarking), for equivalent neutron energies ranging from ~100 keV up to tens of MeV. For (n, γ) reactions, measurements have been attempted for select nuclei in various mass regions (A ~ 90, 150 and 235) and for these the agreement with directly measured data is less good. The various experimental techniques employed will be described as well as the current state of the experimental data. Some future directions will be described. Reactions on unstable nuclei are important in a wide variety of nuclear physics scenarios. Cross sections for neutron (or light charged particle) induced reactions on target nuclei spanning the chart of the nuclei are important for nuclear astrophysics (r-process, s

  16. Application of molecular endpoints in early life stage salmonid environmental biomonitoring.

    Science.gov (United States)

    Marlatt, Vicki L; Sherrard, Ryan; Kennedy, Chris J; Elphick, James R; Martyniuk, Christopher J

    2016-04-01

    Molecular endpoints can enhance existing whole animal bioassays by more fully characterizing the biological impacts of aquatic pollutants. Laboratory and field studies were used to examine the utility of adopting molecular endpoints for a well-developed in situ early life stage (eyed embryo to onset of swim-up fry) salmonid bioassay to improve diagnostic assessments of water quality in the field. Coastal cutthroat trout (Oncorhynchus clarki clarki) were exposed in the laboratory to the model metal (zinc, 40μg/L) and the polycyclic aromatic hydrocarbon (pyrene, 100μg/L) in water to examine the resulting early life stage salmonid responses. In situ field exposures and bioassays were conducted in parallel to evaluate the water quality of three urban streams in British Columbia (two sites with anthropogenic inputs and one reference site). The endpoints measured in swim-up fry included survival, deformities, growth (weight and length), vitellogenin (vtg) and metallothionein (Mt) protein levels, and hepatic gene expression (e.g., metallothioneins [mta and mtb], endocrine biomarkers [vtg and estrogen receptors, esr] and xenobiotic-metabolizing enzymes [cytochrome P450 1A3, cyp1a3 and glutathione transferases, gstk]). No effects were observed in the zinc treatment, however exposure of swim-up fry to pyrene resulted in decreased survival, deformities and increased estrogen receptor alpha (er1) mRNA levels. In the field exposures, xenobiotic-metabolizing enzymes (cyp1a3, gstk) and zinc transporter (zntBigM103) mRNA were significantly increased in swim-up fry deployed at the sites with more anthropogenic inputs compared to the reference site. Cluster analysis revealed that gene expression profiles in individuals from the streams receiving anthropogenic inputs were more similar to each other than to the reference site. Collectively, the results obtained in this study suggest that molecular endpoints may be useful, and potentially more sensitive, indicators of site

  17. Simultaneous inference of a binary composite endpoint and its components

    DEFF Research Database (Denmark)

    Große Ruse, Mareile; Ritz, Christian; Hothorn, Ludwig A.

    2017-01-01

    Binary composite endpoints offer some advantages as a way to succinctly combine evidence from a number of related binary endpoints recorded in the same clinical trial into a single outcome. However, as some concerns about the clinical relevance as well as the interpretation of such composite endp......). The method is compared to the gatekeeping approach and results are provided in the Supplementary Material. In two data examples we show how the procedure may be adapted to handle local significance levels specified through a priori given weights....

  18. Biomarkers in Pediatric ARDS: Future Directions

    Directory of Open Access Journals (Sweden)

    Benjamin E Orwoll

    2016-06-01

    Full Text Available Acute respiratory distress syndrome (ARDS is common among mechanically ventilated children, and accompanies up to 30% of all PICU deaths. Though ARDS diagnosis is based on clinical criteria, biological markers of acute lung damage have been extensively studied in adults and children. Biomarkers of inflammation, alveolar epithelial and capillary endothelial disruption, disordered coagulation, and associated derangements measured in the circulation and other body fluids such as brochoalveolar lavage have improved our understanding of pathobiology of ARDS. The biochemical signature of ARDS has been increasingly well described in adult populations, and this has led to the identification of molecular phenotypes to augment clinical classifications. However, there is a paucity of data from pediatric ARDS patients. Biomarkers and molecular phenotypes have the potential to identify patients at high risk of poor outcomes, and perhaps inform the development of targeted therapies for specific groups of patients. Additionally, because of the lower incidence of and mortality from ARDS in pediatric patients relative to adults and lack of robust clinical predictors of outcome, there is an ongoing interest in biological markers as surrogate outcome measures. The recent definition of pediatric ARDS (pARDS provides additional impetus for measurement of established and novel biomarkers in future pediatric studies in order to further characterize this disease process. This chapter will review the currently available literature and discuss potential future directions for investigation into biomarkers in ARDS among children.

  19. Priority wetland invertebrates as conservation surrogates.

    Science.gov (United States)

    Ormerod, S J; Durance, Isabelle; Terrier, Aurelie; Swanson, Alisa M

    2010-04-01

    Invertebrates are important functionally in most ecosystems, but seldom appraised as surrogate indicators of biological diversity. Priority species might be good candidates; thus, here we evaluated whether three freshwater invertebrates listed in the U.K. Biodiversity Action Plan indicated the richness, composition, and conservation importance of associated wetland organisms as defined respectively by their alpha diversity, beta diversity, and threat status. Sites occupied by each of the gastropods Segmentina nitida, Anisus vorticulus, and Valvata macrostoma had greater species richness of gastropods and greater conservation importance than other sites. Each also characterized species assemblages associated with significant variations between locations in alpha or beta diversity among other mollusks and aquatic macrophytes. Because of their distinct resource requirements, conserving the three priority species extended the range of wetland types under management for nature conservation by 18% and the associated gastropod niche-space by around 33%. Although nonpriority species indicated variations in richness, composition, and conservation importance among other organisms as effectively as priority species, none characterized such a wide range of high-quality wetland types. We conclude that priority invertebrates are no more effective than nonpriority species as indicators of alpha and beta diversity or conservation importance among associated organisms. Nevertheless, conserving priority species can extend the array of distinct environments that are protected for their specialized biodiversity and environmental quality. We suggest that this is a key role for priority species and conservation surrogates more generally, and, on our evidence, can best be delivered through multiple species with contrasting habitat requirements.

  20. Estimating Predictability Redundancy and Surrogate Data Method

    CERN Document Server

    Pecen, L

    1995-01-01

    A method for estimating theoretical predictability of time series is presented, based on information-theoretic functionals---redundancies and surrogate data technique. The redundancy, designed for a chosen model and a prediction horizon, evaluates amount of information between a model input (e.g., lagged versions of the series) and a model output (i.e., a series lagged by the prediction horizon from the model input) in number of bits. This value, however, is influenced by a method and precision of redundancy estimation and therefore it is a) normalized by maximum possible redundancy (given by the precision used), and b) compared to the redundancies obtained from two types of the surrogate data in order to obtain reliable classification of a series as either unpredictable or predictable. The type of predictability (linear or nonlinear) and its level can be further evaluated. The method is demonstrated using a numerically generated time series as well as high-frequency foreign exchange data and the theoretical ...

  1. Developing a Cognition Endpoint for Traumatic Brain Injury Clinical Trials.

    Science.gov (United States)

    Silverberg, Noah D; Crane, Paul K; Dams-O'Connor, Kristen; Holdnack, James; Ivins, Brian J; Lange, Rael T; Manley, Geoffrey T; McCrea, Michael; Iverson, Grant L

    2017-01-15

    Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint.

  2. An Endpoint Estimate for the Commutator of Singular Integrals

    Institute of Scientific and Technical Information of China (English)

    Yong Zhong SUN; Wei Yi SU

    2005-01-01

    It is well known that the commutator Tb of the singular integral operator T with a BMO function b is bounded on Lp(Rn), 1 < p <∞. In this paper, we consider the endpoint estimates for a kind of commutator of singular integrals. A BMO-type estimate for Tb is obtained under the assumption b ∈ LMO.

  3. Chloride and sulphate toxicity to Hydropsyche exocellata (Trichoptera, Hydropsychidae): Exploring intraspecific variation and sub-lethal endpoints

    Energy Technology Data Exchange (ETDEWEB)

    Sala, Miquel [Centre Tecnològic Forestal de Catalunya - CTFC, Solsona, Catalunya (Spain); Faria, Melissa [CESAM, Departamento de Biologia, Universidade de Aveiro, 3810-193 Aveiro (Portugal); Sarasúa, Ignacio [Technische Universität München, Munich, Bayern (Germany); Barata, Carlos [Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona (Spain); Bonada, Núria [Grup de Recerca Freshwater Ecology and Management (FEM), Departament d' Ecologia, Facultat de Biologia, Universitat de Barcelona (UB), Diagonal 643, 08028 Barcelona, Catalonia (Spain); Grup de Recerca Freshwater Ecology and Management (FEM), Departament d' Ecologia, Facultat de Biologia, Institut de Recerca de la Biodiversitat (IRBio), Universitat de Barcelona - UB, Diagonal 643, 08028 Barcelona, Catalonia (Spain); Brucet, Sandra [Aquatic Ecology Group, BETA Tecnio Centre, University of Vic - Central University of Catalonia, Vic, Catalonia (Spain); Catalan Institution for Research and Advanced Studies, ICREA, Barcelona 08010 (Spain); Llenas, Laia; Ponsá, Sergio [Aquatic Ecology Group, BETA Tecnio Centre, University of Vic - Central University of Catalonia, Vic, Catalonia (Spain); Prat, Narcís [Grup de Recerca Freshwater Ecology and Management (FEM), Departament d' Ecologia, Facultat de Biologia, Universitat de Barcelona (UB), Diagonal 643, 08028 Barcelona, Catalonia (Spain); Soares, Amadeu M.V.M. [CESAM, Departamento de Biologia, Universidade de Aveiro, 3810-193 Aveiro (Portugal); and others

    2016-10-01

    The rivers and streams of the world are becoming saltier due to human activities. In spite of the potential damage that salt pollution can cause on freshwater ecosystems, this is an issue that is currently poorly managed. Here we explored intraspecific differences in the sensitivity of freshwater fauna to two major ions (Cl{sup −} and SO{sub 4}{sup 2−}) using the net-spinning caddisfly Hydropsyche exocellata Dufour 1841 (Trichoptera, Hydropsychidae) as a model organism. We exposed H. exocellata to saline solutions (reaching a conductivity of 2.5 mS cm{sup −1}) with Cl{sup −}:SO{sub 4}{sup 2−} ratios similar to those occurring in effluents coming from the meat, mining and paper industries, which release dissolved salts to rivers and streams in Spain. We used two different populations, coming from low and high conductivity streams. To assess toxicity, we measured sub-lethal endpoints: locomotion, symmetry of the food-capturing nets and oxidative stress biomarkers. According to biomarkers and net building, the population historically exposed to lower conductivities (B10) showed higher levels of stress than the population historically exposed to higher conductivities (L102). However, the differences between populations were not strong. For example, net symmetry was lower in the B10 than in the L102 only 48 h after treatment was applied, and biomarkers showed a variety of responses, with no discernable pattern. Also, treatment effects were rather weak, i.e. only some endpoints, and in most cases only in the B10 population, showed a significant response to treatment. The lack of consistent differences between populations and treatments could be related to the high salt tolerance of H. exocellata, since both populations were collected from streams with relatively high conductivities. The sub-lethal effects tested in this study can offer an interesting and promising tool to monitor freshwater salinization by combining physiological and behavioural bioindicators

  4. Modeling hard clinical end-point data in economic analyses.

    Science.gov (United States)

    Kansal, Anuraag R; Zheng, Ying; Palencia, Roberto; Ruffolo, Antonio; Hass, Bastian; Sorensen, Sonja V

    2013-11-01

    The availability of hard clinical end-point data, such as that on cardiovascular (CV) events among patients with type 2 diabetes mellitus, is increasing, and as a result there is growing interest in using hard end-point data of this type in economic analyses. This study investigated published approaches for modeling hard end-points from clinical trials and evaluated their applicability in health economic models with different disease features. A review of cost-effectiveness models of interventions in clinically significant therapeutic areas (CV diseases, cancer, and chronic lower respiratory diseases) was conducted in PubMed and Embase using a defined search strategy. Only studies integrating hard end-point data from randomized clinical trials were considered. For each study included, clinical input characteristics and modeling approach were summarized and evaluated. A total of 33 articles (23 CV, eight cancer, two respiratory) were accepted for detailed analysis. Decision trees, Markov models, discrete event simulations, and hybrids were used. Event rates were incorporated either as constant rates, time-dependent risks, or risk equations based on patient characteristics. Risks dependent on time and/or patient characteristics were used where major event rates were >1%/year in models with fewer health states (rates. The detailed modeling information and terminology varied, sometimes requiring interpretation. Key considerations for cost-effectiveness models incorporating hard end-point data include the frequency and characteristics of the relevant clinical events and how the trial data is reported. When event risk is low, simplification of both the model structure and event rate modeling is recommended. When event risk is common, such as in high risk populations, more detailed modeling approaches, including individual simulations or explicitly time-dependent event rates, are more appropriate to accurately reflect the trial data.

  5. Detection of colorectal neoplasia: Combination of eight blood-based, cancer-associated protein biomarkers.

    Science.gov (United States)

    Wilhelmsen, Michael; Christensen, Ib J; Rasmussen, Louise; Jørgensen, Lars N; Madsen, Mogens R; Vilandt, Jesper; Hillig, Thore; Klaerke, Michael; Nielsen, Knud T; Laurberg, Søren; Brünner, Nils; Gawel, Susan; Yang, Xiaoqing; Davis, Gerard; Heijboer, Annemieke; Martens, Frans; Nielsen, Hans J

    2017-03-15

    Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3 and TIMP-1 were determined in EDTA-plasma using the Abbott ARCHITECT® automated immunoassay platform. Primary endpoints were detection of (i) CRC and high-risk adenoma and (ii) CRC. Logistic regression was performed. Final reduced models were constructed selecting the four biomarkers with the highest likelihood scores. Subjects (N = 4,698) were consecutively included during 2010-2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer and 193 rectal cancer. Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1,342 had nonneoplastic bowell disease and 1,978 subjects had 'clean' colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in the selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the two endpoints; AUCs were 0.76 and 0.84, respectively. The postive predictive value at 90% sensitivity was 25% for endpoint 1 and the negative predictive value was 93%. For endpoint 2, the postive predictive value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC. © 2016 UICC.

  6. A Method of Surrogate Model Construction which Leverages Lower-Fidelity Information using Space Mapping Techniques

    Science.gov (United States)

    2014-03-27

    errors found using the polynomial response surrogate (LS PRM ) overlaid on the data from the space-mapped (SM) surrogate...nonlinear space-mapped surrogate responses, with the least-squares PRM surrogate response plotted for comparison . . . . . . . . . . . . . . . . . 65 42...Percent error comparison between the least-squares space-mapping and the PRM surrogate models derived from samples in the second dataset

  7. Biomarkers in the management of ulcerative colitis: a brief review

    Directory of Open Access Journals (Sweden)

    Hussain, Shabnum

    2011-01-01

    Full Text Available Several attempts have been made in the last two decades to investigate ulcerative colitis (UC patients during the natural course of the disease so as to identify appropriate surrogate markers of disease activity. Most patients with quiescent inflammatory bowel disease have low grade inflammation and it is possible that relapse occurs only once the inflammatory process crosses a critical intensity. Since inflammation is a continuous process, its direct assessment may provide us a quantitative pre-symptomatic measure of imminent relapse. If substantial, it may allow targeted treatment early, to avert relapse or formulate newer therapeutic strategies to maintain symptomatic remission. It is clinically very important to identify these patients at a subclinical stage, noninvasively, by various biomarkers. Biomarkers help to gain an objective measurement of disease activity as symptoms are often subjective. Biomarkers also help to avoid invasive procedures which are often a burden to the patient and the health care system. If an ideal biomarker existed for UC, it would greatly facilitate the work of the gastroenterologist treating these patients. Both “classical” and “emerging” biomarkers of relevance for UC have been studied, but the quest for an ideal biomarker still continues. In this brief review we describe various biomarkers of clinical importance.

  8. Patients’ preferences for selection of endpoints in cardiovascular clinical trials

    Directory of Open Access Journals (Sweden)

    Robert D. Chow

    2014-02-01

    Full Text Available Background: To reduce the duration and overall costs of cardiovascular trials, use of the combined endpoints in trial design has become commonplace. Though this methodology may serve the needs of investigators and trial sponsors, the preferences of patients or potential trial subjects in the trial design process has not been studied. Objective: To determine the preferences of patients in the design of cardiovascular trials. Design: Participants were surveyed in a pilot study regarding preferences among various single endpoints commonly used in cardiovascular trials, preference for single vs. composite endpoints, and the likelihood of compliance with a heart medication if patients similar to them participated in the trial design process. Participants: One hundred adult English-speaking patients, 38% male, from a primary care ambulatory practice located in an urban setting. Key results: Among single endpoints, participants rated heart attack as significantly more important than death from other causes (4.53 vs. 3.69, p=0.004 on a scale of 1–6. Death from heart disease was rated as significantly more important than chest pain (4.73 vs. 2.47, p<0.001, angioplasty/PCI/CABG (4.73 vs. 2.43, p<0.001, and stroke (4.73 vs. 2.43, p<0.001. Participants also expressed a slight preference for combined endpoints over single endpoint (43% vs. 57%, incorporation of the opinions of the study patient population into the design of trials (48% vs. 41% for researchers, and a greater likelihood of medication compliance if patient preferences were considered during trial design (67% indicated a significant to major effect. Conclusions: Patients are able to make judgments and express preferences regarding trial design. They prefer that the opinions of the study population rather than the general population be incorporated into the design of the study. This novel approach to study design would not only incorporate patient preferences into medical decision making, but

  9. Surrogate Modeling for Geometry Optimization in Material Design

    DEFF Research Database (Denmark)

    Rojas Larrazabal, Marielba de la Caridad; Abraham, Yonas B.; Holzwarth, Natalie A.W.;

    2007-01-01

    We propose a new approach based on surrogate modeling for geometry optimization in material design. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)......We propose a new approach based on surrogate modeling for geometry optimization in material design. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)...

  10. Human surrogate neck response to +Gz vertical impact

    NARCIS (Netherlands)

    Rooij, L. van; Uittenbogaard, J.

    2011-01-01

    For the evaluation of impact scenarios with a substantial vertical component, the performance of current human surrogates - the RID 3D hardware dummy and two numerical human models - was evaluated. Volunteer tests with 10G and 6G pulses were compared to reconstructed tests with human surrogates.

  11. Term clouds as surrogates for user generated speech

    NARCIS (Netherlands)

    M. Tsagkias; M. Larson; M. de Rijke

    2008-01-01

    User generated spoken audio remains a challenge for Automatic Speech Recognition (ASR) technology and content-based audio surrogates derived from ASR-transcripts must be error robust. An investigation of the use of term clouds as surrogates for podcasts demonstrates that ASR term clouds closely appr

  12. INTEC SBW Solid Sludge Surrogate Recipe and Validation

    Energy Technology Data Exchange (ETDEWEB)

    Maio, Vince; Janikowski, Stuart; Johnson, Jim; Maio, Vince; Pao, Jenn-Hai

    2004-06-01

    A nonhazardous INTEC tank farm sludge surrogate that incorporated metathesis reactions to generate solids from solutions of known elements present in the radioactive INTEC tank farm sodium-bearing waste sludges was formulated. Elemental analyses, physical property analyses, and filtration testing were performed on waste surrogate and tank farm waste samples, and the results were compared. For testing physical systems associated with moving the tank farm solids, the surrogate described in this report is the best currently available choice. No other available surrogate exhibits the noted similarities in behavior to the sludges. The chemical morphology, particle size distribution, and settling and flow characteristics of the surrogate were similar to those exhibited by the waste sludges. Nonetheless, there is a difference in chemical makeup of the surrogate and the tank farm waste. If a chemical treatment process were to be evaluated for final treatment and disposition of the waste sludges, the surrogate synthesis process would likely require modification to yield a surrogate with a closer matching chemical composition.

  13. Inactivation of Tulane virus, a novel surrogate for human norovirus

    Science.gov (United States)

    Human noroviruses (HuNoVs) are the major cause of non-bacterial epidemics of gastroenteritis. Due to the inability to cultivate HuNoVs and the lack of an efficient small animal model, surrogates are used to study HuNoV biology. Two such surrogates, the feline calicivirus (FCV) and the murine norovir...

  14. Human surrogate neck response to +Gz vertical impact

    NARCIS (Netherlands)

    Rooij, L. van; Uittenbogaard, J.

    2011-01-01

    For the evaluation of impact scenarios with a substantial vertical component, the performance of current human surrogates - the RID 3D hardware dummy and two numerical human models - was evaluated. Volunteer tests with 10G and 6G pulses were compared to reconstructed tests with human surrogates. Add

  15. Space Mapping Optimization of Microwave Circuits Exploiting Surrogate Models

    DEFF Research Database (Denmark)

    Bakr, M. H.; Bandler, J. W.; Madsen, Kaj

    2000-01-01

    A powerful new space-mapping (SM) optimization algorithm is presented in this paper. It draws upon recent developments in both surrogate model-based optimization and modeling of microwave devices, SM optimization is formulated as a general optimization problem of a surrogate model. This model...

  16. Preclinical and human surrogate models of itch

    DEFF Research Database (Denmark)

    Hoeck, Emil August; Marker, Jens Broch; Gazerani, Parisa;

    2016-01-01

    Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine-resistant itch, are lim...... currently applied in animals and humans. This article is protected by copyright. All rights reserved.......Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine-resistant itch......, are limited. Relevant preclinical and human surrogate models of non-histaminergic itch are needed to accelerate the development of novel antipruritics and diagnostic tools. Advances in basic itch research have facilitated the development of diverse models of itch and associated dysesthesiae. While...

  17. Surrogates of plutonium for detection equipment testing

    Science.gov (United States)

    Peerani, Paolo; Tomanin, Alice

    2011-10-01

    Fight against illicit trafficking of nuclear material relies on the possibility to detect nuclear material concealed in vehicles, people or cargo containers. This is done by equipping and training law enforcement and security staff in border stations or other points of access to strategic places and critical infrastructures with radiation detection equipment. The design, development, testing and evaluation of these instruments ideally require the use of real nuclear material to assess, verify and certify their detection performance. Availability of special nuclear material may be an issue, especially for industry, since only few specialized laboratories are licensed for such material. This paper tries to analyse and describe the possibility to use suitable surrogates that may replace the use of real nuclear material in testing the detection capabilities of instruments used in nuclear security.

  18. [Surrogate maternity--literature review and practice].

    Science.gov (United States)

    Pilka, L; Rumpík, D; Pilka, R; Koudelka, M; Prudil, L

    2009-04-01

    This review summarizes opinions on surrogacy including internatinal and governmental organizations attitudes, as well as some religious concerns. Literature review. Reprofit International, Brno, Reproductive medicine and gynecology centre, Zlin, Department of obstetrics and gynecology, Palacky University, Olomouc. The developments in the field of assissted reproduction during the last twenty years have attracted unexpected public interest in some of its ethical and moral aspects. It is very difficult to find a uniform attitude to ethical concerns of assisted conception in plural society. Surrogate mother is defined as a woman who bears and relinquishes a child for another person. The european congress on human reproduction in Barcelona 2008 adopted following résumé on surrogacy: Public opinion has shifted to a position where surrogacy is recognized as an appropriate response to infertility in some circumstances and it is to be expected that this approach will be further strenghtened with stress on positive aspects of familiar life.

  19. Tractable Experiment Design via Mathematical Surrogates

    Energy Technology Data Exchange (ETDEWEB)

    Williams, Brian J. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-02-29

    This presentation summarizes the development and implementation of quantitative design criteria motivated by targeted inference objectives for identifying new, potentially expensive computational or physical experiments. The first application is concerned with estimating features of quantities of interest arising from complex computational models, such as quantiles or failure probabilities. A sequential strategy is proposed for iterative refinement of the importance distributions used to efficiently sample the uncertain inputs to the computational model. In the second application, effective use of mathematical surrogates is investigated to help alleviate the analytical and numerical intractability often associated with Bayesian experiment design. This approach allows for the incorporation of prior information into the design process without the need for gross simplification of the design criterion. Illustrative examples of both design problems will be presented as an argument for the relevance of these research problems.

  20. Biomarkers in mood disorders research: developing new and improved therapeutics

    Directory of Open Access Journals (Sweden)

    MARK J. NICIU

    2014-01-01

    Full Text Available Background Recently, surrogate neurobiological biomarkers that correlate with target engagement and therapeutic response have been developed and tested in early phase studies of mood disorders. Objective The identification of biomarkers could help develop personalized psychiatric treatments that may impact public health. Methods These biomarkers, which are associated with clinical response post-treatment, can be directly validated using multimodal approaches including genetic tools, proteomics/metabolomics, peripheral measures, neuroimaging, biostatistical predictors, and clinical predictors. Results To date, early phase biomarker studies have sought to identify measures that can serve as “biosignatures”, or biological patterns of clinical response. These studies have also sought to identify clinical predictors and surrogate outcomes associated with pathophysiological domains consistently described in the National Institute of Mental Health’s (NIMH new Research Domain Criteria (RDoC. Using the N-methyl-D-aspartate (NMDA antagonist ketamine as an example, we identified changes in several domains (clinical, cognitive, and neurophysiological that predicted ketamine’s rapid and sustained antidepressant effects in individuals with treatment-resistant major depressive disorder (MDD or bipolar depression. Discussion These approaches may ultimately provide clues into the neurobiology of psychiatric disorders and may have enormous impact Backon the development of novel therapeutics.

  1. Maximizing biomarker discovery by minimizing gene signatures

    Directory of Open Access Journals (Sweden)

    Chang Chang

    2011-12-01

    Full Text Available Abstract Background The use of gene signatures can potentially be of considerable value in the field of clinical diagnosis. However, gene signatures defined with different methods can be quite various even when applied the same disease and the same endpoint. Previous studies have shown that the correct selection of subsets of genes from microarray data is key for the accurate classification of disease phenotypes, and a number of methods have been proposed for the purpose. However, these methods refine the subsets by only considering each single feature, and they do not confirm the association between the genes identified in each gene signature and the phenotype of the disease. We proposed an innovative new method termed Minimize Feature's Size (MFS based on multiple level similarity analyses and association between the genes and disease for breast cancer endpoints by comparing classifier models generated from the second phase of MicroArray Quality Control (MAQC-II, trying to develop effective meta-analysis strategies to transform the MAQC-II signatures into a robust and reliable set of biomarker for clinical applications. Results We analyzed the similarity of the multiple gene signatures in an endpoint and between the two endpoints of breast cancer at probe and gene levels, the results indicate that disease-related genes can be preferably selected as the components of gene signature, and that the gene signatures for the two endpoints could be interchangeable. The minimized signatures were built at probe level by using MFS for each endpoint. By applying the approach, we generated a much smaller set of gene signature with the similar predictive power compared with those gene signatures from MAQC-II. Conclusions Our results indicate that gene signatures of both large and small sizes could perform equally well in clinical applications. Besides, consistency and biological significances can be detected among different gene signatures, reflecting the

  2. Sheet metal forming optimization by using surrogate modeling techniques

    Science.gov (United States)

    Wang, Hu; Ye, Fan; Chen, Lei; Li, Enying

    2017-01-01

    Surrogate assisted optimization has been widely applied in sheet metal forming design due to its efficiency. Therefore, to improve the efficiency of design and reduce the product development cycle, it is important for scholars and engineers to have some insight into the performance of each surrogate assisted optimization method and make them more flexible practically. For this purpose, the state-of-the-art surrogate assisted optimizations are investigated. Furthermore, in view of the bottleneck and development of the surrogate assisted optimization and sheet metal forming design, some important issues on the surrogate assisted optimization in support of the sheet metal forming design are analyzed and discussed, involving the description of the sheet metal forming design, off-line and online sampling strategies, space mapping algorithm, high dimensional problems, robust design, some challenges and potential feasible methods. Generally, this paper provides insightful observations into the performance and potential development of these methods in sheet metal forming design.

  3. The Asthma Control Questionnaire as a clinical trial endpoint

    DEFF Research Database (Denmark)

    Barnes, P J; Casale, T B; Dahl, Ronald;

    2014-01-01

    The goal of asthma treatment is to control the disease according to guidelines issued by bodies such as the Global Initiative for Asthma. Effective control is dependent upon evaluation of symptoms, initiation of appropriate treatment and minimization of the progressive adverse effects...... of the disease and its therapies. Although individual outcome measures have been shown to correlate with asthma control, composite endpoints are preferred to enable more accurate and robust monitoring of the health of the individual patient. A number of validated instruments are utilized to capture...... these component endpoints; however, there is no consensus on the optimal instrument for use in clinical trials. The Asthma Control Questionnaire (ACQ) has been shown to be a valid, reliable instrument that allows accurate and reproducible assessment of asthma control that compares favourably with other commonly...

  4. Internal bremsstrahlung endpoint energy of {sup 54}Mn

    Energy Technology Data Exchange (ETDEWEB)

    Hindi, M. M. [Physics Department, Tennessee Technological University, Cookeville, Tennessee 38505 (United States); Larimer, R.-M. [Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 (United States); Norman, E. B. [Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 (United States); Rech, G. A. [Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 (United States)

    2000-05-01

    For {sup 54}Mn there is a discrepancy between the Q{sub EC} obtained from the endpoint energy of the internal bremsstrahlung (IB) spectrum which accompanies the electron capture decay (Q{sub EC}=1353{+-}8 keV) and that obtained from the accepted mass differences (Q{sub EC}=1377{+-}1 keV). This Q value is needed to deduce the partial-half life of the astrophysically interesting {beta}{sup -} decay of {sup 54}Mn from the recently measured {beta}{sup +} partial half-life. To resolve this discrepancy, we have remeasured the endpoint energy of the IB spectrum, by recording coincidences between the IB and the 835-keV {gamma} ray, both detected in Compton-suppressed Ge detectors. The Q{sub EC} we deduce is 1379{+-}8 keV, in agreement with the accepted mass differences. (c) 2000 The American Physical Society.

  5. Environmental diversity as a surrogate for species representation.

    Science.gov (United States)

    Beier, Paul; de Albuquerque, Fábio Suzart

    2015-10-01

    Because many species have not been described and most species ranges have not been mapped, conservation planners often use surrogates for conservation planning, but evidence for surrogate effectiveness is weak. Surrogates are well-mapped features such as soil types, landforms, occurrences of an easily observed taxon (discrete surrogates), and well-mapped environmental conditions (continuous surrogate). In the context of reserve selection, the idea is that a set of sites selected to span diversity in the surrogate will efficiently represent most species. Environmental diversity (ED) is a rarely used surrogate that selects sites to efficiently span multivariate ordination space. Because it selects across continuous environmental space, ED should perform better than discrete surrogates (which necessarily ignore within-bin and between-bin heterogeneity). Despite this theoretical advantage, ED appears to have performed poorly in previous tests of its ability to identify 50 × 50 km cells that represented vertebrates in Western Europe. Using an improved implementation of ED, we retested ED on Western European birds, mammals, reptiles, amphibians, and combined terrestrial vertebrates. We also tested ED on data sets for plants of Zimbabwe, birds of Spain, and birds of Arizona (United States). Sites selected using ED represented European mammals no better than randomly selected cells, but they represented species in the other 7 data sets with 20% to 84% effectiveness. This far exceeds the performance in previous tests of ED, and exceeds the performance of most discrete surrogates. We believe ED performed poorly in previous tests because those tests considered only a few candidate explanatory variables and used suboptimal forms of ED's selection algorithm. We suggest future work on ED focus on analyses at finer grain sizes more relevant to conservation decisions, explore the effect of selecting the explanatory variables most associated with species turnover, and investigate

  6. Using patient management as a surrogate for patient health outcomes in diagnostic test evaluation

    Directory of Open Access Journals (Sweden)

    Staub Lukas P

    2012-02-01

    Full Text Available Abstract Background Before a new test is introduced in clinical practice, evidence is needed to demonstrate that its use will lead to improvements in patient health outcomes. Studies reporting test accuracy may not be sufficient, and clinical trials of tests that measure patient health outcomes are rarely feasible. Therefore, the consequences of testing on patient management are often investigated as an intermediate step in the pathway. There is a lack of guidance on the interpretation of this evidence, and patient management studies often neglect a discussion of the limitations of measuring patient management as a surrogate for health outcomes. Methods We discuss the rationale for measuring patient management, describe the common study designs and provide guidance about how this evidence should be reported. Results Interpretation of patient management studies relies on the condition that patient management is a valid surrogate for downstream patient benefits. This condition presupposes two critical assumptions: the test improves diagnostic accuracy; and the measured changes in patient management improve patient health outcomes. The validity of this evidence depends on the certainty around these critical assumptions and the ability of the study design to minimise bias. Three common designs are test RCTs that measure patient management as a primary endpoint, diagnostic before-after studies that compare planned patient management before and after testing, and accuracy studies that are extended to report on the actual treatment or further tests received following a positive and negative test result. Conclusions Patient management can be measured as a surrogate outcome for test evaluation if its limitations are recognised. The potential consequences of a positive and negative test result on patient management should be pre-specified and the potential patient benefits of these management changes clearly stated. Randomised comparisons will provide

  7. Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants

    Energy Technology Data Exchange (ETDEWEB)

    Huang Qihong; Jin Xidong; Gaillard, Elias T.; Knight, Brian L.; Pack, Franklin D.; Stoltz, James H.; Jayadev, Supriya; Blanchard, Kerry T

    2004-05-18

    Microarray technology continues to gain increased acceptance in the drug development process, particularly at the stage of toxicology and safety assessment. In the current study, microarrays were used to investigate gene expression changes associated with hepatotoxicity, the most commonly reported clinical liability with pharmaceutical agents. Acetaminophen, methotrexate, methapyrilene, furan and phenytoin were used as benchmark compounds capable of inducing specific but different types of hepatotoxicity. The goal of the work was to define gene expression profiles capable of distinguishing the different subtypes of hepatotoxicity. Sprague-Dawley rats were orally dosed with acetaminophen (single dose, 4500 mg/kg for 6, 24 and 72 h), methotrexate (1 mg/kg per day for 1, 7 and 14 days), methapyrilene (100 mg/kg per day for 3 and 7 days), furan (40 mg/kg per day for 1, 3, 7 and 14 days) or phenytoin (300 mg/kg per day for 14 days). Hepatic gene expression was assessed using toxicology-specific gene arrays containing 684 target genes or expressed sequence tags (ESTs). Principal component analysis (PCA) of gene expression data was able to provide a clear distinction of each compound, suggesting that gene expression data can be used to discern different hepatotoxic agents and toxicity endpoints. Gene expression data were applied to the multiplicity-adjusted permutation test and significantly changed genes were categorized and correlated to hepatotoxic endpoints. Repression of enzymes involved in lipid oxidation (acyl-CoA dehydrogenase, medium chain, enoyl CoA hydratase, very long-chain acyl-CoA synthetase) were associated with microvesicular lipidosis. Likewise, subsets of genes associated with hepatotocellular necrosis, inflammation, hepatitis, bile duct hyperplasia and fibrosis have been identified. The current study illustrates that expression profiling can be used to: (1) distinguish different hepatotoxic endpoints; (2) predict the development of toxic endpoints; and

  8. A filament eruption with an apparent reshuffle of endpoints

    Science.gov (United States)

    Filippov, Boris

    2014-08-01

    A filament eruption during 2010 April 30-May 1, which shows the reconnection of one filament leg with a region far away from its initial position, is analysed. Observations from three viewpoints are used for measurements of endpoint coordinates as precise as possible. The northern leg of the erupting prominence loop `jumps' laterally to a latitude lower than the latitude of the original southern endpoint. Thus, the endpoints have reshuffled their positions in the limb view. Although this behaviour could be interpreted as an asymmetric `zipping-like' eruption, it does not look very likely. It seems more likely to represent reconnection of the flux-rope field lines in the northern leg with ambient coronal magnetic field lines rooted in a quiet region far from the filament. From calculations of coronal potential magnetic field, we found that the filament before the eruption was stable to vertical displacements, but was liable to violation of horizontal equilibrium. This is an unusual initiation of an eruption, with a combination of initial horizontal and vertical flux-rope displacements, showing a new and unexpected possibility for the start of an eruptive event.

  9. Challenges assessing clinical endpoints in early Huntington disease

    Science.gov (United States)

    Paulsen, Jane S.; Wang, Chiachi; Duff, Kevin; Barker, Roger; Nance, Martha; Beglinger, Leigh; Moser, David; Williams, Janet K.; Simpson, Sheila; Langbehn, Douglas; van Kammen, Daniel P.

    2010-01-01

    The primary aim of this study was to evaluate the current accepted standard clinical endpoint for the earliest-studied HD participants likely to be recruited into clinical trials. Since the advent of genetic testing for HD, it is possible to identify gene carriers prior to the diagnosis of disease, which opens up the possibility of clinical trials of disease-modifying treatments in clinically asymptomatic persons. Current accepted standard clinical endpoints were examined as part of a multi-national, 32-site, longitudinal, observational study of 786 research participants currently in the HD prodrome (gene-positive but not clinically diagnosed). Clinical signs and symptoms were used to prospectively predict functional loss as assessed by current accepted standard endpoints over 8 years of follow up. Functional capacity measures were not sensitive for HD in the prodrome; over 88% scored at ceiling. Prospective evaluation revealed that the first functional loss was in their accustomed work. In a survival analysis, motor, cognitive, and psychiatric measures were all predictors of job change. To our knowledge, this is the first prospective study ever conducted on the emergence of functional loss secondary to brain disease. We conclude that future clinical trials designed for very early disease will require the development of new and more sensitive measures of real-life function. PMID:20623772

  10. Combination of biomarkers

    DEFF Research Database (Denmark)

    Thurfjell, Lennart; Lötjönen, Jyrki; Lundqvist, Roger

    2012-01-01

    The New National Institute on Aging-Alzheimer's Association diagnostic guidelines for Alzheimer's disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury....

  11. The handbook of biomarkers

    CERN Document Server

    Jain, Kewal K

    2010-01-01

    This handbook describes many different types of biomarkers and their discovery. It also presents the background information needed for the evaluation of biomarkers as well as the essential procedures for their validation and use in clinical trials.

  12. Biomarkers in Veterinary Medicine.

    Science.gov (United States)

    Myers, Michael J; Smith, Emily R; Turfle, Phillip G

    2017-02-08

    This article summarizes the relevant definitions related to biomarkers; reviews the general processes related to biomarker discovery and ultimate acceptance and use; and finally summarizes and reviews, to the extent possible, examples of the types of biomarkers used in animal species within veterinary clinical practice and human and veterinary drug development. We highlight opportunities for collaboration and coordination of research within the veterinary community and leveraging of resources from human medicine to support biomarker discovery and validation efforts for veterinary medicine.

  13. Evidence-based medical perspectives: the evolving role of PSA for early detection, monitoring of treatment response, and as a surrogate end point of efficacy for interventions in men with different clinical risk states for the prevention and progression of prostate cancer.

    Science.gov (United States)

    Lieberman, Ronald

    2004-01-01

    Following FDA approval and introduction into the clinic in the mid-1980s, PSA testing has become arguably the most versatile serum tumor marker in urologic oncology with clinical use for early detection (screening) of prostate cancer (PC), risk stratification for clinical staging, prognosis, intermediate biomarker for monitoring tumor recurrence, and more recently as an intermediate biomarker for assessing therapeutic response to antiandrogens, radiation therapy, and chemotherapy. PSA now routinely guides health care providers for the clinical management of PC over a wide range of clinical risk states for men at risk of PC, after local definitive therapy and after systemic therapy to prevent progression to metastatic bone disease, and to palliate men with hormone refractory prostate cancer (HRPC). To further assess the evidence that supports these clinical applications, this commentary reviews and critically evaluates the emerging body of new data focusing on several recently published seminal articles by D'Amico et al and Thompson et al, the new National Comprehensive Cancer Network 2004 recommendations for starting PSA testing at the age of 40 years old, the latest results from 2 phase 3 randomized, controlled trials of taxane-based regimens showing improved survival for men with HRPC, and the recent US FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer that helped to distill and synthesize the current state of the art and the progress toward validation of PSA metrics (eg, PSA velocity) as a surrogate end point (SE) for treatment efficacy with taxane-based regimens. Furthermore, several randomized, controlled chemoprevention trials in progress evaluating agents such as selenium and vitamin E in high-risk cohorts are well poised to confirm the validity of PSA as an SE for clinical efficacy for the prevention and progression of PC. Although there continues to be a need to validate better biomarkers before diagnosis of PC (more sensitive and specific

  14. Surrogate motherhood as a medical treatment procedure for women's infertility.

    Science.gov (United States)

    Jovic, Olga S

    2011-03-01

    The content of this work is conceived on the research of the consequences of surrogate motherhood as a process of assisted procreation, which represent a way of parenthood in cases when it is not possible to realize parenthood through a natural way. Surrogate motherhood is a process in which a woman (surrogate mother) agrees to carry a pregnancy with the intent to give the child to the couple with whom she has made a contract on surrogate maternity after the birth. This process of conception and birth makes the determination of the child's origin on its mother's side hard to determine, because of the distinction of the genetic and gestation phases of the two women. The concept of surrogate motherhood is to appear in two forms, depending on the existence or the non-existence of the genetic link between the surrogate mother and the child she gives birth to. There are gestation (full) and genetic (partial) surrogates each with different modalities and legal and ethical implications. In Serbia, Infertility Treatment and the Bio-medically Assisted Procreation Act from 2009 explicitly forbids surrogate motherhood, despite the fact that an infertile couple decides to use it, as a rule, after having tried all other treatment procedures, in cases when there is a diagnosis but the conventional treatment applied has not produced the desired results. Given the fact that no one has the right to ignore the sufferings of people who cannot procreate naturally, the medical practice and legal science in our country plead for a formulation of a legal framework in which to apply surrogate motherhood as an infertility treatment, under particular conditions.

  15. Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases.

    Science.gov (United States)

    Lleó, Alberto; Cavedo, Enrica; Parnetti, Lucilla; Vanderstichele, Hugo; Herukka, Sanna Kaisa; Andreasen, Niels; Ghidoni, Roberta; Lewczuk, Piotr; Jeromin, Andreas; Winblad, Bengt; Tsolaki, Magda; Mroczko, Barbara; Visser, Pieter Jelle; Santana, Isabel; Svenningsson, Per; Blennow, Kaj; Aarsland, Dag; Molinuevo, José Luis; Zetterberg, Henrik; Mollenhauer, Brit

    2015-01-01

    Alzheimer disease (AD) and Parkinson disease (PD) are the most common neurodegenerative disorders. For both diseases, early intervention is thought to be essential to the success of disease-modifying treatments. Cerebrospinal fluid (CSF) can reflect some of the pathophysiological changes that occur in the brain, and the number of CSF biomarkers under investigation in neurodegenerative conditions has grown rapidly in the past 20 years. In AD, CSF biomarkers are increasingly being used in clinical practice, and have been incorporated into the majority of clinical trials to demonstrate target engagement, to enrich or stratify patient groups, and to find evidence of disease modification. In PD, CSF biomarkers have not yet reached the clinic, but are being studied in patients with parkinsonism, and are being used in clinical trials either to monitor progression or to demonstrate target engagement and downstream effects of drugs. CSF biomarkers might also serve as surrogate markers of clinical benefit after a specific therapeutic intervention, although additional data are required. It is anticipated that CSF biomarkers will have an important role in trials aimed at disease modification in the near future. In this Review, we provide an overview of CSF biomarkers in AD and PD, and discuss their role in clinical trials.

  16. Mother-daughter in vitro fertilization triplet surrogate pregnancy.

    Science.gov (United States)

    Michelow, M C; Bernstein, J; Jacobson, M J; McLoughlin, J L; Rubenstein, D; Hacking, A I; Preddy, S; Van der Wat, I J

    1988-02-01

    A successful triplet pregnancy has been established in a surrogate gestational mother following the transfer of five embryos fertilized in vitro. The oocytes were donated by her biological daughter, and the sperm obtained from the daughter's husband. The daughter's infertility followed a total abdominal hysterectomy performed for a postpartum hemorrhage as a result of a placenta accreta. Synchronization of both their menstrual cycles was obtained using oral contraceptive suppression for 2 months, followed by stimulation of both the surrogate gestational mother and her daughter such that embryo transfer would occur at least 48 hr after the surrogate gestational mother's own ovulation. This case raises a number of medical, social, psychological, and ethical issues.

  17. Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges.

    Science.gov (United States)

    Kim, Dana; Kim, Young Sam; Shin, Dong Wun; Park, Chang Shin; Kang, Ju Hee

    2016-10-01

    No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.

  18. Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

    Science.gov (United States)

    Kim, Dana; Kim, Young-Sam; Shin, Dong Wun; Park, Chang-Shin

    2016-01-01

    No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.

  19. New sepsis biomarkers

    Directory of Open Access Journals (Sweden)

    Dolores Limongi

    2016-06-01

    Full Text Available Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes. Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity, specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis, timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  20. New sepsis biomarkers

    Institute of Scientific and Technical Information of China (English)

    Dolores Limongi; Cartesio D’Agostini; Marco Ciotti

    2016-01-01

    Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes.Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity,specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis,timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  1. New sepsis biomarkers

    Institute of Scientific and Technical Information of China (English)

    Dolores Limongi; Cartesio DAgostini; Marco Ciotti

    2016-01-01

    Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes. Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity, specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis, timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  2. SURROGATE MOTHER DALAM PERSPEKTIF HUKUM PIDANA INDONESIA

    Directory of Open Access Journals (Sweden)

    Mr. Muntaha

    2013-04-01

    Full Text Available The development of science and technology, in particular in the field of health, has already recently brought a huge advantage and problem in human life. An example of technological marvel that not only requires deep legal thoughts but also at the same time solution is the bio-medical technology advancement of surrogacy. Surrogacy deals with human’s inclination towards reproductive activity. However, it opens up legal complication, in particular with regards to the potential commission of a criminal action as well as to the notion of doctor’s liability. Perkembangan ilmu dan teknologi di bidang kesehatan yang semakin maju dan pesat telah membawa berbagai manfaat dan masalah dalam kehidupan manusia dewasa ini. Salah satu perkembangan yang tidak hanya membutuhkan pemikiran di bidang hukum, tetapi juga sekaligus solusinya adalah mengenai kecanggihan teknologi bio-medis surrogate mother. Surrogacy menyentuh sisi kemanusiaan seorang insan terhadap reproduksi. Akan tetapi, lembaga surrogacy juga membawa komplikasi hukum terutama terkait dengan potensi tindak pidana dan dengan persoalan tanggung jawab dokter.

  3. Polynomial Chaos Surrogates for Bayesian Inference

    KAUST Repository

    Le Maitre, Olivier

    2016-01-06

    The Bayesian inference is a popular probabilistic method to solve inverse problems, such as the identification of field parameter in a PDE model. The inference rely on the Bayes rule to update the prior density of the sought field, from observations, and derive its posterior distribution. In most cases the posterior distribution has no explicit form and has to be sampled, for instance using a Markov-Chain Monte Carlo method. In practice the prior field parameter is decomposed and truncated (e.g. by means of Karhunen- Lo´eve decomposition) to recast the inference problem into the inference of a finite number of coordinates. Although proved effective in many situations, the Bayesian inference as sketched above faces several difficulties requiring improvements. First, sampling the posterior can be a extremely costly task as it requires multiple resolutions of the PDE model for different values of the field parameter. Second, when the observations are not very much informative, the inferred parameter field can highly depends on its prior which can be somehow arbitrary. These issues have motivated the introduction of reduced modeling or surrogates for the (approximate) determination of the parametrized PDE solution and hyperparameters in the description of the prior field. Our contribution focuses on recent developments in these two directions: the acceleration of the posterior sampling by means of Polynomial Chaos expansions and the efficient treatment of parametrized covariance functions for the prior field. We also discuss the possibility of making such approach adaptive to further improve its efficiency.

  4. A Large-Scale Study of Surrogate Physicality and Gesturing on Human–Surrogate Interactions in a Public Space

    Directory of Open Access Journals (Sweden)

    Kangsoo Kim

    2017-07-01

    Full Text Available Technological human surrogates, including robotic and virtual humans, have been popularly used in various scenarios, including training, education, and entertainment. Prior research has investigated the effects of the surrogate’s physicality and gesturing in human perceptions and social influence of the surrogate. However, those studies have been carried out in research laboratories, where the participants were aware that it was an experiment, and the participant demographics are typically relatively narrow—e.g., college students. In this paper, we describe and share results from a large-scale exploratory user study involving 7,685 people in a public space, where they were unaware of the experimental nature of the setting, to investigate the effects of surrogate physicality and gesturing on their behavior during human–surrogate interactions. We evaluate human behaviors using several variables, such as proactivity and reactivity, and proximity. We have identified several interesting phenomena that could lead to hypotheses developed as part of future hypothesis-based studies. Based on the measurements of the variables, we believe people are more likely to be engaged in a human–surrogate interaction when the surrogate is physically present, but movements and gesturing with its body parts have not shown the expected benefits for the interaction engagement. Regarding the demographics of the people in the study, we found higher overall engagement for females than males, and higher reactivity for younger than older people. We discuss implications for practitioners aiming to design a technological surrogate that will directly interact with real humans.

  5. 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...... and the importance of each individual criterion; (2) overall strength of evidence in support of each of the 5 candidate biomarkers as reflecting structural damage endpoints in rheumatoid arthritis (RA) and identification of omissions to the criteria set. RESULTS: The search identified 111 articles. The strength...

  6. Carotenoid status in man: effects on biomarkers of eye, skin and cardiovascular health

    NARCIS (Netherlands)

    Broekmans, W.M.R.

    2002-01-01

    Observational epidemiological studies have consistently shown that a diet rich in carotenoid-containing fruit and vegetables is associated with a reduced risk of chronic diseases. Because intervention studies with hard endpoints are time-consuming and costly, the use of biomarkers cou

  7. Clinical research and methodology: What usage and what hierarchical order for secondary endpoints?

    Science.gov (United States)

    Laporte, Silvy; Diviné, Marine; Girault, Danièle

    2016-02-01

    In a randomised clinical trial, when the result of the primary endpoint shows a significant benefit, the secondary endpoints are scrutinised to identify additional effects of the treatment. However, this approach entails a risk of concluding that there is a benefit for one of these endpoints when such benefit does not exist (inflation of type I error risk). There are mainly two methods used to control the risk of drawing erroneous conclusions for secondary endpoints. The first method consists of distributing the risk over several co-primary endpoints, so as to maintain an overall risk of 5%. The second is the hierarchical test procedure, which consists of first establishing a hierarchy of the endpoints, then evaluating each endpoint in succession according to this hierarchy while the endpoints continue to show statistical significance. This simple method makes it possible to show the additional advantages of treatments and to identify the factors that differentiate them.

  8. Endpoint-based parallel data processing in a parallel active messaging interface of a parallel computer

    Science.gov (United States)

    Archer, Charles J.; Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.

    2014-08-12

    Endpoint-based parallel data processing in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, the compute nodes coupled for data communications through the PAMI, including establishing a data communications geometry, the geometry specifying, for tasks representing processes of execution of the parallel application, a set of endpoints that are used in collective operations of the PAMI including a plurality of endpoints for one of the tasks; receiving in endpoints of the geometry an instruction for a collective operation; and executing the instruction for a collective operation through the endpoints in dependence upon the geometry, including dividing data communications operations among the plurality of endpoints for one of the tasks.

  9. AN ENDPOINT ESTIMATE FOR MAXIMAL MULTILINEAR SINGULAR INTEGRAL OPERATORS

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A weak type endpoint estimate for the maximal multilinear singular integral operator T*Af(x)=supε>0|(f)(x-y)>ε (Ω(x-y)/(|x-y|(n+1)))(A(x)-A(y)-▽A(y)(x-y))f(y)dy| is established, where Ω is homogeneous of degree zero, integrable on the unit sphere and has vanishing moment of order one, and A has derivatives of order one in BMO(Rn). A regularity condition on Ω which implies an LlogL type estimate of T*A is given.

  10. Establishing maintenance intervals based on measurement reliability of engineering endpoints.

    Science.gov (United States)

    James, P J

    2000-01-01

    Methods developed by the metrological community and principles used by the research community were integrated to provide a basis for a periodic maintenance interval analysis system. Engineering endpoints are used as measurement attributes on which to base two primary quality indicators: accuracy and reliability. Also key to establishing appropriate maintenance intervals is the ability to recognize two primary failure modes: random failure and time-related failure. The primary objective of the maintenance program is to avert predictable and preventable device failure, and understanding time-related failures enables service personnel to set intervals accordingly.

  11. Two-temperature LATE-PCR endpoint genotyping

    Directory of Open Access Journals (Sweden)

    Reis Arthur H

    2006-12-01

    Full Text Available Abstract Background In conventional PCR, total amplicon yield becomes independent of starting template number as amplification reaches plateau and varies significantly among replicate reactions. This paper describes a strategy for reconfiguring PCR so that the signal intensity of a single fluorescent detection probe after PCR thermal cycling reflects genomic composition. The resulting method corrects for product yield variations among replicate amplification reactions, permits resolution of homozygous and heterozygous genotypes based on endpoint fluorescence signal intensities, and readily identifies imbalanced allele ratios equivalent to those arising from gene/chromosomal duplications. Furthermore, the use of only a single colored probe for genotyping enhances the multiplex detection capacity of the assay. Results Two-Temperature LATE-PCR endpoint genotyping combines Linear-After-The-Exponential (LATE-PCR (an advanced form of asymmetric PCR that efficiently generates single-stranded DNA and mismatch-tolerant probes capable of detecting allele-specific targets at high temperature and total single-stranded amplicons at a lower temperature in the same reaction. The method is demonstrated here for genotyping single-nucleotide alleles of the human HEXA gene responsible for Tay-Sachs disease and for genotyping SNP alleles near the human p53 tumor suppressor gene. In each case, the final probe signals were normalized against total single-stranded DNA generated in the same reaction. Normalization reduces the coefficient of variation among replicates from 17.22% to as little as 2.78% and permits endpoint genotyping with >99.7% accuracy. These assays are robust because they are consistent over a wide range of input DNA concentrations and give the same results regardless of how many cycles of linear amplification have elapsed. The method is also sufficiently powerful to distinguish between samples with a 1:1 ratio of two alleles from samples comprised of

  12. Two-temperature LATE-PCR endpoint genotyping

    Science.gov (United States)

    Sanchez, J Aquiles; Abramowitz, Jessica D; Salk, Jesse J; Reis, Arthur H; Rice, John E; Pierce, Kenneth E; Wangh, Lawrence J

    2006-01-01

    Background In conventional PCR, total amplicon yield becomes independent of starting template number as amplification reaches plateau and varies significantly among replicate reactions. This paper describes a strategy for reconfiguring PCR so that the signal intensity of a single fluorescent detection probe after PCR thermal cycling reflects genomic composition. The resulting method corrects for product yield variations among replicate amplification reactions, permits resolution of homozygous and heterozygous genotypes based on endpoint fluorescence signal intensities, and readily identifies imbalanced allele ratios equivalent to those arising from gene/chromosomal duplications. Furthermore, the use of only a single colored probe for genotyping enhances the multiplex detection capacity of the assay. Results Two-Temperature LATE-PCR endpoint genotyping combines Linear-After-The-Exponential (LATE)-PCR (an advanced form of asymmetric PCR that efficiently generates single-stranded DNA) and mismatch-tolerant probes capable of detecting allele-specific targets at high temperature and total single-stranded amplicons at a lower temperature in the same reaction. The method is demonstrated here for genotyping single-nucleotide alleles of the human HEXA gene responsible for Tay-Sachs disease and for genotyping SNP alleles near the human p53 tumor suppressor gene. In each case, the final probe signals were normalized against total single-stranded DNA generated in the same reaction. Normalization reduces the coefficient of variation among replicates from 17.22% to as little as 2.78% and permits endpoint genotyping with >99.7% accuracy. These assays are robust because they are consistent over a wide range of input DNA concentrations and give the same results regardless of how many cycles of linear amplification have elapsed. The method is also sufficiently powerful to distinguish between samples with a 1:1 ratio of two alleles from samples comprised of 2:1 and 1:2 ratios of the

  13. Hepatology may have problems with putative surrogate outcome measures

    DEFF Research Database (Denmark)

    Gluud, Christian; Brok, Jesper; Gong, Yan;

    2007-01-01

    hepatitis C, serum bilirubin concentration following ursodeoxycholic acid or immunosuppressants for patients with primary biliary cirrhosis, and nutritional outcomes following artificial nutrition for liver patients may not be valid surrogates for morbidity or mortality. The challenge is to develop reliable...

  14. Fernald Silos 1 & 2 Accelerated Waste Retrieval Program Surrogate Development

    Energy Technology Data Exchange (ETDEWEB)

    Mullen, O Dennis; Erian, Fadel F.

    2002-09-01

    Whitepaper describing the rationale and methodology for development of surrogates to be used for testing retrieval and processing systems for the DOE Fernald Silos 1 & 2 wastes. One significant updating/revision is expected.

  15. THE SURROGATE COLONIZATION OF PALESTINE, 1917-1939

    OpenAIRE

    Atran, Scott

    1989-01-01

    The "surrogate colonization" of Palestine had a foreign power giving to a nonnative group rights over land occupied by an indigenous people. It thus brought into play the complementary and conflicting agendas of three culturally distinguishable parties: British, Jews and Arabs. Each party had both "externalist" [those with no sustained practical experience of day to day life in Palestine] and "internalist" representatives. The surrogate idea was based on a "strategic consensus" involving each...

  16. Surrogate nutrition markers, malnutrition, and adequacy of nutrition support.

    Science.gov (United States)

    Seres, David S

    2005-06-01

    Surrogate nutrition markers are used to assess adequacy of nourishment and to define malnutrition despite evidence that fails to link nourishment, surrogate markers, and outcomes. Markers such as serum levels of albumin, prealbumin, transferrin, and IGF-1 and delayed hypersensitivity and total lymphocyte count may be valid to help stratify risk. However, it is not appropriate to consider these as markers of adequacy of nourishment in the sick patient.

  17. Emotional experiences in surrogate mothers: A qualitative study

    OpenAIRE

    Hoda Ahmari Tehran; Shohreh Tashi; Nahid Mehran; Narges Eskandari; Tahmineh Dadkhah Tehrani

    2014-01-01

    Background: Surrogacy is one of the new techniques of assisted reproduction technology in which a woman carries and bears a child for another woman. In Iran, many Shia clerics and jurists considered it permissible so there is no religious prohibition for it. In addition to the risk of physical complications for complete surrogate mothers, the possibility of psychological complications resulted from emotional attachment to a living creature in the surrogate mother as another injury requires co...

  18. Human surrogate models of neuropathic pain: validity and limitations.

    Science.gov (United States)

    Binder, Andreas

    2016-02-01

    Human surrogate models of neuropathic pain in healthy subjects are used to study symptoms, signs, and the hypothesized underlying mechanisms. Although different models are available, different spontaneous and evoked symptoms and signs are inducible; 2 key questions need to be answered: are human surrogate models conceptually valid, ie, do they share the sensory phenotype of neuropathic pain states, and are they sufficiently reliable to allow consistent translational research?

  19. Magnetometer Response of Commonly Found Munitions Items and Munitions Surrogates

    Science.gov (United States)

    2012-01-12

    Predicted minimum magnetometer anomaly strength for a variety of munitions and surrogate items at a burial depth corresponding to 11x their respective...Response Live Site Demonstrations. The authors would like to thank Craig Murray of Parsons and Stephen Billings of Sky Research for their...variety of munitions and surrogate items at a burial depth corresponding to 11x their respective diameter. The sensor is assumed to be deployed as part

  20. Biomarkers in clinical medicine.

    Science.gov (United States)

    Chen, Xiao-He; Huang, Shuwen; Kerr, David

    2011-01-01

    Biomarkers have been used in clinical medicine for decades. With the rise of genomics and other advances in molecular biology, biomarker studies have entered a whole new era and hold promise for early diagnosis and effective treatment of many diseases. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention (1). They can be classified into five categories based on their application in different disease stages: 1) antecedent biomarkers to identify the risk of developing an illness, 2) screening biomarkers to screen for subclinical disease, 3) diagnostic biomarkers to recognize overt disease, 4) staging biomarkers to categorise disease severity, and 5) prognostic biomarkers to predict future disease course, including recurrence, response to therapy, and monitoring efficacy of therapy (1). Biomarkers can indicate a variety of health or disease characteristics, including the level or type of exposure to an environmental factor, genetic susceptibility, genetic responses to environmental exposures, markers of subclinical or clinical disease, or indicators of response to therapy. This chapter will focus on how these biomarkers have been used in preventive medicine, diagnostics, therapeutics and prognostics, as well as public health and their current status in clinical practice.

  1. Proteomic Approaches in Biomarker Discovery: New Perspectives in Cancer Diagnostics

    Directory of Open Access Journals (Sweden)

    Petra Hudler

    2014-01-01

    Full Text Available Despite remarkable progress in proteomic methods, including improved detection limits and sensitivity, these methods have not yet been established in routine clinical practice. The main limitations, which prevent their integration into clinics, are high cost of equipment, the need for highly trained personnel, and last, but not least, the establishment of reliable and accurate protein biomarkers or panels of protein biomarkers for detection of neoplasms. Furthermore, the complexity and heterogeneity of most solid tumours present obstacles in the discovery of specific protein signatures, which could be used for early detection of cancers, for prediction of disease outcome, and for determining the response to specific therapies. However, cancer proteome, as the end-point of pathological processes that underlie cancer development and progression, could represent an important source for the discovery of new biomarkers and molecular targets for tailored therapies.

  2. Cortical plasticity as a new endpoint measurement for chronic pain

    Directory of Open Access Journals (Sweden)

    Zhuo Min

    2011-07-01

    Full Text Available Abstract Animal models of chronic pain are widely used to investigate basic mechanisms of chronic pain and to evaluate potential novel drugs for treating chronic pain. Among the different criteria used to measure chronic pain, behavioral responses are commonly used as the end point measurements. However, not all chronic pain conditions can be easily measured by behavioral responses such as the headache, phantom pain and pain related to spinal cord injury. Here I propose that cortical indexes, that indicate neuronal plastic changes in pain-related cortical areas, can be used as endpoint measurements for chronic pain. Such cortical indexes are not only useful for those chronic pain conditions where a suitable animal model is lacking, but also serve as additional screening methods for potential drugs to treat chronic pain in humans. These cortical indexes are activity-dependent immediate early genes, electrophysiological identified plastic changes and biochemical assays of signaling proteins. It can be used to evaluate novel analgesic compounds that may act at peripheral or spinal sites. I hope that these new cortical endpoint measurements will facilitate our search for new, and more effective, pain medicines, and help to reduce false lead drug targets.

  3. Design and analysis of crossover trials for absorbing binary endpoints.

    Science.gov (United States)

    Nason, Martha; Follmann, Dean

    2010-09-01

    The crossover is a popular and efficient trial design used in the context of patient heterogeneity to assess the effect of treatments that act relatively quickly and whose benefit disappears with discontinuation. Each patient can serve as her own control as within-individual treatment and placebo responses are compared. Conventional wisdom is that these designs are not appropriate for absorbing binary endpoints, such as death or HIV infection. We explore the use of crossover designs in the context of these absorbing binary endpoints and show that they can be more efficient than the standard parallel group design when there is heterogeneity in individuals' risks. We also introduce a new two-period design where first period "survivors" are rerandomized for the second period. This design combines the crossover design with the parallel design and achieves some of the efficiency advantages of the crossover design while ensuring that the second period groups are comparable by randomization. We discuss the validity of the new designs and evaluate both a mixture model and a modified Mantel-Haenszel test for inference. The mixture model assumes no carryover or period effects while the Mantel-Haenszel approach conditions out period effects. Simulations are used to compare the different designs and an example is provided to explore practical issues in implementation.

  4. Critical endpoint for deconfinement in matrix and other effective models

    CERN Document Server

    Kashiwa, Kouji; Skokov, Vladimir V

    2012-01-01

    We consider the position of the deconfining critical endpoint, where the first order transition for deconfinement is washed out by the presence of massive, dynamical quarks. We use an effective matrix model, employed previously to analyze the transition in the pure glue theory. If the param- eters of the pure glue theory are unaffected by the presence of dynamical quarks, and if the quarks only contribute perturbatively, then for three colors and three degenerate quark flavors this quark mass is very heavy, m_de \\sim 2.5 GeV, while the critical temperature, T_de, barely changes, \\sim 1% below that in the pure glue theory. The location of the deconfining critical endpoint is a sensitive test to differentiate between effective models. For example, models with a logarithmic potential for the Polyakov loop give much smaller values of the quark mass, m_de \\sim 1 GeV, and a large shift in T_de \\sim 10% lower than that in the pure glue theory.

  5. Financial Surrogate Decision Making: Lessons from Applied Experimental Philosophy.

    Science.gov (United States)

    Feltz, Adam

    2016-09-20

    An estimated 1 in 4 elderly Americans need a surrogate to make decisions at least once in their lives. With an aging population, that number is almost certainly going to increase. This paper focuses on financial surrogate decision making. To illustrate some of the empirical and moral implications associated with financial surrogate decision making, two experiments suggest that default choice settings can predictably influence some surrogate financial decision making. Experiment 1 suggested that when making hypothetical financial decisions, surrogates tended to stay with default settings (OR = 4.37, 95% CI 1.52, 12.48). Experiment 2 replicated and extended this finding suggesting that in a different context (OR = 2.27, 95% CI 1.1, 4.65). Experiment 2 also suggested that those who were more numerate were less likely to be influenced by default settings than the less numerate, but only when the decision is whether to "opt in" (p = .05). These data highlight the importance of a recent debate about "nudging." Defaults are common methods to nudge people to make desirable choices while allowing the liberty to choose otherwise. Some of the ethics of using default settings to nudge surrogate decision makers are discussed.

  6. Reliability-based design optimization with progressive surrogate models

    Science.gov (United States)

    Kanakasabai, Pugazhendhi; Dhingra, Anoop K.

    2014-12-01

    Reliability-based design optimization (RBDO) has traditionally been solved as a nested (bilevel) optimization problem, which is a computationally expensive approach. Unilevel and decoupled approaches for solving the RBDO problem have also been suggested in the past to improve the computational efficiency. However, these approaches also require a large number of response evaluations during optimization. To alleviate the computational burden, surrogate models have been used for reliability evaluation. These approaches involve construction of surrogate models for the reliability computation at each point visited by the optimizer in the design variable space. In this article, a novel approach to solving the RBDO problem is proposed based on a progressive sensitivity surrogate model. The sensitivity surrogate models are built in the design variable space outside the optimization loop using the kriging method or the moving least squares (MLS) method based on sample points generated from low-discrepancy sampling (LDS) to estimate the most probable point of failure (MPP). During the iterative deterministic optimization, the MPP is estimated from the surrogate model for each design point visited by the optimizer. The surrogate sensitivity model is also progressively updated for each new iteration of deterministic optimization by adding new points and their responses. Four example problems are presented showing the relative merits of the kriging and MLS approaches and the overall accuracy and improved efficiency of the proposed approach.

  7. Cystatin C: a candidate biomarker for amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Meghan E Wilson

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurologic disease characterized by progressive motor neuron degeneration. Clinical disease management is hindered by both a lengthy diagnostic process and the absence of effective treatments. Reliable panels of diagnostic, surrogate, and prognostic biomarkers are needed to accelerate disease diagnosis and expedite drug development. The cysteine protease inhibitor cystatin C has recently gained interest as a candidate diagnostic biomarker for ALS, but further studies are required to fully characterize its biomarker utility. We used quantitative enzyme-linked immunosorbent assay (ELISA to assess initial and longitudinal cerebrospinal fluid (CSF and plasma cystatin C levels in 104 ALS patients and controls. Cystatin C levels in ALS patients were significantly elevated in plasma and reduced in CSF compared to healthy controls, but did not differ significantly from neurologic disease controls. In addition, the direction of longitudinal change in CSF cystatin C levels correlated to the rate of ALS disease progression, and initial CSF cystatin C levels were predictive of patient survival, suggesting that cystatin C may function as a surrogate marker of disease progression and survival. These data verify prior results for reduced cystatin C levels in the CSF of ALS patients, identify increased cystatin C levels in the plasma of ALS patients, and reveal correlations between CSF cystatin C levels to both ALS disease progression and patient survival.

  8. SITDEM: A simulation tool for disease/endpoint models of association studies based on single nucleotide polymorphism genotypes

    Science.gov (United States)

    Oh, Jung Hun; Deasy, Joseph O.

    2016-01-01

    The association analysis between single nucleotide polymorphisms (SNPs) and disease or endpoint in genome-wide association studies (GWAS) has been considered as a powerful strategy for investigating genetic susceptibility and for identifying significant biomarkers. The statistical analysis approaches with simulated data have been widely used to review experimental designs and performance measurements. In recent years, a number of authors have proposed methods for the simulation of biological data in the genomic field. However, these methods use large-scale genomic data as a reference to simulate experiments, which may limit the use of the methods in the case where the data in specific studies are not available. Few methods use experimental results or observed parameters for simulation. The goal of this study is to develop a Web application called SITDEM to simulate disease/endpoint models in three different approaches based on only parameters observed in GWAS. In our simulation, a key task is to compute the probability of genotypes. Based on that, we randomly sample simulation data. Simulation results are shown as a function of p-value against odds ratio or relative risk of a SNP in dominant and recessive models. Our simulation results show the potential of SITDEM for simulating genotype data. SITDEM could be particularly useful for investigating the relationship among observed parameters for target SNPs and for estimating the number of variables (SNPs) required to result in significant p-values in multiple comparisons. The proposed simulation tool is freely available at http://www.snpmodel.com. PMID:24480173

  9. Sepsis biomarkers: a review

    Science.gov (United States)

    2010-01-01

    Introduction Biomarkers can be useful for identifying or ruling out sepsis, identifying patients who may benefit from specific therapies or assessing the response to therapy. Methods We used an electronic search of the PubMed database using the key words "sepsis" and "biomarker" to identify clinical and experimental studies which evaluated a biomarker in sepsis. Results The search retrieved 3370 references covering 178 different biomarkers. Conclusions Many biomarkers have been evaluated for use in sepsis. Most of the biomarkers had been tested clinically, primarily as prognostic markers in sepsis; relatively few have been used for diagnosis. None has sufficient specificity or sensitivity to be routinely employed in clinical practice. PCT and CRP have been most widely used, but even these have limited ability to distinguish sepsis from other inflammatory conditions or to predict outcome. PMID:20144219

  10. Biomarkers in sarcoidosis.

    Science.gov (United States)

    Chopra, Amit; Kalkanis, Alexandros; Judson, Marc A

    2016-11-01

    Numerous biomarkers have been evaluated for the diagnosis, assessment of disease activity, prognosis, and response to treatment in sarcoidosis. In this report, we discuss the clinical and research utility of several biomarkers used to evaluate sarcoidosis. Areas covered: The sarcoidosis biomarkers discussed include serologic tests, imaging studies, identification of inflammatory cells and genetic analyses. Literature was obtained from medical databases including PubMed and Web of Science. Expert commentary: Most of the biomarkers examined in sarcoidosis are not adequately specific or sensitive to be used in isolation to make clinical decisions. However, several sarcoidosis biomarkers have an important role in the clinical management of sarcoidosis when they are coupled with clinical data including the results of other biomarkers.

  11. Beyond multi-fractals: surrogate time series and fields

    Science.gov (United States)

    Venema, V.; Simmer, C.

    2007-12-01

    Most natural complex are characterised by variability on a large range of temporal and spatial scales. The two main methodologies to generate such structures are Fourier/FARIMA based algorithms and multifractal methods. The former is restricted to Gaussian data, whereas the latter requires the structure to be self-similar. This work will present so-called surrogate data as an alternative that works with any (empirical) distribution and power spectrum. The best-known surrogate algorithm is the iterative amplitude adjusted Fourier transform (IAAFT) algorithm. We have studied six different geophysical time series (two clouds, runoff of a small and a large river, temperature and rain) and their surrogates. The power spectra and consequently the 2nd order structure functions were replicated accurately. Even the fourth order structure function was more accurately reproduced by the surrogates as would be possible by a fractal method, because the measured structure deviated too strong from fractal scaling. Only in case of the daily rain sums a fractal method could have been more accurate. Just as Fourier and multifractal methods, the current surrogates are not able to model the asymmetric increment distributions observed for runoff, i.e., they cannot reproduce nonlinear dynamical processes that are asymmetric in time. Furthermore, we have found differences for the structure functions on small scales. Surrogate methods are especially valuable for empirical studies, because the time series and fields that are generated are able to mimic measured variables accurately. Our main application is radiative transfer through structured clouds. Like many geophysical fields, clouds can only be sampled sparsely, e.g. with in-situ airborne instruments. However, for radiative transfer calculations we need full 3-dimensional cloud fields. A first study relating the measured properties of the cloud droplets and the radiative properties of the cloud field by generating surrogate cloud

  12. Biomarkers for Parkinson's disease.

    Science.gov (United States)

    Sherer, Todd B

    2011-04-20

    Biomarkers for detecting the early stages of Parkinson's disease (PD) could accelerate development of new treatments. Such biomarkers could be used to identify individuals at risk for developing PD, to improve early diagnosis, to track disease progression with precision, and to test the efficacy of new treatments. Although some progress has been made, there are many challenges associated with developing biomarkers for detecting PD in its earliest stages.

  13. On the application of an environmental radiological assessment system to an anthropomorphic surrogate.

    Science.gov (United States)

    Brown, Justin E; Hosseini, Ali; Dowdall, Mark

    2014-01-01

    Recent developments have seen the expansion of the system of radiological protection for humans to one including protection of the environment against detrimental effects of radiation exposure, although a fully developed framework for integration of human and ecological risk assessment for radionuclides is only at an early stage. In the context of integration, significant differences exist between assessment methodologies for humans and the environment in terms of transfer, exposure, and dosimetry. The aim of this elaboration was to explore possible implications of the simplifications made within the system of environmental radiological protection in terms of the efficacy and robustness of dose-rate predictions. A comparison was conducted between human radiological assessment and environmental radiological assessment for an anthropomorphic surrogate, the results for which, produced by both the environmental and human-oriented risk assessment systems, were critically compared and contrasted. The adopted approach split the calculations into several parts, these being 1) physical transfer in an ecosystem, 2) transfer to humans, 3) internal doses to humans, and 4) external doses to humans. The calculations were carried out using both a human radiological assessment and ecological risk assessment system for the same surrogate. The results of this comparison provided indications as to where the 2 systems are amenable to possible integration and where such integration may prove difficult. Initial stage transport models seem to be an obvious component amenable for integration, although complete integration is arguably unattainable as the differences between endpoints mean that the relevant outputs from the models will not be the same. For the transfer and dosimetry components of 2 typical methodologies, it seems that the efficacy of the environmental system is radionuclide-dependent, the predictions given by the environmental system for (90) Sr and (60) Co being

  14. Computation of eigenfunctions and eigenvalues for the Sturm-Liouville problem with Dirichlet boundary conditions at the left endpoint and Neumann conditions at the right endpoint

    Science.gov (United States)

    Khapaev, M. M.; Khapaeva, T. M.

    2016-10-01

    A functional-based variational method is proposed for finding the eigenfunctions and eigenvalues in the Sturm-Liouville problem with Dirichlet boundary conditions at the left endpoint and Neumann conditions at the right endpoint. Computations are performed for three potentials: sin(( x-π)2/π), cos(4 x), and a high nonisosceles triangle.

  15. Surrogate Modeling of Deformable Joint Contact using Artificial Neural Networks

    Science.gov (United States)

    Eskinazi, Ilan; Fregly, Benjamin J.

    2016-01-01

    Deformable joint contact models can be used to estimate loading conditions for cartilage-cartilage, implant-implant, human-orthotic, and foot-ground interactions. However, contact evaluations are often so expensive computationally that they can be prohibitive for simulations or optimizations requiring thousands or even millions of contact evaluations. To overcome this limitation, we developed a novel surrogate contact modeling method based on artificial neural networks (ANNs). The method uses special sampling techniques to gather input-output data points from an original (slow) contact model in multiple domains of input space, where each domain represents a different physical situation likely to be encountered. For each contact force and torque output by the original contact model, a multi-layer feed-forward ANN is defined, trained, and incorporated into a surrogate contact model. As an evaluation problem, we created an ANN-based surrogate contact model of an artificial tibiofemoral joint using over 75,000 evaluations of a fine-grid elastic foundation (EF) contact model. The surrogate contact model computed contact forces and torques about 1000 times faster than a less accurate coarse grid EF contact model. Furthermore, the surrogate contact model was seven times more accurate than the coarse grid EF contact model within the input domain of a walking motion. For larger input domains, the surrogate contact model showed the expected trend of increasing error with increasing domain size. In addition, the surrogate contact model was able to identify out-of-contact situations with high accuracy. Computational contact models created using our proposed ANN approach may remove an important computational bottleneck from musculoskeletal simulations or optimizations incorporating deformable joint contact models. PMID:26220591

  16. Versatile Endpoint Storage Security with Trusted Integrity Modules

    DEFF Research Database (Denmark)

    Gonzalez, Javier; Bonnet, Philippe

    2014-01-01

    Net), or because they are constrained to specific hardware/software combinations (e.g., McAfee’s DeepSafe). In this paper, we propose a solution for personal devices equipped with a Trusted Execution Environment and a Secure Element. We propose Trusted Integrity Modules, separated by hardware from the operating...... system and applications, that guarantee the durability, confidentiality and integrity of a configurable subset of the filesystem data and meta-data. While, we detail our design with the Linux virtual file system, we expect that our results can be applied to a range of different file systems. As Trusted...... Execution Environments also become available in Cloud environments, we envisage that Trusted Integrity Modules could constitute the solution of choice for endpoint storage security on both clients and servers....

  17. Biodegradation of naphthenic acid surrogates by axenic cultures.

    Science.gov (United States)

    Yue, Siqing; Ramsay, Bruce A; Ramsay, Juliana A

    2015-07-01

    This is the first study to report that bacteria from the genera Ochrobactrum, Brevundimonas and Bacillus can be isolated by growth on naphthenic acids (NAs) extracted from oil sands process water (OSPW). These pure cultures were screened for their ability to use a range of aliphatic, cyclic and aromatic NA surrogates in 96-well microtiter plates using water-soluble tetrazolium redox dyes (Biolog Redox Dye H) as the indicator of metabolic activity. Of the three cultures, Ochrobactrum showed most metabolic activity on the widest range of NA surrogates. Brevundomonas and especially Ochrobactrum had higher metabolic activity on polycyclic aromatic compounds than other classes of NA surrogates. Bacillus also oxidized a wide range of NA surrogates but not as well as Ochrobactrum. Using this method to characterize NA utilisation, one can identify which NAs or NA classes in OSPW are more readily degraded. Since aromatic NAs have been shown to have an estrogenic effect and polycyclic monoaromatic compounds have been suggested to pose the greatest environmental threat among the NAs, these bacterial genera may play an important role in detoxification of OSPW. Furthermore, this study demonstrates that bacteria belonging to the genera Ochrobactrum and Bacillus can also degrade surrogates of tricyclic NAs.

  18. Searching for Dynamical Earthquake Precursors with Surrogate Data

    Science.gov (United States)

    Lynch, J.; Revenaugh, J.; Georgopoulos, A.

    2007-12-01

    Surrogate data methods are resampling techniques related to the modern statistical bootstrap. The nonlinear dynamics community has promoted surrogate data as a useful tool for establishing the presence of nonlinear dynamics in experimental observations before applying more specific techniques such as nonlinear prediction. We propose to use surrogate data tests to search for evidence of transient nonlinear dynamics in seismographic data that act as a proxy for earthquake triggering mechanisms, such as fluid flow in the fault zone, failure cascades and slow prefatory slip, that signal changes in the coupling between geological boundaries. We will analyze the vertical component of broadband seismographic data recorded at 20Hz by the CI network of approximately 100 stations located throughout Southern California. We will focus on a period of six hours prior to seismic events of magnitude 4-5 located inside the CI network. Each seismographic record will be scanned for short, non-overlapping segments that pass a moderate stationarity criterion. We will then apply surrogate tests to each qualifying segment using three discriminating statistics: time reversal asymmetry, delay vector variance and zeroth-order nonlinear prediction error. We will correlate the results with known seismic activity and examine the spatial and temporal distribution of the surrogate test results for potential dynamical earthquake precursors.

  19. Interim decision-making strategies in adaptive designs for population selection using time-to-event endpoints.

    Science.gov (United States)

    Uozumi, Ryuji; Hamada, Chikuma

    2017-01-01

    Adaptive designs in oncology clinical trials with interim analyses for population selection could be used in the development of targeted therapies if a predefined biomarker hypothesis exists. In this article, we consider an interim analysis using overall survival (OS), progression-free survival (PFS), and both OS and PFS, to determine whether the whole population or only the biomarker-positive population should continue into the subsequent stage of the trial, whereas the final decision is made based on OS data only. In order to increase the probability of selecting the most appropriate population at the interim analysis, we propose an interim decision-making strategy in adaptive designs with correlated endpoints considering the post-progression survival (PPS) magnitudes. In our approach, the interim decision is made on the basis of predictive power by incorporating information on OS as well as PFS to supplement the incomplete OS data. Simulation studies assuming a targeted therapy demonstrated that our interim decision-making procedure performs well in terms of selecting the proper population, especially under a scenario in which PPS affects the correlation between OS and PFS.

  20. Respiratory Toxicity Biomarkers

    Science.gov (United States)

    The advancement in high throughput genomic, proteomic and metabolomic techniques have accelerated pace of lung biomarker discovery. A recent growth in the discovery of new lung toxicity/disease biomarkers have led to significant advances in our understanding of pathological proce...

  1. Transcutaneous oxygen pressure as a surrogate index of lower limb amputation.

    Science.gov (United States)

    Nishio, Hiroomi; Minakata, Kenji; Kawaguchi, Atsushi; Kumagai, Motoyuki; Ikeda, Takafumi; Shimizu, Akira; Yokode, Masayuki; Morita, Satoshi; Sakata, Ryuzo

    2016-12-01

    A large number of clinical trials of therapeutic angiogenesis in patients with critical limb ischemia have been conducted in recent years. However, limb amputation, which is used as a primary endpoint in such studies, is not often required in Japan, which can make it difficult to carry out related clinical trials. Transcutaneous oxygen pressure (TcPO2) is widely used to evaluate the severity of limb ischemia, to decide the level of amputation, and to predict wound healing after limb amputation. The aim of the present study was to elucidate whether TcPO2 can be a surrogate index of limb ischemia, and to define an appropriate cutoff value for wound healing after limb amputation using meta-analysis. A computer search was performed to identify studies describing the association between TcPO2 and limb ischemic events. From these, studies focused on wound healing after limb amputation were combined and analyzed. Eleven studies were identified for inclusion in this analysis. The analysis demonstrated that TcPO2 20 mmHg was a valid cutoff value for limb amputation and TcPO2 30 mmHg would be an appropriate value for wound healing after limb amputation. TcPO2 of 20 and 30 mmHg were considered appropriate cutoff values for limb amputation and wound healing after amputation, respectively.

  2. Biomarkers of Reflux Disease.

    Science.gov (United States)

    Kia, Leila; Pandolfino, John E; Kahrilas, Peter J

    2016-06-01

    Gastroesophageal reflux disease (GERD) encompasses an array of disorders unified by the reflux of gastric contents. Because there are many potential disease manifestations, esophageal and extraesophageal, there is no single biomarker of the entire disease spectrum; a set of GERD biomarkers that each quantifies specific aspects of GERD-related pathology might be needed. We review recent reports of biomarkers of GERD, specifically in relation to endoscopically negative esophageal disease and excluding conventional pH-impedance monitoring. We consider histopathologic biomarkers, baseline impedance, and serologic assays to determine that most markers are based on manifestations of impaired esophageal mucosal integrity, which is based on increased ionic and molecular permeability, and/or destruction of tight junctions. Impaired mucosal integrity quantified by baseline mucosal impedance, proteolytic fragments of junctional proteins, or histopathologic features has emerged as a promising GERD biomarker.

  3. Biomarkers in Parkinson's disease.

    Science.gov (United States)

    Morgan, John C; Mehta, Shyamal H; Sethi, Kapil D

    2010-11-01

    Biomarkers are objectively measured characteristics that are indicators of normal biological processes, pathogenic processes, or responses to therapeutic interventions. To date, clinical assessment remains the gold standard in the diagnosis of Parkinson's disease (PD) and clinical rating scales are well established as the gold standard for tracking progression of PD. Researchers have identified numerous potential biomarkers that may aid in the differential diagnosis of PD and/or tracking disease progression. Clinical, genetic, blood and cerebrospinal fluid (proteomics, transcriptomics, metabolomics), and neuroimaging biomarkers may provide useful tools in the diagnosis of PD and in measuring disease progression and response to therapies. Some potential biomarkers are inexpensive and do not require much technical expertise, whereas others are expensive or require specialized equipment and technical skills. Many potential biomarkers in PD show great promise; however, they need to be assessed for their sensitivity and specificity over time in large and varied samples of patients with and without PD.

  4. On consensus biomarker selection

    Directory of Open Access Journals (Sweden)

    Gambin Anna

    2007-05-01

    Full Text Available Abstract Background Recent development of mass spectrometry technology enabled the analysis of complex peptide mixtures. A lot of effort is currently devoted to the identification of biomarkers in human body fluids like serum or plasma, based on which new diagnostic tests for different diseases could be constructed. Various biomarker selection procedures have been exploited in recent studies. It has been noted that they often lead to different biomarker lists and as a consequence, the patient classification may also vary. Results Here we propose a new approach to the biomarker selection problem: to apply several competing feature ranking procedures and compute a consensus list of features based on their outcomes. We validate our methods on two proteomic datasets for the diagnosis of ovarian and prostate cancer. Conclusion The proposed methodology can improve the classification results and at the same time provide a unified biomarker list for further biological examinations and interpretation.

  5. Modulation of cigarette smoke-related end-points in mutagenesis and carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    De Flora, Silvio; D' Agostini, Francesco; Balansky, Roumen; Camoirano, Anna; Bennicelli, Carlo; Bagnasco, Maria; Cartiglia, Cristina; Tampa, Elena; Longobardi, Maria Grazia; Lubet, Ronald A.; Izzotti, Alberto

    2003-03-01

    The epidemic of lung cancer and the increase of other tumours and chronic degenerative diseases associated with tobacco smoking have represented one of the most dramatic catastrophes of the 20th century. The control of this plague is one of the major challenges of preventive medicine for the next decades. The imperative goal is to refrain from smoking. However, chemoprevention by dietary and/or pharmacological agents provides a complementary strategy, which can be targeted not only to current smokers but also to former smokers and passive smokers. This article summarises the results of studies performed in our laboratories during the last 10 years, and provides new data generated in vitro, in experimental animals and in humans. We compared the ability of 63 putative chemopreventive agents to inhibit the bacterial mutagenicity of mainstream cigarette smoke. Modulation by ethanol and the mechanisms involved were also investigated both in vitro and in vivo. Several studies evaluated the effects of dietary chemopreventive agents towards smoke-related intermediate biomarkers in various cells, tissues and organs of rodents. The investigated end-points included metabolic parameters, adducts to haemoglobin, bulky adducts to nuclear DNA, oxidative DNA damage, adducts to mitochondrial DNA, apoptosis, cytogenetic damage in alveolar macrophages, bone marrow and peripheral blood erytrocytes, proliferation markers, and histopathological alterations. The agents tested in vivo included N-acetyl-L-cysteine, 1,2-dithiole-3-thione, oltipraz, phenethyl isothiocyanate, 5,6-benzoflavone, and sulindac. We started applying multigene expression analysis to chemoprevention research, and postulated that an optimal agent should not excessively alter per se the physiological background of gene expression but should be able to attenuate the alterations produced by cigarette smoke or other carcinogens. We are working to develop an animal model for the induction of lung tumours following exposure

  6. Love as a regulative ideal in surrogate decision making.

    Science.gov (United States)

    Stonestreet, Erica Lucast

    2014-10-01

    This discussion aims to give a normative theoretical basis for a "best judgment" model of surrogate decision making rooted in a regulative ideal of love. Currently, there are two basic models of surrogate decision making for incompetent patients: the "substituted judgment" model and the "best interests" model. The former draws on the value of autonomy and responds with respect; the latter draws on the value of welfare and responds with beneficence. It can be difficult to determine which of these two models is more appropriate for a given patient, and both approaches may seem inadequate for a surrogate who loves the patient. The proposed "best judgment" model effectively draws on the values incorporated in each of the traditional standards, but does so because these values are important to someone who loves a patient, since love responds to the patient as the specific person she is.

  7. Surrogate modeling for initial rotational stiffness of welded tubular joints

    Directory of Open Access Journals (Sweden)

    M.R. Garifullin

    2016-10-01

    Full Text Available Recently, buildings and structures erected in Russia and abroad have to comply with stringent economic requirements. Buildings should not only be reliable and safe, have a beautiful architectural design, but also meet the criteria of rationality and energy efficiency. In practice, this usually means the need for additional comparative analysis in order to determine the optimal solution to the engineering task. Usually such an analysis is time-consuming and requires huge computational efforts. In this regard, surrogate modeling can be an effective tool for solving such problems. This article provides a brief description of surrogate models and the basic techniques of their construction, describes the construction process of a surrogate model to calculate initial rotational stiffness of welded RHS joints made of high strength steel (HSS.

  8. Analysis of biomarker utility using a PBPK/PD model for carbaryl

    Directory of Open Access Journals (Sweden)

    Martin Blake Phillips

    2014-11-01

    Full Text Available There are many types of biomarkers; the two common ones are biomarkers of exposure and biomarkers of effect. The utility of a biomarker for estimating exposures or predicting risks depends on the strength of the correlation between biomarker concentrations and exposure/effects. In the current study, a combined exposure and physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD model of carbaryl was used to demonstrate the use of computational modeling for providing insight into the selection of biomarkers for different purposes. The Cumulative and Aggregate Risk Evaluation System (CARES was used to generate exposure profiles, including magnitude and timing, for use as inputs to the PBPK/PD model. The PBPK/PD model was then used to predict blood concentrations of carbaryl and urine concentrations of its principal metabolite, 1-naphthol (1-N, as biomarkers of exposure. The PBPK/PD model also predicted acetylcholinesterase (AChE inhibition in red blood cells (RBC as a biomarker of effect. The correlations of these simulated biomarker concentrations with intake doses or brain AChE inhibition (as a surrogate of effects were analyzed using a linear regression model. Results showed that 1-N in urine is a better biomarker of exposure than carbaryl in blood, and that 1-N in urine is correlated with the dose averaged over the last two days of the simulation. They also showed that RBC AChE inhibition is an appropriate biomarker of effect. This computational approach can be applied to a wide variety of chemicals to facilitate quantitative analysis of biomarker utility.

  9. Disinfection byproduct regulatory compliance surrogates and bromide-associated risk.

    Science.gov (United States)

    Kolb, Chelsea; Francis, Royce A; VanBriesen, Jeanne M

    2017-08-01

    Natural and anthropogenic factors can alter bromide concentrations in drinking water sources. Increasing source water bromide concentrations increases the formation and alters the speciation of disinfection byproducts (DBPs) formed during drinking water treatment. Brominated DBPs are more toxic than their chlorinated analogs, and thus have a greater impact on human health. However, DBPs are regulated based on the mass sum of DBPs within a given class (e.g., trihalomethanes and haloacetic acids), not based on species-specific risk or extent of bromine incorporation. The regulated surrogate measures are intended to protect against not only the species they directly represent, but also against unregulated DBPs that are not routinely measured. Surrogates that do not incorporate effects of increasing bromide may not adequately capture human health risk associated with drinking water when source water bromide is elevated. The present study analyzes trihalomethanes (THMs), measured as TTHM, with varying source water bromide concentrations, and assesses its correlation with brominated THM, TTHM risk and species-specific THM concentrations and associated risk. Alternative potential surrogates are evaluated to assess their ability to capture THM risk under different source water bromide concentration conditions. The results of the present study indicate that TTHM does not adequately capture risk of the regulated species when source water bromide concentrations are elevated, and thus would also likely be an inadequate surrogate for many unregulated brominated species. Alternative surrogate measures, including THM3 and the bromodichloromethane concentration, are more robust surrogates for species-specific THM risk at varying source water bromide concentrations. Copyright © 2017. Published by Elsevier B.V.

  10. Can biomarkers help us hit targets in difficult-to-treat asthma?

    Science.gov (United States)

    Fricker, Michael; Heaney, Liam G; Upham, John W

    2017-04-01

    Biomarkers may be a key foundation for the precision medicine of the future. In this article, we review current knowledge regarding biomarkers in difficult-to-treat asthma and their ability to guide the use of both conventional asthma therapies and novel (targeted) therapies. Biomarkers (as measured by tests including prednisolone and cortisol assays and the fractional exhaled nitric oxide (NO) suppression test) show promise in the assessment and management of non-adherence to inhaled and oral corticosteroids. Multiple markers of type 2 inflammation have been developed, including eosinophils in sputum and blood, exhaled NO, serum IgE and periostin. Although these show potential in guiding the selection of novel interventions for refractory type 2 inflammation in asthma, and in determining if the desired response is being achieved, it is becoming clear that different biomarkers reflect distinct components of the complex type 2 inflammatory pathways. Less progress has been made in identifying biomarkers for use in difficult-to-treat asthma that is not associated with type 2 inflammation. The future is likely to see further biomarker discovery, direct measurements of individual cytokines rather than surrogates of their activity and the increasing use of biomarkers in combination. If the promise of biomarkers is to be fulfilled, they will need to provide useful information that aids clinical decision-making, rather than being 'just another test' for clinicians to order.

  11. Fast Prediction and Evaluation of Gravitational Waveforms Using Surrogate Models

    Directory of Open Access Journals (Sweden)

    Scott E. Field

    2014-07-01

    Full Text Available We propose a solution to the problem of quickly and accurately predicting gravitational waveforms within any given physical model. The method is relevant for both real-time applications and more traditional scenarios where the generation of waveforms using standard methods can be prohibitively expensive. Our approach is based on three offline steps resulting in an accurate reduced order model in both parameter and physical dimensions that can be used as a surrogate for the true or fiducial waveform family. First, a set of m parameter values is determined using a greedy algorithm from which a reduced basis representation is constructed. Second, these m parameters induce the selection of m time values for interpolating a waveform time series using an empirical interpolant that is built for the fiducial waveform family. Third, a fit in the parameter dimension is performed for the waveform’s value at each of these m times. The cost of predicting L waveform time samples for a generic parameter choice is of order O(mL+mc_{fit} online operations, where c_{fit} denotes the fitting function operation count and, typically, m≪L. The result is a compact, computationally efficient, and accurate surrogate model that retains the original physics of the fiducial waveform family while also being fast to evaluate. We generate accurate surrogate models for effective-one-body waveforms of nonspinning binary black hole coalescences with durations as long as 10^{5}M, mass ratios from 1 to 10, and for multiple spherical harmonic modes. We find that these surrogates are more than 3 orders of magnitude faster to evaluate as compared to the cost of generating effective-one-body waveforms in standard ways. Surrogate model building for other waveform families and models follows the same steps and has the same low computational online scaling cost. For expensive numerical simulations of binary black hole coalescences, we thus anticipate extremely large speedups in

  12. Optimization using surrogate models - by the space mapping technique

    DEFF Research Database (Denmark)

    Søndergaard, Jacob

    2003-01-01

    mapping surrogate has a lower approximation error for long steps. For short steps, however, the Taylor model of the expensive model is best, due to exact interpolation at the model origin. Five algorithms for space mapping optimization are presented and the numerical performance is evaluated. Three...... conditions are satisfied. So hybrid methods, combining the space mapping technique with classical optimization methods, should be used if convergence to high accuracy is wanted. Approximation abilities of the space mapping surrogate are compared with those of a Taylor model of the expensive model. The space...

  13. Optimization using surrogate models - by the space mapping technique

    DEFF Research Database (Denmark)

    Søndergaard, Jacob

    2003-01-01

    mapping surrogate has a lower approximation error for long steps. For short steps, however, the Taylor model of the expensive model is best, due to exact interpolation at the model origin. Five algorithms for space mapping optimization are presented and the numerical performance is evaluated. Three...... conditions are satisfied. So hybrid methods, combining the space mapping technique with classical optimization methods, should be used if convergence to high accuracy is wanted. Approximation abilities of the space mapping surrogate are compared with those of a Taylor model of the expensive model. The space...

  14. [Biomarkers in Alzheimer's disease].

    Science.gov (United States)

    García-Ribas, G; López-Sendón Moreno, J L; García-Caldentey, J

    2014-04-01

    The new diagnostic criteria for Alzheimer's disease (AD) include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. Three CSF biomarkers, Aß42, total tau, and phosphorylated tau, reflect the core pathological features of AD. It is already known that these pathological processes of AD starts decades before the first symptoms, so these biomarkers may provide means of early disease detection. At least three stages of AD could be identified: preclinical AD, mild cognitive impairment due to AD, and dementia due to AD. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review the actual research on blood-based biomarkers. Recent studies on healthy elderly subjects and on carriers of dominantly inherited AD mutations have also found biomarker changes that allow separate groups in these preclinical stages. These studies may aid for segregate populations in clinical trials and objectively evaluate if there are changes over the pathological processes of AD. Limits to widespread use of CSF biomarkers, apart from the invasive nature of the process itself, is the higher coefficient of variation for the analyses between centres. It requires strict pre-analytical and analytical procedures that may make feasible multi-centre studies and global cut-off points for the different stages of AD.

  15. A Few Endpoint Geodesic Restriction Estimates for Eigenfunctions

    Science.gov (United States)

    Chen, Xuehua; Sogge, Christopher D.

    2014-07-01

    We prove a couple of new endpoint geodesic restriction estimates for eigenfunctions. In the case of general 3-dimensional compact manifolds, after a TT* argument, simply by using the L 2-boundedness of the Hilbert transform on , we are able to improve the corresponding L 2-restriction bounds of Burq, Gérard and Tzvetkov (Duke Math J 138:445-486, 2007) and Hu (Forum Math 6:1021-1052, 2009). Also, in the case of 2-dimensional compact manifolds with nonpositive curvature, we obtain improved L 4-estimates for restrictions to geodesics, which, by Hölder's inequality and interpolation, implies improved L p -bounds for all exponents p ≥ 2. We do this by using oscillatory integral theorems of Hörmander (Ark Mat 11:1-11, 1973), Greenleaf and Seeger (J Reine Angew Math 455:35-56, 1994) and Phong and Stein (Int Math Res Notices 4:49-60, 1991), along with a simple geometric lemma (Lemma 3.2) about properties of the mixed-Hessian of the Riemannian distance function restricted to pairs of geodesics in Riemannian surfaces. We are also able to get further improvements beyond our new results in three dimensions under the assumption of constant nonpositive curvature by exploiting the fact that, in this case, there are many totally geodesic submanifolds.

  16. Responsiveness of endpoints in osteoporosis clinical trials--an update.

    Science.gov (United States)

    Cranney, A; Welch, V; Tugwell, P; Wells, G; Adachi, J D; McGowan, J; Shea, B

    1999-01-01

    As an update of our earlier paper, published as part of the Outcome Measures in Rheumatology Clinical Trials (OMERACT 3) proceedings in 1996, we surveyed the types of outcomes incorporated in recent clinical trials. A literature search was conducted on MEDLINE and Current Contents, from January 1996 to March 1998, using the search strategy recommended by the Cochrane Collaboration for the identification of randomized controlled trials (RCT). Two independent reviewers selected trials according to inclusion criteria. The same reviewers extracted data on clinical and radiographic fractures, pain, quality of life, and bone mineral density (BMD). Seventy-four RCT conducted on bone loss in postmenopausal women were identified. Most trials incorporated biochemical markers and BMD as outcome measures. Fewer trials included vertebral fractures, pain, height, and quality of life. The responsiveness is presented in terms of the sample size needed per group to show a statistically significant difference. The most responsive outcomes were pain, BMD, and biochemical markers. The number needed to treat to prevent one vertebral fracture ranged from 13 to 54, depending on the intervention and population. Investigators should examine the characteristics of the patient population and the nature of the intervention in determining the sample size required to demonstrate a significant effect. The selection of endpoints should be based on their responsiveness, feasibility, and the importance of using standardized outcomes. Standardized outcomes greatly facilitate the synthesis of available information into systematic reviews by groups such as the Cochrane Collaboration.

  17. Critical endpoint in the presence of a chiral chemical potential

    CERN Document Server

    Cui, Zhu-Fang; Lu, Ya; Roberts, Craig D; Schmidt, Sebastian M; Xu, Shu-Sheng; Zong, Hong-Shi

    2016-01-01

    A class of Polyakov-loop-modified Nambu--Jona-Lasinio (PNJL) models have been used to support a conjecture that numerical simulations of lattice-regularized quantum chromodynamics (QCD) defined with a chiral chemical potential can provide information about the existence and location of a critical endpoint in the QCD phase diagram drawn in the plane spanned by baryon chemical potential and temperature. That conjecture is challenged by conflicts between the model results and analyses of the same problem using simulations of lattice-regularized QCD (lQCD) and well-constrained Dyson-Schwinger equation (DSE) studies. We find the conflict is resolved in favor of the lQCD and DSE predictions when both a physically-motivated regularization is employed to suppress the contribution of high-momentum quark modes in the definition of the effective potential connected with the PNJL models and the four-fermion coupling in those models does not react strongly to changes in the mean-field that is assumed to mock-up Polyakov l...

  18. Commentary: statistics for biomarkers.

    Science.gov (United States)

    Lovell, David P

    2012-05-01

    This short commentary discusses Biomarkers' requirements for the reporting of statistical analyses in submitted papers. It is expected that submitters will follow the general instructions of the journal, the more detailed guidance given by the International Committee of Medical Journal Editors, the specific guidelines developed by the EQUATOR network, and those of various specialist groups. Biomarkers expects that the study design and subsequent statistical analyses are clearly reported and that the data reported can be made available for independent assessment. The journal recognizes that there is continuing debate about different approaches to statistical science. Biomarkers appreciates that the field continues to develop rapidly and encourages the use of new methodologies.

  19. Metabolic products as biomarkers

    Science.gov (United States)

    Melancon, M.J.; Alscher, R.; Benson, W.; Kruzynski, G.; Lee, R.F.; Sikka, H.C.; Spies, R.B.; Huggett, Robert J.; Kimerle, Richard A.; Mehrle, Paul M.=; Bergman, Harold L.

    1992-01-01

    Ideally, endogenous biomarkers would indicate both exposure and environmental effects of toxic chemicals; however, such comprehensive biochemical and physiological indices are currently being developed and, at the present time, are unavailable for use in environmental monitoring programs. Continued work is required to validate the use of biochemical and physiological stress indices as useful components of monitoring programs. Of the compounds discussed only phytochelatins and porphyrins are currently in biomarkers in a useful state; however, glutathione,metallothioneins, stress ethylene, and polyamines are promising as biomarkers in environmental monitoring.

  20. Drop-out from cardiovascular magnetic resonance in a randomized controlled trial of ST-elevation myocardial infarction does not cause selection bias on endpoints.

    Science.gov (United States)

    Laursen, Peter Nørkjær; Holmvang, L; Kelbæk, H; Vejlstrup, N; Engstrøm, T; Lønborg, J

    2017-07-01

    The extent of selection bias due to drop-out in clinical trials of ST-elevation myocardial infarction (STEMI) using cardiovascular magnetic resonance (CMR) as surrogate endpoints is unknown. We sought to interrogate the characteristics and prognosis of patients who dropped out before acute CMR assessment compared to CMR-participants in a previously published double-blinded, placebo-controlled all-comer trial with CMR outcome as the primary endpoint. Baseline characteristics and composite endpoint of all-cause mortality, heart failure and re-infarction after 30 days and 5 years of follow-up were assessed and compared between CMR-drop-outs and CMR-participants using the trial screening log and the Eastern Danish Heart Registry. The drop-out rate from acute CMR was 28% (n = 92). These patients had a significantly worse clinical risk profile upon admission as evaluated by the TIMI-risk score (3.7 (± 2.1) vs 4.0 (± 2.6), p = 0.043) and by left ventricular ejection fraction (43 (± 9) vs. 47 (± 10), p = 0.029). CMR drop-outs had a higher incidence of known hypertension (39% vs. 35%, p = 0.043), known diabetes (14% vs. 7%, p = 0.025), known cardiac disease (11% vs. 3%, p = 0.013) and known renal function disease (5% vs. 0%, p = 0.007). However, the 30-day and 5-years composite endpoint rate was not significantly higher among the CMR drop-out ((HR 1.43 (95%-CI 0.5; 3.97) (p = 0.5)) and (HR 1.31 (95%-CI 0.84; 2.05) (p = 0.24)). CMR-drop-outs had a higher incidence of cardiovascular risk factors at baseline, a worse clinical risk profile upon admission. However, no significant difference was observed in the clinical endpoints between the groups.

  1. A combined superiority and non-inferiority approach to multiple endpoints in clinical trials.

    Science.gov (United States)

    Bloch, Daniel A; Lai, Tze Leung; Su, Zheng; Tubert-Bitter, Pascale

    2007-03-15

    Treatment comparisons in clinical trials often involve multiple endpoints. By making use of bootstrap tests, we develop a new non-parametric approach to multiple-endpoint testing that can be used to demonstrate non-inferiority of a new treatment for all endpoints and superiority for some endpoint when it is compared to an active control. It is shown that this approach does not incur a large multiplicity cost in sample size to achieve reasonable power and that it can incorporate complex dependencies in the multivariate distributions of all outcome variables for the two treatments via bootstrap resampling. Copyright (c) 2006 John Wiley & Sons, Ltd.

  2. A signal processing method for the friction-based endpoint detection system of a CMP process

    Energy Technology Data Exchange (ETDEWEB)

    Xu Chi; Guo Dongming; Jin Zhuji; Kang Renke, E-mail: xuchi_dut@163.com [Key Laboratory for Precision and Non-Traditional Machining Technology of Ministry of Education, Dalian University of Technology, Dalian 116024 (China)

    2010-12-15

    A signal processing method for the friction-based endpoint detection system of a chemical mechanical polishing (CMP) process is presented. The signal process method uses the wavelet threshold denoising method to reduce the noise contained in the measured original signal, extracts the Kalman filter innovation from the denoised signal as the feature signal, and judges the CMP endpoint based on the feature of the Kalman filter innovation sequence during the CMP process. Applying the signal processing method, the endpoint detection experiments of the Cu CMP process were carried out. The results show that the signal processing method can judge the endpoint of the Cu CMP process. (semiconductor technology)

  3. Opportunities and challenges of clinical trials in cardiology using composite primary endpoints

    Institute of Scientific and Technical Information of China (English)

    Geraldine; Rauch; Bernhard; Rauch; Svenja; Schüler; Meinhard; Kieser

    2015-01-01

    In clinical trials, the primary efficacy endpoint often corresponds to a so-called "composite endpoint". Composite endpoints combine several events of interest within a single outcome variable. Thereby it is intended to enlarge the expected effect size and thereby increase the power of the study. However, composite endpoints also come along with serious challenges and problems. On the one hand, composite endpoints may lead to difficulties during the planning phase of a trial with respect to the sample size calculation, asthe expected clinical effect of an intervention on the composite endpoint depends on the effects on its single components and their correlations. This may lead to wrong assumptions on the sample size needed. Too optimistic assumptions on the expected effect may lead to an underpowered of the trial, whereas a too conservatively estimated effect results in an unnecessarily high sample size. On the other hand, the interpretation of composite endpoints may be difficult, as the observed effect of the composite does not necessarily reflect the effects of the single components. Therefore the demonstration of the clinical efficacy of a new intervention by exclusively evaluating the composite endpoint may be misleading. The present paper summarizes results and recommendations of the latest research addressing the above mentioned problems in the planning, analysis and interpretation of clinical trials with composite endpoints, thereby providing a practical guidance for users.

  4. Impact of weighted composite compared to traditional composite endpoints for the design of randomized controlled trials.

    Science.gov (United States)

    Bakal, Jeffrey A; Westerhout, Cynthia M; Armstrong, Paul W

    2015-12-01

    Composite endpoints are commonly used in cardiovascular clinical trials. When using a composite endpoint a subject is considered to have an event when the first component endpoint has occurred. The use of composite endpoints offers the ability to incorporate several clinically important endpoint events thereby augmenting the event rate and increasing statistical power for a given sample size. One assumption of the composite is that all component events are of equal clinical importance. This assumption is rarely achieved given the diversity of component endpoints included. One means of adjusting for this diversity is to adjust the outcomes using severity weights determined a priori. The use of a weighted endpoint also allows for the incorporation of multiple endpoints per patient. Although weighting the outcomes lowers the effective number of events, it offers additional information that reduces the variance of the estimate. We created a series of simulation studies to examine the effect on power as the individual components of a typical composite were changed. In one study, we noted that the weighted composite was able to offer discriminative power when the component outcomes were altered, while the traditional method was not. In the other study, we noted that the weighted composite offered a similar level of power to the traditional composite when the change was driven by the more severe endpoints.

  5. Blood plasma clinical-chemical parameters as biomarker endpoints for organohalogen contaminant exposure in Norwegian raptor nestlings

    DEFF Research Database (Denmark)

    Sonne, Christian; Bustnes, Jan O; Herzke, Dorte

    2012-01-01

    Raptors are exposed to biomagnifying and toxic organohalogenated compounds (OHCs) such as organochlorines, brominated flame retardants and perfluorinated compounds. To investigate how OHC exposure may affect biochemical pathways we collected blood plasma from Norwegian northern goshawk (n=56......), golden eagle (n=12) and white-tailed eagle (n=36) nestlings during three consecutive breeding seasons. We found that blood plasma concentrations of calcium, sodium, creatinine, cholesterol, albumin, total protein, urea, inorganic phosphate, protein:creatinine, urea:creatinine and uric acid...

  6. Blood plasma clinical-chemical parameters as biomarker endpoints for organohalogen contaminant exposure in Norwegian raptor nestlings

    DEFF Research Database (Denmark)

    Sonne, Christian; Bustnes, Jan O.; Herzke, Dorte;

    2012-01-01

    ), golden eagle (n=12) and white-tailed eagle (n=36) nestlings during three consecutive breeding seasons. We found that blood plasma concentrations of calcium, sodium, creatinine, cholesterol, albumin, total protein, urea, inorganic phosphate, protein:creatinine, urea:creatinine and uric acid...... were also negatively correlated to PCBs and PFCs, respectively. The most significant relationships were found for the highly contaminated northern goshawks and white-tailed eagles. The statistical relationships between OHCs and BCCPs indicate that biochemical pathways could be influenced while...... it is uncertain if such changes have any health effects. The OHC concentrations were below concentrations causing reproductive toxicity in adults of other raptor species but similar to those of concern for endocrine disruption of thyroid hormones in e.g., bald eagles....

  7. Summary of Remediated Nitrate Salt Surrogate Formulation and Testing

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Geoffrey Wayne [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Leonard, Philip [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Hartline, Ernest Leon [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Tian, Hongzhao [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-05-05

    High Explosives Science and Technology (M-7) completed all required formulation and testing of Remediated Nitrate Salt (RNS) surrogates on April 27, 2016 as specified in PLAN-TA9-2443 Rev B, "Remediated Nitrate Salt (RNS) Surrogate Formulation and Testing Standard Procedure", released February 16, 2016. This report summarizes the results of the work and also includes additional documentation required in that test plan. All formulation and testing was carried out according to PLAN-TA9-2443 Rev B. The work was carried out in three rounds, with the full matrix of samples formulated and tested in each round. Results from the first round of formulation and testing were documented in memorandum M7-J6-6042, " Results from First Round of Remediated Nitrate Salt Surrogate Formulation and Testing." Results from the second round of formulation and testing were documented in M7-16-6053 , "Results from the Second Round of Remediated Nitrate Salt Surrogate Formulation and Testing." Initial results from the third round were documented in M7-16-6057, "Initial Results from the Third Round of Remediated Nitrate Salt Formulation and Testing."

  8. Frequency response as a surrogate eigenvalue problem in topology optimization

    DEFF Research Database (Denmark)

    Andreassen, Erik; Ferrari, Federico; Sigmund, Ole

    2017-01-01

    This article discusses the use of frequency response surrogates for eigenvalue optimization problems in topology optimization that may be used to avoid solving the eigenvalue problem. The motivation is to avoid complications that arise from multiple eigenvalues and the computational complexity as...

  9. GENERATING SOPHISTICATED SPATIAL SURROGATES USING THE MIMS SPATIAL ALLOCATOR

    Science.gov (United States)

    The Multimedia Integrated Modeling System (MIMS) Spatial Allocator is open-source software for generating spatial surrogates for emissions modeling, changing the map projection of Shapefiles, and performing other types of spatial allocation that does not require the use of a comm...

  10. Strength Reliability Analysis of Turbine Blade Using Surrogate Models

    Directory of Open Access Journals (Sweden)

    Wei Duan

    2014-05-01

    Full Text Available There are many stochastic parameters that have an effect on the reliability of steam turbine blades performance in practical operation. In order to improve the reliability of blade design, it is necessary to take these stochastic parameters into account. In this study, a variable cross-section twisted blade is investigated and geometrical parameters, material parameters and load parameters are considered as random variables. A reliability analysis method as a combination of a Finite Element Method (FEM, a surrogate model and Monte Carlo Simulation (MCS, is applied to solve the blade reliability analysis. Based on the blade finite element parametrical model and the experimental design, two kinds of surrogate models, Polynomial Response Surface (PRS and Artificial Neural Network (ANN, are applied to construct the approximation analytical expressions between the blade responses (including maximum stress and deflection and random input variables, which act as a surrogate of finite element solver to drastically reduce the number of simulations required. Then the surrogate is used for most of the samples needed in the Monte Carlo method and the statistical parameters and cumulative distribution functions of the maximum stress and deflection are obtained by Monte Carlo simulation. Finally, the probabilistic sensitivities analysis, which combines the magnitude of the gradient and the width of the scatter range of the random input variables, is applied to evaluate how much the maximum stress and deflection of the blade are influenced by the random nature of input parameters.

  11. Biomarker time out.

    Science.gov (United States)

    Petzold, Axel; Bowser, Robert; Calabresi, Paolo; Zetterberg, Henrik; Uitdehaag, Bernard M J

    2014-10-01

    The advancement of knowledge relies on scientific investigations. The timing between asking a question and data collection defines if a study is prospective or retrospective. Prospective studies look forward from a point in time, are less prone to bias and are considered superior to retrospective studies. This conceptual framework conflicts with the nature of biomarker research. New candidate biomarkers are discovered in a retrospective manner. There are neither resources nor time for prospective testing in all cases. Relevant sources for bias are not covered. Ethical questions arise through the time penalty of an overly dogmatic concept. The timing of sample collection can be separated from testing biomarkers. Therefore the moment of formulating a hypothesis may be after sample collection was completed. A conceptual framework permissive to asking research questions without the obligation to bow to the human concept of calendar time would simplify biomarker research, but will require new safeguards against bias.

  12. amphibian_biomarker_data

    Data.gov (United States)

    U.S. Environmental Protection Agency — Amphibian metabolite data used in Snyder, M.N., Henderson, W.M., Glinski, D.G., Purucker, S. T., 2017. Biomarker analysis of american toad (Anaxyrus americanus) and...

  13. Biomarkers in the pathogenesis, diagnosis, and treatment of psoriasis

    Directory of Open Access Journals (Sweden)

    Molteni S

    2012-09-01

    Full Text Available Silvia Molteni, Eva RealiLaboratory of Translational Immunology, Istituto Ortopedico Galeazzi, Milan, ItalyAbstract: Development of psoriasis results from a complex interplay between genetically predisposing factors and environmental triggers that give rise to a self-sustaining pathogenic cycle involving T cells, dendritic cells, connective tissue, and skin epithelium. From 5% to 40% of patients with psoriasis also develop psoriatic arthritis, and increasing evidence indicates an association with other systemic manifestations, including cardiovascular disease and the metabolic syndrome. In psoriatic disease, there is a need for development of biomarkers for assessment of disease severity, for prediction of the outcome of therapeutic interventions, and for distinction between the different clinical variants of the disease. A field of great importance is identification of biomarkers for prediction of development of comorbidities, such as arthritis, cardiovascular disease, and the metabolic syndrome. Genetic determinants of psoriasis and their products not only give an important insight into the pathogenesis of the disease, but may also function as markers of risk for developing cutaneous psoriasis or psoriatic arthritis. So far, there are limited validation data to support the use of candidate biomarkers in clinical practice. Here we review the data from several studies on some of the most promising candidate biomarkers for cutaneous psoriasis and psoriatic arthritis, for the detection of systemic inflammation, and for use as endpoints for therapeutic interventions. Attention is focused on the molecules that take part in the interplay giving rise to psoriasis and on gene products that may represent a link between predisposing genetic factors and the immune and inflammatory processes involved in pathogenesis of the disease. Finally, we provide an overview on how biomarkers can offer insights into the pathogenesis and natural history of psoriasis

  14. Recent Progress in the Development of Diesel Surrogate Fuels

    Energy Technology Data Exchange (ETDEWEB)

    Pitz, W J

    2009-09-04

    There has been much recent progress in the area of surrogate fuels for diesel. In the last few years, experiments and modeling have been performed on higher molecular weight components of relevance to diesel fuel such as n-hexadecane (n-cetane) and 2,2,4,4,6,8,8-heptamethylnonane (iso-cetane). Chemical kinetic models have been developed for all the n-alkanes up to 16 carbon atoms. Also, there has been much experimental and modeling work on lower molecular weight surrogate components such as n-decane and do-decane which are most relevant to jet fuel surrogates, but are also relevant to diesel surrogates where simulation of the full boiling point range is desired. For the cycloalkanes, experimental work on decalin and tetralin recently has been published. For multi-component surrogate fuel mixtures, recent work on modeling of these mixtures and comparisons to real diesel fuel is reviewed. Detailed chemical kinetic models for surrogate fuels are very large in size. Significant progress also has been made in improving the mechanism reduction tools that are needed to make these large models practicable in multidimensional reacting flow simulations of diesel combustion. Nevertheless, major research gaps remain. In the case of iso-alkanes, there are experiments and modeling work on only one of relevance to diesel: iso-cetane. Also, the iso-alkanes in diesel are lightly branched and no detailed chemical kinetic models or experimental investigations are available for such compounds. More components are needed to fill out the iso-alkane boiling point range. For the aromatic class of compounds, there has been no new work for compounds in the boiling point range of diesel. Most of the new work has been on alkyl aromatics that are of the range C7 to C8, below the C10 to C20 range that is needed. For the chemical class of cycloalkanes, experiments and modeling on higher molecular weight components are warranted. Finally for multi-component surrogates needed to treat real diesel

  15. Recent Progress in the Development of Diesel Surrogate Fuels

    Energy Technology Data Exchange (ETDEWEB)

    Pitz, W J; Mueller, C J

    2009-12-09

    There has been much recent progress in the area of surrogate fuels for diesel. In the last few years, experiments and modeling have been performed on higher molecular weight components of relevance to diesel fuel such as n-hexadecane (n-cetane) and 2,2,4,4,6,8,8-heptamethylnonane (iso-cetane). Chemical kinetic models have been developed for all the n-alkanes up to 16 carbon atoms. Also, there has been much experimental and modeling work on lower molecular weight surrogate components such as n-decane and n-dodecane that are most relevant to jet fuel surrogates, but are also relevant to diesel surrogates where simulation of the full boiling point range is desired. For two-ring compounds, experimental work on decalin and tetralin recently has been published. For multi-component surrogate fuel mixtures, recent work on modeling of these mixtures and comparisons to real diesel fuel is reviewed. Detailed chemical kinetic models for surrogate fuels are very large in size. Significant progress also has been made in improving the mechanism reduction tools that are needed to make these large models practicable in multi-dimensional reacting flow simulations of diesel combustion. Nevertheless, major research gaps remain. In the case of iso-alkanes, there are experiments and modeling work on only one of relevance to diesel: iso-cetane. Also, the iso-alkanes in diesel are lightly branched and no detailed chemical kinetic models or experimental investigations are available for such compounds. More components are needed to fill out the iso-alkane boiling point range. For the aromatic class of compounds, there has been no new work for compounds in the boiling point range of diesel. Most of the new work has been on alkyl aromatics that are of the range C7 to C8, below the C10 to C20 range that is needed. For the chemical class of cycloalkanes, experiments and modeling on higher molecular weight components are warranted. Finally for multi-component surrogates needed to treat real

  16. Development of a Human Cranial Bone Surrogate for Impact Studies.

    Science.gov (United States)

    Roberts, Jack C; Merkle, Andrew C; Carneal, Catherine M; Voo, Liming M; Johannes, Matthew S; Paulson, Jeff M; Tankard, Sara; Uy, O Manny

    2013-01-01

    In order to replicate the fracture behavior of the intact human skull under impact it becomes necessary to develop a material having the mechanical properties of cranial bone. The most important properties to replicate in a surrogate human skull were found to be the fracture toughness and tensile strength of the cranial tables as well as the bending strength of the three-layer (inner table-diplöe-outer table) architecture of the human skull. The materials selected to represent the surrogate cranial tables consisted of two different epoxy resins systems with random milled glass fiber to enhance the strength and stiffness and the materials to represent the surrogate diplöe consisted of three low density foams. Forty-one three-point bending fracture toughness tests were performed on nine material combinations. The materials that best represented the fracture toughness of cranial tables were then selected and formed into tensile samples and tested. These materials were then used with the two surrogate diplöe foam materials to create the three-layer surrogate cranial bone samples for three-point bending tests. Drop tower tests were performed on flat samples created from these materials and the fracture patterns were very similar to the linear fractures in pendulum impacts of intact human skulls, previously reported in the literature. The surrogate cranial tables had the quasi-static fracture toughness and tensile strength of 2.5 MPa√ m and 53 ± 4.9 MPa, respectively, while the same properties of human compact bone were 3.1 ± 1.8 MPa√ m and 68 ± 18 MPa, respectively. The cranial surrogate had a quasi-static bending strength of 68 ± 5.7 MPa, while that of cranial bone was 82 ± 26 MPa. This material/design is currently being used to construct spherical shell samples for drop tower and ballistic tests.

  17. Current advances in biomarkers for targeted therapy in triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Fleisher B

    2016-10-01

    Full Text Available Brett Fleisher,1 Charlotte Clarke,2 Sihem Ait-Oudhia1 1Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, 2Department of Translational Research, UT MD Anderson Cancer Center, Houston, TX, USA Abstract: Triple-negative breast cancer (TNBC is a complex heterogeneous disease characterized by the absence of three hallmark receptors: human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor. Compared to other breast cancer subtypes, TNBC is more aggressive, has a higher prevalence in African-Americans, and more frequently affects younger patients. Currently, TNBC lacks clinically accepted targets for tailored therapy, warranting the need for candidate biomarkers. BiomarkerBase, an online platform used to find biomarkers reported in clinical trials, was utilized to screen all potential biomarkers for TNBC and select only the ones registered in completed TNBC trials through clinicaltrials.gov. The selected candidate biomarkers were classified as surrogate, prognostic, predictive, or pharmacodynamic (PD and organized by location in the blood, on the cell surface, in the cytoplasm, or in the nucleus. Blood biomarkers include vascular endothelial growth factor/vascular endothelial growth factor receptor and interleukin-8 (IL-­8; cell surface biomarkers include EGFR, insulin-like growth factor binding protein, c-Kit, c-Met, and PD-L1; cytoplasm biomarkers include PIK3CA, pAKT/S6/p4E-BP1, PTEN, ALDH1, and the PIK3CA/AKT/mTOR-related metabolites; and nucleus biomarkers include BRCA1, the glucocorticoid receptor, TP53, and Ki67. Candidate biomarkers were further organized into a “cellular protein network” that demonstrates potential connectivity. This review provides an inventory and reference point for promising biomarkers for breakthrough targeted therapies in TNBC. Keywords: anti-cancer directed pharmacotherapy, difficult

  18. Theranostic Biomarkers for Schizophrenia

    Science.gov (United States)

    Nikolac Perkovic, Matea; Nedic Erjavec, Gordana; Svob Strac, Dubravka; Uzun, Suzana; Kozumplik, Oliver; Pivac, Nela

    2017-01-01

    Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide. PMID:28358316

  19. Theranostic Biomarkers for Schizophrenia.

    Science.gov (United States)

    Perkovic, Matea Nikolac; Erjavec, Gordana Nedic; Strac, Dubravka Svob; Uzun, Suzana; Kozumplik, Oliver; Pivac, Nela

    2017-03-30

    Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.

  20. Biomarkers for neuromyelitis optica.

    Science.gov (United States)

    Chang, Kuo-Hsuan; Ro, Long-Sun; Lyu, Rong-Kuo; Chen, Chiung-Mei

    2015-02-02

    Neuromyelitis optica (NMO) is an acquired, heterogeneous inflammatory disorder, which is characterized by recurrent optic neuritis and longitudinally extensive spinal cord lesions. The discovery of the serum autoantibody marker, anti-aquaporin 4 (anti-AQP4) antibody, revolutionizes our understanding of pathogenesis of NMO. In addition to anti-AQP4 antibody, other biomarkers for NMO are also reported. These candidate biomarkers are particularly involved in T helper (Th)17 and astrocytic damages, which play a critical role in the development of NMO lesions. Among them, IL-6 in the peripheral blood is associated with anti-AQP4 antibody production. Glial fibrillary acidic protein (GFAP) in CSF demonstrates good correlations with clinical severity of NMO relapses. Detecting these useful biomarkers may be useful in the diagnosis and evaluation of disease activity of NMO. Development of compounds targeting these biomarkers may provide novel therapeutic strategies for NMO. This article will review the related biomarker studies in NMO and discuss the potential therapeutics targeting these biomarkers.

  1. Hall et al., 2016 Artificial Turf Surrogate Surface Methods Paper Data File

    Data.gov (United States)

    U.S. Environmental Protection Agency — Mercury dry deposition data quantified via static water surrogate surface (SWSS) and artificial turf surrogate surface (ATSS) collectors. This dataset is associated...

  2. Is Doubling of Serum Creatinine a Valid Clinical 'Hard' Endpoint in Clinical Nephrology Trials?

    NARCIS (Netherlands)

    Lambers Heerspink, H. J.; Perkovic, V.; de Zeeuw, D.

    2011-01-01

    The composite of end stage renal disease (ESRD), doubling of serum creatinine and (renal) death, is a frequently used endpoint in randomized clinical trials in nephrology. Doubling of serum creatinine is a well-accepted part of this endpoint because a doubling of serum creatinine reflects a large su

  3. Sequential optimization of strip bending process using multiquadric radial basis function surrogate models

    NARCIS (Netherlands)

    Havinga, Gosse Tjipke; van den Boogaard, Antonius H.; Klaseboer, G.

    2013-01-01

    Surrogate models are used within the sequential optimization strategy for forming processes. A sequential improvement (SI) scheme is used to refine the surrogate model in the optimal region. One of the popular surrogate modeling methods for SI is Kriging. However, the global response of Kriging mode

  4. Multi-Toxic Endpoints of the Foodborne Mycotoxins in Nematode Caenorhabditis elegans.

    Science.gov (United States)

    Yang, Zhendong; Xue, Kathy S; Sun, Xiulan; Tang, Lili; Wang, Jia-Sheng

    2015-12-02

    Aflatoxins B₁ (AFB₁), deoxynivalenol (DON), fumonisin B₁ (FB₁), T-2 toxin (T-2), and zearalenone (ZEA) are the major foodborne mycotoxins of public health concerns. In the present study, the multiple toxic endpoints of these naturally-occurring mycotoxins were evaluated in Caenorhabditis elegans model for their lethality, toxic effects on growth and reproduction, as well as influence on lifespan. We found that the lethality endpoint was more sensitive for T-2 toxicity with the EC50 at 1.38 mg/L, the growth endpoint was relatively sensitive for AFB₁ toxic effects, and the reproduction endpoint was more sensitive for toxicities of AFB₁, FB₁, and ZEA. Moreover, the lifespan endpoint was sensitive to toxic effects of all five tested mycotoxins. Data obtained from this study may serve as an important contribution to knowledge on assessment of mycotoxin toxic effects, especially for assessing developmental and reproductive toxic effects, using the C. elegans model.

  5. An endpoint damage oriented model for life cycle environmental impact assessment of buildings in China

    Institute of Scientific and Technical Information of China (English)

    GU LiJing; LIN BoRong; GU DaoJin; ZHU YingXin

    2008-01-01

    The midpoint impact assessment methodology and several weighting methods that are currently used by most building Life cycle assessment (LCA) researchers in China, still have some shortcomings. In order to make the evaluation results have better temporal and spatial applicability, the endpoint impact assessment methodology was adopted in this paper. Based on the endpoint damage oriented concept, four endpoints of resource exhaustion, energy exhaustion, human health damage and ecosystem damage were selected according to the situation of China and the specialties of the building industry. Subsequently the formula for calculating each endpoint, the background value for normalization and the weighting factors were defined. Following that, an endpoint damage oriented model to evaluate the life cycle environmental impact of buildings in China was established. This model can produce an integrated indicator for environmental impact, and consequently provides references for directing the sustainable building design.

  6. 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...... initiation of the study. SUMMARY: Application of the methodology outlined above should result in a more efficient and effective approach to the development of cancer biomarkers as well as the reporting of cancer biomarker studies. With rigorous application, all stakeholders, and especially patients, would...

  7. Systematic Review and Meta-analysis of the Association Between Exposure to Environmental Tobacco Smoke and Periodontitis Endpoints Among Nonsmokers.

    Science.gov (United States)

    Akinkugbe, Aderonke A; Slade, Gary D; Divaris, Kimon; Poole, Charles

    2016-11-01

    A systematic review was conducted to summarize the epidemiological evidence on environmental tobacco smoke (ETS) exposure and prevalent periodontitis endpoints among nonsmokers. We searched PubMed, EMBASE, Web of Science, Pro-Quest dissertations, and conference proceedings of a dental research association. We included studies from which prevalence odds ratios (POR) could be extracted for periodontitis determined by examiner measurements of clinical attachment level (CAL) and/or probing pocket depth (PD) or self-report of missing teeth. Studies determined ETS exposure by self-report or biomarker (cotinine) levels. For studies reporting CAL and/or PD (n = 6), associations were stronger with cotinine-measured exposure (n = 3; random effects POR [95% prediction interval] = 1.63 (0.90, 2.96)) than self-reported exposure (n = 3; random effects POR = 1.15 (0.68, 1.96)). There was no meaningful difference in summary estimate for studies reporting CAL and/or PD endpoint (n = 6; random effects POR = 1.34 (0.93, 1.94)) as opposed to tooth loss (n = 2; random effects POR = 1.33 (0.52, 3.40)). There appears to be a positive association between exposure to ETS and prevalent periodontitis endpoints among nonsmokers, the magnitude of which depended mostly on the method of ETS assessment. The notoriety of ETS is often discussed in terms of its associations with cancer, chronic conditions like cardiovascular diseases, and respiratory illnesses in children. However, very little attention is paid to its association with oral diseases, especially periodontitis. Periodontitis affects a large proportion of the population and is a major cause of tooth loss. This study summarized the epidemiologic association between exposure to ETS and periodontitis among nonsmokers. Although the findings are consistent with a positive association, methodological weaknesses relating to study design, assessment of ETS, periodontitis, and adjustment covariates were highlighted and recommendations for

  8. Biomarkers of sepsis

    Science.gov (United States)

    2013-01-01

    Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate’s effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high. PMID:23480440

  9. 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.

  10. Biomarkers intersect with the exposome.

    Science.gov (United States)

    Rappaport, Stephen M

    2012-09-01

    The exposome concept promotes use of omic tools for discovering biomarkers of exposure and biomarkers of disease in studies of diseased and healthy populations. A two-stage scheme is presented for profiling omic features in serum to discover molecular biomarkers and then for applying these biomarkers in follow-up studies. The initial component, referred to as an exposome-wide-association study (EWAS), employs metabolomics and proteomics to interrogate the serum exposome and, ultimately, to identify, validate and differentiate biomarkers of exposure and biomarkers of disease. Follow-up studies employ knowledge-driven designs to explore disease causality, prevention, diagnosis, prognosis and treatment.

  11. Very Short Literature Survey From Supervised Learning To Surrogate Modeling

    CERN Document Server

    Brusan, Altay

    2012-01-01

    The past century was era of linear systems. Either systems (especially industrial ones) were simple (quasi)linear or linear approximations were accurate enough. In addition, just at the ending decades of the century profusion of computing devices were available, before then due to lack of computational resources it was not easy to evaluate available nonlinear system studies. At the moment both these two conditions changed, systems are highly complex and also pervasive amount of computation strength is cheap and easy to achieve. For recent era, a new branch of supervised learning well known as surrogate modeling (meta-modeling, surface modeling) has been devised which aimed at answering new needs of modeling realm. This short literature survey is on to introduce surrogate modeling to whom is familiar with the concepts of supervised learning. Necessity, challenges and visions of the topic are considered.

  12. A Parallel and Distributed Surrogate Model Implementation for Computational Steering

    KAUST Repository

    Butnaru, Daniel

    2012-06-01

    Understanding the influence of multiple parameters in a complex simulation setting is a difficult task. In the ideal case, the scientist can freely steer such a simulation and is immediately presented with the results for a certain configuration of the input parameters. Such an exploration process is however not possible if the simulation is computationally too expensive. For these cases we present in this paper a scalable computational steering approach utilizing a fast surrogate model as substitute for the time-consuming simulation. The surrogate model we propose is based on the sparse grid technique, and we identify the main computational tasks associated with its evaluation and its extension. We further show how distributed data management combined with the specific use of accelerators allows us to approximate and deliver simulation results to a high-resolution visualization system in real-time. This significantly enhances the steering workflow and facilitates the interactive exploration of large datasets. © 2012 IEEE.

  13. The Theory and Practice of Surrogate Decision-Making.

    Science.gov (United States)

    Wendler, David

    2017-01-01

    When a patient lacks decision-making capacity and has not left a clear advance directive, there is now widespread agreement that patient-designated and next-of-kin surrogates should implement substituted judgment within a process of shared decision-making. Specifically, after discussing the "best scientific evidence available, as well as the patient's values, goals, and preferences" with the patient's clinicians, the patient-designated or next-of-kin surrogate should attempt to determine what decision the patient would have made in the circumstances. To the extent that this approach works, it seems to provide about as much respect for the autonomy of incapacitated patients as we could ask for. But, as articles in this issue of the Report by Jeffrey Berger and by Ellen Robinson and colleagues emphasize, reality presents challenges. © 2017 The Hastings Center.

  14. 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.

  15. Inflammatory biomarkers and cancer

    DEFF Research Database (Denmark)

    Rasmussen, Line Jee Hartmann; Schultz, Martin; Gaardsting, Anne

    2017-01-01

    In Denmark, patients with serious nonspecific symptoms and signs of cancer (NSSC) are referred to the diagnostic outpatient clinics (DOCs) where an accelerated cancer diagnostic program is initiated. Various immunological and inflammatory biomarkers have been associated with cancer, including...... soluble urokinase plasminogen activator receptor (suPAR) and the pattern recognition receptors (PRRs) pentraxin-3, mannose-binding lectin, ficolin-1, ficolin-2 and ficolin-3. We aimed to evaluate these biomarkers and compare their diagnostic ability to classical biomarkers for diagnosing cancer...... in patients with NSSC. Patients were included from the DOC, Department of Infectious Diseases, Copenhagen University Hospital Hvidovre. Patients were given a final diagnosis based on the combined results from scans, blood work and physical examination. Weight loss, Charlson score and previous cancer were...

  16. The use of protozoa in ecotoxicology: application of multiple endpoint tests of the ciliate E. crassus for the evaluation of sediment quality in coastal marine ecosystems.

    Science.gov (United States)

    Gomiero, A; Dagnino, A; Nasci, C; Viarengo, A

    2013-01-01

    Despite an increasing number of surveys describing adverse effects of contaminated sediments on marine organisms, few studies have addressed protists. In this study, the free-crawling marine ciliate Euplotes crassus was evaluated as the test organism for the screening of sediment toxicity using sediments from both coastal and estuarine sites of the Venice Lagoon (Marghera harbour [MH], Valle Millecampi [MV], Murano island [MI] and Lido inlet [LI]). Two endpoints of high ecological value, mortality (Mry) and replication rate (RpR), were assessed in combination with the two sublethal biomarkers of stress, endocytotic rate (Ecy) and lysosomal membrane stability (NRRT). The results showed a significant inhibition of RpR, Ecy and NRRT paralleled by a small and insignificantly increased Mry of the exposed specimens. Our results thus demonstrate that only a combination of mortality and sublethal biomarkers was able to characterise an exposure-related stress syndrome. The suite of biomarkers described here was also able to detect and resolve a pollution-induced stress syndrome at an early stage of pollution. The contamination level of the sediments was assessed using chemical analysis, by estimating bioavailability and by computing a toxic pressure coefficient (TPC) to account for potential additive effects of different pollutants. The observed biological responses were consistent with the contamination levels in sediments, suggesting a high potential for using Protozoa in bioassays to assess environmental risk in coastal marine systems.

  17. Commercial agencies and surrogate motherhood: a transaction cost approach.

    Science.gov (United States)

    Galbraith, Mhairi; McLachlan, Hugh V; Swales, J Kim

    2005-03-01

    In this paper we investigate the legal arrangements involved in UK surrogate motherhood from a transaction-cost perspective. We outline the specific forms the transaction costs take and critically comment on the way in which the UK institutional and organisational arrangements at present adversely influence transaction costs. We then focus specifically on the potential role of surrogacy agencies and look at UK and US evidence on commercial and voluntary agencies. Policy implications follow.

  18. Quantification of the Relationship between Surrogate Fuel Structure and Performance

    Science.gov (United States)

    2012-07-31

    cycloperoxy-5-yl (BICYC5.O2) and bicyclo[2,2,1]hexene peroxy (C2O2H221) radicals . The latter route leads to the formation of vinyl ketene and the formyl ...3089 selection of stable molecule and radicals . The adopted calculation method for the determination of such data is outlined in Appendix 1...chemistry of aromatic fuel components used in surrogate fuels and the importance of the cyclopentadi- enyl radical in poly-aromatic hydrocarbon (PAH

  19. Biopolicies and biotechnologies: reflections on surrogate maternity in India

    OpenAIRE

    Mónica Amador

    2010-01-01

    This article explores the impact of biotechnology, particularly on assisted reproductive technologies such as surrogate motherhood. The study is based on interviews and field work conducted in the city of Hyderabad in India within the frame of the seminar on “Research Methodology” given by Dr. Rohan D´Souza at the Centre for Studies in Science Policy at the Jawaharlal Nehru University in India. The theoretical framework of this analysis focuses on exploring concepts such as cyborg (Haraway,19...

  20. Regression calibration with more surrogates than mismeasured variables

    KAUST Repository

    Kipnis, Victor

    2012-06-29

    In a recent paper (Weller EA, Milton DK, Eisen EA, Spiegelman D. Regression calibration for logistic regression with multiple surrogates for one exposure. Journal of Statistical Planning and Inference 2007; 137: 449-461), the authors discussed fitting logistic regression models when a scalar main explanatory variable is measured with error by several surrogates, that is, a situation with more surrogates than variables measured with error. They compared two methods of adjusting for measurement error using a regression calibration approximate model as if it were exact. One is the standard regression calibration approach consisting of substituting an estimated conditional expectation of the true covariate given observed data in the logistic regression. The other is a novel two-stage approach when the logistic regression is fitted to multiple surrogates, and then a linear combination of estimated slopes is formed as the estimate of interest. Applying estimated asymptotic variances for both methods in a single data set with some sensitivity analysis, the authors asserted superiority of their two-stage approach. We investigate this claim in some detail. A troubling aspect of the proposed two-stage method is that, unlike standard regression calibration and a natural form of maximum likelihood, the resulting estimates are not invariant to reparameterization of nuisance parameters in the model. We show, however, that, under the regression calibration approximation, the two-stage method is asymptotically equivalent to a maximum likelihood formulation, and is therefore in theory superior to standard regression calibration. However, our extensive finite-sample simulations in the practically important parameter space where the regression calibration model provides a good approximation failed to uncover such superiority of the two-stage method. We also discuss extensions to different data structures.

  1. Biopolicies and biotechnologies: reflections on surrogate maternity in India

    OpenAIRE

    Mónica Amador

    2010-01-01

    This article explores the impact of biotechnology, particularly on assisted reproductive technologies such as surrogate motherhood. The study is based on interviews and field work conducted in the city of Hyderabad in India within the frame of the seminar on “Research Methodology” given by Dr. Rohan D´Souza at the Centre for Studies in Science Policy at the Jawaharlal Nehru University in India. The theoretical framework of this analysis focuses on exploring concepts such as cyborg (Haraway,19...

  2. Diaphragm as an anatomic surrogate for lung tumor motion

    CERN Document Server

    Cervino, Laura I; Sandhu, Ajay; Jiang, Steve B

    2009-01-01

    Lung tumor motion due to respiration poses a challenge in the application of modern three-dimensional conformal radiotherapy. Direct tracking of the lung tumor during radiation therapy is very difficult without implanted fiducial markers. Indirect tracking relies on the correlation of the tumor's motion and the surrogate's motion. The present paper presents an analysis of the correlation between the tumor motion and the diaphragm motion in order to evaluate the potential use of diaphragm as a surrogate for tumor motion. We have analyzed the correlation between diaphragm motion and superior-inferior lung tumor motion in 32 fluoroscopic image sequences from 10 lung cancer patients. A simple linear model and a more complex linear model that accounts for phase delays between the two motions have been used. Results show that the diaphragm is a good surrogate for tumor motion prediction for most patients, resulting in an average correlation factor of 0.94 and 0.98 with each model respectively. The model that accoun...

  3. The Confucian bioethics of surrogate decision making: its communitarian roots.

    Science.gov (United States)

    Fan, Ruiping

    2011-10-01

    The family is the exemplar community of Chinese society. This essay explores how Chinese communitarian norms, expressed in thick commitments to the authority and autonomy of the family, are central to contemporary Chinese bioethics. In particular, it focuses on the issue of surrogate decision making to illustrate the Confucian family-grounded communitarian bioethics. The essay first describes the way in which the family, in Chinese bioethics, functions as a whole to provide consent for significant medical and surgical interventions when a patient has lost decision-making capacity. It is argued that the practice of not having an established order for surrogate decision makers (e.g., spouse, children, and then parents), as it is done in the United States, reflects the acknowledgment that the family as a social reality cannot be reduced to a stereotype of the appropriate order of default decision makers. This description of the family as being in authority to make surrogate decisions for an incompetent family member is enriched by an elaboration of the differences among the concepts of patient autonomy, family autonomy, and moral autonomy. The Chinese model, as well as the Confucian communitarian life of families, engages a family autonomy that is supported by a Confucian understanding of moral autonomy, rather than individual autonomy. Finally, the issue of possible conflicts between patient and family interests in relation to a patient's past wishes in the Chinese model is addressed in light of the role of the physician.

  4. Evaluation of bone surrogates for indirect and direct ballistic fractures.

    Science.gov (United States)

    Bir, Cynthia; Andrecovich, Chris; DeMaio, Marlene; Dougherty, Paul J

    2016-04-01

    The mechanism of injury for fractures to long bones has been studied for both direct ballistic loading as well as indirect. However, the majority of these studies have been conducted on both post-mortem human subjects (PMHS) and animal surrogates which have constraints in terms of storage, preparation and testing. The identification of a validated bone surrogate for use in forensic, medical and engineering testing would provide the ability to investigate ballistic loading without these constraints. Two specific bone surrogates, Sawbones and Synbone, were evaluated in comparison to PMHS for both direct and indirect ballistic loading. For the direct loading, the mean velocity to produce fracture was 121 ± 19 m/s for the PMHS, which was statistically different from the Sawbones (140 ± 7 m/s) and Synbone (146 ± 3 m/s). The average distance to fracture in the indirect loading was .70 cm for the PMHS. The Synbone had a statistically similar average distance to fracture (.61 cm, p=0.54) however the Sawbones average distance to fracture was statistically different (.41 cm, pballistic testing was not identified and future work is warranted.

  5. Surrogate Assisted Design Optimization of an Air Turbine

    Directory of Open Access Journals (Sweden)

    Rameez Badhurshah

    2014-01-01

    Full Text Available Surrogates are cheaper to evaluate and assist in designing systems with lesser time. On the other hand, the surrogates are problem dependent and they need evaluation for each problem to find a suitable surrogate. The Kriging variants such as ordinary, universal, and blind along with commonly used response surface approximation (RSA model were used in the present problem, to optimize the performance of an air impulse turbine used for ocean wave energy harvesting by CFD analysis. A three-level full factorial design was employed to find sample points in the design space for two design variables. A Reynolds-averaged Navier Stokes solver was used to evaluate the objective function responses, and these responses along with the design variables were used to construct the Kriging variants and RSA functions. A hybrid genetic algorithm was used to find the optimal point in the design space. It was found that the best optimal design was produced by the universal Kriging while the blind Kriging produced the worst. The present approach is suggested for renewable energy application.

  6. SU-F-BRF-10: Deformable MRI to CT Validation Employing Same Day Planning MRI for Surrogate Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Padgett, K; Stoyanova, R; Johnson, P; Dogan, N; Pollack, A [University of Miami School of Medicine, Miami, FL (United States); Piper, J; Javorek, A [MIM Software, Inc., Beachwood, OH (United States)

    2014-06-15

    Purpose: To compare rigid and deformable registrations of the prostate in the multi-modality setting (diagnostic-MRI to planning-CT) by utilizing a planning-MRI as a surrogate. The surrogate allows for the direct quantitative analysis which can be difficult in the multi-modality domain where intensity mapping differs. Methods: For ten subjects, T2 fast-spin-echo images were acquired at two different time points, the first several weeks prior to planning (diagnostic-MRI) and the second on the same day in which the planning CT was collected (planning-MRI). Significant effort in patient positioning and bowel/bladder preparation was undertaken to minimize distortion of the prostate in all datasets. The diagnostic-MRI was deformed to the planning-CT utilizing a commercially available deformable registration algorithm synthesized from local registrations. The deformed MRI was then rigidly aligned to the planning MRI which was used as the surrogate for the planning-CT. Agreement between the two MRI datasets was scored using intensity based metrics including Pearson correlation and normalized mutual information, NMI. A local analysis was performed by looking only within the prostate, proximal seminal vesicles, penile bulb and combined areas. A similar method was used to assess a rigid registration between the diagnostic-MRI and planning-CT. Results: Utilizing the NMI, the deformable registrations were superior to the rigid registrations in 9 of 10 cases demonstrating a 15.94% improvement (p-value < 0.001) within the combined area. The Pearson correlation showed similar results with the deformable registration superior in the same number of cases and demonstrating a 6.97% improvement (p-value <0.011). Conclusion: Validating deformable multi-modality registrations using spatial intensity based metrics is difficult due to the inherent differences in intensity mapping. This population provides an ideal testing ground for MRI to CT deformable registrations by obviating the need

  7. Biomarkers for systemic lupus erythematosus.

    Science.gov (United States)

    Ahearn, Joseph M; Liu, Chau-Ching; Kao, Amy H; Manzi, Susan

    2012-04-01

    The urgent need for lupus biomarkers was demonstrated in September 2011 during a Workshop sponsored by the Food and Drug Administration: Potential Biomarkers Predictive of Disease Flare. After 2 days of discussion and more than 2 dozen presentations from thought leaders in both industry and academia, it became apparent that highly sought biomarkers to predict lupus flare have not yet been identified. Even short of the elusive biomarker of flare, few biomarkers for systemic lupus erythematosus (SLE) diagnosis, monitoring, and stratification have been validated and employed for making clinical decisions. This lack of reliable, specific biomarkers for SLE hampers proper clinical management of patients with SLE and impedes development of new lupus therapeutics. As such, the intensity of investigation to identify lupus biomarkers is climbing a steep trajectory, lending cautious optimism that a validated panel of biomarkers for lupus diagnosis, monitoring, stratification, and prediction of flare may soon be in hand.

  8. A Dynamical Modeling Approach for Analysis of Longitudinal Clinical Trials in the Presence of Missing Endpoints.

    Science.gov (United States)

    Banks, H T; Hu, Shuhua; Rosenberg, Eric

    2017-01-01

    Randomized longitudinal clinical trials are the gold standard to evaluate the effectiveness of interventions among different patient treatment groups. However, analysis of such clinical trials becomes difficult in the presence of missing data, especially in the case where the study endpoints become difficult to measure because of subject dropout rates or/and the time to discontinue the assigned interventions are different among the patient groups. Here we report on using a validated mathematical model combined with an inverse problem approach to predict the values for the missing endpoints. A small randomized HIV clinical trial where endpoints for most of patients are missing is used to demonstrate this approach.

  9. Effectiveness of biological surrogates for predicting patterns of marine biodiversity: a global meta-analysis.

    Directory of Open Access Journals (Sweden)

    Camille Mellin

    Full Text Available The use of biological surrogates as proxies for biodiversity patterns is gaining popularity, particularly in marine systems where field surveys can be expensive and species richness high. Yet, uncertainty regarding their applicability remains because of inconsistency of definitions, a lack of standard methods for estimating effectiveness, and variable spatial scales considered. We present a Bayesian meta-analysis of the effectiveness of biological surrogates in marine ecosystems. Surrogate effectiveness was defined both as the proportion of surrogacy tests where predictions based on surrogates were better than random (i.e., low probability of making a Type I error; P and as the predictability of targets using surrogates (R(2. A total of 264 published surrogacy tests combined with prior probabilities elicited from eight international experts demonstrated that the habitat, spatial scale, type of surrogate and statistical method used all influenced surrogate effectiveness, at least according to either P or R(2. The type of surrogate used (higher-taxa, cross-taxa or subset taxa was the best predictor of P, with the higher-taxa surrogates outperforming all others. The marine habitat was the best predictor of R(2, with particularly low predictability in tropical reefs. Surrogate effectiveness was greatest for higher-taxa surrogates at a <10-km spatial scale, in low-complexity marine habitats such as soft bottoms, and using multivariate-based methods. Comparisons with terrestrial studies in terms of the methods used to study surrogates revealed that marine applications still ignore some problems with several widely used statistical approaches to surrogacy. Our study provides a benchmark for the reliable use of biological surrogates in marine ecosystems, and highlights directions for future development of biological surrogates in predicting biodiversity.

  10. Sensitivity of the sea snail Gibbula umbilicalis to mercury exposure--linking endpoints from different biological organization levels.

    Science.gov (United States)

    Cabecinhas, Adriana S; Novais, Sara C; Santos, Sílvia C; Rodrigues, Andreia C M; Pestana, João L T; Soares, Amadeu M V M; Lemos, Marco F L

    2015-01-01

    Mercury contamination is a common phenomenon in the marine environment and for this reason it is important to develop cost-effective and relevant tools to assess its toxic effects on a number of different species. To evaluate the possible effects of Hg in the sea snail Gibbula umbilicalis, animals were exposed to increasing concentrations of the contaminant in the ionic form for 96 h. After this exposure period, mortality, feeding and flipping behavior, the activity of the biomarkers glutathione S-transferase, superoxide dismutase, catalase, lactate dehydrogenase and cholinesterase, the levels of lipid peroxidation and cellular energy allocation were measured. After 96 h of exposure to the highest Hg concentration (≈LC20), there was a significant inhibition of the cholinesterase activity as well as impairment in the flipping behavior and post-exposure feeding of the snails. Cholinesterase inhibition was correlated with the impairment of behavioral responses also caused by exposure to Hg. These endpoints, including the novel flipping test, revealed sensitivity to Hg and might be used as relevant early warning indicators of prospective effects at higher biological organization levels, making these parameters potential tools for environmental risk assessment. The proposed test species showed sensitivity to Hg and proved to be a suitable and resourceful species to be used in ecotoxicological testing to assess effects of other contaminants in marine ecosystems.

  11. Statistical methods for down-selection of treatment regimens based on multiple endpoints, with application to HIV vaccine trials.

    Science.gov (United States)

    Huang, Ying; Gilbert, Peter B; Fu, Rong; Janes, Holly

    2016-09-20

    SummaryBiomarker endpoints measuring vaccine-induced immune responses are essential to HIV vaccine development because of their potential to predict the effect of a vaccine in preventing HIV infection. A vaccine's immune response profile observed in phase I immunogenicity studies is a key factor in determining whether it is advanced for further study in phase II and III efficacy trials. The multiplicity of immune variables and scientific uncertainty in their relative importance, however, pose great challenges to the development of formal algorithms for selecting vaccines to study further. Motivated by the practical need to identify a set of promising vaccines from a pool of candidate regimens for inclusion in an upcoming HIV vaccine efficacy trial, we propose a new statistical framework for the selection of vaccine regimens based on their immune response profile. In particular, we propose superiority and non-redundancy criteria to be achieved in down-selection, and develop novel statistical algorithms that integrate hypothesis testing and ranking for selecting vaccine regimens satisfying these criteria. Performance of the proposed selection algorithms are evaluated through extensive numerical studies. We demonstrate the application of the proposed methods through the comparison of immune responses between several HIV vaccine regimens. The methods are applicable to general down-selection applications in clinical trials.

  12. Emerging Biomarkers in Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    McNamara, Mairéad G.; Sahebjam, Solmaz; Mason, Warren P., E-mail: warren.mason@uhn.ca [Pencer Brain Tumor Centre, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9 (Canada)

    2013-08-22

    Glioblastoma, the most common primary brain tumor, has few available therapies providing significant improvement in survival. Molecular signatures associated with tumor aggressiveness as well as with disease progression and their relation to differences in signaling pathways implicated in gliomagenesis have recently been described. A number of biomarkers which have potential in diagnosis, prognosis and prediction of response to therapy have been identified and along with imaging modalities could contribute to the clinical management of GBM. Molecular biomarkers including O(6)-methlyguanine-DNA-methyltransferase (MGMT) promoter and deoxyribonucleic acid (DNA) methylation, loss of heterozygosity (LOH) of chromosomes 1p and 19q, loss of heterozygosity 10q, isocitrate dehydrogenase (IDH) mutations, epidermal growth factor receptor (EGFR), epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, phosphatase and tensin homolog (PTEN), p16INK4a gene, cytochrome c oxidase (CcO), phospholipid metabolites, telomerase messenger expression (hTERT messenger ribonucleic acid [mRNA]), microRNAs (miRNAs), cancer stem cell markers and imaging modalities as potential biomarkers are discussed. Inclusion of emerging biomarkers in prospective clinical trials is warranted in an effort for more effective personalized therapy in the future.

  13. Biomarkers for anorexia nervosa

    DEFF Research Database (Denmark)

    Sjøgren, Jan Magnus

    2017-01-01

    Biomarkers for anorexia nervosa (AN) which reflect the pathophysiology and relate to the aetiology of the disease, are warranted and could bring us one step closer to targeted treatment of AN. Some leads may be found in the biochemistry which often is found disturbed in AN, although normalization...

  14. Neuroimaging Biomarkers for Psychosis

    Science.gov (United States)

    Hager, Brandon M.

    2015-01-01

    Background Biomarkers provide clinicians with a predictable model for the diagnosis, treatment and follow-up of medical ailments. Psychiatry has lagged behind other areas of medicine in the identification of biomarkers for clinical diagnosis and treatment. In this review, we investigated the current state of neuroimaging as it pertains to biomarkers for psychosis. Methods We reviewed systematic reviews and meta-analyses of the structural (sMRI), functional (fMRI), diffusion-tensor (DTI), Positron emission tomography (PET) and spectroscopy (MRS) studies of subjects at-risk or those with an established schizophrenic illness. Only articles reporting effect-sizes and confidence intervals were included in an assessment of robustness. Results Out of the identified meta-analyses and systematic reviews, 21 studies met the inclusion criteria for assessment. There were 13 sMRI, 4 PET, 3 MRS, and 1 DTI studies. The search terms included in the current review encompassed familial high risk (FHR), clinical high risk (CHR), First episode (FES), Chronic (CSZ), schizophrenia spectrum disorders (SSD), and healthy controls (HC). Conclusions Currently, few neuroimaging biomarkers can be considered ready for diagnostic use in patients with psychosis. At least in part, this may be related to the challenges inherent in the current symptom-based approach to classifying these disorders. While available studies suggest a possible value of imaging biomarkers for monitoring disease progression, more systematic research is needed. To date, the best value of imaging data in psychoses has been to shed light on questions of disease pathophysiology, especially through the characterization of endophenotypes. PMID:25883891

  15. Metabolomics in diagnosis and biomarker discovery of colorectal cancer.

    Science.gov (United States)

    Zhang, Aihua; Sun, Hui; Yan, Guangli; Wang, Ping; Han, Ying; Wang, Xijun

    2014-04-01

    Colorectal cancer (CRC), a major public health concern, is the second leading cause of cancer death in developed countries. There is a need for better preventive strategies to improve the patient outcome that is substantially influenced by cancer stage at the time of diagnosis. Patients with early stage colorectal have a significant higher 5-year survival rates compared to patients diagnosed at late stage. Although traditional colonoscopy remains the effective means to diagnose CRC, this approach generally suffers from poor patient compliance. Thus, it is important to develop more effective methods for early diagnosis of this disease process, also there is an urgent need for biomarkers to diagnose CRC, assess disease severity, and prognosticate course. Increasing availability of high-throughput methodologies open up new possibilities for screening new potential candidates for identifying biomarkers. Fortunately, metabolomics, the study of all metabolites produced in the body, considered most closely related to a patient's phenotype, can provide clinically useful biomarkers applied in CRC, and may now open new avenues for diagnostics. It has a largely untapped potential in the field of oncology, through the analysis of the cancer metabolome to identify marker metabolites defined here as surrogate indicators of physiological or pathophysiological states. In this review we take a closer look at the metabolomics used within the field of colorectal cancer. Further, we highlight the most interesting metabolomics publications and discuss these in detail; additional studies are mentioned as a reference for the interested reader. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  16. 78 FR 73199 - Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs...

    Science.gov (United States)

    2013-12-05

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application; Availability AGENCY: Food... guidances to industry on ``Bioavailability and Bioequivalence Studies for Orally Administered Drug...

  17. A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard.

    Science.gov (United States)

    Won, Jennifer R; Gao, Dongxia; Chow, Christine; Cheng, Jinjin; Lau, Sherman Y H; Ellis, Matthew J; Perou, Charles M; Bernard, Philip S; Nielsen, Torsten O

    2013-11-01

    Gene expression profiling of breast cancer delineates a particularly aggressive subtype referred to as 'basal-like', which comprises ∼15% of all breast cancers, afflicts younger women and is refractory to endocrine and anti-HER2 therapies. Immunohistochemical surrogate definitions for basal-like breast cancer, such as the clinical ER/PR/HER2 triple-negative phenotype and models incorporating positive expression for CK5 (CK5/6) and/or EGFR are heavily cited. However, many additional biomarkers for basal-like breast cancer have been described in the literature. A parallel comparison of 46 proposed immunohistochemical biomarkers of basal-like breast cancer was performed against a gene expression profile gold standard on a tissue microarray containing 42 basal-like and 80 non-basal-like breast cancer cases. Ki67 and PPH3 were the most sensitive biomarkers (both 92%) positively expressed in the basal-like subtype, whereas CK14, IMP3 and NGFR were the most specific (100%). Among biomarkers surveyed, loss of INPP4B (a negative regulator of phosphatidylinositol signaling) was 61% sensitive and 99% specific with the highest odds ratio (OR) at 108, indicating the strongest association with basal-like breast cancer. Expression of nestin, a common marker of neural progenitor cells that is also associated with the triple-negative/basal-like phenotype and poor breast cancer prognosis, possessed the second highest OR at 29 among the 46 biomarkers surveyed, as well as 54% sensitivity and 96% specificity. As a positively expressed biomarker, nestin possesses technical advantages over INPP4B that make it a more ideal biomarker for identification of basal-like breast cancer. The comprehensive immunohistochemical biomarker survey presented in this study is a necessary step for determining an optimized surrogate immunopanel that best defines basal-like breast cancer in a practical and clinically accessible way.

  18. Finite-size effects and the search for the critical endpoint in heavy ion collisions

    CERN Document Server

    Palhares, Leticia F; Kodama, Takeshi

    2009-01-01

    We discuss how the finiteness of the system created in a heavy-ion collision affects possible signatures of the QCD critical endpoint. We show sizable results for the modifications of the chiral phase diagram at volume scales typically encountered in current heavy-ion collisions and address the applicability of finite-size scaling as a tool in the experimental search for the critical endpoint.

  19. Autonomous Sub-Pixel Satellite Track Endpoint Determination for Space Based Images

    Energy Technology Data Exchange (ETDEWEB)

    Simms, L M

    2011-03-07

    An algorithm for determining satellite track endpoints with sub-pixel resolution in spaced-based images is presented. The algorithm allows for significant curvature in the imaged track due to rotation of the spacecraft capturing the image. The motivation behind the subpixel endpoint determination is first presented, followed by a description of the methodology used. Results from running the algorithm on real ground-based and simulated spaced-based images are shown to highlight its effectiveness.

  20. SpEnD: Linked Data SPARQL Endpoints Discovery Using Search Engines

    OpenAIRE

    Yumusak, Semih; Dogdu, Erdogan; KODAZ, Halife; Kamilaris, Andreas

    2016-01-01

    In this study, a novel metacrawling method is proposed for discovering and monitoring linked data sources on the Web. We implemented the method in a prototype system, named SPARQL Endpoints Discovery (SpEnD). SpEnD starts with a "search keyword" discovery process for finding relevant keywords for the linked data domain and specifically SPARQL endpoints. Then, these search keywords are utilized to find linked data sources via popular search engines (Google, Bing, Yahoo, Yandex). By using this ...

  1. Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval

    Science.gov (United States)

    2015-10-01

    Award Number: W81XWH-11-1-0639 TITLE: Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval PRINCIPAL...SEP 2014 – 29 SEP 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-11-1-0639 Development of Pain Endpoint Models for Use in Prostate Cancer...standard methods for measuring pain palliation and pain progression in prostate cancer clinical trials that are feasible, methodologically rigorous, and

  2. Surrogate model based iterative ensemble smoother for subsurface flow data assimilation

    Science.gov (United States)

    Chang, Haibin; Liao, Qinzhuo; Zhang, Dongxiao

    2017-02-01

    Subsurface geological formation properties often involve some degree of uncertainty. Thus, for most conditions, uncertainty quantification and data assimilation are necessary for predicting subsurface flow. The surrogate model based method is one common type of uncertainty quantification method, in which a surrogate model is constructed for approximating the relationship between model output and model input. Based on the prediction ability, the constructed surrogate model can be utilized for performing data assimilation. In this work, we develop an algorithm for implementing an iterative ensemble smoother (ES) using the surrogate model. We first derive an iterative ES scheme using a regular routine. In order to utilize surrogate models, we then borrow the idea of Chen and Oliver (2013) to modify the Hessian, and further develop an independent parameter based iterative ES formula. Finally, we establish the algorithm for the implementation of iterative ES using surrogate models. Two surrogate models, the PCE surrogate and the interpolation surrogate, are introduced for illustration. The performances of the proposed algorithm are tested by synthetic cases. The results show that satisfactory data assimilation results can be obtained by using surrogate models that have sufficient accuracy.

  3. Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials.

    NARCIS (Netherlands)

    Punt, C.J.A.; Buyse, M.; Kohne, C.H.; Hohenberger, P.; Labianca, R.; Schmoll, H.J.; Pahlman, L.; Sobrero, A.; Douillard, J.Y.

    2007-01-01

    Disease-free survival is increasingly being used as the primary endpoint of most trials testing adjuvant treatments in cancer. Other frequently used endpoints include overall survival, recurrence-free survival, and time to recurrence. These endpoints are often defined differently in different trials

  4. Physiological and lavage fluid cytological and biochemical endpoints of toxicity in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Lehnert, B.E.

    1992-12-31

    Exposure of the respiratory tract to toxic materials can result in a variety of physiologic disturbances that can serve as endpoints of toxicity. In addition to a brief review of commonly assessed physiologic endpoints, attention is given in the first component of this report to the use of both nose breathing and ``mouth`` breathing rats in toxicity studies that involve measurements of ventilatory functional changes in response to test atmospheres. Additionally, the usefulness of maximum oxygen consumption, or VO{sub 2max}, as a physiologic endpoint of toxicity that uses exercising rats after exposure to test atmospheres is described, along with an introduction to post-exposure exercise as an important behavioral activity that can markedly impact on the severity of acute lung injury caused by pneumoedematogenic materials. The second component of this report focuses on bronchoalveolar lavage and cytological and biochemical endpoints that can be assessed in investigations of the toxicities of test materials. As will be shown herein, some of the biochemical endpoints of toxicity, especially, can sensitively detect subtle injury to the lower respiratory tract that may escape detection by changes in some other conventional endpoints of toxicity, including lung gravimetric increases and histopathological alterations.

  5. Physiological and lavage fluid cytological and biochemical endpoints of toxicity in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Lehnert, B.E.

    1992-01-01

    Exposure of the respiratory tract to toxic materials can result in a variety of physiologic disturbances that can serve as endpoints of toxicity. In addition to a brief review of commonly assessed physiologic endpoints, attention is given in the first component of this report to the use of both nose breathing and mouth'' breathing rats in toxicity studies that involve measurements of ventilatory functional changes in response to test atmospheres. Additionally, the usefulness of maximum oxygen consumption, or VO[sub 2max], as a physiologic endpoint of toxicity that uses exercising rats after exposure to test atmospheres is described, along with an introduction to post-exposure exercise as an important behavioral activity that can markedly impact on the severity of acute lung injury caused by pneumoedematogenic materials. The second component of this report focuses on bronchoalveolar lavage and cytological and biochemical endpoints that can be assessed in investigations of the toxicities of test materials. As will be shown herein, some of the biochemical endpoints of toxicity, especially, can sensitively detect subtle injury to the lower respiratory tract that may escape detection by changes in some other conventional endpoints of toxicity, including lung gravimetric increases and histopathological alterations.

  6. Quality of Documentation as a Surrogate Marker for Awareness and Training Effectiveness of PHTLS-Courses. Part of the Prospective Longitudinal Mixed-Methods EPPTC-Trial.

    Science.gov (United States)

    Häske, David; Beckers, Stefan K; Hofmann, Marzellus; Lefering, Rolf; Gliwitzky, Bernhard; Wölfl, Christoph C; Grützner, Paul; Stöckle, Ulrich; Dieroff, Marc; Münzberg, Matthias

    2017-01-01

    Care for severely injured patients requires multidisciplinary teamwork. A decrease in the number of accident victims ultimately affects the routine and skills. PHTLS ("Pre-Hospital Trauma Life Support") courses are established two-day courses for medical and non-medical rescue service personnel, aimed at improving the pre-hospital care of trauma patients worldwide. The study aims the examination of the quality of documentation before and after PHTLS courses as a surrogate endpoint of training effectiveness and awareness. This was a prospective pre-post intervention trial and was part of the mixed-method longitudinal EPPTC (Effect of Paramedic Training on Pre-Hospital Trauma Care) study, evaluating subjective and objective changes among participants and real patient care, as a result of PHTLS courses. The courses provide an overview of the SAMPLE approach for interrogation of anamnestic information, which is believed to be responsible for patient safety as relevant, among others, "Allergies," "Medication," and "Patient History" (AMP). The focus of the course is not the documentation. In total, 320 protocols were analyzed before and after the training. The PHTLS course led to a significant increase (p PHTLS course showed a significant increase in the information content. In summary, we showed that PHTLS training improves documentation quality, which we used as a surrogate endpoint for learning effectiveness and awareness. In this regard, we demonstrated that participants use certain parts of training in real life, thereby suggesting that the learning methods of PHTLS training are effective. These results, however, do not indicate whether patient care has changed.

  7. Uncertainty quantification of squeal instability via surrogate modelling

    Science.gov (United States)

    Nobari, Amir; Ouyang, Huajiang; Bannister, Paul

    2015-08-01

    One of the major issues that car manufacturers are facing is the noise and vibration of brake systems. Of the different sorts of noise and vibration, which a brake system may generate, squeal as an irritating high-frequency noise costs the manufacturers significantly. Despite considerable research that has been conducted on brake squeal, the root cause of squeal is still not fully understood. The most common assumption, however, is mode-coupling. Complex eigenvalue analysis is the most widely used approach to the analysis of brake squeal problems. One of the major drawbacks of this technique, nevertheless, is that the effects of variability and uncertainty are not included in the results. Apparently, uncertainty and variability are two inseparable parts of any brake system. Uncertainty is mainly caused by friction, contact, wear and thermal effects while variability mostly stems from the manufacturing process, material properties and component geometries. Evaluating the effects of uncertainty and variability in the complex eigenvalue analysis improves the predictability of noise propensity and helps produce a more robust design. The biggest hurdle in the uncertainty analysis of brake systems is the computational cost and time. Most uncertainty analysis techniques rely on the results of many deterministic analyses. A full finite element model of a brake system typically consists of millions of degrees-of-freedom and many load cases. Running time of such models is so long that automotive industry is reluctant to do many deterministic analyses. This paper, instead, proposes an efficient method of uncertainty propagation via surrogate modelling. A surrogate model of a brake system is constructed in order to reproduce the outputs of the large-scale finite element model and overcome the issue of computational workloads. The probability distribution of the real part of an unstable mode can then be obtained by using the surrogate model with a massive saving of

  8. Compaction behavior of surrogate degraded emplaced WIPP waste.

    Energy Technology Data Exchange (ETDEWEB)

    Broome, Scott Thomas [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Bronowski, David R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Kuthakun, Souvanny James [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Herrick, Courtney Grant [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Pfeifle, Thomas W. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2014-03-01

    The present study results are focused on laboratory testing of surrogate waste materials. The surrogate wastes correspond to a conservative estimate of degraded Waste Isolation Pilot Plant (WIPP) containers and TRU waste materials at the end of the 10,000 year regulatory period. Testing consists of hydrostatic, triaxial, and uniaxial strain tests performed on surrogate waste recipes that were previously developed by Hansen et al. (1997). These recipes can be divided into materials that simulate 50% and 100% degraded waste by weight. The percent degradation indicates the anticipated amount of iron corrosion, as well as the decomposition of cellulosics, plastics, and rubbers (CPR). Axial, lateral, and volumetric strain and axial, lateral, and pore stress measurements were made. Two unique testing techniques were developed during the course of the experimental program. The first involves the use of dilatometry to measure sample volumetric strain under a hydrostatic condition. Bulk moduli of the samples measured using this technique were consistent with those measured using more conventional methods. The second technique involved performing triaxial tests under lateral strain control. By limiting the lateral strain to zero by controlling the applied confining pressure while loading the specimen axially in compression, one can maintain a right-circular cylindrical geometry even under large deformations. This technique is preferred over standard triaxial testing methods which result in inhomogeneous deformation or (3z(Bbarreling(3y. (BManifestations of the inhomogeneous deformation included non-uniform stress states, as well as unrealistic Poissons ratios (> 0.5) or those that vary significantly along the length of the specimen. Zero lateral strain controlled tests yield a more uniform stress state, and admissible and uniform values of Poissons ratio.

  9. Biopolicies and biotechnologies: reflections on surrogate maternity in India

    Directory of Open Access Journals (Sweden)

    Mónica Amador

    2010-07-01

    Full Text Available This article explores the impact of biotechnology, particularly on assisted reproductive technologies such as surrogate motherhood. The study is based on interviews and field work conducted in the city of Hyderabad in India within the frame of the seminar on “Research Methodology” given by Dr. Rohan D´Souza at the Centre for Studies in Science Policy at the Jawaharlal Nehru University in India. The theoretical framework of this analysis focuses on exploring concepts such as cyborg (Haraway,1991 and subaltern subject (Spivak, 1998 in the context of biotechnological production in India

  10. Surrogate based approaches to parameter inference in ocean models

    KAUST Repository

    Knio, Omar

    2016-01-06

    This talk discusses the inference of physical parameters using model surrogates. Attention is focused on the use of sampling schemes to build suitable representations of the dependence of the model response on uncertain input data. Non-intrusive spectral projections and regularized regressions are used for this purpose. A Bayesian inference formalism is then applied to update the uncertain inputs based on available measurements or observations. To perform the update, we consider two alternative approaches, based on the application of Markov Chain Monte Carlo methods or of adjoint-based optimization techniques. We outline the implementation of these techniques to infer dependence of wind drag, bottom drag, and internal mixing coefficients.

  11. Multi-level assessment of chronic toxicity of estuarine sediments with the amphipod Gammarus locusta: II. Organism and population-level endpoints.

    Science.gov (United States)

    Costa, Filipe O; Neuparth, Teresa; Correia, Ana D; Costa, Maria Helena

    2005-07-01

    This study aimed to test the performance of the amphipod Gammarus locusta (L.) in chronic sediment toxicity tests. It constitutes part of a multi-level assessment of chronic toxicity of estuarine sediments, integrating organism and population-level endpoints with biochemical markers responses. Here we account for organism and population-level effects, while biomarker responses were reported in a companion article. Five moderately contaminated sediments from Sado and Tagus estuaries were tested, comprising 3 muddy and 2 sandy sediments. These sediments either did not show acute toxicity or were diluted with control sediment as much as required to remove acute toxicity. Subsequent chronic tests consisted of 28-day exposures with survival, individual growth and reproductive traits as endpoints. Two of the muddy sediments induced higher growth rates in the amphipods, and improved reproductive traits. This was understood to be a consequence of the amount of organic matter in the sediment, which was nutritionally beneficial to the amphipods, while concurrently decreasing contaminant bioavailability. Biomarker responses did not reveal toxicant-induced stress in amphipods exposed to these sediments. One of the sandy sediments was acutely toxic at 50% dilution, but in contrast stimulated amphipod growth when diluted 75%. This was presumed to be an indication of a hormetic response. Finally the two remaining contaminated sediments showed pronounced chronic toxicity, affecting survival and reproduction. The sex ratio of survivors was highly biased towards females, and offspring production was severely impaired. The particulars of the responses of this amphipod were examined, as well as strengths versus limitations of the sediment test. This study illustrates the utility of this chronic test for toxicity assessment of contaminated estuarine sediments, with potential application all along Atlantic Europe.

  12. Lung Cancer Biomarkers.

    Science.gov (United States)

    Villalobos, Pamela; Wistuba, Ignacio I

    2017-02-01

    The molecular characterization of lung cancer has changed the classification and treatment of these tumors, becoming an essential component of pathologic diagnosis and oncologic therapy decisions. Through the recognition of novel biomarkers, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocations, it is possible to identify subsets of patients who benefit from targeted molecular therapies. The success of targeted anticancer therapies and new immunotherapy approaches has created a new paradigm of personalized therapy and has led to accelerated development of new drugs for lung cancer treatment. This article focuses on clinically relevant cancer biomarkers as targets for therapy and potential new targets for drug development. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. [New effect biomarkers].

    Science.gov (United States)

    De Palma, G; Corradi, M; Mutti, A; Baccarelli, A; Pesatori, A; Bertazzi, P A

    2004-01-01

    The major research goals for researchers developing biomarkers of effect are the development and validation of biomarkers that permit the prediction of the risk of disease in individuals and groups. One important objective is to prevent human cancer. This article reviews the most recent analytical methodologies, validation studies and field trials together with auditing and quality assessment of the necessary data based on scientific grounds. Consideration is given to new developments in the relatively young field of toxicogenomics, possibly leading to the identification of early changes that may lead to both cancer and non-cancer end points. Although the creation and development of reliable databases integrating information from genomic and proteomic research programmes should offer a contribution to the prediction of risks and prevention of diseases related to chemical exposure, the most promising future application of these technologies lies in the molecular diagnosis of diseases whose nosography will probably be redefined.

  14. Diesel Surrogate Fuels for Engine Testing and Chemical-Kinetic Modeling: Compositions and Properties

    Science.gov (United States)

    Mueller, Charles J.; Cannella, William J.; Bays, J. Timothy; Bruno, Thomas J.; DeFabio, Kathy; Dettman, Heather D.; Gieleciak, Rafal M.; Huber, Marcia L.; Kweon, Chol-Bum; McConnell, Steven S.; Pitz, William J.; Ratcliff, Matthew A.

    2016-01-01

    The primary objectives of this work were to formulate, blend, and characterize a set of four ultralow-sulfur diesel surrogate fuels in quantities sufficient to enable their study in single-cylinder-engine and combustion-vessel experiments. The surrogate fuels feature increasing levels of compositional accuracy (i.e., increasing exactness in matching hydrocarbon structural characteristics) relative to the single target diesel fuel upon which the surrogate fuels are based. This approach was taken to assist in determining the minimum level of surrogate-fuel compositional accuracy that is required to adequately emulate the performance characteristics of the target fuel under different combustion modes. For each of the four surrogate fuels, an approximately 30 L batch was blended, and a number of the physical and chemical properties were measured. This work documents the surrogate-fuel creation process and the results of the property measurements. PMID:27330248

  15. Fast and accurate prediction of numerical relativity waveforms from binary black hole mergers using surrogate models

    CERN Document Server

    Blackman, Jonathan; Galley, Chad R; Szilagyi, Bela; Scheel, Mark A; Tiglio, Manuel; Hemberger, Daniel A

    2015-01-01

    Simulating a binary black hole coalescence by solving Einstein's equations is computationally expensive, requiring days to months of supercomputing time. In this paper, we construct an accurate and fast-to-evaluate surrogate model for numerical relativity (NR) waveforms from non-spinning binary black hole coalescences with mass ratios from $1$ to $10$ and durations corresponding to about $15$ orbits before merger. Our surrogate, which is built using reduced order modeling techniques, is distinct from traditional modeling efforts. We find that the full multi-mode surrogate model agrees with waveforms generated by NR to within the numerical error of the NR code. In particular, we show that our modeling strategy produces surrogates which can correctly predict NR waveforms that were {\\em not} used for the surrogate's training. For all practical purposes, then, the surrogate waveform model is equivalent to the high-accuracy, large-scale simulation waveform but can be evaluated in a millisecond to a second dependin...

  16. Biomarkers of Selenium Status

    Directory of Open Access Journals (Sweden)

    Gerald F. Combs, Jr.

    2015-03-01

    Full Text Available The essential trace element, selenium (Se, has multiple biological activities, which depend on the level of Se intake. Relatively low Se intakes determine the expression of selenoenzymes in which it serves as an essential constituent. Higher intakes have been shown to have anti-tumorigenic potential; and very high Se intakes can produce adverse effects. This hierarchy of biological activities calls for biomarkers informative at different levels of Se exposure. Some Se-biomarkers, such as the selenoproteins and particularly GPX3 and SEPP1, provide information about function directly and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se-treatment. They are useful under conditions of Se intake within the range of regulated selenoprotein expression, e.g., for humans <55 μg/day and for animals <20 μg/kg diet. Other Se-biomarkers provide information indirectly through inferences based on Se levels of foods, tissues, urine or feces. They can indicate the likelihood of deficiency or adverse effects, but they do not provide direct evidence of either condition. Their value is in providing information about Se status over a wide range of Se intake, particularly from food forms. There is need for additional Se biomarkers particularly for assessing Se status in non-deficient individuals for whom the prospects of cancer risk reduction and adverse effects risk are the primary health considerations. This would include determining whether supranutritional intakes of Se may be required for maximal selenoprotein expression in immune surveillance cells. It would also include developing methods to determine low molecular weight Se-metabolites, i.e., selenoamino acids and methylated Se-metabolites, which to date have not been detectable in biological specimens. Recent analytical advances using tandem liquid chromatography-mass spectrometry suggest prospects for detecting these metabolites.

  17. Progression-free survival, post-progression survival, and tumor response as surrogate markers for overall survival in patients with extensive small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Hisao Imai

    2015-01-01

    Full Text Available Objectives: The effects of first-line chemotherapy on overall survival (OS might be confounded by subsequent therapies in patients with small cell lung cancer (SCLC. We examined whether progression-free survival (PFS, post-progression survival (PPS, and tumor response could be valid surrogate endpoints for OS after first-line chemotherapies for patients with extensive SCLC using individual-level data. Methods: Between September 2002 and November 2012, we analyzed 49 cases of patients with extensive SCLC who were treated with cisplatin and irinotecan as first-line chemotherapy. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. Results: Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.97, p < 0.05, R 2 = 0.94, PFS was moderately correlated with OS (r = 0.58, p < 0.05, R 2 = 0.24, and tumor shrinkage was weakly correlated with OS (r = 0.37, p < 0.05, R 2 = 0.13. The best response to second-line treatment, and the number of regimens employed after progression beyond first-line chemotherapy were both significantly associated with PPS ( p ≤ 0.05. Conclusion: PPS is a potential surrogate for OS in patients with extensive SCLC. Our findings also suggest that subsequent treatment after disease progression following first-line chemotherapy may greatly influence OS.

  18. Biomarkers of Ovarian Reserve

    Directory of Open Access Journals (Sweden)

    William E. Roudebush

    2008-01-01

    Full Text Available The primary function of the female ovary is the production of a mature and viable oocyte capable of fertilization and subsequent embryo development and implantation. At birth, the ovary contains a finite number of oocytes available for folliculogenesis. This finite number of available oocytes is termed “the ovarian reserve”. The determination of ovarian reserve is important in the assessment and treatment of infertility. As the ovary ages, the ovarian reserve will decline. Infertility affects approximately 15-20% of reproductive aged couples. The most commonly used biomarker assay to assess ovarian reserve is the measurement of follicle stimulating hormone (FSH on day 3 of the menstrual cycle. However, antimüllerian hormone and inhibin-B are other biomarkers of ovarian reserve that are gaining in popularity since they provide direct determination of ovarian status, whereas day 3 FSH is an indirect measurement. This review examines the physical tools and the hormone biomarkers used to evaluate ovarian reserve.

  19. Combining endangered plants and animals as surrogates to identify priority conservation areas in Yunnan, China

    OpenAIRE

    Feiling Yang; Jinming Hu; Ruidong Wu

    2016-01-01

    Suitable surrogates are critical for identifying optimal priority conservation areas (PCAs) to protect regional biodiversity. This study explored the efficiency of using endangered plants and animals as surrogates for identifying PCAs at the county level in Yunnan, southwest China. We ran the Dobson algorithm under three surrogate scenarios at 75% and 100% conservation levels and identified four types of PCAs. Assessment of the protection efficiencies of the four types of PCAs showed that end...

  20. Surrogate Mobility and Orientation Affect the Early Neurobehavioral Development of Infant Rhesus Macaques (Macaca mulatta)

    OpenAIRE

    Amanda M Dettmer; Ruggerio, Angela M.; Novak, Melinda A.; Meyer, Jerrold S.; Suomi, Stephen J.

    2008-01-01

    A biological mother’s movement appears necessary for optimal development in infant monkeys. However, nursery-reared monkeys are typically provided with inanimate surrogate mothers that move very little. The purpose of this study was to evaluate the effects of a novel, highly mobile surrogate mother on motor development, exploration, and reactions to novelty. Six infant rhesus macaques (Macaca mulatta) were reared on mobile hanging surrogates (MS) and compared to six infants reared on standard...

  1. Potential biomarkers for monitoring therapeutic response in patients with CIDP.

    Science.gov (United States)

    Dalakas, Marinos C

    2011-06-01

    Although the majority of patients with CIDP variably respond to intravenous immunoglobulin (IVIg), steroids, or plasmapheresis, 30% of them are unresponsive or insufficiently responsive to these therapies. The heterogeneity in therapeutic responses necessitates the need to search for biomarkers to determine the most suitable therapy from the outset and explore the best means for monitoring disease activity. The ICE study, which led to the first FDA-approved indication for IVIg in CIDP, has shown that maintenance therapy prevents relapses and axonal loss. In this paper, the multiple actions exerted by IVIg on the immunoregulatory network of CIDP are discussed as potential predictors of response to therapies. Emerging molecular markers, promising in identifying responders to IVIg from non-responders, include modulation of FcγRIIB receptors on monocytes and genome-wide transcription studies related to inflammatory mediators, demyelination, or axonal degeneration. Skin biopsies, Peripheral Blood Lymhocytes, CSF, and sera are accessible surrogate tissues for further exploring these molecules during therapies.

  2. Circulating DNA as Potential Biomarker for Cancer Individualized Therapy

    Institute of Scientific and Technical Information of China (English)

    Yu Shaorong; Liu Baorui; Lu Jianwei; Feng Jifeng

    2013-01-01

    Cancer individualized therapy often requires for gene mutation analysis of tumor tissue. However, tumor tissue is not always available in clinical practice, particularly from patients with refractory and recurrence disease. Even if patients have sufifcient tumor tissue for detection, as development of cancer, the gene status and drug sensitivity of tumor tissues could also change. Hence, screening mutations from primary tumor tissues becomes useless, it’s necessary to ifnd a surrogate tumor tissue for individualized gene screening. Circulating DNA is digested rapidly from blood, which could provide real-time information of the released fragment and make the real-time detection possible. Therefore, it’s expected that circulating DNA could be a potential tumor biomarker for cancer individualized therapy. This review focuses on the biology and clinical utility of circulating DNA mainly on gene mutation detection. Besides, its current status and possible direction in this research area is summarized and discussed objectively.

  3. IDBD: infectious disease biomarker database.

    Science.gov (United States)

    Yang, In Seok; Ryu, Chunsun; Cho, Ki Joon; Kim, Jin Kwang; Ong, Swee Hoe; Mitchell, Wayne P; Kim, Bong Su; Oh, Hee-Bok; Kim, Kyung Hyun

    2008-01-01

    Biomarkers enable early diagnosis, guide molecularly targeted therapy and monitor the activity and therapeutic responses across a variety of diseases. Despite intensified interest and research, however, the overall rate of development of novel biomarkers has been falling. Moreover, no solution is yet available that efficiently retrieves and processes biomarker information pertaining to infectious diseases. Infectious Disease Biomarker Database (IDBD) is one of the first efforts to build an easily accessible and comprehensive literature-derived database covering known infectious disease biomarkers. IDBD is a community annotation database, utilizing collaborative Web 2.0 features, providing a convenient user interface to input and revise data online. It allows users to link infectious diseases or pathogens to protein, gene or carbohydrate biomarkers through the use of search tools. It supports various types of data searches and application tools to analyze sequence and structure features of potential and validated biomarkers. Currently, IDBD integrates 611 biomarkers for 66 infectious diseases and 70 pathogens. It is publicly accessible at http://biomarker.cdc.go.kr and http://biomarker.korea.ac.kr.

  4. Evaluation of the use of surrogate Laminaria digitata in eco-hydraulic laboratory experiments

    Institute of Scientific and Technical Information of China (English)

    PAUL Maike; HENRY Pierre-Yves T

    2014-01-01

    Inert surrogates can avoid husbandry and adaptation problems of live vegetation in laboratories. Surrogates are generally used for experiments on vegetation-hydrodynamics interactions, but it is unclear how well they replicate field conditions. Here, surrogates for the brown macroalgae Laminaria digitata were developed to reproduce its hydraulic roughness. Plant shape, stiffness and buoyancy of L. digitata were evaluated and compared to the properties of inert materials. Different surrogate materials and shapes were exposed to unidirectional flow. It is concluded that buoyancy is an important factor in low flow conditions and a basic shape might be sufficient to model complex shaped plants resulting in the same streamlined shape.

  5. Detailed chemical kinetic oxidation mechanism for a biodiesel surrogate

    Energy Technology Data Exchange (ETDEWEB)

    Herbinet, O; Pitz, W J; Westbrook, C K

    2007-09-20

    A detailed chemical kinetic mechanism has been developed and used to study the oxidation of methyl decanoate, a surrogate for biodiesel fuels. This model has been built by following the rules established by Curran et al. for the oxidation of n-heptane and it includes all the reactions known to be pertinent to both low and high temperatures. Computed results have been compared with methyl decanoate experiments in an engine and oxidation of rapeseed oil methyl esters in a jet stirred reactor. An important feature of this mechanism is its ability to reproduce the early formation of carbon dioxide that is unique to biofuels and due to the presence of the ester group in the reactant. The model also predicts ignition delay times and OH profiles very close to observed values in shock tube experiments fueled by n-decane. These model capabilities indicate that large n-alkanes can be good surrogates for large methyl esters and biodiesel fuels to predict overall reactivity, but some kinetic details, including early CO{sub 2} production from biodiesel fuels, can be predicted only by a detailed kinetic mechanism for a true methyl ester fuel. The present methyl decanoate mechanism provides a realistic kinetic tool for simulation of biodiesel fuels.

  6. Detailed chemical kinetic oxidation mechanism for a biodiesel surrogate

    Energy Technology Data Exchange (ETDEWEB)

    Herbinet, O; Pitz, W J; Westbrook, C K

    2007-09-17

    A detailed chemical kinetic mechanism has been developed and used to study the oxidation of methyl decanoate, a surrogate for biodiesel fuels. This model has been built by following the rules established by Curran et al. for the oxidation of n-heptane and it includes all the reactions known to be pertinent to both low and high temperatures. Computed results have been compared with methyl decanoate experiments in an engine and oxidation of rapeseed oil methyl esters in a jet stirred reactor. An important feature of this mechanism is its ability to reproduce the early formation of carbon dioxide that is unique to biofuels and due to the presence of the ester group in the reactant. The model also predicts ignition delay times and OH profiles very close to observed values in shock tube experiments fueled by n-decane. These model capabilities indicate that large n-alkanes can be good surrogates for large methyl esters and biodiesel fuels to predict overall reactivity, but some kinetic details, including early CO2 production from biodiesel fuels, can be predicted only by a detailed kinetic mechanism for a true methyl ester fuel. The present methyl decanoate mechanism provides a realistic kinetic tool for simulation of biodiesel fuels.

  7. Simultaneous Thermal Analysis of Remediated Nitrate Salt Surrogates

    Energy Technology Data Exchange (ETDEWEB)

    Wayne, David Matthew [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-05-13

    The actinide engineering and science group (MET-1) have completed simultaneous thermal analysis and offgas analysis by mass spectrometry (STA-MS) of remediated nitrate salt (RNS) surrogates formulated by the high explosives science and technology group (M-7). The 1.0 to 1.5g surrogate samples were first analyzed as received, then a new set was analyzed with 100-200mL 10M HNO3 +0.3 MHF added, and a third set was analyzed after 200 mL of a concentrated Pu-AM spike (in 10M HNO3 +0.3 MHF) was added. The acid and spike solutions were formulated by the actinide analytical chemistry group (C-AAC) using reagent-grade HNO3 and HF, which was also used to dissolve a small quantity of mixed, high-fired PuO2/ AmO2 oxide.

  8. Detailed chemical kinetic oxidation mechanism for a biodiesel surrogate

    Energy Technology Data Exchange (ETDEWEB)

    Herbinet, O; Pitz, W J; Westbrook, C K

    2007-09-20

    A detailed chemical kinetic mechanism has been developed and used to study the oxidation of methyl decanoate, a surrogate for biodiesel fuels. This model has been built by following the rules established by Curran et al. for the oxidation of n-heptane and it includes all the reactions known to be pertinent to both low and high temperatures. Computed results have been compared with methyl decanoate experiments in an engine and oxidation of rapeseed oil methyl esters in a jet stirred reactor. An important feature of this mechanism is its ability to reproduce the early formation of carbon dioxide that is unique to biofuels and due to the presence of the ester group in the reactant. The model also predicts ignition delay times and OH profiles very close to observed values in shock tube experiments fueled by n-decane. These model capabilities indicate that large n-alkanes can be good surrogates for large methyl esters and biodiesel fuels to predict overall reactivity, but some kinetic details, including early CO{sub 2} production from biodiesel fuels, can be predicted only by a detailed kinetic mechanism for a true methyl ester fuel. The present methyl decanoate mechanism provides a realistic kinetic tool for simulation of biodiesel fuels.

  9. Detailed chemical kinetic oxidation mechanism for a biodiesel surrogate

    Energy Technology Data Exchange (ETDEWEB)

    Herbinet, O; Pitz, W J; Westbrook, C K

    2007-09-17

    A detailed chemical kinetic mechanism has been developed and used to study the oxidation of methyl decanoate, a surrogate for biodiesel fuels. This model has been built by following the rules established by Curran et al. for the oxidation of n-heptane and it includes all the reactions known to be pertinent to both low and high temperatures. Computed results have been compared with methyl decanoate experiments in an engine and oxidation of rapeseed oil methyl esters in a jet stirred reactor. An important feature of this mechanism is its ability to reproduce the early formation of carbon dioxide that is unique to biofuels and due to the presence of the ester group in the reactant. The model also predicts ignition delay times and OH profiles very close to observed values in shock tube experiments fueled by n-decane. These model capabilities indicate that large n-alkanes can be good surrogates for large methyl esters and biodiesel fuels to predict overall reactivity, but some kinetic details, including early CO2 production from biodiesel fuels, can be predicted only by a detailed kinetic mechanism for a true methyl ester fuel. The present methyl decanoate mechanism provides a realistic kinetic tool for simulation of biodiesel fuels.

  10. Premixed flame chemistry of a gasoline primary reference fuel surrogate

    KAUST Repository

    Selim, Hatem

    2017-03-10

    Investigating the combustion chemistry of gasoline surrogate fuels promises to improve detailed reaction mechanisms used for simulating their combustion. In this work, the combustion chemistry of one of the simplest, but most frequently used gasoline surrogates – primary reference fuel 84 (PRF 84, 84 vol% iso-octane and 16 vol% n-heptane), has been examined in a stoichiometric premixed laminar flame. Time-of-flight mass spectrometry coupled with a vacuum ultraviolet (VUV) synchrotron light source for species photoionization was used. Reactants, major end-products, stable intermediates, free radicals, and isomeric species were detected and quantified. Numerical simulations were conducted using a detailed chemical kinetic model with the most recently available high temperature sub-mechanisms for iso-octane and heptane, built on the top of an updated pentane isomers model and AramcoMech 2.0 (C0C4) base chemistry. A detailed interpretation of the major differences between the mechanistic pathways of both fuel components is given. A comparison between the experimental and numerical results is depicted and rate of production and sensitivity analyses are shown for the species with considerable disagreement between the experimental and numerical findings.

  11. Bayesian Calibration of the Community Land Model using Surrogates

    Energy Technology Data Exchange (ETDEWEB)

    Ray, Jaideep; Hou, Zhangshuan; Huang, Maoyi; Sargsyan, K.; Swiler, Laura P.

    2015-01-01

    We present results from the Bayesian calibration of hydrological parameters of the Community Land Model (CLM), which is often used in climate simulations and Earth system models. A statistical inverse problem is formulated for three hydrological parameters, conditioned on observations of latent heat surface fluxes over 48 months. Our calibration method uses polynomial and Gaussian process surrogates of the CLM, and solves the parameter estimation problem using a Markov chain Monte Carlo sampler. Posterior probability densities for the parameters are developed for two sites with different soil and vegetation covers. Our method also allows us to examine the structural error in CLM under two error models. We find that accurate surrogate models can be created for CLM in most cases. The posterior distributions lead to better prediction than the default parameter values in CLM. Climatologically averaging the observations does not modify the parameters’ distributions significantly. The structural error model reveals a correlation time-scale which can potentially be used to identify physical processes that could be contributing to it. While the calibrated CLM has a higher predictive skill, the calibration is under-dispersive.

  12. Fractional flow reserve as a surrogate for inducible myocardial ischaemia.

    Science.gov (United States)

    van de Hoef, Tim P; Meuwissen, Martijn; Escaned, Javier; Davies, Justin E; Siebes, Maria; Spaan, Jos A E; Piek, Jan J

    2013-08-01

    Documentation of inducible myocardial ischaemia, related to the coronary stenosis of interest, is of increasing importance in lesion selection for percutaneous coronary intervention (PCI). Fractional flow reserve (FFR) is an easily understood, routine diagnostic modality that has become part of daily clinical practice, and is used as a surrogate technique for noninvasive assessment of myocardial ischaemia. However, the application of a single, discrete, cut-off value for FFR-guided lesion selection for PCI, and its adoption in contemporary revascularization guidelines, has limited the requirement for a thorough understanding of the physiological basis of FFR. This limitation constitutes an obstacle for the adequate use and interpretation of this technique, and also for the understanding of new and future modalities of physiological functional intracoronary testing. In this Review, we revisit the fundamental elements of coronary physiology in the absence or presence of coronary artery disease. We provide insight into three essential characteristics of FFR as a diagnostic tool in contemporary clinical practice--the theoretical framework of FFR and its associated limitations; the characteristics and role of FFR as a surrogate for noninvasively assessed myocardial ischaemia; and the requirement and associated caveats of potent vasodilatory drugs to induce maximal vasodilatation of the coronary vascular bed.

  13. The development of radioactive sample surrogates for training and exercises

    Energy Technology Data Exchange (ETDEWEB)

    Martha Finck; Bevin Brush; Dick Jansen; David Chamberlain; Don Dry; George Brooks; Margaret Goldberg

    2012-03-01

    The development of radioactive sample surrogates for training and exercises Source term information is required for to reconstruct a device used in a dispersed radiological dispersal device. Simulating a radioactive environment to train and exercise sampling and sample characterization methods with suitable sample materials is a continued challenge. The Idaho National Laboratory has developed and permitted a Radioactive Response Training Range (RRTR), an 800 acre test range that is approved for open air dispersal of activated KBr, for training first responders in the entry and exit from radioactively contaminated areas, and testing protocols for environmental sampling and field characterization. Members from the Department of Defense, Law Enforcement, and the Department of Energy participated in the first contamination exercise that was conducted at the RRTR in the July 2011. The range was contaminated using a short lived radioactive Br-82 isotope (activated KBr). Soil samples contaminated with KBr (dispersed as a solution) and glass particles containing activated potassium bromide that emulated dispersed radioactive materials (such as ceramic-based sealed source materials) were collected to assess environmental sampling and characterization techniques. This presentation summarizes the performance of a radioactive materials surrogate for use as a training aide for nuclear forensics.

  14. Pan masala advertisements are surrogate for tobacco products.

    Science.gov (United States)

    Sushma, C; Sharang, C

    2005-01-01

    Pan masala is a comparatively recent habit in India and is marketed with and without tobacco. Advertisements of tobacco products have been banned in India since 1st May 2004. The advertisements of plain pan masala, which continue in Indian media, have been suspected to be surrogate for tobacco products bearing the same name. The study was carried out to assess whether these advertisements were for the intended product, or for tobacco products with same brand name. The programme of a popular television Hindi news channel was watched for a 24-h period. Programmes on the same channel and its English counterpart were watched on different days to assess whether the advertisements were repeated. The total duration of telecast of a popular brand of plain pan masala (Pan Parag) was multiplied by the rate charged by the channel to provide the cost of advertisement of this product. The total sale value of the company was multiplied by the proportion of usage of plain pan masala out of gutka plus pan masala habit as observed from a different study, to provide the annual sale value of plain pan masala product under reference. The annual sale value of plain Pan Parag was estimated to be Rs. 67.1 million. The annual cost of the advertisement of the same product on two television channels was estimated at Rs. 244.6 million. The advertisements of plain pan masala seen on Indian television are a surrogate for the tobacco products bearing the same name.

  15. Defining useful surrogates for user participation in online medical learning.

    LENUS (Irish Health Repository)

    Beddy, Peter

    2012-02-01

    "School for Surgeons" is a web-based distance learning program which provides online clinical-based tutorials to surgical trainees. Our aim was to determine surrogates of active participation and to assess the efficacy of methods to improve usage. Server logs of the 82 participants in the "School for Surgeons" were assessed for the two terms of the first year of the program. Data collected included total time online, mean session time, page requests, numbers of sessions online and the total number of assignments. An intervention regarding comparative peer usage patterns was delivered to the cohort between terms one and two. Of the 82 trainees enrolled, 83% (85% second term) logged into the program. Of all participants 88% (97% second term) submitted at least one assignment. Median submissions were four (eight second term) per trainee. Assignment submission closely correlated with number of sessions, total time online, downloads and page requests. Peer-based comparative feedback resulted in a significant increase in the number of assignments submitted (p < 0.01). Despite its recent introduction, "School for Surgeons" has a good participation rate. Assignment submission is a valid surrogate for usage. Students can be encouraged to move from passive observation to active participation in a virtual learning environment by providing structured comparative feedback ranking their performance.

  16. Proper Orthogonal Decomposition as Surrogate Model for Aerodynamic Optimization

    Directory of Open Access Journals (Sweden)

    Valentina Dolci

    2016-01-01

    Full Text Available A surrogate model based on the proper orthogonal decomposition is developed in order to enable fast and reliable evaluations of aerodynamic fields. The proposed method is applied to subsonic turbulent flows and the proper orthogonal decomposition is based on an ensemble of high-fidelity computations. For the construction of the ensemble, fractional and full factorial planes together with central composite design-of-experiment strategies are applied. For the continuous representation of the projection coefficients in the parameter space, response surface methods are employed. Three case studies are presented. In the first case, the boundary shape of the problem is deformed and the flow past a backward facing step with variable step slope is studied. In the second case, a two-dimensional flow past a NACA 0012 airfoil is considered and the surrogate model is constructed in the (Mach, angle of attack parameter space. In the last case, the aerodynamic optimization of an automotive shape is considered. The results demonstrate how a reduced-order model based on the proper orthogonal decomposition applied to a small number of high-fidelity solutions can be used to generate aerodynamic data with good accuracy at a low cost.

  17. Bayesian calibration of the Community Land Model using surrogates

    Energy Technology Data Exchange (ETDEWEB)

    Ray, Jaideep; Hou, Zhangshuan; Huang, Maoyi; Swiler, Laura Painton

    2014-02-01

    We present results from the Bayesian calibration of hydrological parameters of the Community Land Model (CLM), which is often used in climate simulations and Earth system models. A statistical inverse problem is formulated for three hydrological parameters, conditional on observations of latent heat surface fluxes over 48 months. Our calibration method uses polynomial and Gaussian process surrogates of the CLM, and solves the parameter estimation problem using a Markov chain Monte Carlo sampler. Posterior probability densities for the parameters are developed for two sites with different soil and vegetation covers. Our method also allows us to examine the structural error in CLM under two error models. We find that surrogate models can be created for CLM in most cases. The posterior distributions are more predictive than the default parameter values in CLM. Climatologically averaging the observations does not modify the parameters' distributions significantly. The structural error model reveals a correlation time-scale which can be used to identify the physical process that could be contributing to it. While the calibrated CLM has a higher predictive skill, the calibration is under-dispersive.

  18. PROFILEing idiopathic pulmonary fibrosis: rethinking biomarker discovery

    Directory of Open Access Journals (Sweden)

    Toby M. Maher

    2013-06-01

    Full Text Available Despite major advances in the understanding of the pathogenesis of idiopathic pulmonary fibrosis (IPF, diagnosis and management of the condition continue to pose significant challenges. Clinical management of IPF remains unsatisfactory due to limited availability of effective drug therapies, a lack of accurate indicators of disease progression, and an absence of simple short-term measures of therapeutic response. The identification of more accurate predictors of prognosis and survival in IPF would facilitate counseling of patients and their families, aid communication among clinicians, and would guide optimal timing of referral for transplantation. Improvements in molecular techniques have led to the identification of new disease pathways and a more targeted approach to the development of novel anti-fibrotic agents. However, despite an increased interest in biomarkers of IPF disease progression there are a lack of measures that can be used in early phase clinical trials. Careful longitudinal phenotyping of individuals with IPF together with the application of novel omics-based technology should provide important insights into disease pathogenesis and should address some of the major issues holding back drug development in IPF. The PROFILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints study is a currently enrolling, prospective cohort study designed to tackle these issues.

  19. Metabolomics for Biomarker Discovery in Gastroenterological Cancer

    Science.gov (United States)

    Nishiumi, Shin; Suzuki, Makoto; Kobayashi, Takashi; Matsubara, Atsuki; Azuma, Takeshi; Yoshida, Masaru

    2014-01-01

    The study of the omics cascade, which involves comprehensive investigations based on genomics, transcriptomics, proteomics, metabolomics, etc., has developed rapidly and now plays an important role in life science research. Among such analyses, metabolome analysis, in which the concentrations of low molecular weight metabolites are comprehensively analyzed, has rapidly developed along with improvements in analytical technology, and hence, has been applied to a variety of research fields including the clinical, cell biology, and plant/food science fields. The metabolome represents the endpoint of the omics cascade and is also the closest point in the cascade to the phenotype. Moreover, it is affected by variations in not only the expression but also the enzymatic activity of several proteins. Therefore, metabolome analysis can be a useful approach for finding effective diagnostic markers and examining unknown pathological conditions. The number of studies involving metabolome analysis has recently been increasing year-on-year. Here, we describe the findings of studies that used metabolome analysis to attempt to discover biomarker candidates for gastroenterological cancer and discuss metabolome analysis-based disease diagnosis. PMID:25003943

  20. Vertical Flume Testing of WIPP Surrogate Waste Materials

    Science.gov (United States)

    Herrick, C. G.; Schuhen, M.; Kicker, D.

    2013-12-01

    The Waste Isolation Pilot Plant (WIPP) is a U.S. Department of Energy geological repository for the permanent disposal of defense-related transuranic (TRU) waste. The waste is emplaced in rooms excavated in the bedded Salado salt formation at a depth of 655 m below ground surface. After emplacement of the waste, the repository will be sealed and decommissioned. The DOE demonstrates compliance with 40 CFR 194 by means of performance assessment (PA) calculations conducted by Sandia National Laboratories. WIPP PA calculations estimate the probability and consequences of radionuclide releases for a 10,000 year regulatory period. Human intrusion scenarios include cases in which a future borehole is drilled through the repository. Drilling mud flowing up the borehole will apply a hydrodynamic shear stress to the borehole wall which could result in erosion of the waste and radionuclides being carried up the borehole. WIPP PA uses the parameter TAUFAIL to represent the shear strength of the degraded waste. The hydrodynamic shear strength can only be measured experimentally by flume testing. Flume testing is typically performed horizontally, mimicking stream or ocean currents. However, in a WIPP intrusion event, the drill bit would penetrate the degraded waste and drilling mud would flow up the borehole in a predominantly vertical direction. In order to simulate this, a flume was designed and built so that the eroding fluid enters an enclosed vertical channel from the bottom and flows up past a specimen of surrogate waste material. The sample is pushed into the current by a piston attached to a step motor. A qualified data acquisition system controls and monitors the fluid's flow rate, temperature, pressure, and conductivity and the step motor's operation. The surrogate materials used correspond to a conservative estimate of degraded TRU waste at the end of the regulatory period. The recipes were previously developed by SNL based on anticipated future states of the waste

  1. Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques.

    Directory of Open Access Journals (Sweden)

    John G Hattersley

    Full Text Available We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR. Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6 ± 1.0 years, BMI 31.5 ± 0.4 kg/m(2; 30 males. HEP-IR was defined by measuring endogenous-glucose-production (EGP with [6-6(2H(2] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control. All five indices produced comparable prediction of HEP-IR, explaining 39-56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r(2 = 27-32% on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P<0.001. However, when validated against the alternative dataset all indices performed comparably with the standard homeostasis model assessment for insulin resistance (HOMA-IR (r = 0.54, P<0.001. Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations.

  2. Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques.

    Science.gov (United States)

    Hattersley, John G; Möhlig, Matthias; Roden, Michael; Arafat, Ayman M; Loeffelholz, Christian V; Nowotny, Peter; Machann, Jürgen; Hierholzer, Johannes; Osterhoff, Martin; Khan, Michael; Pfeiffer, Andreas F H; Weickert, Martin O

    2012-01-01

    We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6 ± 1.0 years, BMI 31.5 ± 0.4 kg/m(2); 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6-6(2)H(2)] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39-56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r(2) = 27-32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, Presistance (HOMA-IR) (r = 0.54, P<0.001). Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations.

  3. The contribution of physicochemical properties to multiple in vitro cytotoxicity endpoints.

    Science.gov (United States)

    Lu, Shuyan; Jessen, Bart; Strock, Christopher; Will, Yvonne

    2012-06-01

    Attrition due to safety reasons remains a serious problem for the pharmaceutical industry. This has prompted efforts to develop early predictive in vitro screens that can assist in selecting compounds with a more desirable safety profile early on in the drug discovery process. Here we examined the relationship between physicochemical properties, such as partition coefficient (clogP), topological polar surface area (TPSA), acid dissociation constant (pK(a)), and in vitro mechanistic endpoints generated using a high content imaging approach. We demonstrate in our initial analysis that compounds with clogP>2 and pK(a)>5.5 flagged more endpoints than compounds with clogP ≤ 2 and pK(a) ≤ 5.5. In contrast, TPSA did not stand on its own in predicting cytotoxicity. When this knowledge was applied to eight different mechanistic cytotoxicity endpoints (cell loss, apoptosis, ER stress, DNA fragmentation, mitochondrial potential, nuclear size, neutral lipids/steatosis and lysosomal mass), we found that compounds with such properties preferentially flagged in the lysosomal endpoint. We also saw a slight enrichment of such compounds in the endpoints cell loss, DNA fragmentation and nuclear size. We demonstrate that lysosomal compound accumulation is a potential contributor to cell death and possibly organ toxicity.

  4. Latent variable indirect response modeling of categorical endpoints representing change from baseline.

    Science.gov (United States)

    Hu, Chuanpu; Xu, Zhenhua; Mendelsohn, Alan M; Zhou, Honghui

    2013-02-01

    Accurate exposure-response modeling is important in drug development. Methods are still evolving in the use of mechanistic, e.g., indirect response (IDR) models to relate discrete endpoints, mostly of the ordered categorical form, to placebo/co-medication effect and drug exposure. When the discrete endpoint is derived using change-from-baseline measurements, a mechanistic exposure-response modeling approach requires adjustment to maintain appropriate interpretation. This manuscript describes a new modeling method that integrates a latent-variable representation of IDR models with standard logistic regression. The new method also extends to general link functions that cover probit regression or continuous clinical endpoint modeling. Compared to an earlier latent variable approach that constrained the baseline probability of response to be 0, placebo effect parameters in the new model formulation are more readily interpretable and can be separately estimated from placebo data, thus allowing convenient and robust model estimation. A general inherent connection of some latent variable representations with baseline-normalized standard IDR models is derived. For describing clinical response endpoints, Type I and Type III IDR models are shown to be equivalent, therefore there are only three identifiable IDR models. This approach was applied to data from two phase III clinical trials of intravenously administered golimumab for the treatment of rheumatoid arthritis, where 20, 50, and 70% improvement in the American College of Rheumatology disease severity criteria were used as efficacy endpoints. Likelihood profiling and visual predictive checks showed reasonable parameter estimation precision and model performance.

  5. Assessing multiple endpoints of atrazine ingestion on gravid Northern Watersnakes (Nerodia sipedon) and their offspring.

    Science.gov (United States)

    Neuman-Lee, Lorin A; Gaines, Karen F; Baumgartner, Kyle A; Voorhees, Jaymie R; Novak, James M; Mullin, Stephen J

    2014-09-01

    Ecotoxicological studies that focus on a single endpoint might not accurately and completely represent the true ecological effects of a contaminant. Exposure to atrazine, a widely used herbicide, disrupts endocrine function and sexual development in amphibians, but studies involving live-bearing reptiles are lacking. This study tracks several effects of atrazine ingestion from female Northern Watersnakes (Nerodia sipedon) to their offspring exposed in utero. Twenty-five gravid N. sipedon were fed fish dosed with one of the four levels of atrazine (0, 2, 20, or 200 ppb) twice weekly for the entirety of their gestation period. Endpoints for the mothers included blood estradiol levels measured weekly and survival more than 3 months. Endpoints for the offspring included morphometrics, clutch sex ratio, stillbirth, and asymmetry of dorsal scales and jaw length. Through these multiple endpoints, we show that atrazine ingestion can disrupt estradiol production in mothers, increase the likelihood of mortality from infection, alter clutch sex ratio, cause a higher proportion of stillborn offspring, and affect scale symmetry. We emphasize the need for additional research involving other reptile species using multiple endpoints to determine the full range of impacts of contaminant exposure. Copyright © 2013 Wiley Periodicals, Inc., a Wiley company.

  6. Multi-Toxic Endpoints of the Foodborne Mycotoxins in Nematode Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Zhendong Yang

    2015-12-01

    Full Text Available Aflatoxins B1 (AFB1, deoxynivalenol (DON, fumonisin B1 (FB1, T-2 toxin (T-2, and zearalenone (ZEA are the major foodborne mycotoxins of public health concerns. In the present study, the multiple toxic endpoints of these naturally-occurring mycotoxins were evaluated in Caenorhabditis elegans model for their lethality, toxic effects on growth and reproduction, as well as influence on lifespan. We found that the lethality endpoint was more sensitive for T-2 toxicity with the EC50 at 1.38 mg/L, the growth endpoint was relatively sensitive for AFB1 toxic effects, and the reproduction endpoint was more sensitive for toxicities of AFB1, FB1, and ZEA. Moreover, the lifespan endpoint was sensitive to toxic effects of all five tested mycotoxins. Data obtained from this study may serve as an important contribution to knowledge on assessment of mycotoxin toxic effects, especially for assessing developmental and reproductive toxic effects, using the C. elegans model.

  7. Early diagnosis of complex diseases by molecular biomarkers, network biomarkers, and dynamical network biomarkers.

    Science.gov (United States)

    Liu, Rui; Wang, Xiangdong; Aihara, Kazuyuki; Chen, Luonan

    2014-05-01

    Many studies have been carried out for early diagnosis of complex diseases by finding accurate and robust biomarkers specific to respective diseases. In particular, recent rapid advance of high-throughput technologies provides unprecedented rich information to characterize various disease genotypes and phenotypes in a global and also dynamical manner, which significantly accelerates the study of biomarkers from both theoretical and clinical perspectives. Traditionally, molecular biomarkers that distinguish disease samples from normal samples are widely adopted in clinical practices due to their ease of data measurement. However, many of them suffer from low coverage and high false-positive rates or high false-negative rates, which seriously limit their further clinical applications. To overcome those difficulties, network biomarkers (or module biomarkers) attract much attention and also achieve better performance because a network (or subnetwork) is considered to be a more robust form to characterize diseases than individual molecules. But, both molecular biomarkers and network biomarkers mainly distinguish disease samples from normal samples, and they generally cannot ensure to identify predisease samples due to their static nature, thereby lacking ability to early diagnosis. Based on nonlinear dynamical theory and complex network theory, a new concept of dynamical network biomarkers (DNBs, or a dynamical network of biomarkers) has been developed, which is different from traditional static approaches, and the DNB is able to distinguish a predisease state from normal and disease states by even a small number of samples, and therefore has great potential to achieve "real" early diagnosis of complex diseases. In this paper, we comprehensively review the recent advances and developments on molecular biomarkers, network biomarkers, and DNBs in particular, focusing on the biomarkers for early diagnosis of complex diseases considering a small number of samples and high

  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

    DEFF Research Database (Denmark)

    Hagmar, L; Bonassi, S; Strömberg, U;

    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...... 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...

  9. A critique of biomarkers in environmental toxicology: A case study in birds

    Energy Technology Data Exchange (ETDEWEB)

    Bellward, G.D. [Univ. of British Columbia, Vancouver, British Columbia (Canada)

    1995-12-31

    The authors have been testing the hypothesis that exposure to elevated levels of 2,3,7,8-TCDD and similarly-acting compounds derived from pulp mill effluent adversely affects the reproductive capacity of colonies of great blue herons and double crested cormorants in the local area. Their objectives included developing quantitative TCDD dose-response curves for various toxicologically relevant endpoints in birds, with the goal of finding an appropriate environmental biomarker of dioxin exposure and toxicity. Potential biomarkers studied included ethoxyresorufin O-deethylase (EROD) as a measure of cytochrome P-450 1-A activity, and various hormonally-relevant end-points as measures of dioxin toxicity. The animal model used was the newly hatched chick, after in ovo exposure either in the laboratory or from the environment. Because the TEQ approach is based to a large extent on the use of in vitro and in vivo biomarkers, this study provides a useful example of one of the simplest in vivo models. The authors were able to construct hepatic EROD dose-response curves from the environmentally exposed heron and cormorant chicks, and from TCDD egg injections both early and late in the incubation period. Domestic chicken and pigeons were used as control species. The EROD induction data from the late injection pigeon study was very helpful for predicting appropriate doses for use in the early injection experiments, and for the wild avian species. However, the data was too limited to use for accurately predicting such endpoints as mortality, or effects at the lower end of the dose-response curves. Using various toxic equivalency factors, TEQs for the environmental data were calculated, and compared to the laboratory derived dose-response curves for TCDD. Using specific examples from this environmental case study, the strengths and weaknesses of the use of biomarkers and the TEQ approach will be discussed.

  10. Biomarker Identification Using Text Mining

    Directory of Open Access Journals (Sweden)

    Hui Li

    2012-01-01

    Full Text Available Identifying molecular biomarkers has become one of the important tasks for scientists to assess the different phenotypic states of cells or organisms correlated to the genotypes of diseases from large-scale biological data. In this paper, we proposed a text-mining-based method to discover biomarkers from PubMed. First, we construct a database based on a dictionary, and then we used a finite state machine to identify the biomarkers. Our method of text mining provides a highly reliable approach to discover the biomarkers in the PubMed database.

  11. Biomarkers in Lysosomal Storage Diseases

    Directory of Open Access Journals (Sweden)

    Joaquin Bobillo Lobato

    2016-12-01

    Full Text Available A biomarker is generally an analyte that indicates the presence and/or extent of a biological process, which is in itself usually directly linked to the clinical manifestations and outcome of a particular disease. The biomarkers in the field of lysosomal storage diseases (LSDs have particular relevance where spectacular therapeutic initiatives have been achieved, most notably with the introduction of enzyme replacement therapy (ERT. There are two main types of biomarkers. The first group is comprised of those molecules whose accumulation is directly enhanced as a result of defective lysosomal function. These molecules represent the storage of the principal macro-molecular substrate(s of a specific enzyme or protein, whose function is deficient in the given disease. In the second group of biomarkers, the relationship between the lysosomal defect and the biomarker is indirect. In this group, the biomarker reflects the effects of the primary lysosomal defect on cell, tissue, or organ functions. There is no “gold standard” among biomarkers used to diagnosis and/or monitor LSDs, but there are a number that exist that can be used to reasonably assess and monitor the state of certain organs or functions. A number of biomarkers have been proposed for the analysis of the most important LSDs. In this review, we will summarize the most promising biomarkers in major LSDs and discuss why these are the most promising candidates for screening systems.

  12. A review of selection-based tests of abiotic surrogates for species representation.

    Science.gov (United States)

    Beier, Paul; Sutcliffe, Patricia; Hjort, Jan; Faith, Daniel P; Pressey, Robert L; Albuquerque, Fabio

    2015-06-01

    Because conservation planners typically lack data on where species occur, environmental surrogates--including geophysical settings and climate types--have been used to prioritize sites within a planning area. We reviewed 622 evaluations of the effectiveness of abiotic surrogates in representing species in 19 study areas. Sites selected using abiotic surrogates represented more species than an equal number of randomly selected sites in 43% of tests (55% for plants) and on average improved on random selection of sites by about 8% (21% for plants). Environmental diversity (ED) (42% median improvement on random selection) and biotically informed clusters showed promising results and merit additional testing. We suggest 4 ways to improve performance of abiotic surrogates. First, analysts should consider a broad spectrum of candidate variables to define surrogates, including rarely used variables related to geographic separation, distance from coast, hydrology, and within-site abiotic diversity. Second, abiotic surrogates should be defined at fine thematic resolution. Third, sites (the landscape units prioritized within a planning area) should be small enough to ensure that surrogates reflect species' environments and to produce prioritizations that match the spatial resolution of conservation decisions. Fourth, if species inventories are available for some planning units, planners should define surrogates based on the abiotic variables that most influence species turnover in the planning area. Although species inventories increase the cost of using abiotic surrogates, a modest number of inventories could provide the data needed to select variables and evaluate surrogates. Additional tests of nonclimate abiotic surrogates are needed to evaluate the utility of conserving nature's stage as a strategy for conservation planning in the face of climate change. © 2015 Society for Conservation Biology.

  13. Chiral Biomarkers in Meteorites

    Science.gov (United States)

    Hoover, Richard B.

    2010-01-01

    The chirality of organic molecules with the asymmetric location of group radicals was discovered in 1848 by Louis Pasteur during his investigations of the rotation of the plane of polarization of light by crystals of sodium ammonium paratartrate. It is well established that the amino acids in proteins are exclusively Levorotary (L-aminos) and the sugars in DNA and RNA are Dextrorotary (D-sugars). This phenomenon of homochirality of biological polymers is a fundamental property of all life known on Earth. Furthermore, abiotic production mechanisms typically yield recemic mixtures (i.e. equal amounts of the two enantiomers). When amino acids were first detected in carbonaceous meteorites, it was concluded that they were racemates. This conclusion was taken as evidence that they were extraterrestrial and produced by abiologically. Subsequent studies by numerous researchers have revealed that many of the amino acids in carbonaceous meteorites exhibit a significant L-excess. The observed chirality is much greater than that produced by any currently known abiotic processes (e.g. Linearly polarized light from neutron stars; Circularly polarized ultraviolet light from faint stars; optically active quartz powders; inclusion polymerization in clay minerals; Vester-Ulbricht hypothesis of parity violations, etc.). This paper compares the measured chirality detected in the amino acids of carbonaceous meteorites with the effect of these diverse abiotic processes. IT is concluded that the levels observed are inconsistent with post-arrival biological contamination or with any of the currently known abiotic production mechanisms. However, they are consistent with ancient biological processes on the meteorite parent body. This paper will consider these chiral biomarkers in view of the detection of possible microfossils found in the Orgueil and Murchison carbonaceous meteorites. Energy dispersive x-ray spectroscopy (EDS) data obtained on these morphological biomarkers will be

  14. Radiation acquisition and RBF neural network analysis on BOF end-point control

    Science.gov (United States)

    Zhao, Qi; Wen, Hong-yuan; Zhou, Mu-chun; Chen, Yan-ru

    2008-12-01

    There are some problems in Basic Oxygen Furnace (BOF) steelmaking end-point control technology at present. A new BOF end-point control model was designed, which was based on the character of carbon oxygen reaction in Basic Oxygen Furnace steelmaking process. The image capture and transformation system was established by Video for Windows (VFW) library function, which is a video software development package promoted by Microsoft Corporation. In this paper, the Radial Basic Function (RBF) neural network model was established by using the real-time acquisition information. The input parameters can acquire easily online and the output parameter is the end-point time, which can compare with the actual value conveniently. The experience results show that the predication result is ideal and the experiment results show the model can work well in the steelmaking adverse environment.

  15. The Feynman trajectories: determining the path of a protein using fixed-endpoint assays.

    Science.gov (United States)

    Ketteler, Robin

    2010-03-01

    Richard Feynman postulated in 1948 that the path of an electron can be best described by the sum or functional integral of all possible trajectories rather than by the notion of a single, unique trajectory. As a consequence, the position of an electron does not harbor any information about the paths that contributed to this position. This observation constitutes a classical endpoint observation. The endpoint assay is the desired type of experiment for high-throughput screening applications, mainly because of limitations in data acquisition and handling. Quite contrary to electrons, it is possible to extract information about the path of a protein using endpoint assays, and these types of applications are reviewed in this article.

  16. Cervical spinal cord injury:tailoring clinical trial endpoints to relfect meaningful functional improvements

    Institute of Scientific and Technical Information of China (English)

    Lisa M Bond; Lisa McKerracher

    2014-01-01

    Cervical spinal cord injury (SCI) results in partial to full paralysis of the upper and lower extrem-ities. Traditional primary endpoints for acute SCI clinical trials are too broad to assess functional recovery in cervical subjects, raising the possibility of false positive outcomes in trials for cervical SCI. Endpoints focused on the recovery of hand and arm control (e.g., upper extremity motor score, motor level change) show the most potential for use as primary outcomes in upcoming trials of cervical SCI. As the field moves forward, the most reliable way to ensure meaningful clinical testing in cervical subjects may be the development of a composite primary endpoint that measures both neurological recovery and functional improvement.

  17. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design

    DEFF Research Database (Denmark)

    Parving, Hans-Henrik; Brenner, Barry M; McMurray, John J V;

    2009-01-01

    , resuscitated death, myocardial infarction, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline serum creatinine concentration. Secondary endpoints include a composite CV endpoint and a composite renal endpoint. CONCLUSION: ALTITUDE will determine...... the residual renal and cardiovascular risk still remains high. Aliskiren a novel oral direct renin inhibitor that unlike ACEi and ARBs, lowers plasma renin activity, angiotensin I and angiotensin II levels, may thereby provide greater benefit compared to ACEi or ARB alone. METHODS: The primary objective...... of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily, reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment (including ACEi or ARB). ALTITUDE is an international, randomized, double-blind, placebo-controlled, parallel-group study...

  18. A Robust Algorithm for Real-time Endpoint Detection in the Noisy Mobile Environments

    Institute of Scientific and Technical Information of China (English)

    WUBian; RENXiaolin; LIUChongqing; ZHANGYaxin

    2003-01-01

    In speech recognition, the endpoint detection must be robust to noise. In low SNR situations, the conventional energy-based endpoint detection algorithms often fail and the performance of speech recognizer usually degrades distinctly, especially when in mobile environments, the background noise changes dramatically. In this paper, we propose a new algorithm that improves the endpoint detection for speech recognition in low SNR and in various noisy environments. The described algorithm not only uses multiple features but introduces a decision logic to increase the robustness in both low SNR and various noisy mobile environments. To evaluate the new algorithm, we carry out experiments in various noisy mobile environments (e.g. railway station, airport, street etc), and the performance of the algorithm is significantly improved, especially in low SNR situations. At the same time, the proposed algorithm has a low complexity and is suitable for real time embedded systems.

  19. Swimming speed alteration in the early developmental stages of Paracentrotus lividus sea urchin as ecotoxicological endpoint.

    Science.gov (United States)

    Morgana, Silvia; Gambardella, Chiara; Falugi, Carla; Pronzato, Roberto; Garaventa, Francesca; Faimali, Marco

    2016-04-01

    Behavioral endpoints have been used for decades to assess chemical impacts at concentrations unlikely to cause mortality. With recently developed techniques, it is possible to investigate the swimming behavior of several organisms under laboratory conditions. The aims of this study were: i) assessing for the first time the feasibility of swimming speed analysis of the early developmental stage sea urchin Paracentrotus lividus by an automatic recording system ii) investigating any Swimming Speed Alteration (SSA) on P. lividus early stages exposed to a chemical reference; iii) identifying the most suitable stage for SSA test. Results show that the swimming speed of all the developmental stages was easily recorded. The swimming speed was inhibited as a function of toxicant concentration. Pluteus were the most appropriate stage for evaluating SSA in P. lividus as ecotoxicological endpoint. Finally, swimming of sea urchin early stages represents a sensitive endpoint to be considered in ecotoxicological investigations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Towards Improved Biomarker Research

    DEFF Research Database (Denmark)

    Kjeldahl, Karin

    This thesis takes a look at the data analytical challenges associated with the search for biomarkers in large-scale biological data such as transcriptomics, proteomics and metabolomics data. These studies aim to identify genes, proteins or metabolites which can be associated with e.g. a diet, dis...... is used both for regression and classification purposes. This method has proven its strong worth in the multivariate data analysis throughout an enormous range of applications; a very classic data type is near infrared (NIR) data, but many similar data types have also be very successful...

  1. Degree of target utilization influences the location of movement endpoint distributions.

    Science.gov (United States)

    Slifkin, Andrew B; Eder, Jeffrey R

    2017-03-01

    According to dominant theories of motor control, speed and accuracy are optimized when, on the average, movement endpoints are located at the target center and when the variability of the movement endpoint distributions is matched to the width of the target (viz., Meyer, Abrams, Kornblum, Wright, & Smith, 1988). The current study tested those predictions. According to the speed-accuracy trade-off, expanding the range of variability to the amount permitted by the limits of the target boundaries allows for maximization of movement speed while centering the distribution on the target center prevents movement errors that would have occurred had the distribution been off center. Here, participants (N=20) were required to generate 100 consecutive targeted hand movements under each of 15 unique conditions: There were three movement amplitude requirements (80, 160, 320mm) and within each there were five target widths (5, 10, 20, 40, 80mm). According to the results, it was only at the smaller target widths (5, 10mm) that movement endpoint distributions were centered on the target center and the range of movement endpoint variability matched the range specified by the target boundaries. As target width increased (20, 40, 80mm), participants increasingly undershot the target center and the range of movement endpoint variability increasingly underestimated the variability permitted by the target region. The degree of target center undershooting was strongly predicted by the difference between the size of the target and the amount of movement endpoint variability, i.e., the amount of unused space in the target. The results suggest that participants have precise knowledge of their variability relative to that permitted by the target, and they use that knowledge to systematically reduce the travel distance to targets. The reduction in travel distance across the larger target widths might have resulted in greater cost savings than those associated with increases in speed

  2. Biomarkers for noninvasive biochemical diagnosis of nonalcoholic steatohepatitis: Tools or decorations?

    Institute of Scientific and Technical Information of China (English)

    Yusuf Yilmaz; Enver Dolar

    2009-01-01

    In light of the growing epidemics of nonalcoholic fatty liver disease (NAFLD), identification and validation of the novel biochemical surrogate markers for nonalcoholic steatohepatitis (NASH) are paramount to reduce the necessity for liver biopsy. The availability of such markers has t remendous potent ial to radically alter the management strategies of NAFLD patients and to monitor the disease activity. Although current biomarkers do not entirely fulfill the many requirements for the identification of patients with NASH, they should not discourage our quest, but remind us that we need to cognize the challenges ahead.

  3. Calculation of a velocity distribution from particle trajectory end-points.

    Science.gov (United States)

    Rasmussen, Lowell A.

    1983-01-01

    The longitudinal component of the velocity of a particle at or near a glacier surface is considered, its position as a function of time being termed its trajectory. Functional relationships are derived for obtaining the trajectory from the spatial distribution of velocity and for obtaining the velocity distribution from the trajectory. It is established that the trajectory end-points impose only an integral condition on the velocity distribution and that no individual point on the velocity distribution can be determined if only the end-points are known.-from Author

  4. Verifying Elimination Programs with a Special Emphasis on Cysticercosis Endpoints and Postelimination Surveillance

    Directory of Open Access Journals (Sweden)

    Sukwan Handali

    2012-01-01

    Full Text Available Methods are needed for determining program endpoints or postprogram surveillance for any elimination program. Cysticercosis has the necessary effective strategies and diagnostic tools for establishing an elimination program; however, tools to verify program endpoints have not been determined. Using a statistical approach, the present study proposed that taeniasis and porcine cysticercosis antibody assays could be used to determine with a high statistical confidence whether an area is free of disease. Confidence would be improved by using secondary tests such as the taeniasis coproantigen assay and necropsy of the sentinel pigs.

  5. Top predators: hot or not? A call for systematic assessment of biodiversity surrogates

    NARCIS (Netherlands)

    Cabeza, M.; Arponen, A.; Teeffelen, van A.J.A.

    2008-01-01

    argue that top predators are justified conservation surrogates based on a case study where raptor presence is associated with high species richness of birds, butterflies and trees. 2. We question the methodology as well as the applicability of their results, and clarify differences between surrogate

  6. Comparison of surrogate models with different methods in groundwater remediation process

    Indian Academy of Sciences (India)

    Jiannan Luo; Wenxi Lu

    2014-10-01

    Surrogate modelling is an effective tool for reducing computational burden of simulation optimization. In this article, polynomial regression (PR), radial basis function artificial neural network (RBFANN), and kriging methods were compared for building surrogate models of a multiphase flow simulation model in a simplified nitrobenzene contaminated aquifer remediation problem. In the model accuracy analysis process, a 10-fold cross validation method was adopted to evaluate the approximation accuracy of the three surrogate models. The results demonstrated that: RBFANN surrogate model and kriging surrogate model had acceptable approximation accuracy, and further that kriging model’s approximation accuracy was slightly higher than RBFANN model. However, the PR model demonstrated unacceptably poor approximation accuracy. Therefore, the RBFANN and kriging surrogates were selected and used in the optimization process to identify the most cost-effective remediation strategy at a nitrobenzene-contaminated site. The optimal remediation costs obtained with the two surrogate-based optimization models were similar, and had similar computational burden. These two surrogate-based optimization models are efficient tools for optimal groundwater remediation strategy identification.

  7. Someone to Lean on: Assessment and Implications of Social Surrogate Use in Childhood

    Science.gov (United States)

    Arbeau, Kimberley A.; Coplan, Robert J.; Matheson, Adrienne

    2012-01-01

    A social surrogate is a person who helps a shy individual deal with the stresses of a social situation. Previous research has only investigated social surrogate use in adults. The purpose of the current study was to develop and evaluate a new self-report measure of social surrogacy in middle childhood and to explore the implications of this…

  8. Critical review of norovirus surrogates in food safety research: rationale for considering volunteer studies

    Science.gov (United States)

    The inability to propagate human norovirus (NoV) or to clearly differentiate infectious from noninfectious virus particles have led to the use of surrogate viruses, like feline calicivirus (FCV) and murine norovirus-1 (MNV), which are propagatable in cell culture. The use of surrogates is predicate...

  9. Somatic coliphages as surrogates for enteroviruses in sludge hygienization treatments.

    Science.gov (United States)

    Martín-Díaz, Julia; Casas-Mangas, Raquel; García-Aljaro, Cristina; Blanch, Anicet R; Lucena, Francisco

    2016-01-01

    Conventional bacterial indicators present serious drawbacks giving information about viral pathogens persistence during sludge hygienization treatments. This calls for the search of alternative viral indicators. Somatic coliphages' (SOMCPH) ability for acting as surrogates for enteroviruses was assessed in 47 sludge samples subjected to novel treatment processes. SOMCPH, infectious enteroviruses and genome copies of enteroviruses were monitored. Only one of these groups, the bacteriophages, was present in the sludge at concentrations that allowed the evaluation of treatment's performance. An indicator/pathogen relationship of 4 log10 (PFU/g dw) was found between SOMCPH and infective enteroviruses and their detection accuracy was assessed. The obtained results and the existence of rapid and standardized methods encourage the inclusion of SOMCPH quantification in future sludge directives. In addition, an existing real-time quantitative polymerase chain reaction (RT-qPCR) for enteroviruses was adapted and applied.

  10. A Rigorous Framework for Optimization of Expensive Functions by Surrogates

    Science.gov (United States)

    Booker, Andrew J.; Dennis, J. E., Jr.; Frank, Paul D.; Serafini, David B.; Torczon, Virginia; Trosset, Michael W.

    1998-01-01

    The goal of the research reported here is to develop rigorous optimization algorithms to apply to some engineering design problems for which design application of traditional optimization approaches is not practical. This paper presents and analyzes a framework for generating a sequence of approximations to the objective function and managing the use of these approximations as surrogates for optimization. The result is to obtain convergence to a minimizer of an expensive objective function subject to simple constraints. The approach is widely applicable because it does not require, or even explicitly approximate, derivatives of the objective. Numerical results are presented for a 31-variable helicopter rotor blade design example and for a standard optimization test example.

  11. Sparse polynomial surrogates for aerodynamic computations with random inputs

    CERN Document Server

    Savin, Eric; Peter, Jacques

    2015-01-01

    This paper deals with some of the methodologies used to construct polynomial surrogate models based on generalized polynomial chaos (gPC) expansions for applications to uncertainty quantification (UQ) in aerodynamic computations. A core ingredient in gPC expansions is the choice of a dedicated sampling strategy, so as to define the most significant scenarios to be considered for the construction of such metamodels. A desirable feature of the proposed rules shall be their ability to handle several random inputs simultaneously. Methods to identify the relative "importance" of those variables or uncertain data shall be ideally considered as well. The present work is more particularly dedicated to the development of sampling strategies based on sparsity principles. Sparse multi-dimensional cubature rules based on general one-dimensional Gauss-Jacobi-type quadratures are first addressed. These sets are non nested, but they are well adapted to the probability density functions with compact support for the random in...

  12. High-Temperature Oxidation of Plutonium Surrogate Metals and Alloys

    Energy Technology Data Exchange (ETDEWEB)

    Sparks, Joshua C. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Krantz, Kelsie E. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Christian, Jonathan H. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Washington, II, Aaron L. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2016-07-27

    The Plutonium Management and Disposition Agreement (PMDA) is a nuclear non-proliferation agreement designed to remove 34 tons of weapons-grade plutonium from Russia and the United States. While several removal options have been proposed since the agreement was first signed in 2000, processing the weapons-grade plutonium to mixed-oxide (MOX) fuel has remained the leading candidate for achieving the goals of the PMDA. However, the MOX program has received its share of criticisms, which causes its future to be uncertain. One alternative pathway for plutonium disposition would involve oxidizing the metal followed by impurity down blending and burial in the Waste Isolation Pilot Plant (WIPP) in Carlsbad, New Mexico. This pathway was investigated by use of a hybrid microwave and a muffle furnace with Fe and Al as surrogate materials. Oxidation occurred similarly in the microwave and muffle furnace; however, the microwave process time was significantly faster.

  13. Protein prosthesis: β-peptides as reverse-turn surrogates.

    Science.gov (United States)

    Arnold, Ulrich; Huck, Bayard R; Gellman, Samuel H; Raines, Ronald T

    2013-03-01

    The introduction of non-natural modules could provide unprecedented control over folding/unfolding behavior, conformational stability, and biological function of proteins. Success requires the interrogation of candidate modules in natural contexts. Here, expressed protein ligation is used to replace a reverse turn in bovine pancreatic ribonuclease (RNase A) with a synthetic β-dipeptide: β²-homoalanine-β³-homoalanine. This segment is known to adopt an unnatural reverse-turn conformation that contains a 10-membered ring hydrogen bond, but one with a donor-acceptor pattern opposite to that in the 10-membered rings of natural reverse turns. The RNase A variant has intact enzymatic activity, but unfolds more quickly and has diminished conformational stability relative to native RNase A. These data indicate that hydrogen-bonding pattern merits careful consideration in the selection of beneficial reverse-turn surrogates. Copyright © 2012 The Protein Society.

  14. Argan oil improves surrogate markers of CVD in humans.

    Science.gov (United States)

    Sour, Souad; Belarbi, Meriem; Khaldi, Darine; Benmansour, Nassima; Sari, Nassima; Nani, Abdelhafid; Chemat, Farid; Visioli, Francesco

    2012-06-01

    Limited - though increasing - evidence suggests that argan oil might be endowed with potential healthful properties, mostly in the areas of CVD and prostate cancer. We sought to comprehensively determine the effects of argan oil supplementation on the plasma lipid profile and antioxidant status of a group of healthy Algerian subjects, compared with matched controls. A total of twenty healthy subjects consumed 15 g/d of argan oil - with toasted bread - for breakfast, during 4 weeks (intervention group), whereas twenty matched controls followed their habitual diet, but did not consume argan oil. The study lasted 30 d. At the end of the study, argan oil-supplemented subjects exhibited higher plasma vitamin E concentrations, lower total and LDL-cholesterol, lower TAG and improved plasma and cellular antioxidant profile, when compared with controls. In conclusion, we showed that Algerian argan oil is able to positively modulate some surrogate markers of CVD, through mechanisms which warrant further investigation.

  15. Cholesterol paradox: a correlate does not a surrogate make.

    Science.gov (United States)

    DuBroff, Robert

    2017-03-01

    The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world. Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect. The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol in high-risk patients with coronary disease. This clinical trial adds to a growing volume of knowledge that challenges the validity of the cholesterol hypothesis and the utility of cholesterol as a surrogate end point. Inadvertently, the cholesterol hypothesis may have even contributed to this pandemic. This perspective critically reviews this evidence and our reluctance to acknowledge contradictory information.

  16. Biomarkers in Vasculitis

    Science.gov (United States)

    Monach, Paul A.

    2014-01-01

    Purpose of review Better biomarkers are needed for guiding management of patients with vasculitis. Large cohorts and technological advances had led to an increase in pre-clinical studies of potential biomarkers. Recent findings The most interesting markers described recently include a gene expression signature in CD8+ T cells that predicts tendency to relapse or remain relapse-free in ANCA-associated vasculitis, and a pair of urinary proteins that are elevated in Kawasaki disease but not other febrile illnesses. Both of these studies used “omics” technologies to generate and then test hypotheses. More conventional hypothesis-based studies have indicated that the following circulating proteins have potential to improve upon clinically available tests: pentraxin-3 in giant cell arteritis and Takayasu’s arteritis; von Willebrand factor antigen in childhood central nervous system vasculitis; eotaxin-3 and other markers related to eosinophils or Th2 immune responses in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome); and MMP-3, TIMP-1, and CXCL13 in ANCA-associated vasculitis. Summary New markers testable in blood and urine have the potential to assist with diagnosis, staging, assessment of current disease activity, and prognosis. However, the standards for clinical usefulness, in particular the demonstration of either very high sensitivity or very high specificity, have yet to be met for clinically relevant outcomes. PMID:24257367

  17. Technological advances in suspended-sediment surrogate monitoring

    Science.gov (United States)

    Gray, John R.; Gartner, Jeffrey W.

    2009-01-01

    Surrogate technologies to continuously monitor suspended sediment show promise toward supplanting traditional data collection methods requiring routine collection and analysis of water samples. Commercially available instruments operating on bulk optic (turbidity), laser optic, pressure difference, and acoustic backscatter principles are evaluated based on cost, reliability, robustness, accuracy, sample volume, susceptibility to biological fouling, and suitable range of mass concentration and particle size distribution. In situ turbidimeters are widely used. They provide reliable data where the point measurements can be reliably correlated to the river's mean cross section concentration value, effects of biological fouling can be minimized, and concentrations remain below the sensor's upper measurement limit. In situ laser diffraction instruments have similar limitations and can cost 6 times the approximate $5000 purchase price of a turbidimeter. However, laser diffraction instruments provide volumetric-concentration data in 32 size classes. Pressure differential instruments measure mass density in a water column, thus integrating substantially more streamflow than a point measurement. They are designed for monitoring medium-to-large concentrations, are generally unaffected by biological fouling, and cost about the same as a turbidimeter. However, their performance has been marginal in field applications. Acoustic Doppler profilers use acoustic backscatter to measure suspended sediment concentrations in orders of magnitude more streamflow than do instruments that rely on point measurements. The technology is relatively robust and generally immune to effects of biological fouling. Cost of a single-frequency device is about double that of a turbidimeter. Multifrequency arrays also provide the potential to resolve concentrations by clay silt versus sand size fractions. Multifrequency hydroacoustics shows the most promise for revolutionizing collection of continuous

  18. Effectiveness of chitosan on the inactivation of enteric viral surrogates.

    Science.gov (United States)

    Davis, Robert; Zivanovic, Svetlana; D'Souza, Doris H; Davidson, P Michael

    2012-10-01

    Chitosan is known to have bactericidal and antifungal activity. Although human noroviruses are the leading cause of non-bacterial gastroenteritis, information on the efficacy of chitosan against foodborne viruses is very limited. The objective of this work was to determine the effectiveness of different molecular weight chitosans against the cultivable human norovirus and enteric virus surrogates, feline calicivirus, FCV-F9, murine norovirus, MNV-1, and bacteriophages, MS2 and phiX174. Five purified chitosans (53, 222, 307, 421, ~1150 kDa) were dissolved in water, 1% acetic acid, or aqueous HCl pH = 4.3, sterilized by membrane filtration, and mixed with equal volume of virus to obtain a final concentration of 0.7% chitosan and 5 log(10) PFU/ml virus. Virus-chitosan suspensions were incubated for 3 h at 37 °C. Untreated viruses in PBS, in PBS with acetic acid, and in PBS with HCl were tested as controls. Each experiment was run in duplicate and replicated at least twice. Water-soluble chitosan (53 kDa) reduced phiX174, MS2, FCV-F9 and MNV-1 titers by 0.59, 2.44, 3.36, and 0.34 log(10) PFU/ml respectively. Chitosans in acetic acid decreased phiX174 by 1.19-1.29, MS2 by 1.88-5.37, FCV-F9 by 2.27-2.94, and MNV-1 by 0.09-0.28 log(10) PFU/ml, respectively. Increasing the MW of chitosan corresponded with an increasing antiviral effect on MS2, but did not appear to play a role for the other three tested viral surrogates. Overall, chitosan treatments showed the greatest reduction for FCV-F9, and MS2 followed by phiX174, and with no significant effect on MNV-1.

  19. Potential cryptosporidium surrogates and evaluation of compressible oocysts

    Energy Technology Data Exchange (ETDEWEB)

    Li, S.Y.; Goodrich, J.A.; Owens, J.H. [Environmental Protection Agency, Cincinnati, OH (United States)] [and others

    1995-10-01

    Cryptosporidium has been recognized as an important waterborne agent of gastroenteritis and a biological contaminant in drinking water. The widespread presence of Cryptosporidium in surface source water and either untreated or insufficiently treated drinking water has led to Cryptosporidium outbreaks in the United States and worldwide. Among the conventional control practices, filtration and high temperature distillation appear to be the potentially viable technologies for protection against Cryptosporidium in drinking water. As employed in many water plants, filtration is likely to be the most practical treatment technology utilized for Cryptosporidium removal in the near future. Consequently, accurate and reliable methods for evaluation of Cryptosporidium removal rates for filtration-based systems are necessary to assist States in determining drinking water quality and complying with the up-coming national standard for Cryptosporidium in drinking water. Furthermore, searching for reliable and non-hazardous surrogates for evaluation of treatment plant efficiency has been intensified because of the potential health risk associated with Cryptosporidium. Additionally, during the filtration procedure Cryptosporidium may squeeze and fold through pores size of the filtration systems that are smaller than the diameter of the organism; a fraction of these Cryptosporidium oocysts may still remain a certain degree of viability. These uncertainties are critical for the evaluation and optimization of filtration-based physical treatment systems. The in-house research studies described below consist of two parts. One is a potential surrogate study using bag filtration systems at the US EPA Test & Evaluation Facility in Cincinnati, Ohio. The second is Cryptosporidium compressibility and viability investigation.

  20. Surrogate-assisted feature extraction for high-throughput phenotyping.

    Science.gov (United States)

    Yu, Sheng; Chakrabortty, Abhishek; Liao, Katherine P; Cai, Tianrun; Ananthakrishnan, Ashwin N; Gainer, Vivian S; Churchill, Susanne E; Szolovits, Peter; Murphy, Shawn N; Kohane, Isaac S; Cai, Tianxi

    2017-04-01

    Phenotyping algorithms are capable of accurately identifying patients with specific phenotypes from within electronic medical records systems. However, developing phenotyping algorithms in a scalable way remains a challenge due to the extensive human resources required. This paper introduces a high-throughput unsupervised feature selection method, which improves the robustness and scalability of electronic medical record phenotyping without compromising its accuracy. The proposed Surrogate-Assisted Feature Extraction (SAFE) method selects candidate features from a pool of comprehensive medical concepts found in publicly available knowledge sources. The target phenotype's International Classification of Diseases, Ninth Revision and natural language processing counts, acting as noisy surrogates to the gold-standard labels, are used to create silver-standard labels. Candidate features highly predictive of the silver-standard labels are selected as the final features. Algorithms were trained to identify patients with coronary artery disease, rheumatoid arthritis, Crohn's disease, and ulcerative colitis using various numbers of labels to compare the performance of features selected by SAFE, a previously published automated feature extraction for phenotyping procedure, and domain experts. The out-of-sample area under the receiver operating characteristic curve and F -score from SAFE algorithms were remarkably higher than those from the other two, especially at small label sizes. SAFE advances high-throughput phenotyping methods by automatically selecting a succinct set of informative features for algorithm training, which in turn reduces overfitting and the needed number of gold-standard labels. SAFE also potentially identifies important features missed by automated feature extraction for phenotyping or experts.

  1. Pan masala advertisements are surrogate for tobacco products

    Directory of Open Access Journals (Sweden)

    Sushma C

    2005-01-01

    Full Text Available BACKGROUND: Pan masala is a comparatively recent habit in India and is marketed with and without tobacco. Advertisements of tobacco products have been banned in India since 1st May 2004. The advertisements of plain pan masala, which continue in Indian media, have been suspected to be surrogate for tobacco products bearing the same name. The study was carried out to assess whether these advertisements were for the intended product, or for tobacco products with same brand name. MATERIALS AND METHODS: The programme of a popular television Hindi news channel was watched for a 24-h period. Programmes on the same channel and its English counterpart were watched on different days to assess whether the advertisements were repeated. The total duration of telecast of a popular brand of plain pan masala (Pan Parag was multiplied by the rate charged by the channel to provide the cost of advertisement of this product. The total sale value of the company was multiplied by the proportion of usage of plain pan masala out of gutka plus pan masala habit as observed from a different study, to provide the annual sale value of plain pan masala product under reference. RESULTS: The annual sale value of plain Pan Parag was estimated to be Rs. 67.1 million. The annual cost of the advertisement of the same product on two television channels was estimated at Rs. 244.6 million. CONCLUSION: The advertisements of plain pan masala seen on Indian television are a surrogate for the tobacco products bearing the same name.

  2. Learning image based surrogate relevance criterion for atlas selection in segmentation

    Science.gov (United States)

    Zhao, Tingting; Ruan, Dan

    2016-06-01

    Picking geometrically relevant atlases from the whole training set is crucial to multi-atlas based image segmentation, especially with extensive data of heterogeneous quality in the Big Data era. Unfortunately, there is very limited understanding of how currently used image similarity criteria reveal geometric relevance, let alone the optimization of them. This paper aims to develop a good image based surrogate relevance criterion to best reflect the underlying inaccessible geometric relevance in a learning context. We cast this surrogate learning problem into an optimization framework, by encouraging the image based surrogate to behave consistently with geometric relevance during training. In particular, we desire a criterion to be small for image pairs with similar geometry and large for those with significantly different segmentation geometry. Validation experiments on corpus callosum segmentation demonstrate the improved quality of the learned surrogate compared to benchmark surrogate candidates.

  3. Blood Biomarkers of Ischemic Stroke

    National Research Council Canada - National Science Library

    Jickling, Glen C; Sharp, Frank R

    2011-01-01

    .... Though many candidate blood based biomarkers for ischemic stroke have been identified, none are currently used in clinical practice. With further well designed study and careful validation, the development of blood biomarkers to improve the care of patients with ischemic stroke may be achieved.

  4. Biomarkers of spontaneous preterm birth

    DEFF Research Database (Denmark)

    Polettini, Jossimara; Cobo, Teresa; Kacerovsky, Marian

    2017-01-01

    Despite decades of research on risk indicators of spontaneous preterm birth (PTB), reliable biomarkers are still not available to screen or diagnose high-risk pregnancies. Several biomarkers in maternal and fetal compartments have been mechanistically linked to PTB, but none of them are reliable...

  5. Which biomarkers reveal neonatal sepsis?

    Directory of Open Access Journals (Sweden)

    Kun Wang

    Full Text Available We address the identification of optimal biomarkers for the rapid diagnosis of neonatal sepsis. We employ both canonical correlation analysis (CCA and sparse support vector machine (SSVM classifiers to select the best subset of biomarkers from a large hematological data set collected from infants with suspected sepsis from Yale-New Haven Hospital's Neonatal Intensive Care Unit (NICU. CCA is used to select sets of biomarkers of increasing size that are most highly correlated with infection. The effectiveness of these biomarkers is then validated by constructing a sparse support vector machine diagnostic classifier. We find that the following set of five biomarkers capture the essential diagnostic information (in order of importance: Bands, Platelets, neutrophil CD64, White Blood Cells, and Segs. Further, the diagnostic performance of the optimal set of biomarkers is significantly higher than that of isolated individual biomarkers. These results suggest an enhanced sepsis scoring system for neonatal sepsis that includes these five biomarkers. We demonstrate the robustness of our analysis by comparing CCA with the Forward Selection method and SSVM with LASSO Logistic Regression.

  6. Role of biomarkers in monitoring exposures to chemicals: present position, future prospects.

    Science.gov (United States)

    Watson, William P; Mutti, Antonio

    2004-01-01

    Biomarkers are becoming increasingly important in toxicology and human health. Many research groups are carrying out studies to develop biomarkers of exposure to chemicals and apply these for human monitoring. There is considerable interest in the use and application of biomarkers to identify the nature and amounts of chemical exposures in occupational and environmental situations. Major research goals are to develop and validate biomarkers that reflect specific exposures and permit the prediction of the risk of disease in individuals and groups. One important objective is to prevent human cancer. This review presents a commentary and consensus views about the major developments on biomarkers for monitoring human exposure to chemicals. A particular emphasis is on monitoring exposures to carcinogens. Significant developments in the areas of new and existing biomarkers, analytical methodologies, validation studies and field trials together with auditing and quality assessment of data are discussed. New developments in the relatively young field of toxicogenomics possibly leading to the identification of individual susceptibility to both cancer and non-cancer endpoints are also considered. The construction and development of reliable databases that integrate information from genomic and proteomic research programmes should offer a promising future for the application of these technologies in the prediction of risks and prevention of diseases related to chemical exposures. Currently adducts of chemicals with macromolecules are important and useful biomarkers especially for certain individual chemicals where there are incidences of occupational exposure. For monitoring exposure to genotoxic compounds protein adducts, such as those formed with haemoglobin, are considered effective biomarkers for determining individual exposure doses of reactive chemicals. For other organic chemicals, the excreted urinary metabolites can also give a useful and complementary indication of

  7. Alpha-1 antitrypsin and granulocyte colony-stimulating factor as serum biomarkers of disease severity in ulcerative colitis

    DEFF Research Database (Denmark)

    Soendergaard, Christoffer; Nielsen, Ole Haagen; Seidelin, Jakob Benedict

    2015-01-01

    biomarkers are currently needed for identification of patients with mild or moderate disease activity. Using a commercially available platform, we aimed at identifying serum biomarkers that are able to grade the disease severity. METHODS: Serum samples from 65 patients with UC with varying disease activity......-stimulating factor produced a predictive model with an AUC of 0.72 when differentiating mild and moderate UC, and an AUC of 0.96 when differentiating moderate and severe UC, the latter being as reliable as CRP. CONCLUSIONS: Alpha-1 antitrypsin is identified as a potential serum biomarker of mild-to-moderate disease......BACKGROUND: Initial assessment of patients with ulcerative colitis (UC) is challenging and relies on apparent clinical symptoms and measurements of surrogate markers (e.g., C-reactive protein [CRP] or similar acute phase proteins). As CRP only reliably identifies patients with severe disease, novel...

  8. Toll-Like Receptors and Cytokines as Surrogate Biomarkers for Evaluating Vaginal Immune Response following Microbicide Administration

    Directory of Open Access Journals (Sweden)

    Sadhana M. Gupta

    2008-01-01

    Full Text Available Topical microbicides are intended for frequent use by women in reproductive age. Hence, it is essential to evaluate their impact on mucosal immune function in the vagina. In the present study, we evaluated nisin, a naturally occurring antimicrobial peptide (AMP, for its efficacy as an intravaginal microbicide. Its effect on the vaginal immune function was determined by localizing Toll-like receptors (TLRs-3, 9 and cytokines (IL-4, 6 , 10 and TNF-α in the rabbit cervicovaginal epithelium following intravaginal administration of high dose of nisin gel for 14 consecutive days. The results revealed no alteration in the expression of TLRs and cytokines at both protein and mRNA levels. However, in SDS gel-treated group, the levels were significantly upregulated with the induction of NF-κB signalling cascade. Thus, TLRs and cytokines appear as sensitive indicators for screening immunotoxic potential of candidate microbicides.

  9. A computational methodology for formulating gasoline surrogate fuels with accurate physical and chemical kinetic properties

    KAUST Repository

    Ahmed, Ahfaz

    2015-03-01

    Gasoline is the most widely used fuel for light duty automobile transportation, but its molecular complexity makes it intractable to experimentally and computationally study the fundamental combustion properties. Therefore, surrogate fuels with a simpler molecular composition that represent real fuel behavior in one or more aspects are needed to enable repeatable experimental and computational combustion investigations. This study presents a novel computational methodology for formulating surrogates for FACE (fuels for advanced combustion engines) gasolines A and C by combining regression modeling with physical and chemical kinetics simulations. The computational methodology integrates simulation tools executed across different software platforms. Initially, the palette of surrogate species and carbon types for the target fuels were determined from a detailed hydrocarbon analysis (DHA). A regression algorithm implemented in MATLAB was linked to REFPROP for simulation of distillation curves and calculation of physical properties of surrogate compositions. The MATLAB code generates a surrogate composition at each iteration, which is then used to automatically generate CHEMKIN input files that are submitted to homogeneous batch reactor simulations for prediction of research octane number (RON). The regression algorithm determines the optimal surrogate composition to match the fuel properties of FACE A and C gasoline, specifically hydrogen/carbon (H/C) ratio, density, distillation characteristics, carbon types, and RON. The optimal surrogate fuel compositions obtained using the present computational approach was compared to the real fuel properties, as well as with surrogate compositions available in the literature. Experiments were conducted within a Cooperative Fuels Research (CFR) engine operating under controlled autoignition (CAI) mode to compare the formulated surrogates against the real fuels. Carbon monoxide measurements indicated that the proposed surrogates

  10. Biomarkers in inflammatory bowel diseases

    DEFF Research Database (Denmark)

    Bennike, Tue; Birkelund, Svend; Stensballe, Allan

    2014-01-01

    with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future...... development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content......) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine...

  11. Epigenetic biomarkers in liver cancer.

    Science.gov (United States)

    Banaudha, Krishna K; Verma, Mukesh

    2015-01-01

    Liver cancer (hepatocellular carcinoma or HCC) is a major cancer worldwide. Research in this field is needed to identify biomarkers that can be used for early detection of the disease as well as new approaches to its treatment. Epigenetic biomarkers provide an opportunity to understand liver cancer etiology and evaluate novel epigenetic inhibitors for treatment. Traditionally, liver cirrhosis, proteomic biomarkers, and the presence of hepatitis viruses have been used for the detection and diagnosis of liver cancer. Promising results from microRNA (miRNA) profiling and hypermethylation of selected genes have raised hopes of identifying new biomarkers. Some of these epigenetic biomarkers may be useful in risk assessment and for screening populations to identify who is likely to develop cancer. Challenges and opportunities in the field are discussed in this chapter.

  12. Meeting report: Measuring endocrine-sensitive endpoints within the first years of life

    DEFF Research Database (Denmark)

    Arbuckle, T.E.; Hauser, R.; Swan, S.H.

    2008-01-01

    An international workshop tided "Assessing Endocrine-Related Endpoints within the First Years of Life" was held 30 April-1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-...

  13. 77 FR 49447 - Endpoints for Clinical Trials in Kidney Transplantation; Public Workshop

    Science.gov (United States)

    2012-08-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Endpoints for Clinical Trials in Kidney Transplantation; Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public workshop. The Food and Drug Administration (FDA) is announcing...

  14. Reporting and evaluation of HIV-related clinical endpoints in two multicenter international clinical trials

    DEFF Research Database (Denmark)

    Lifson, A; Rahme, FS; Belloso, WH;

    2006-01-01

    PURPOSE: The processes for reporting and review of progression of HIV disease clinical endpoints are described for two large phase III international clinical trials. METHOD: SILCAAT and ESPRIT are multicenter randomized HIV trials evaluating the impact of interleukin-2 on disease progression...

  15. Subjective endpoints in clinical trials: the case for blinded independent central review

    Directory of Open Access Journals (Sweden)

    Walovitch R

    2013-09-01

    Full Text Available Richard Walovitch,1 Bin Yao,2 Patrick Chokron,1 Helen Le,1 Glenn Bubley3 1WorldCare Clinical, LLC, Boston, MA, USA; 2Amgen, Inc, Thousand Oaks, CA, USA; 3Director of Genitourinary Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA Abstract: Primary efficacy and safety endpoints in clinical trials are often subjective assessments made by site personnel. For international confirmatory trials conducted over broad geographic regions and different clinical practice settings, variability in these subjective assessments can be substantial. Centralized endpoint assessment committees (EACs offer a mechanism through which to reduce assessment bias and potentially increase assessment precision and accuracy, particularly in open-label trials. An overview of regulatory agencies' rationales for an EAC is reviewed. In addition, the two main types of EACs, the blinded independent central review, and the consensus panel are compared. Selection of endpoints for EAC evaluation and design of EAC process to maximize EAC value proposition are also discussed. Keywords: endpoint assessment committee, FDA, central review, BICR, adjudication, consensus panel

  16. Systematic adjudication of myocardial infarction end-points in an international clinical trial

    NARCIS (Netherlands)

    K.W. Mahaffey (Kenneth); R.A. Harrington (Robert Alex); K.M. Akkerhuis (Martijn); N.S. Kleiman (Neal); L.G. Berdan (Lisa); B.S. Crenshaw (Brian); B.E. Tardiff (Barbara); C.B. Granger (Christopher); I. DeJong (Ingrid); M. Bhapkar (Manju); P. Widimsky (Petr); R. Corbalon (Ramón); K.L. Lee (Kerry); J.W. Deckers (Jaap); M.L. Simoons (Maarten); E.J. Topol (Eric); R.M. Califf (Robert)

    2001-01-01

    textabstractBackground. Clinical events committees (CEC) are used routinely to adjudicate suspected end-points in cardiovascular trials, but little information has been published about the various processes used. We reviewed results of the CEC process used to identify and adjudicate suspected

  17. Systematic adjudication of myocardial infarction end-points in an international clinical trial.

    NARCIS (Netherlands)

    K.W. Mahaffey (Kenneth); R.A. Harrington (Robert Alex); N.S. Kleiman (Neal); L.G. Berdan (Lisa); B.S. Crenshaw (Brian); B.E. Tardiff (Barbara); C.B. Granger (Christopher); I. DeJong (Ingrid); M. Bhapkar (Manju); P. Widimsky (Petr); R. Corbalon (Ramón); K.L. Lee (Kerry); J.W. Deckers (Jaap); M.L. Simoons (Maarten); E.J. Topol (Eric); R.M. Califf (Robert); K.M. Akkerhuis (Martijn)

    2001-01-01

    textabstractBACKGROUND: Clinical events committees (CEC) are used routinely to adjudicate suspected end-points in cardiovascular trials, but little information has been published about the various processes used. We reviewed results of the CEC process used to identify and adjudicate suspected

  18. End-point construction and systematic titration error in linear titration curves-complexation reactions

    NARCIS (Netherlands)

    Coenegracht, P.M.J.; Duisenberg, A.J.M.

    1975-01-01

    The systematic titration error which is introduced by the intersection of tangents to hyperbolic titration curves is discussed. The effects of the apparent (conditional) formation constant, of the concentration of the unknown component and of the ranges used for the end-point construction are consid

  19. Development of a Computer Model for Prediction of PCB Degradation Endpoints

    Energy Technology Data Exchange (ETDEWEB)

    Just, E.M.; Klasson, T.

    1999-12-07

    Several researchers have demonstrated the transformation if polychlorinated biphenyls (PCBs) by both aerobic and anaerobic bacteria. This transformation, or conversion, is characteristic and often dependent on PCB congener structure and in addition, dictates the products or endpoints. Since transformation is linked to microbial activities, bioremediation has been hailed as a possible solution for PCB-contaminated soils and sediments, and several demonstration activities have verified laboratory results. This paper presents results from mathematical modeling of PCB transformation as a means of predicting possible endpoints of bioremediation. Since transformation can be influenced by both starting composition of the PCBs and microbial activity, this paper systematically evaluates several of the most common transformation patterns. The predicted data are also compared with experimental results. For example, the correlation between laboratory-observed and predicted endpoint data was, in some cases, as good as 0.98 (perfect correlation = 1.0). In addition to predicting chemical endpoints, the possible human effects of the PCBs are discussed through the use of documented dioxin-like toxicity and accumulation in humans before and after transformation.

  20. Coulometric Titration of Ethylenediaminetetraacetate (EDTA) with Spectrophotometric Endpoint Detection: An Experiment for the Instrumental Analysis Laboratory

    Science.gov (United States)

    Williams, Kathryn R.; Young, Vaneica Y.; Killian, Benjamin J.

    2011-01-01

    Ethylenediaminetetraacetate (EDTA) is commonly used as an anticoagulant in blood-collection procedures. In this experiment for the instrumental analysis laboratory, students determine the quantity of EDTA in commercial collection tubes by coulometric titration with electrolytically generated Cu[superscript 2+]. The endpoint is detected…

  1. Baseline characteristics in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE)

    DEFF Research Database (Denmark)

    Parving, Hans-Henrik; Brenner, Barry M; McMurray, John J V

    2012-01-01

    Patients with type 2 diabetes are at enhanced risk for macro- and microvascular complications. Albuminuria and/or reduced kidney function further enhances the vascular risk. We initiated the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). Aliskiren, a novel direct renin...

  2. The Regular Free-Endpoint Linear Quadratic Problem with Indefinite Cost

    NARCIS (Netherlands)

    Trentelman, Hendrikus

    1989-01-01

    This paper studies an open problem in the context of linear quadratic optimal control, the free-endpoint regular linear quadratic problem with indefinite cost functional. It is shown that the optimal cost for this problem is given by a particular solution of the algebraic Riccati equation. This

  3. Transmission assessment surveys (TAS) to define endpoints for lymphatic filariasis mass drug administration

    DEFF Research Database (Denmark)

    Chu, Brian K.; Deming, Michael; Biritwum, Nana-Kwadwo

    2013-01-01

    Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached...

  4. Development of an in vitro genotoxicity screening assay: combining different genotoxic endpoints

    NARCIS (Netherlands)

    Mahabir, A.G.

    2010-01-01

    Genotoxic agents are a major threat to the integritiy of chromosomes and viability of cells, specially if the damage is not repaired, because it can lead to chromosome instability, cell cycle arrest, cell dysfunction, induction of apoptosis or carcinogenesis. For genotoxicity, two main endpoints are

  5. A comparative study of classical and biochemical endpoints for phytotoxicity testing of chlorobenzoic acids

    Institute of Scientific and Technical Information of China (English)

    LI Pei-jun; YIN Pei-jie; ZHOU Qi-xing; SHI Xing-qun; XIONG Xian-zhe

    2005-01-01

    The phytotoxicity of chlorobenzoic acids(CBAs) was studied and the biochemical endpoints' suitability and sensibility was evaluated. Two terrestrial plant species in the same family were exposed to different concentrations of CBAS and tested their germination according to the guideline of Organization for Economic Cooperation and Development(OECP, 1984). The results showed that CBA doseinhibition rate of classical endpoint had the distinct linear relationship in the range of 10%-50% inhibition rate for root elongation( p <0.01), and the dose variances of CBAs had the greater influence on the inhibition rate of germination than on inhibition rate of root elongation. The CBA dose half effect concentration-inhibition rate of two antioxidant enzyme activity superoxide dismutase(SOD) and catalase (CAT) had the quadratic relationship, and CBA dose-inhibition rate of the peroxides(POD) activity had the linear relationship( p<0.05). Comparing the half effect concentration (EC50 ) of two kinds of endpoints, the POD activity was more sensitive than classical endpoint, however, SOD and CAT activity were not sensitive in the experiment.

  6. AN EXISTENCE THEOREM OF POSITIVE SOLUTIONS FOR ELASTIC BEAM EQUATION WITH BOTH FIXED END-POINTS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    By using the degree theory on cone an existence theorem of positive solution for a class of fourth-order two-point BVP's is obtained. This class of BVP's usually describes the deformation of the elastic beam with both fixed end-points.

  7. SEMICONDUCTOR TECHNOLOGY A signal processing method for the friction-based endpoint detection system of a CMP process

    Science.gov (United States)

    Chi, Xu; Dongming, Guo; Zhuji, Jin; Renke, Kang

    2010-12-01

    A signal processing method for the friction-based endpoint detection system of a chemical mechanical polishing (CMP) process is presented. The signal process method uses the wavelet threshold denoising method to reduce the noise contained in the measured original signal, extracts the Kalman filter innovation from the denoised signal as the feature signal, and judges the CMP endpoint based on the feature of the Kalman filter innovation sequence during the CMP process. Applying the signal processing method, the endpoint detection experiments of the Cu CMP process were carried out. The results show that the signal processing method can judge the endpoint of the Cu CMP process.

  8. Establishing mussel behavior as a biomarker in ecotoxicology.

    Science.gov (United States)

    Hartmann, Jason T; Beggel, Sebastian; Auerswald, Karl; Stoeckle, Bernhard C; Geist, Juergen

    2016-01-01

    Most freshwater mussel species of the Unionoida are endangered, presenting a conservation issue as they are keystone species providing essential services for aquatic ecosystems. As filter feeders with limited mobility, mussels are highly susceptible to water pollution. Despite their exposure risk, mussels are underrepresented in standard ecotoxicological methods. This study aimed to demonstrate that mussel behavioral response to a chemical stressor is a suitable biomarker for the advancement of ecotoxicology methods that aids mussel conservation. Modern software and Hall sensor technology enabled mussel filtration behavior to be monitored real-time at very high resolution. With this technology, we present our method using Anodonta anatina and record their response to de-icing salt pollution. The experiment involved an environmentally relevant 'pulse-exposure' design simulating three subsequent inflow events. Three sublethal endpoints were investigated, Filtration Activity, Transition Frequency (number of changes from opened to closed, or vice versa) and Avoidance Behavior. The mussels presented a high variation in filtration behavior, behaving asynchronously. At environmentally relevant de-icing salt exposure scenarios, A. anatina behavior patterns were significantly affected. Treated mussels' Filtration Activity decreased during periods of very high and long de-icing salt exposure (pecotoxicology studies. Avoidance Behavior proved to be a potentially suitable endpoint for calculating mussel behavior effect concentration. Therefore we recommend adult mussel behavior as a suitable biomarker for future ecotoxicological research. This method could be applied to other bivalve species and for physical and environmental stressors, such as particulate matter and temperature. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Molecular biomarkers of neurodegeneration.

    Science.gov (United States)

    Höglund, Kina; Salter, Hugh

    2013-11-01

    Neuronal dysfunction and degeneration are central events of a number of major diseases with significant unmet need. Neuronal dysfunction may not necessarily be the result of cell death, but may also be due to synaptic damage leading to impaired neuronal cell signaling or long-term potentiation. Once degeneration occurs, it is unclear whether axonal or synaptic loss comes first or whether this precedes neuronal cell death. In this review we summarize the pathophysiology of four major neurodegenerative diseases; Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig's disease) For each of these diseases, we describe how biochemical biomarkers are currently understood in relation to the pathophysiology and in terms of neuronal biology, and we discuss the clinical and diagnostic utility of these potential tools, which are at present limited. We discuss how markers may be used to drive drug development and clinical practice.

  10. Towards Improved Biomarker Research

    DEFF Research Database (Denmark)

    Kjeldahl, Karin

    This thesis takes a look at the data analytical challenges associated with the search for biomarkers in large-scale biological data such as transcriptomics, proteomics and metabolomics data. These studies aim to identify genes, proteins or metabolites which can be associated with e.g. a diet...... is used both for regression and classification purposes. This method has proven its strong worth in the multivariate data analysis throughout an enormous range of applications; a very classic data type is near infrared (NIR) data, but many similar data types have also be very successful....... On that background, the general characteristics of omics data are described and related to the characteristics of classical NIR-type data. This shows that omics data, which are generally much bigger data sets than classical data, are not just simple extensions of NIR data. The sample type, analytical method...

  11. Biomarkers for lymphoma

    Science.gov (United States)

    Zangar, Richard C.; Varnum, Susan M.

    2014-09-02

    A biomarker, method, test kit, and diagnostic system for detecting the presence of lymphoma in a person are disclosed. The lymphoma may be Hodgkin's lymphoma or non-Hodgkin's lymphoma. The person may be a high-risk subject. In one embodiment, a plasma sample from a person is obtained. The level of at least one protein listed in Table S3 in the plasma sample is measured. The level of at least one protein in the plasma sample is compared with the level in a normal or healthy subject. The lymphoma is diagnosed based upon the level of the at least one protein in the plasma sample in comparison to the normal or healthy level.

  12. Inflammatory biomarkers for AMD.

    Science.gov (United States)

    Stanton, Chloe M; Wright, Alan F

    2014-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness worldwide, affecting an estimated 50 million individuals aged over 65 years.Environmental and genetic risk-factors implicate chronic inflammation in the etiology of AMD, contributing to the formation of drusen, retinal pigment epithelial cell dysfunction and photoreceptor cell death. Consistent with a role for chronic inflammation in AMD pathogenesis, several inflammatory mediators, including complement components, chemokines and cytokines, are elevated at both the local and systemic levels in AMD patients. These mediators have diverse roles in the alternative complement pathway, including recruitment of inflammatory cells, activation of the inflammasome, promotion of neovascularisation and in the resolution of inflammation. The utility of inflammatory biomarkers in assessing individual risk and progression of the disease is controversial. However, understanding the role of these inflammatory mediators in AMD onset, progression and response to treatment may increase our knowledge of disease pathogenesis and provide novel therapeutic options in the future.

  13. Surfactant protein D, Club cell protein 16, Pulmonary and activation-regulated chemokine, C-reactive protein, and Fibrinogen biomarker variation in chronic obstructive lung disease

    DEFF Research Database (Denmark)

    Johansson, Sofie Lock; Vestbo, J.; Sorensen, G. L.

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a multifaceted condition that cannot be fully described by the severity of airway obstruction. The limitations of spirometry and clinical history have prompted researchers to investigate a multitude of surrogate biomarkers of disease for the assessm......Chronic obstructive pulmonary disease (COPD) is a multifaceted condition that cannot be fully described by the severity of airway obstruction. The limitations of spirometry and clinical history have prompted researchers to investigate a multitude of surrogate biomarkers of disease...... for the assessment of patients, prediction of risk, and guidance of treatment. The aim of this review is to provide a comprehensive summary of observations for a selection of recently investigated pulmonary inflammatory biomarkers (Surfactant protein D (SP-D), Club cell protein 16 (CC-16), and Pulmonary...... and activation-regulated chemokine (PARC/CCL-18)) and systemic inflammatory biomarkers (C-reactive protein (CRP) and fibrinogen) with COPD. The relevance of these biomarkers for COPD is discussed in terms of their biological plausibility, their independent association to disease and hard clinical outcomes...

  14. Design of cohort studies in chronic diseases using routinely collected databases when a prescription is used as surrogate outcome

    Directory of Open Access Journals (Sweden)

    Egger Peter

    2011-04-01

    Full Text Available Abstract Background There has been little research on design of studies based on routinely collected data when the clinical endpoint of interest is not recorded, but can be inferred from a prescription. This often happens when exploring the effect of a drug on chronic diseases. Using the LifeLink claims database in studying the possible anti-inflammatory effects of statins in rheumatoid arthritis (RA, oral steroids (OS were treated as surrogate of inflammatory flare-ups. We compared two cohort study designs, the first using time to event outcomes and the second using quantitative amount of the surrogate. Methods RA patients were extracted from the LifeLink database. In the first study, patients were split into two sub-cohorts based on whether they were using OS within a specified time window of the RA index date (first record of RA. Using Cox models we evaluated the association between time-varying exposure to statins and (i initiation of OS therapy in the non-users of OS at RA index date and (ii cessation of OS therapy in the users of OS at RA index date. In the second study, we matched new statin users to non users on age and sex. Zero inflated negative binomial models were used to contrast the number of days' prescriptions of OS in the year following date of statin initiation for the two exposure groups. Results In the unmatched study, the statin exposure hazard ratio (HR of initiating OS in the 31451 non-users of OS at RA index date was 0.96(95% CI 0.9,1.1 and the statin exposure HR of cessation of OS therapy in the 6026 users of OS therapy at RA index date was 0.95 (0.87,1.05. In the matched cohort of 6288 RA patients the statin exposure rate ratio for duration on OS therapy was 0.88(0.76,1.02. There was digit preference for outcomes in multiples of 7 and 30 days. Conclusions The 'time to event' study design was preferable because it better exploits information on all available patients and provides a degree of robustness toward confounding

  15. Assessment of the efficacy of functional food ingredients-introducing the concept "kinetics of biomarkers".

    Science.gov (United States)

    Verhagen, Hans; Coolen, Stefan; Duchateau, Guus; Hamer, Mark; Kyle, Janet; Rechner, Andreas

    2004-07-13

    Functional foods are "foods and beverages with claimed health benefits based on scientific evidence". Health claims need to be substantiated scientifically. The future of functional foods will heavily rely on proven efficacy in well-controlled intervention studies with human volunteers. In order to have the maximum output of human trials, improvements are needed with respect to study design and optimization of study protocols. Efficacy at realistic intake levels needs to be established in studies with humans via the use of suitable biomarkers, unless the endpoint can be measured directly. The human body is able to deal with chemical entities irrespective of their origin, and the pharmaceutical terms "absorption, distribution, metabolism and excretion" have their equivalent when biomarkers are concerned. Whereas only "diurnal variation" or "circadian rhythm" is sometimes considered, little attention is paid to "kinetics of biomarkers". "Kinetics of biomarkers" comprises "formation, distribution, metabolism and excretion". However, this is at present neither an established science nor common practice in nutrition research on functional foods. As a consequence, sampling times and matrices, for example, are chosen on the basis of historical practice and convenience (for volunteers and scientists) but not on the basis of in depth insight. The concept of kinetics of biomarkers is illustrated by a variety of readily comprehensible examples, such as malaria, cholesterol, polyphenols, glutathione-S-transferase alpha, F2-isoprostanes, interleukin-6, and plasma triacylglycerides.

  16. [Novel biomarkers for diabetic nephropathy].

    Science.gov (United States)

    Araki, Shin-ichi

    2014-02-01

    Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. An early clinical sign of this complication is an increase of urinary albumin excretion, called microalbuminuria, which is not only a predictor of the progression of nephropathy, but also an independent risk factor for cardiovascular disease. Although microalbuminuria is clinically important to assess the prognosis of diabetic patients, it may be insufficient as an early and specific biomarker of diabetic nephropathy because of a large day-to-day variation and lack of a good correlation of microalbuminuria with renal dysfunction and pathohistological changes. Thus, more sensitive and specific biomarkers are needed to improve the diagnostic capability of identifying patients at high risk. The factors involved in renal tubulo-interstitial damage, the production and degradation of extracellular matrix, microinflammation, etc., are investigated as candidate molecules. Despite numerous efforts so far, the assessment of these biomarkers is still a subject of ongoing investigations. Recently, a variety of omics and quantitative techniques in systems biology are rapidly emerging in the field of biomarker discovery, including proteomics, transcriptomics, and metabolomics, and they have been applied to search for novel putative biomarkers of diabetic nephropathy. Novel biomarkers or their combination with microalbuminuria provide a better diagnostic accuracy than microalbuminuria alone, and may be useful for establishing personal medicine. Furthermore, the identification of novel biomarkers may provide insight into the mechanisms underlying diabetic nephropathy.

  17. Laboratory Testing of Waste Isolation Pilot Plant Surrogate Waste Materials

    Science.gov (United States)

    Broome, S.; Bronowski, D.; Pfeifle, T.; Herrick, C. G.

    2011-12-01

    The Waste Isolation Pilot Plant (WIPP) is a U.S. Department of Energy geological repository for the permanent disposal of defense-related transuranic (TRU) waste. The waste is emplaced in rooms excavated in the bedded Salado salt formation at a depth of 655 m below the ground surface. After emplacement of the waste, the repository will be sealed and decommissioned. WIPP Performance Assessment modeling of the underground material response requires a full and accurate understanding of coupled mechanical, hydrological, and geochemical processes and how they evolve with time. This study was part of a broader test program focused on room closure, specifically the compaction behavior of waste and the constitutive relations to model this behavior. The goal of this study was to develop an improved waste constitutive model. The model parameters are developed based on a well designed set of test data. The constitutive model will then be used to realistically model evolution of the underground and to better understand the impacts on repository performance. The present study results are focused on laboratory testing of surrogate waste materials. The surrogate wastes correspond to a conservative estimate of the degraded containers and TRU waste materials after the 10,000 year regulatory period. Testing consists of hydrostatic, uniaxial, and triaxial tests performed on surrogate waste recipes that were previously developed by Hansen et al. (1997). These recipes can be divided into materials that simulate 50% and 100% degraded waste by weight. The percent degradation indicates the anticipated amount of iron corrosion, as well as the decomposition of cellulosics, plastics, and rubbers. Axial, lateral, and volumetric strain and axial and lateral stress measurements were made. Two unique testing techniques were developed during the course of the experimental program. The first involves the use of dilatometry to measure sample volumetric strain under a hydrostatic condition. Bulk

  18. A general framework to learn surrogate relevance criterion for atlas based image segmentation

    Science.gov (United States)

    Zhao, Tingting; Ruan, Dan

    2016-09-01

    Multi-atlas based image segmentation sees great opportunities in the big data era but also faces unprecedented challenges in identifying positive contributors from extensive heterogeneous data. To assess data relevance, image similarity criteria based on various image features widely serve as surrogates for the inaccessible geometric agreement criteria. This paper proposes a general framework to learn image based surrogate relevance criteria to better mimic the behaviors of segmentation based oracle geometric relevance. The validity of its general rationale is verified in the specific context of fusion set selection for image segmentation. More specifically, we first present a unified formulation for surrogate relevance criteria and model the neighborhood relationship among atlases based on the oracle relevance knowledge. Surrogates are then trained to be small for geometrically relevant neighbors and large for irrelevant remotes to the given targets. The proposed surrogate learning framework is verified in corpus callosum segmentation. The learned surrogates demonstrate superiority in inferring the underlying oracle value and selecting relevant fusion set, compared to benchmark surrogates.

  19. Surrogate mobility and orientation affect the early neurobehavioral development of infant rhesus macaques (Macaca mulatta).

    Science.gov (United States)

    Dettmer, Amanda M; Ruggiero, Angela M; Novak, Melinda A; Meyer, Jerrold S; Suomi, Stephen J

    2008-05-01

    A biological mother's movement appears necessary for optimal development in infant monkeys. However, nursery-reared monkeys are typically provided with inanimate surrogate mothers that move very little. The purpose of this study was to evaluate the effects of a novel, highly mobile surrogate mother on motor development, exploration, and reactions to novelty. Six infant rhesus macaques (Macaca mulatta) were reared on mobile hanging surrogates (MS) and compared to six infants reared on standard stationary rocking surrogates (RS) and to 9-15 infants reared with their biological mothers (MR) for early developmental outcome. We predicted that MS infants would develop more similarly to MR infants than RS infants. In neonatal assessments conducted at Day 30, both MS and MR infants showed more highly developed motor activity than RS infants on measures of grasping (p = .009), coordination (p = .038), spontaneous crawl (p = .009), and balance (p = .003). At 2-3 months of age, both MS and MR infants displayed higher levels of exploration in the home cage than RS infants (p = .016). In a novel situation in which only MS and RS infants were tested, MS infants spent less time near their surrogates in the first five minutes of the test session than RS infants (p = .05), indicating a higher level of comfort. Collectively, these results suggest that when nursery-rearing of infant monkeys is necessary, a mobile hanging surrogate may encourage more normative development of gross motor skills and exploratory behavior and may serve as a useful alternative to stationary or rocking surrogates.

  20. A general framework to learn surrogate relevance criterion for atlas based image segmentation.

    Science.gov (United States)

    Zhao, Tingting; Ruan, Dan

    2016-09-07

    Multi-atlas based image segmentation sees great opportunities in the big data era but also faces unprecedented challenges in identifying positive contributors from extensive heterogeneous data. To assess data relevance, image similarity criteria based on various image features widely serve as surrogates for the inaccessible geometric agreement criteria. This paper proposes a general framework to learn image based surrogate relevance criteria to better mimic the behaviors of segmentation based oracle geometric relevance. The validity of its general rationale is verified in the specific context of fusion set selection for image segmentation. More specifically, we first present a unified formulation for surrogate relevance criteria and model the neighborhood relationship among atlases based on the oracle relevance knowledge. Surrogates are then trained to be small for geometrically relevant neighbors and large for irrelevant remotes to the given targets. The proposed surrogate learning framework is verified in corpus callosum segmentation. The learned surrogates demonstrate superiority in inferring the underlying oracle value and selecting relevant fusion set, compared to benchmark surrogates.

  1. Development of Parkinson's disease biomarkers.

    Science.gov (United States)

    Prakash, Kumar M; Tan, Eng-King

    2010-12-01

    Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting over 6 million people worldwide. It is anticipated that the number of affected individuals may increase significantly in the most populous nations by 2030. During the past 20 years, much progress has been made in identifying and assessing various potential clinical, biochemical, imaging and genetic biomarkers for PD. Despite the wealth of information, development of a validated biomarker for PD is still ongoing. It is hoped that reliable and well-validated biomarkers will provide critical clues to assist in the diagnosis and management of Parkinson's disease patients in the near future.

  2. Evaluation of the use of salivary lead levels as a surrogate of blood lead or plasma lead levels in lead exposed subjects

    Energy Technology Data Exchange (ETDEWEB)

    Barbosa, Fernando [Universidade de Sao Paulo, Departamento de Analises Clinicas, Toxicologicas e Bromatologicas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Ribeirao Preto, SP (Brazil); Correa Rodrigues, Maria H.; Buzalaf, Maria R. [Universidade de Sao Paulo, Departamento de Ciencias Biologicas/Bioquimica, Faculdade de Odontologia de Bauru, Bauru, SP (Brazil); Krug, Francisco J. [Universidade de Sao Paulo, Centro de Energia Nuclear na Agricultura, Piracicaba, SP (Brazil); Gerlach, Raquel F. [Universidade de Sao Paulo, Departamento de Morfologia, Estomatologia e Fisiologia, Faculdade de Odontologia de Ribeirao Preto, Ribeirao Preto, SP (Brazil); Tanus-Santos, Jose E. [Universidade de Sao Paulo, Departamento de Farmacologia, Faculdade de Medicina de Ribeirao Preto, Ribeirao Preto, SP (Brazil)

    2006-10-15

    We conducted a study to evaluate the use of parotid salivary lead (Pb-saliva) levels as a surrogate of the blood lead (Pb-B) or plasma lead levels (Pb-P) to diagnose lead exposure. The relationship between these biomarkers was assessed in a lead exposed population. Pb-saliva and Pb-P were determined by inductively coupled plasma mass spectrometry, while in whole blood lead was determined by graphite furnace atomic absorption spectrometry. We studied 88 adults (31 men and 57 women) from 18 to 60 years old. Pb-saliva levels varied from 0.05 to 4.4 {mu}g/l, with a mean of 0.85 {mu}g/l. Blood lead levels varied from 32.0 to 428.0 {mu}g/l in men (mean 112.3 {mu}g/l) and from 25.0 to 263.0 {mu}g/l (mean 63.5 {mu}g/l) in women. Corresponding Pb-Ps were 0.02-2.50 {mu}g/l (mean 0.77 {mu}g/l) and 0.03-1.6 {mu}g/l (mean 0.42 {mu}g/l) in men and women, respectively. A weak correlation was found between Log Pb-saliva and Log Pb-B (r=0.277, P<0.008), and between Log Pb-saliva and Log Pb-P (r=0.280, P=0.006). The Pb-saliva/Pb-P ratio ranged from 0.20 to 18.0. Age or gender does not affect Pb-saliva levels or Pb-saliva/Pb-P ratio. Taken together, these results suggest that salivary lead may not be used as a biomarker to diagnose lead exposure nor as a surrogate of plasma lead levels at least for low to moderately lead exposed population. (orig.)

  3. Results from Second Round of Remediated Nitrate Salt Surrogate Formulation and Testing

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Geoffrey Wayne [Los Alamos National Laboratory; Leonard, Philip [Los Alamos National Laboratory; Hartline, Ernest Leon [Los Alamos National Laboratory; Tian, Hongzhao [Los Alamos National Laboratory

    2016-04-04

    High Explosives and Technology (M-7) completed the second round of formulation and testing of Remediated Nitrate Salt (RNS) surrogates on March 17, 2016. This report summarizes the results of the work and also includes additional documentation required under test plan PLAN-TA9-2443 Rev B, "Remediated Nitrate Salt (RNS) Surrogate Formulation and Testing Standard Procedure", released February 16, 2016. All formulation and testing was carried out according to PLAN-TA9-2443 Rev B. Results from the first round of formulation and testing were documented in memorandum M7-16-6042, "Results from First Round of Remediated Nitrate Salt Surrogate Formulation and Testing."

  4. Assessing the potential of surrogate EPS to mimic natural biofilm mechanical properties

    Science.gov (United States)

    Thom, Moritz; Schimmels, Stefan

    2017-04-01

    Biofilms growing on benthic sediments may increase the resistance towards erosion considerably by the sticky nature of extracellular polymeric substances (EPS). The EPS is a biopolymer which is secreted by the microorganisms inhabiting the biofilm matrix and may be regarded as natural glue. However, laboratory studies on the biostabilization effect mediated by biofilms are often hampered by the unavailability of "environmental" flumes in which light intensities, water temperature and nutrient content can be controlled. To allow investigations on biostabilization in "traditional" flume settings the use of surrogate materials is studied. Another advantage of using appropriate surrogates is the potential to reduce the experimental time, as compared to cultivating natural biofilms, the surrogates can readily be designed to mimic biofilms at different growth stages. Furthermore, the use of surrogates which are expected to have more homogeneous mechanical properties could facilitate fundamental studies to improve our knowledge on biostabilization. Even though a number of studies have already utilized EPS surrogates it is not clear how to mix them to correctly mimic natural EPS mechanical properties. In this study the adhesiveness (a measure of stickiness) on the surface of several EPS surrogates (e.g. Xanthan Gum, sodium alginate) is measured. These surrogates which are originally used in the food industry as rheology modifiers are mixed by adding water to a powder at a desired concentration (C). The measured surface adhesion of different surrogates at different concentrations ranged from 0.5 to 6.7 N/m2, which is well in line with values found for laboratory cultured biofilms. We found that the surrogate characteristics differed largely especially in regard to a) the response of the adhesiveness to increased concentrations (powder to water) and b) in their rheological characteristics. A seemingly promising surrogate for the use in biostabilization studies is Xanthan Gum

  5. Children of surrogate mothers: psychological well-being, family relationships and experiences of surrogacy.

    Science.gov (United States)

    Jadva, V; Imrie, S

    2014-01-01

    What impact does surrogacy have on the surrogates' own children? The children of surrogate mothers do not experience any negative consequences as a result of their mother's decision to be a surrogate, irrespective of whether or not the surrogate uses her own egg. Participants were recruited as part of a study of the long-term effects of surrogacy for surrogates and their family members. Data were collected from 36 children of surrogates at a single time point. Participants whose mother had been a surrogate 5-15 years prior to interview and who were aged over 12 years were eligible to take part. Thirty-six participants (14 male and 22 female) aged 12-25 years were interviewed (response rate = 52%). Questionnaires assessing psychological health and family functioning were administered. Forty-four per cent (15) of participants' mothers had undergone gestational surrogacy, 39% (14) had used their own egg (genetic surrogacy) and 19% (7) had completed both types of surrogacy. Most surrogates' children (86%, 31) had a positive view of their mother's surrogacy. Forty-seven per cent (17) of children were in contact with the surrogacy child and all reported good relationships with him/her. Forty per cent (14) of children referred to the child as a sibling or half-sibling and this did not differ between genetic and gestational surrogacy. Most children (89%, 32), reported a positive view of family life, with all enjoying spending time with their mother. Mean scores on the questionnaire assessments of psychological health and self-esteem were within the normal range and did not differ by surrogacy type. The sample size for this study was relatively small and not all children chose to take part, therefore their views cannot be known. Nevertheless, this is the first study to assess the experiences of surrogacy from the perspective of the surrogates' own children. There may be some bias from the inclusion of siblings from the same family. Findings of this study show that family

  6. Efficient Calibration of Computationally Intensive Groundwater Models through Surrogate Modelling with Lower Levels of Fidelity

    Science.gov (United States)

    Razavi, S.; Anderson, D.; Martin, P.; MacMillan, G.; Tolson, B.; Gabriel, C.; Zhang, B.

    2012-12-01

    Many sophisticated groundwater models tend to be computationally intensive as they rigorously represent detailed scientific knowledge about the groundwater systems. Calibration (model inversion), which is a vital step of groundwater model development, can require hundreds or thousands of model evaluations (runs) for different sets of parameters and as such demand prohibitively large computational time and resources. One common strategy to circumvent this computational burden is surrogate modelling which is concerned with developing and utilizing fast-to-run surrogates of the original computationally intensive models (also called fine models). Surrogates can be either based on statistical and data-driven models such as kriging and neural networks or simplified physically-based models with lower fidelity to the original system (also called coarse models). Fidelity in this context refers to the degree of the realism of a simulation model. This research initially investigates different strategies for developing lower-fidelity surrogates of a fine groundwater model and their combinations. These strategies include coarsening the fine model, relaxing the numerical convergence criteria, and simplifying the model geological conceptualisation. Trade-offs between model efficiency and fidelity (accuracy) are of special interest. A methodological framework is developed for coordinating the original fine model with its lower-fidelity surrogates with the objective of efficiently calibrating the parameters of the original model. This framework is capable of mapping the original model parameters to the corresponding surrogate model parameters and also mapping the surrogate model response for the given parameters to the original model response. This framework is general in that it can be used with different optimization and/or uncertainty analysis techniques available for groundwater model calibration and parameter/predictive uncertainty assessment. A real-world computationally

  7. One universal common endpoint in mouse models of amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Jesse A Solomon

    Full Text Available There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS. Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs, CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex, and CS 5 (CS 4 plus righting reflex >20 s. The age (d; mean ± SD at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001. There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001, CS 4 and CS 4+ (r = 0.96, P<0.001, and CS 4+ and CS 5 (r = 0.98, P<0.001, with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046 and CS 5 (P = 0.006, respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001 from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS?

  8. Effectiveness of amphibians as biodiversity surrogates in pond conservation.

    Science.gov (United States)

    Ilg, Christiane; Oertli, Beat

    2017-04-01

    Amphibian decline has led to worldwide conservation efforts, including the identification and designation of sites for their protection. These sites could also play an important role in the conservation of other freshwater taxa. In 89 ponds in Switzerland, we assessed the effectiveness of amphibians as a surrogate for 4 taxonomic groups that occur in the same freshwater ecosystems as amphibians: dragonflies, aquatic beetles, aquatic gastropods, and aquatic plants. The ponds were all of high value for amphibian conservation. Cross-taxon correlations were tested for species richness and conservation value, and Mantel tests were used to investigate community congruence. Species richness, conservation value, and community composition of amphibians were weakly congruent with these measures for the other taxonomic groups. Paired comparisons for the 5 groups considered showed that for each metric, amphibians had the lowest degree of congruence. Our results imply that site designation for amphibian conservation will not necessarily provide protection for freshwater biodiversity as a whole. To provide adequate protection for freshwater species, we recommend other taxonomic groups be considered in addition to amphibians in the prioritization and site designation process. © 2016 Society for Conservation Biology.

  9. Numerical investigation for erratic behavior of Kriging surrogate model

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Hyun Gil; Yi, Seul Gi [KAIST, Daejeon (Korea, Republic of); Choi, Seong Im [Virginia Polytechnic Institute and State University, Blacksburg (United States)

    2014-09-15

    Kriging model is one of popular spatial/temporal interpolation models in engineering field since it could reduce the time resources for the expensive analysis. But generation of the Kriging model is hardly a sinecure because internal semi-variogram structure of the Kriging often reveals numerically unstable or erratic behaviors. In present study, the issues in the maximum likelihood estimation which are the vital-parts of the construction of the Kriging model, is investigated. These issues are divided into two aspects; Issue I is for the erratic response of likelihood function itself, and Issue II is for numerically unstable behaviors in the correlation matrix. For both issues, studies for specific circumstances which might raise the issue, and the reason of that are conducted. Some practical ways further are suggested to cope with them. Furthermore, the issue is studied for practical problem; aerodynamic performance coefficients of two-dimensional airfoil predicted by CFD analysis. Result shows that such erratic behavior of Kriging surrogate model can be effectively resolved by proposed solution. In conclusion, it is expected this paper could be helpful to prevent such an erratic and unstable behavior.

  10. Protected Gold Nanoparticles with Thioethers and Amines As Surrogate Ligands

    Directory of Open Access Journals (Sweden)

    M. Rafiq H. Siddiqui

    2013-01-01

    Full Text Available Dodecyl sulfide, dodecyl amine, and hexylamine were shown to act as surrogate ligands (L via metastable gold nanoparticles. By collating analytical and spectroscopic data obtained simultaneously, empirical formula Au24L was assigned. These impurity-free nanoparticles obtained in near quantitative yields showing exceptional gold assays (up to 98%Au were prepared by a modification of the two-phase method. Replacement reactions on the Au24L showed that Au:L ratios may be increased (up to Au55:L (L= (H25C122S or decreased (Au12:L (L= H2NC12H25 and H2NC6H13 as desired. This work encompassing the role of analytical techniques used, that is, elemental analysis, variable temperature 1H NMR, FAB mass spectrometry, UV-Vis spectroscopy, thin film X-ray diffraction, and high-resolution electron microscopy (HREM has implications in the study of size control, purity, stability, and metal assays of gold nanoparticles.

  11. Investigation of ethosomes as surrogate carriers for bioactives

    Directory of Open Access Journals (Sweden)

    Devina Verma

    2016-01-01

    Full Text Available Background: Ethosomal vesicular system delivering a bioactive phytochemical, chrysin, was developed for transdermal delivery to increase its permeability and penetrability. Materials and Methods: Ethosomal system was optimized by keeping lecithin and ethanol concentration as independent variable while size and size distribution were taken as dependent variables. The optimized formulation was then subjected to various in vitro characterization parameters. Results: Ethosomal vesicle with an optimum size and polydispersity index of 134 ± 35 nm and 0.153, respectively, and entrapment efficiency of 80.05 ± 2.6% was considered as optimized and subjected to characterization. The scanning electron microscopy and transmission electron microscopy showed spherical entities with uniform surface whereas in vitro permeation and retention study showed the sustained mode of drug release and better skin retention as compared to hydroethanolic solution of the drug. The confocal laser scanning microscopy study reiterated high penetrability of vesicles into the skin. Histopathological and Fourier transform infrared spectroscopy analysis revealed its mechanism of penetration. Conclusion : The study thus demonstrated the ability of the ethosomal vesicles as surrogate carriers for delivery of bioactive agents through the skin for better amelioration of skin inflammation and other diseases.

  12. Genotoxic and teratogenic effect of freshwater sediment samples from the Rhine and Elbe River (Germany) in zebrafish embryo using a multi-endpoint testing strategy.

    Science.gov (United States)

    Garcia-Käufer, M; Gartiser, S; Hafner, C; Schiwy, S; Keiter, S; Gründemann, C; Hollert, H

    2015-11-01

    The embryotoxic potential of three model sediment samples with a distinct and well-characterized pollutant burden from the main German river basins Rhine and Elbe was investigated. The Fish Embryo Contact Test (FECT) in zebrafish (Danio rerio) was applied and submitted to further development to allow for a comprehensive risk assessment of such complex environmental samples. As particulate pollutants are constructive constituents of sediments, they underlay episodic source-sink dynamics, becoming available to benthic organisms. As bioavailability of xenobiotics is a crucial factor for ecotoxicological hazard, we focused on the direct particle-exposure pathway, evaluating throughput-capable endpoints and considering toxicokinetics. Fish embryo and larvae were exposed toward reconstituted (freeze-dried) sediment samples on a microcosm-scale experimental approach. A range of different developmental embryonic stages were considered to gain knowledge of potential correlations with metabolic competence during the early embryogenesis. Morphological, physiological, and molecular endpoints were investigated to elucidate induced adverse effects, placing particular emphasis on genomic instability, assessed by the in vivo comet assay. Flow cytometry was used to investigate the extent of induced cell death, since cytotoxicity can lead to confounding effects. The implementation of relative toxicity indices further provides inter-comparability between samples and related studies. All of the investigated sediments represent a significant ecotoxicological hazard by disrupting embryogenesis in zebrafish. Beside the induction of acute toxicity, morphological and physiological embryotoxic effects could be identified in a concentration-response manner. Increased DNA strand break frequency was detected after sediment contact in characteristic non-monotonic dose-response behavior due to overlapping cytotoxic effects. The embryonic zebrafish toxicity model along with the in vivo comet

  13. Urinary Biomarkers of Brain Diseases

    Directory of Open Access Journals (Sweden)

    Manxia An

    2015-12-01

    Full Text Available Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.

  14. Improving tuberculosis diagnostics with biomarkers

    Directory of Open Access Journals (Sweden)

    Shu CC

    2015-05-01

    Full Text Available Chin-Chung Shu,1,2 Jann-Yuan Wang,2 Li-Na Lee,2,3 Chong-Jen Yu,2 Kwen-Tay Luh3 1Department of Traumatology, 2Department of Internal Medicine, 3Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan Abstract: Although many laboratory methods have been developed to expedite the diagnosis of active tuberculosis (TB and Mycobacterium tuberculosis (Mtb infection, delays in diagnosis remain a major problem in clinical practice. Biomarkers may contribute favorably or unfavorably to TB diagnosis in a clinical suspect TB case with inconclusive diagnostic findings. A good understanding of the effectiveness and practical limitations of these biomarkers is important to improve diagnosis. This review summarizes currently used biomarkers, mainly as validation, and focuses on latent TB infection, active pulmonary TB, and tuberculous pleural effusion. Keywords: tuberculosis, biomarker, diagnosis, latent tuberculosis infection, pleural effusion 

  15. Procalcitonine als biomarker voor infecties

    NARCIS (Netherlands)

    de Jonge, J C; de Lange, D W; Bij de Vaate, E A; van Leeuwen, H; Arends, J E

    2016-01-01

    - Inappropriate use of antibiotics in patients without bacterial infection contributes significantly to worldwide antibiotic resistance.- The goal of this review is to summarise evidence from randomised trials investigating the value of the biomarker procalcitonin (PCT) in patients with symptoms of

  16. Biomarkers of latent TB infection

    DEFF Research Database (Denmark)

    Ruhwald, Morten; Ravn, Pernille

    2009-01-01

    For the last 100 years, the tuberculin skin test (TST) has been the only diagnostic tool available for latent TB infection (LTBI) and no biomarker per se is available to diagnose the presence of LTBI. With the introduction of M. tuberculosis-specific IFN-gamma release assays (IGRAs), a new area...... of in vitro immunodiagnostic tests for LTBI based on biomarker readout has become a reality. In this review, we discuss existing evidence on the clinical usefulness of IGRAs and the indefinite number of potential new biomarkers that can be used to improve diagnosis of latent TB infection. We also present...... early data suggesting that the monocyte-derived chemokine inducible protein-10 may be useful as a novel biomarker for the immunodiagnosis of latent TB infection....

  17. Biomarkers for preclinical Alzheimer's disease.

    Science.gov (United States)

    Tan, Chen-Chen; Yu, Jin-Tai; Tan, Lan

    2014-01-01

    Currently, there is a pressing need to shift the focus to accurate detection of the earliest phase of increasingly preclinical Alzheimer's disease (AD). Meanwhile, the growing recognition that the pathophysiological process of AD begins many years prior to clinically obvious symptoms and the concept of a presymptomatic or preclinical stage of AD are becoming more widely accepted. Advances in clinical identification of new measurements will be critical not only in the discovery of sensitive, specific, and reliable biomarkers of preclinical AD but also in the development of tests that will aid in the early detection and differential diagnosis of dementia and in monitoring disease progression. The goal of this review is to provide an overview of biomarkers for preclinical AD, with emphasis on neuroimaging and neurochemical biomarkers. We conclude with a discussion of emergent directions for AD biomarker research.

  18. Linking biomarkers to reproductive success of caged fathead minnows in streams with increasing urbanization

    Science.gov (United States)

    Crago, J.; Corsi, S.R.; Weber, D.; Bannerman, R.; Klaper, R.

    2011-01-01

    Reproductive and oxidative stress biomarkers have been recommended as tools to assess the health of aquatic organisms. Though validated in the laboratory, there are few studies that tie a change in gene expression to adverse reproductive or population outcomes in the field. This paper looked at 17 streams with varying degrees of urbanization to assess the use of biomarkers associated with reproduction or stress in predicting reproductive success of fathead minnows. In addition, the relationship between biomarkers and water quality measures in streams with varying degrees of urbanization was examined. Liver vitellogenin mRNA was correlated with reproduction within a period of 11. d prior to sampling irrespective of habitat, but its correlation with egg output declined at 12. d and beyond indicating its usefulness as a short-term biomarker but its limits as a biomarker of total reproductive output. Stress biomarkers such as glutathione S-transferase may be better correlated with factors affecting reproduction over a longer term. There was a significant correlation between GST mRNA and a variety of anthropogenic pollutants. There was also an inverse correlation between glutathione S-transferase and the amount of the watershed designated as wetland. Egg production over the 21-d was negatively correlated with the amount of urbanization and positively correlated to wetland habitats. This study supports the development of multiple biomarkers linking oxidative stress and other non-reproductive endpoints to changes in aquatic habitats will be useful for predicting the health of fish populations and identifying the environmental factors that may need mitigation for sustainable population management. ?? 2010 Elsevier Ltd.

  19. Detection of Bordetella pertussis from Clinical Samples by Culture and End-Point PCR in Malaysian Patients

    Directory of Open Access Journals (Sweden)

    Tan Xue Ting

    2013-01-01

    Full Text Available Pertussis or whooping cough is a highly infectious respiratory disease caused by Bordetella pertussis. In vaccinating countries, infants, adolescents, and adults are relevant patients groups. A total of 707 clinical specimens were received from major hospitals in Malaysia in year 2011. These specimens were cultured on Regan-Lowe charcoal agar and subjected to end-point PCR, which amplified the repetitive insertion sequence IS481 and pertussis toxin promoter gene. Out of these specimens, 275 were positive: 4 by culture only, 6 by both end-point PCR and culture, and 265 by end-point PCR only. The majority of the positive cases were from ≤3 months old patients (77.1% (. There was no significant association between type of samples collected and end-point PCR results (. Our study showed that the end-point PCR technique was able to pick up more positive cases compared to culture method.

  20. Biomarkers of replicative senescence revisited

    DEFF Research Database (Denmark)

    Nehlin, Jan

    2016-01-01

    Biomarkers of replicative senescence can be defined as those ultrastructural and physiological variations as well as molecules whose changes in expression, activity or function correlate with aging, as a result of the gradual exhaustion of replicative potential and a state of permanent cell cycle...... with their chronological age and present health status, help define their current rate of aging and contribute to establish personalized therapy plans to reduce, counteract or even avoid the appearance of aging biomarkers....

  1. Biomarkers of satiation and satiety.

    Science.gov (United States)

    de Graaf, Cees; Blom, Wendy A M; Smeets, Paul A M; Stafleu, Annette; Hendriks, Henk F J

    2004-06-01

    This review's objective is to give a critical summary of studies that focused on physiologic measures relating to subjectively rated appetite, actual food intake, or both. Biomarkers of satiation and satiety may be used as a tool for assessing the satiating efficiency of foods and for understanding the regulation of food intake and energy balance. We made a distinction between biomarkers of satiation or meal termination and those of meal initiation related to satiety and between markers in the brain [central nervous system (CNS)] and those related to signals from the periphery to the CNS. Various studies showed that physicochemical measures related to stomach distension and blood concentrations of cholecystokinin and glucagon-like peptide 1 are peripheral biomarkers associated with meal termination. CNS biomarkers related to meal termination identified by functional magnetic resonance imaging and positron emission tomography are indicators of neural activity related to sensory-specific satiety. These measures cannot yet serve as a tool for assessing the satiating effect of foods, because they are not yet feasible. CNS biomarkers related to satiety are not yet specific enough to serve as biomarkers, although they can distinguish between extreme hunger and fullness. Three currently available biomarkers for satiety are decreases in blood glucose in the short term (2-4 d) negative energy balance; and ghrelin concentrations, which have been implicated in both short-term and long-term energy balance. The next challenge in this research area is to identify food ingredients that have an effect on biomarkers of satiation, satiety, or both. These ingredients may help consumers to maintain their energy intake at a level consistent with a healthy body weight.

  2. Finite-size effects, pseudocritical quantities and signatures of the chiral critical endpoint of QCD

    CERN Document Server

    Palhares, L F; Kodama, T

    2009-01-01

    We investigate finite-size effects on the phase diagram of strong interactions, and discuss their influence (and utility) on experimental signatures in high-energy heavy ion collisions. We calculate the modification of the pseudocritical transition line and isentropic trajectories, and discuss how this affects proposed signatures of the chiral critical endpoint. We argue that a finite-size scaling analysis may be crucial in the process of data analysis in the Beam Energy Scan program at RHIC and in future experiments at FAIR-GSI. We propose the use of extrapolations, full scaling plots and a chi-squared method as tools for searching the critical endpoint of QCD and determining its universality class.

  3. In-situ end-point detection during ion-beam etching of multilayer dielectric gratings

    Institute of Scientific and Technical Information of China (English)

    Hua Lin; Lifeng Li; Lijiang Zeng

    2005-01-01

    @@ An in-situ end-point detection technique for ion-beam etching is presented. A laser beam of the same wavelength and polarization as those in the intended application of the grating is fed into the vacuum chamber, and the beam retro-diffracted by the grating under etching is extracted and detected outside the chamber. This arrangement greatly simplifies the end-point detection. Modeling the grating diffraction with a rigorous diffraction grating computer program, we can satisfactorily simulate the evolution of the diffraction intensity during the etching process and consequently, we can accurately predict the end-point.Employing the proposed technique, we have reproducibly fabricated multilayer dielectric gratings with diffraction efficiencies of more than 92%.

  4. Construction of Endpoint Constrained Cubic Rational Curve with Chord-Length Parameterization

    Institute of Scientific and Technical Information of China (English)

    LI Pei-pei; ZHANG Xin; ZHANG Ai-wu

    2013-01-01

    This paper discusses the problem that constructing a curve to satisfy the given endpoint constraints and chord-length parameters. Based on the research of Lu, the curve construction method for the entire tangent angles region 0 1(α,α)∈(-π,π) × (-π,π) is given. Firstly, to ensure the weights are always positive, the three characteristics of cubic rational Bezier curve is proved, then the segment construction idea for the other tangent angles are presented in view of the three characteristics. The curve constructed with the new method satisfies the endpoint constraint and chord-length parameters, it’s G1 continuous in every segment curve, and the shapes of the curve are well.

  5. A mixed approach for proving non-inferiority in clinical trials with binary endpoints.

    Science.gov (United States)

    Rousson, Valentin; Seifert, Burkhardt

    2008-04-01

    When a new treatment is compared to an established one in a randomized clinical trial, it is standard practice to statistically test for non-inferiority rather than for superiority. When the endpoint is binary, one usually compares two treatments using either an odds-ratio or a difference of proportions. In this paper, we propose a mixed approach which uses both concepts. One first defines the non-inferiority margin using an odds-ratio and one ultimately proves non-inferiority statistically using a difference of proportions. The mixed approach is shown to be more powerful than the conventional odds-ratio approach when the efficacy of the established treatment is known (with good precision) and high (e.g. with more than 56% of success). The gain of power achieved may lead in turn to a substantial reduction in the sample size needed to prove non-inferiority. The mixed approach can be generalized to ordinal endpoints.

  6. Coulometric trace determination of water by using Karl Fischer reagent and potentiometric end-point detection.

    Science.gov (United States)

    Cedergren, A

    1974-06-01

    A new approach to the determination of water via the Karl Fischer reaction is described. Iodine is coulometrically generated and the end-point corresponding to a slight excess of iodine, is detected potentiometrically with a non-polarized platinum electrode. Samples of 1-500 mul containing 0.05-200 mug of water were analysed with a standard deviation of 0.015 mug in the range 0.05-20 mug of H(2)O. A specially constructed electrolysis cell was used in combination with an LKB 16300 Coulometric Analyzer and the time for a complete analysis was 1-4 min, depending on sample size. The reagent composition has been optimized in order to enhance the rate of the main reaction and to minimize the extent of side-reactions. Decreasing the temperature reduced the extent of side-reactions. The displacement of end-point potential on dilution was studied and a correction is discussed.

  7. Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials

    Science.gov (United States)

    Gottlieb, Klaus; Dawson, Jill; Hussain, Fez; Murray, Joseph A.

    2015-01-01

    Celiac disease is a lifelong disorder for which there is currently only one known, effective treatment: a gluten-free diet. New treatment approaches have recently emerged; several drugs are in Phase 2 trials and results appear promising; however, discussion around regulatory endpoints is in its infancy. We will briefly discuss the drugs that are under development and then shift our attention to potential trial endpoints, such as patient-reported outcomes, histology, serology, gene expression analysis and other tests. We will outline the differing requirements for proof-of-concept Phase 2 trials and Phase 3 registration trials, with a particular emphasis on current thinking in regulatory agencies. We conclude our paper with recommendations and a glossary of regulatory terms, to enable readers who are less familiar with regulatory language to take maximum advantage of this review. PMID:25725041

  8. Motor Power Signal Analysis for End-Point Detection of Chemical Mechanical Planarization

    Directory of Open Access Journals (Sweden)

    Hongkai Li

    2017-06-01

    Full Text Available In the integrated circuit (IC manufacturing, in-situ end-point detection (EPD is an important issue in the chemical mechanical planarization (CMP process. In the paper, we chose the motor power signal of the polishing platen as the monitoring object. We then used the moving average method, which was appropriate for in-situ calculation process and made it easy to code for software development, to smooth the signal curve, and then studied the signal variation during the actual CMP process. The results demonstrated that the motor power signal contained the end-point feature of the metal layer removal, and the processed signal curve facilitated the feature extraction and it was relatively steady before and after the layer transition stage. In addition, the motor power signal variation of the polishing head was explored and further analysis of time delay was performed.

  9. 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

  10. A multiple endpoint approach to predict the hepatotoxicity of pharmaceuticals in vitro

    OpenAIRE

    Truisi, Germaine Loredana

    2014-01-01

    A new approach was evaluated to predict the hepatotoxic potential of pharmaceuticals. For this purpose, primary rat and human hepatocytes cultured in an optimised sandwich configuration were used; thus, allowing the long-term, repeat-dosing of drugs. The strategy based on the evaluation of multiple endpoints, including cytotoxicity, biokinetic profiling, transcriptomics and proteomics. Pharmaceuticals with known toxicities and pharmacokinetic properties were used as model compounds.

  11. Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval

    Science.gov (United States)

    2016-10-01

    substantially impair functioning and quality of life. Regulatory standards for the design of symptom endpoints have evolved substantially over the...1d. Submit protocol to departmental review committees at UNC (Month 14) Completed – NOV 2012 1e. Obtain IRB approval at UNC (Months 19) Note...Cabozantinib demonstrated clinically meaningful pain palliation, reduced or eliminated patients’ narcotic use, and improved patient functioning , thus

  12. Muscle Synergies Heavily Influence the Neural Control of Arm Endpoint Stiffness and Energy Consumption.

    Science.gov (United States)

    Inouye, Joshua M; Valero-Cuevas, Francisco J

    2016-02-01

    Much debate has arisen from research on muscle synergies with respect to both limb impedance control and energy consumption. Studies of limb impedance control in the context of reaching movements and postural tasks have produced divergent findings, and this study explores whether the use of synergies by the central nervous system (CNS) can resolve these findings and also provide insights on mechanisms of energy consumption. In this study, we phrase these debates at the conceptual level of interactions between neural degrees of freedom and tasks constraints. This allows us to examine the ability of experimentally-observed synergies--correlated muscle activations--to control both energy consumption and the stiffness component of limb endpoint impedance. In our nominal 6-muscle planar arm model, muscle synergies and the desired size, shape, and orientation of endpoint stiffness ellipses, are expressed as linear constraints that define the set of feasible muscle activation patterns. Quadratic programming allows us to predict whether and how energy consumption can be minimized throughout the workspace of the limb given those linear constraints. We show that the presence of synergies drastically decreases the ability of the CNS to vary the properties of the endpoint stiffness and can even preclude the ability to minimize energy. Furthermore, the capacity to minimize energy consumption--when available--can be greatly affected by arm posture. Our computational approach helps reconcile divergent findings and conclusions about task-specific regulation of endpoint stiffness and energy consumption in the context of synergies. But more generally, these results provide further evidence that the benefits and disadvantages of muscle synergies go hand-in-hand with the structure of feasible muscle activation patterns afforded by the mechanics of the limb and task constraints. These insights will help design experiments to elucidate the interplay between synergies and the mechanisms

  13. Scientific and Societal Considerations in Selecting Assessment Endpoints for Environmental Decision Making

    Directory of Open Access Journals (Sweden)

    Elizabeth M. Strange

    2002-01-01

    Full Text Available It is sometimes argued that, from an ecological point of view, population-, community-, and ecosystem-level endpoints are more relevant than individual-level endpoints for assessing the risks posed by human activities to the sustainability of natural resources. Yet society values amenities provided by natural resources that are not necessarily evaluated or protected by assessment tools that focus on higher levels of biological organization. For example, human-caused stressors can adversely affect recreational opportunities that are valued by society even in the absence of detectable population-level reductions in biota. If protective measures are not initiated until effects at higher levels of biological organization are apparent, natural resources that are ecologically important or highly valued by the public may not be adequately protected. Thus, environmental decision makers should consider both scientific and societal factors in selecting endpoints for ecological risk assessments. At the same time, it is important to clearly distinguish the role of scientists, which is to evaluate ecological effects, from the role of policy makers, which is to determine how to address the uncertainty in scientific assessment in making environmental decisions and to judge what effects are adverse based on societal values and policy goals.

  14. Scientific and societal considerations in selecting assessment endpoints for environmental decision making.

    Science.gov (United States)

    Strange, Elizabeth M; Lipton, Joshua; Beltman, Douglas; Snyder, Blaine D

    2002-03-08

    It is sometimes argued that, from an ecological point of view, population-, community-, and ecosystem-level endpoints are more relevant than individual-level endpoints for assessing the risks posed by human activities to the sustainability of natural resources. Yet society values amenities provided by natural resources that are not necessarily evaluated or protected by assessment tools that focus on higher levels of biological organization. For example, human-caused stressors can adversely affect recreational opportunities that are valued by society even in the absence of detectable population-level reductions in biota. If protective measures are not initiated until effects at higher levels of biological organization are apparent, natural resources that are ecologically important or highly valued by the public may not be adequately protected. Thus, environmental decision makers should consider both scientific and societal factors in selecting endpoints for ecological risk assessments. At the same time, it is important to clearly distinguish the role of scientists, which is to evaluate ecological effects, from the role of policy makers, which is to determine how to address the uncertainty in scientific assessment in making environmental decisions and to judge what effects are adverse based on societal values and policy goals.

  15. Reduction of animal suffering in rabies vaccine potency testing by introduction of humane endpoints.

    Science.gov (United States)

    Takayama-Ito, Mutsuyo; Lim, Chang-Kweng; Nakamichi, Kazuo; Kakiuchi, Satsuki; Horiya, Madoka; Posadas-Herrera, Guillermo; Kurane, Ichiro; Saijo, Masayuki

    2017-03-01

    Potency controls of inactivated rabies vaccines for human use are confirmed by the National Institutes of Health challenge test in which lethal infection with severe neurological symptoms should be observed in approximately half of the mice inoculated with the rabies virus. Weight loss, decreased body temperature, and the presence of rabies-associated neurological signs have been proposed as humane endpoints. The potential for reduction of animal suffering by introducing humane endpoints in the potency test for inactivated rabies vaccine for human use was investigated. The clinical signs were scored and body weight was monitored. The average times to death following inoculation were 10.49 and 10.99 days post-inoculation (dpi) by the potency and challenge control tests, respectively, whereas the average times to showing Score-2 signs (paralysis, trembling, and coma) were 6.26 and 6.55 dpi, respectively. Body weight loss of more than 15% appeared at 5.82 and 6.42 dpi. The data provided here support the introduction of obvious neuronal signs combined with a body weight loss of ≥15% as a humane endpoint to reduce the time of animal suffering by approximately 4 days. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

  16. End-point impedance measurements across dominant and nondominant hands and robotic assistance with directional damping.

    Science.gov (United States)

    Erden, Mustafa Suphi; Billard, Aude

    2015-06-01

    The goal of this paper is to perform end-point impedance measurements across dominant and nondominant hands while doing airbrush painting and to use the results for developing a robotic assistance scheme. We study airbrush painting because it resembles in many ways manual welding, a standard industrial task. The experiments are performed with the 7 degrees of freedom KUKA lightweight robot arm. The robot is controlled in admittance using a force sensor attached at the end-point, so as to act as a free-mass and be passively guided by the human. For impedance measurements, a set of nine subjects perform 12 repetitions of airbrush painting, drawing a straight-line on a cartoon horizontally placed on a table, while passively moving the airbrush mounted on the robot's end-point. We measure hand impedance during the painting task by generating sudden and brief external forces with the robot. The results show that on average the dominant hand displays larger impedance than the nondominant in the directions perpendicular to the painting line. We find the most significant difference in the damping values in these directions. Based on this observation, we develop a "directional damping" scheme for robotic assistance and conduct a pilot study with 12 subjects to contrast airbrush painting with and without robotic assistance. Results show significant improvement in precision with both dominant and nondominant hands when using robotic assistance.

  17. Toxicity assessment through multiple endpoint bioassays in soils posing environmental risk according to regulatory screening values.

    Science.gov (United States)

    Rodriguez-Ruiz, A; Asensio, V; Zaldibar, B; Soto, M; Marigómez, I

    2014-01-01

    Toxicity profiles of two soils (a brownfield in Legazpi and an abandoned iron mine in Zugaztieta; Basque Country) contaminated with several metals (As, Zn, Pb and Cu in Legazpi; Zn, Pb, Cd and Cu in Zugaztieta) and petroleum hydrocarbons (in Legazpi) were determined using a multi-endpoint bioassay approach. Investigated soils exceeded screening values (SVs) of regulatory policies in force (Basque Country; Europe). Acute and chronic toxicity bioassays were conducted with a selected set of test species (Vibrio fischeri, Dictyostelium discoideum, Lactuca sativa, Raphanus sativus and Eisenia fetida) in combination with chemical analysis of soils and elutriates, as well as with bioaccumulation studies in earthworms. The sensitivity of the test species and the toxicity endpoints varied depending on the soil. It was concluded that whilst Zugaztieta soil showed very little or no toxicity, Legazpi soil was toxic according to almost all the toxicity tests (solid phase Microtox, D. discoideum inhibition of fruiting body formation and developmental cycle solid phase assays, lettuce seed germination and root elongation test, earthworm acute toxicity and reproduction tests, D. discoideum cell viability and replication elutriate assays). Thus, albeit both soils had similar SVs, their ecotoxicological risk, and therefore the need for intervening, was different for each soil as unveiled after toxicity profiling based on multiple endpoint bioassays. Such a toxicity profiling approach is suitable to be applied for scenario-targeted soil risk assessment in those cases where applicable national/regional soil legislation based on SVs demands further toxicity assessment.

  18. Autoregressive transitional ordinal model to test for treatment effect in neurological trials with complex endpoints

    Directory of Open Access Journals (Sweden)

    Lorenzo G. Tanadini

    2016-11-01

    Full Text Available Abstract Background A number of potential therapeutic approaches for neurological disorders have failed to provide convincing evidence of efficacy, prompting pharmaceutical and health companies to discontinue their involvement in drug development. Limitations in the statistical analysis of complex endpoints have very likely had a negative impact on the translational process. Methods We propose a transitional ordinal model with an autoregressive component to overcome previous limitations in the analysis of Upper Extremity Motor Scores, a relevant endpoint in the field of Spinal Cord Injury. Statistical power and clinical interpretation of estimated treatment effects of the proposed model were compared to routinely employed approaches in a large simulation study of two-arm randomized clinical trials. A revisitation of a key historical trial provides further comparison between the different analysis approaches. Results The proposed model outperformed all other approaches in virtually all simulation settings, achieving on average 14 % higher statistical power than the respective second-best performing approach (range: -1 %, +34 %. Only the transitional model allows treatment effect estimates to be interpreted as conditional odds ratios, providing clear interpretation and visualization. Conclusion The proposed model takes into account the complex ordinal nature of the endpoint under investigation and explicitly accounts for relevant prognostic factors such as lesion level and baseline information. Superior statistical power, combined with clear clinical interpretation of estimated treatment effects and widespread availability in commercial software, are strong arguments for clinicians and trial scientists to adopt, and further extend, the proposed approach.

  19. Midwest Surrogate Species and Prairie Reconstruction Funding Final Report, FY 2016

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Final report on funding received from the Natural Resources Program Center to support surrogate species planning and implementation and the Prairie Reconstruction...

  20. Surrogate Models for Online Monitoring and Process Troubleshooting of NBR Emulsion Copolymerization

    Directory of Open Access Journals (Sweden)

    Chandra Mouli R. Madhuranthakam

    2016-03-01

    Full Text Available Chemical processes with complex reaction mechanisms generally lead to dynamic models which, while beneficial for predicting and capturing the detailed process behavior, are not readily amenable for direct use in online applications related to process operation, optimisation, control, and troubleshooting. Surrogate models can help overcome this problem. In this research article, the first part focuses on obtaining surrogate models for emulsion copolymerization of nitrile butadiene rubber (NBR, which is usually produced in a train of continuous stirred tank reactors. The predictions and/or profiles for several performance characteristics such as conversion, number of polymer particles, copolymer composition, and weight-average molecular weight, obtained using surrogate models are compared with those obtained using the detailed mechanistic model. In the second part of this article, optimal flow profiles based on dynamic optimisation using the surrogate models are obtained for the production of NBR emulsions with the objective of minimising the off-specification product generated during grade transitions.

  1. An Efficient Constraint Boundary Sampling Method for Sequential RBDO Using Kriging Surrogate Model

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jihoon; Jang, Junyong; Kim, Shinyu; Lee, Tae Hee [Hanyang Univ., Seoul (Korea, Republic of); Cho, Sugil; Kim, Hyung Woo; Hong, Sup [Korea Research Institute of Ships and Ocean Engineering, Busan (Korea, Republic of)

    2016-06-15

    Reliability-based design optimization (RBDO) requires a high computational cost owing to its reliability analysis. A surrogate model is introduced to reduce the computational cost in RBDO. The accuracy of the reliability depends on the accuracy of the surrogate model of constraint boundaries in the surrogated-model-based RBDO. In earlier researches, constraint boundary sampling (CBS) was proposed to approximate accurately the boundaries of constraints by locating sample points on the boundaries of constraints. However, because CBS uses sample points on all constraint boundaries, it creates superfluous sample points. In this paper, efficient constraint boundary sampling (ECBS) is proposed to enhance the efficiency of CBS. ECBS uses the statistical information of a kriging surrogate model to locate sample points on or near the RBDO solution. The efficiency of ECBS is verified by mathematical examples.

  2. Endospore surface properties of commonly used Bacillus anthracis surrogates vary in aqueous solution

    Science.gov (United States)

    The hydrophobic character and electrophoretic mobility of microorganisms are vital aspects of understanding their interactions with the environment. These properties are fundamental in fate-and-transport, physiological, and virulence studies, and thus integral in surrogate select...

  3. Trimethylsilylethynyl ketones as surrogates for ethynyl ketones in the double Michael reaction.

    Science.gov (United States)

    Holeman, Derrick S; Rasne, Ravindra M; Grossman, Robert B

    2002-05-01

    Trimethylsilylethynyl ketones can be desilylated in the presence of a tethered carbon diacid and induced to undergo a double Michael reaction in situ. The trimethylsilylethynyl ketones can serve as surrogates of ethynyl ketones that are difficult to prepare or isolate.

  4. Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 2: endpoint definitions: A consensus document from the Mitral Valve Academic Research Consortium.

    Science.gov (United States)

    Stone, Gregg W; Adams, David H; Abraham, William T; Kappetein, Arie Pieter; Généreux, Philippe; Vranckx, Pascal; Mehran, Roxana; Kuck, Karl-Heinz; Leon, Martin B; Piazza, Nicolo; Head, Stuart J; Filippatos, Gerasimos; Vahanian, Alec S

    2015-08-01

    Mitral regurgitation (MR) is one of the most prevalent valve disorders and has numerous aetiologies, including primary (organic) MR, due to underlying degenerative/structural mitral valve (MV) pathology, and secondary (functional) MR, which is principally caused by global or regional left ventricular remodelling and/or severe left atrial dilation. Diagnosis and optimal management of MR requires integration of valve disease and heart failure specialists, MV cardiac surgeons, interventional cardiologists with expertise in structural heart disease, and imaging experts. The introduction of trans- catheter MV therapies has highlighted the need for a consensus approach to pragmatic clinical trial design and uniform endpoint definitions to evaluate outcomes in patients with MR. The Mitral Valve Academic Research Consortium is a collaboration between leading academic research organizations and physician-scientists specializing in MV disease from the United States and Europe. Three in-person meetings were held in Virginia and New York during which 44 heart failure, valve, and imaging experts, MV surgeons and interventional cardiologists, clinical trial specialists and statisticians, and representatives from the U.S. Food and Drug Administration considered all aspects of MV pathophysiology, prognosis, and therapies, culminating in a 2-part document describing consensus recommendations for clinical trial design (Part 1) and endpoint definitions (Part 2) to guide evaluation of transcatheter and surgical therapies for MR. The adoption of these recommendations will afford robustness and consistency in the comparative effectiveness evaluation of new devices and approaches to treat MR. These principles may be useful for regulatory assessment of new transcatheter MV devices, as well as for monitoring local and regional outcomes to guide quality improvement initiatives.

  5. Idaho National Laboratory Test Area North: Application of Endpoints to Guide Adaptive Remediation at a Complex Site: INL Test Area North: Application of Endpoints

    Energy Technology Data Exchange (ETDEWEB)

    Lee, M. Hope [PNNL Soil and Groundwater Program; Truex, Mike [PNNL; Freshley, Mark [PNNL; Wellman, Dawn [PNNL

    2016-09-01

    Complex sites are defined as those with difficult subsurface access, deep and/or thick zones of contamination, large areal extent, subsurface heterogeneities that limit the effectiveness of remediation, or where long-term remedies are needed to address contamination (e.g., because of long-term sources or large extent). The Test Area North at the Idaho National Laboratory, developed for nuclear fuel operations and heavy metal manufacturing, is used as a case study. Liquid wastes and sludge from experimental facilities were disposed in an injection well, which contaminated the subsurface aquifer located deep within fractured basalt. The wastes included organic, inorganic, and low-level radioactive constituents, with the focus of this case study on trichloroethylene. The site is used as an example of a systems-based framework that provides a structured approach to regulatory processes established for remediation under existing regulations. The framework is intended to facilitate remedy decisions and implementation at complex sites where restoration may be uncertain, require long timeframes, or involve use of adaptive management approaches. The framework facilitates site, regulator, and stakeholder interactions during the remedial planning and implementation process by using a conceptual model description as a technical foundation for decisions, identifying endpoints, which are interim remediation targets or intermediate decision points on the path to an ultimate end, and maintaining protectiveness during the remediation process. At the Test Area North, using a structured approach to implementing concepts in the endpoint framework, a three-component remedy is largely functioning as intended and is projected to meet remedial action objectives by 2095 as required. The remedy approach is being adjusted as new data become available. The framework provides a structured process for evaluating and adjusting the remediation approach, allowing site owners, regulators, and

  6. Significance of Including a Surrogate Arousal for Sleep Apnea-Hypopnea Syndrome Diagnosis by Respiratory Polygraphy

    Science.gov (United States)

    Masa, Juan F.; Corral, Jaime; Gomez de Terreros, Javier; Duran-Cantolla, Joaquin; Cabello, Marta; Hernández-Blasco, Luis; Monasterio, Carmen; Alonso, Alberto; Chiner, Eusebi; Aizpuru, Felipe; Zamorano, Jose; Cano, Ricardo; Montserrat, Jose M.; Garcia-Ledesma, Estefania; Pereira, Ricardo; Cancelo, Laura; Martinez, Angeles; Sacristan, Lirios; Salord, Neus; Carrera, Miguel; Sancho-Chust, José N.; Embid, Cristina

    2013-01-01

    Rationale: Respiratory polygraphy is an accepted alternative to polysomnography (PSG) for sleep apnea/hypopnea syndrome (SAHS) diagnosis, although it underestimates the apnea-hypopnea index (AHI) because respiratory polygraphy cannot identify arousals. Objectives: We performed a multicentric, randomized, blinded crossover study to determine the agreement between home respiratory polygraphy (HRP) and PSG, and between simultaneous respiratory polygraphy (respiratory polygraphy with PSG) (SimultRP) and PSG by means of 2 AHI scoring protocols with or without hyperventilation following flow reduction considered as a surrogate arousal. Methods: We included suspected SAHS patients from 8 hospitals. They were assigned to home and hospital protocols at random. We determined the agreement between respiratory polygraphy AHI and PSG AHI scorings using Bland and Altman plots and diagnostic agreement using receiver operating characteristic (ROC) curves. The agreement in therapeutic decisions (continuous positive airway pressure treatment or not) between HRP and PSG scorings was done with likelihood ratios and post-test probability calculations. Results: Of 366 randomized patients, 342 completed the protocol. AHI from HRP scorings (with and without surrogate arousal) had similar agreement with PSG. AHI from SimultRP with surrogate arousal scoring had better agreement with PSG than AHI from SimultRP without surrogate arousal. HRP with surrogate arousal scoring had slightly worse ROC curves than HRP without surrogate arousal, and the opposite was true for SimultRP scorings. HRP with surrogate arousal showed slightly better agreement with PSG in therapeutic decisions than for HRP without surrogate arousal. Conclusion: Incorporating a surrogate arousal measure into HRP did not substantially increase its agreement with PSG when compared with the usual procedure (HRP without surrogate arousal). Citation: Masa JF; Corral J; Gomez de Terreros J; Duran-Cantolla J; Cabello M; Hern

  7. Using multiscale spatial models to assess potential surrogate habitat for an imperiled reptile.

    Directory of Open Access Journals (Sweden)

    Jennifer M Fill

    Full Text Available In evaluating conservation and management options for species, practitioners might consider surrogate habitats at multiple scales when estimating available habitat or modeling species' potential distributions based on suitable habitats, especially when native environments are rare. Species' dependence on surrogates likely increases as optimal habitat is degraded and lost due to anthropogenic landscape change, and thus surrogate habitats may be vital for an imperiled species' survival in highly modified landscapes. We used spatial habitat models to examine a potential surrogate habitat for an imperiled ambush predator (eastern diamondback rattlesnake, Crotalus adamanteus; EDB at two scales. The EDB is an apex predator indigenous to imperiled longleaf pine ecosystems (Pinus palustris of the southeastern United States. Loss of native open-canopy pine savannas and woodlands has been suggested as the principal cause of the species' extensive decline. We examined EDB habitat selection in the Coastal Plain tidewater region to evaluate the role of marsh as a potential surrogate habitat and to further quantify the species' habitat requirements at two scales: home range (HR and within the home range (WHR. We studied EDBs using radiotelemetry and employed an information-theoretic approach and logistic regression to model habitat selection as use vs.We failed to detect a positive association with marsh as a surrogate habitat at the HR scale; rather, EDBs exhibited significantly negative associations with all landscape patches except pine savanna. Within home range selection was characterized by a negative association with forest and a positive association with ground cover, which suggests that EDBs may use surrogate habitats of similar structure, including marsh, within their home ranges. While our HR analysis did not support tidal marsh as a surrogate habitat, marsh may still provide resources for EDBs at smaller scales.

  8. Surrogate end points in women's health research: science, protoscience, and pseudoscience.

    Science.gov (United States)

    Grimes, David A; Schulz, Kenneth F; Raymond, Elizabeth G

    2010-04-01

    A surrogate end point (e.g., a laboratory test or image) serves as a proxy for a clinical end point of importance (e.g., fracture, thrombosis, or death). Adoption and use of surrogate end points lacking validation, especially in cardiovascular medicine, have caused thousands of patients' deaths, a serious violation of the ethical principle of beneficence. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  9. Chromosome translocations measured by fluorescence in-situ hybridization: A promising biomarker

    Energy Technology Data Exchange (ETDEWEB)

    Lucas, J.N.; Straume, T.

    1995-10-01

    A biomarker for exposure and risk assessment would be most useful if it employs an endpoint that is highly quantitative, is stable with time, and is relevant to human risk. Recent advances in chromosome staining using fluorescence in situ hybridization (FISH) facilitate fast and reliable measurement of reciprocal translocations, a kind of DNA damage linked to both prior exposure and risk. In contrast to other biomarkers available, the frequency of reciprocal translocations in individuals exposed to whole-body radiation is stable with time post exposure, has a rather small inter-individual variability, and can be measured accurately at the low levels. Here, the authors discuss results from their studies demonstrating that chromosome painting can be used to reconstruct radiation dose for workers exposed within the dose limits, for individuals exposed a long time ago, and even for those who have been diagnosed with leukemia but not yet undergone therapy.

  10. Multi-biomarker Profiling and Recurrent Hospitalizations in Heart Failure

    Directory of Open Access Journals (Sweden)

    Antoni Bayes-Genis

    2016-10-01

    Full Text Available Background: Despite advances in pharmacologic therapy and devices, patients with heart failure (HF continue to have significant rehospitalization rates and risk prediction remains challenging. We sought to explore the value of a multi-biomarker panel (including NT-proBNP, hs-TnT, and ST2 on top of clinical assessment for long-term prediction of recurrent hospitalizations in HF.Methods and Results: NT-proBNP, hs-TnT, and ST2 levels were measured in 891 consecutive ambulatory HF patients. The independent association between the multi-biomarker panel and recurrent hospitalizations was assessed through a multivariable negative binomial regression and expressed as incidence rates ratios. McFadden pseudoR2 and goodness-of-fit measures were also used. The total number of unplanned hospitalizations (all-cause, cardiovascular CV-, and HF-related were selected as the primary endpoints. At a mean follow-up of 4.2±2.1 years, 1623 all-cause hospitalizations in 498 patients (55.9%, 710 CV-related hospitalizations in 331 patients (37.2%, and 444 HF-related hospitalizations in 214 patients (24.1% were registered. The crude incidence of all-cause, CV-, and HF-related recurrent hospitalizations was significantly higher for patients with the multi-biomarker panel above the cut-point (hs-TnT>14 ng/L, NT-proBNP>1000 ng/L, and ST2>35 ng/mL (all P<0.001. For all-cause, CV-, and HF-related recurrent hospitalizations, the McFadden R2, Akaike information criterion, and Bayesian information criterion supported the superiority of incorporating the multi-biomarker panel into a clinical predictive model.Conclusions: A multi-biomarker approach that incorporates NT-proBNP, hs-TnT, and ST2 better identifies HF patients at risk for recurrent hospitalizations. Elucidation of new biophysiological targets for recurrent hospitalizations may identify patient profiles for focused intervention.

  11. Comparison of burrowing and stimuli-evoked pain behaviors as end-points in rat models of inflammatory pain and peripheral neuropathic pain

    Directory of Open Access Journals (Sweden)

    Arjun eMuralidharan

    2016-05-01

    Full Text Available Establishment and validation of ethologically-relevant, non-evoked behavioral end-points as surrogate measures of spontaneous pain in rodent pain models has been proposed as a means to improve preclinical to clinical research translation in the pain field. Here, we compared the utility of burrowing behavior with hypersensitivity to applied mechanical stimuli for pain assessment in rat models of chronic inflammatory and peripheral neuropathic pain. Briefly, groups of male Sprague-Dawley rats were habituated to the burrowing environment and trained over a 5-day period. Rats that burrowed ≤450g of gravel on any two days of the individual training phase were excluded from the study. The remaining rats received either a unilateral intraplantar injection of Freund’s complete adjuvant (FCA or saline, or underwent unilateral chronic constriction injury (CCI of the sciatic nerve- or sham-surgery. Baseline burrowing behavior and evoked pain behaviors were assessed prior to model induction, and twice-weekly until study completion on day 14. For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws. Although burrowing behavior also decreased in a temporal manner for both FCA- and CCI-rats, there was considerable inter-animal variability. By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter-animal variability. Our data collectively show that burrowing behavior is altered in rodent models of chronic inflammatory pain and peripheral neuropathic pain. However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability.

  12. Desorption of a methamphetamine surrogate from wallboard under remediation conditions

    Science.gov (United States)

    Poppendieck, Dustin; Morrison, Glenn; Corsi, Richard

    2015-04-01

    Thousands of homes in the United States are found to be contaminated with methamphetamine each year. Buildings used to produce illicit methamphetamine are typically remediated by removing soft furnishings and stained materials, cleaning and sometimes encapsulating surfaces using paint. Methamphetamine that has penetrated into paint films, wood and other permanent materials can be slowly released back into the building air over time, exposing future occupants and re-contaminating furnishings. The objective of this study was to determine the efficacy of two wallboard remediation techniques for homes contaminated with methamphetamine: 1) enhancing desorption by elevating temperature and relative humidity while ventilating the interior space, and 2) painting over affected wallboard to seal the methamphetamine in place. The emission of a methamphetamine surrogate, N-isopropylbenzylamine (NIBA), from pre-dosed wallboard chambers over 20 days at 32 °C and two values of relative humidity were studied. Emission rates from wallboard after 15 days at 32 °C ranged from 35 to 1400 μg h-1 m-2. Less than 22% of the NIBA was removed from the chambers over three weeks. Results indicate that elevating temperatures during remediation and latex painting of impacted wallboard will not significantly reduce freebase methamphetamine emissions from wallboard. Raising the relative humidity from 27% to 49% increased the emission rates by a factor of 1.4. A steady-state model of a typical home using the emission rates from this study and typical residential building parameters and conditions shows that adult inhalation reference doses for methamphetamine will be reached when approximately 1 g of methamphetamine is present in the wallboard of a house.

  13. Survival of norovirus surrogate on various food-contact surfaces.

    Science.gov (United States)

    Kim, An-Na; Park, Shin Young; Bae, San-Cheong; Oh, Mi-Hwa; Ha, Sang-Do

    2014-09-01

    Norovirus (NoV) is an environmental threat to humans, which spreads easily from one infected person to another, causing foodborne and waterborne diseases. Therefore, precautions against NoV infection are important in the preparation of food. The aim of this study was to investigate the survival of murine norovirus (MNV), as a NoV surrogate, on six different food-contact surfaces: ceramic, wood, rubber, glass, stainless steel, and plastic. We inoculated 10(5) PFU of MNV onto the six different surface coupons that were then kept at room temperature for 28 days. On the food-contact surfaces, the greatest reduction in MNV was 2.28 log10 PFU/coupon, observed on stainless steel, while the lowest MNV reduction was 1.29 log10 PFU/coupon, observed on wood. The rank order of MNV reduction, from highest to lowest, was stainless steel, plastic, rubber, glass, ceramic, and wood. The values of d R (time required to reduce the virus by 90%) on survival plots of MNV determined by a modified Weibull model were 277.60 h (R(2) = 0.99) on ceramic, 492.59 h (R(2) = 0.98) on wood, 173.56 h on rubber (R(2) = 0.98), 97.18 h (R(2) = 0.94) on glass, 91.76 h (R(2) = 0.97) on stainless steel, and 137.74 h (R(2) = 0.97) on plastic. The infectivity of MNV on all food-contact surfaces remained after 28 days. These results show that MNV persists in an infective state on various food-contact surfaces for long periods. This study may provide valuable information for the control of NoV on various food-contact surfaces, in order to prevent foodborne disease.

  14. Composite Sampling Approaches for Bacillus anthracis Surrogate Extracted from Soil.

    Directory of Open Access Journals (Sweden)

    Brian France

    Full Text Available Any release of anthrax spores in the U.S. would require action to decontaminate the site and restore its use and operations as rapidly as possible. The remediation activity would require environmental sampling, both initially to determine the extent of contamination (hazard mapping and post-decon to determine that the site is free of contamination (clearance sampling. Whether the spore contamination is within a building or outdoors, collecting and analyzing what could be thousands of samples can become the factor that limits the pace of restoring operations. To address this sampling and analysis bottleneck and decrease the time needed to recover from an anthrax contamination event, this study investigates the use of composite sampling. Pooling or compositing of samples is an established technique to reduce the number of analyses required, and its use for anthrax spore sampling has recently been investigated. However, use of composite sampling in an anthrax spore remediation event will require well-documented and accepted methods. In particular, previous composite sampling studies have focused on sampling from hard surfaces; data on soil sampling are required to extend the procedure to outdoor use. Further, we must consider whether combining liquid samples, thus increasing the volume, lowers the sensitivity of detection and produces false negatives. In this study, methods to composite bacterial spore samples from soil are demonstrated. B. subtilis spore suspensions were used as a surrogate for anthrax spores. Two soils (Arizona Test Dust and sterilized potting soil were contaminated and spore recovery with composites was shown to match individual sample performance. Results show that dilution can be overcome by concentrating bacterial spores using standard filtration methods. This study shows that composite sampling can be a viable method of pooling samples to reduce the number of analysis that must be performed during anthrax spore remediation.

  15. Composite Sampling Approaches for Bacillus anthracis Surrogate Extracted from Soil

    Science.gov (United States)

    France, Brian; Bell, William; Chang, Emily; Scholten, Trudy

    2015-01-01

    Any release of anthrax spores in the U.S. would require action to decontaminate the site and restore its use and operations as rapidly as possible. The remediation activity would require environmental sampling, both initially to determine the extent of contamination (hazard mapping) and post-decon to determine that the site is free of contamination (clearance sampling). Whether the spore contamination is within a building or outdoors, collecting and analyzing what could be thousands of samples can become the factor that limits the pace of restoring operations. To address this sampling and analysis bottleneck and decrease the time needed to recover from an anthrax contamination event, this study investigates the use of composite sampling. Pooling or compositing of samples is an established technique to reduce the number of analyses required, and its use for anthrax spore sampling has recently been investigated. However, use of composite sampling in an anthrax spore remediation event will require well-documented and accepted methods. In particular, previous composite sampling studies have focused on sampling from hard surfaces; data on soil sampling are required to extend the procedure to outdoor use. Further, we must consider whether combining liquid samples, thus increasing the volume, lowers the sensitivity of detection and produces false negatives. In this study, methods to composite bacterial spore samples from soil are demonstrated. B. subtilis spore suspensions were used as a surrogate for anthrax spores. Two soils (Arizona Test Dust and sterilized potting soil) were contaminated and spore recovery with composites was shown to match individual sample performance. Results show that dilution can be overcome by concentrating bacterial spores using standard filtration methods. This study shows that composite sampling can be a viable method of pooling samples to reduce the number of analysis that must be performed during anthrax spore remediation. PMID:26714315

  16. Composite Sampling Approaches for Bacillus anthracis Surrogate Extracted from Soil.

    Science.gov (United States)

    France, Brian; Bell, William; Chang, Emily; Scholten, Trudy

    2015-01-01

    Any release of anthrax spores in the U.S. would require action to decontaminate the site and restore its use and operations as rapidly as possible. The remediation activity would require environmental sampling, both initially to determine the extent of contamination (hazard mapping) and post-decon to determine that the site is free of contamination (clearance sampling). Whether the spore contamination is within a building or outdoors, collecting and analyzing what could be thousands of samples can become the factor that limits the pace of restoring operations. To address this sampling and analysis bottleneck and decrease the time needed to recover from an anthrax contamination event, this study investigates the use of composite sampling. Pooling or compositing of samples is an established technique to reduce the number of analyses required, and its use for anthrax spore sampling has recently been investigated. However, use of composite sampling in an anthrax spore remediation event will require well-documented and accepted methods. In particular, previous composite sampling studies have focused on sampling from hard surfaces; data on soil sampling are required to extend the procedure to outdoor use. Further, we must consider whether combining liquid samples, thus increasing the volume, lowers the sensitivity of detection and produces false negatives. In this study, methods to composite bacterial spore samples from soil are demonstrated. B. subtilis spore suspensions were used as a surrogate for anthrax spores. Two soils (Arizona Test Dust and sterilized potting soil) were contaminated and spore recovery with composites was shown to match individual sample performance. Results show that dilution can be overcome by concentrating bacterial spores using standard filtration methods. This study shows that composite sampling can be a viable method of pooling samples to reduce the number of analysis that must be performed during anthrax spore remediation.

  17. Interactions between Human Norovirus Surrogates and Acanthamoeba spp.

    Science.gov (United States)

    Hsueh, Tun-Yun; Gibson, Kristen E

    2015-06-15

    Human noroviruses (HuNoVs) are the most common cause of food-borne disease outbreaks, as well as virus-related waterborne disease outbreaks in the United States. Here, we hypothesize that common free-living amoebae (FLA)-ubiquitous in the environment, known to interact with pathogens, and frequently isolated from water and fresh produce-could potentially act as reservoirs of HuNoV and facilitate the environmental transmission of HuNoVs. To investigate FLA as reservoirs for HuNoV, the interactions between two Acanthamoeba species, A. castellanii and A. polyphaga, as well as two HuNoV surrogates, murine norovirus type 1 (MNV-1) and feline calicivirus (FCV), were evaluated. The results showed that after 1 h of amoeba-virus incubation at 25°C, 490 and 337 PFU of MNV-1/ml were recovered from A. castellanii and A. polyphaga, respectively, while only few or no FCVs were detected. In addition, prolonged interaction of MNV-1 with amoebae was investigated for a period of 8 days, and MNV-1 was demonstrated to remain stable at around 200 PFU/ml from day 2 to day 8 after virus inoculation in A. castellanii. Moreover, after a complete amoeba life cycle (i.e., encystment and excystment), infectious viruses could still be detected. To determine the location of virus associated with amoebae, immunofluorescence experiments were performed and showed MNV-1 transitioning from the amoeba surface to inside the amoeba over a 24-h period. These results are significant to the understanding of how HuNoVs may interact with other microorganisms in the environment in order to aid in its persistence and survival, as well as potential transmission in water and to vulnerable food products such as fresh produce.

  18. Design, development, and analysis of a surrogate for pulmonary injury prediction.

    Science.gov (United States)

    Danelson, Kerry A; Gayzik, F Scott; Stern, Amber Rath; Hoth, J Jason; Stitzel, Joel D

    2011-10-01

    Current anthropomorphic test devices (ATDs) measure chest acceleration and deflection to assess risk of injury to the thorax. This study presents a lung surrogate prototype designed to expand the injury assessment capabilities of ATDs to include a risk measure for pulmonary contusion (PC). The surrogate augments these existing measures by providing pressure data specific to the lung and its lobes. The prototype was created from a rendering of a 50th percentile male lung inflated to normal inspiration, obtained from clinical CT data. Surrogate size, lobe volume, and airway cross sections were selected to match the morphology of the lung. Elastomeric urethane was molded via rapid prototyping to create a functional prototype. Pressure sensors in each of the five terminal airways independently monitored pressure traces in the lobes during impacts to the surrogate. Software was created to analyze the surrogate impact pressure data, determine the lobe with the greatest pressure rise for a particular impact, and estimate the initial speed of surface deformation. Calibration testing indicates an approximately linear relationship between peak lobe pressure and surface impact speed. No type I or II errors were demonstrated during lobe detection testing. During repeatability testing, the standard deviation was between 2 and 4% of the mean peak pressure. Ongoing research will focus on correlating surrogate data, pressure pulses, or surface deformation, to risk functions for PC.

  19. Adaptive surrogate model based multi-objective transfer trajectory optimization between different libration points

    Science.gov (United States)

    Peng, Haijun; Wang, Wei

    2016-10-01

    An adaptive surrogate model-based multi-objective optimization strategy that combines the benefits of invariant manifolds and low-thrust control toward developing a low-computational-cost transfer trajectory between libration orbits around the L1 and L2 libration points in the Sun-Earth system has been proposed in this paper. A new structure for a multi-objective transfer trajectory optimization model that divides the transfer trajectory into several segments and gives the dominations for invariant manifolds and low-thrust control in different segments has been established. To reduce the computational cost of multi-objective transfer trajectory optimization, a mixed sampling strategy-based adaptive surrogate model has been proposed. Numerical simulations show that the results obtained from the adaptive surrogate-based multi-objective optimization are in agreement with the results obtained using direct multi-objective optimization methods, and the computational workload of the adaptive surrogate-based multi-objective optimization is only approximately 10% of that of direct multi-objective optimization. Furthermore, the generating efficiency of the Pareto points of the adaptive surrogate-based multi-objective optimization is approximately 8 times that of the direct multi-objective optimization. Therefore, the proposed adaptive surrogate-based multi-objective optimization provides obvious advantages over direct multi-objective optimization methods.

  20. Modeling of Heating and Evaporation of FACE I Gasoline Fuel and its Surrogates

    KAUST Repository

    Elwardani, Ahmed Elsaid

    2016-04-05

    The US Department of Energy has formulated different gasoline fuels called \\'\\'Fuels for Advanced Combustion Engines (FACE)\\'\\' to standardize their compositions. FACE I is a low octane number gasoline fuel with research octane number (RON) of approximately 70. The detailed hydrocarbon analysis (DHA) of FACE I shows that it contains 33 components. This large number of components cannot be handled in fuel spray simulation where thousands of droplets are directly injected in combustion chamber. These droplets are to be heated, broken-up, collided and evaporated simultaneously. Heating and evaporation of single droplet FACE I fuel was investigated. The heating and evaporation model accounts for the effects of finite thermal conductivity, finite liquid diffusivity and recirculation inside the droplet, referred to as the effective thermal conductivity/effective diffusivity (ETC/ED) model. The temporal variations of the liquid mass fractions of the droplet components were used to characterize the evaporation process. Components with similar evaporation characteristics were merged together. A representative component was initially chosen based on the highest initial mass fraction. Three 6 components surrogates, Surrogate 1-3, that match evaporation characteristics of FACE I have been formulated without keeping same mass fractions of different hydrocarbon types. Another two surrogates (Surrogate 4 and 5) were considered keeping same hydrocarbon type concentrations. A distillation based surrogate that matches measured distillation profile was proposed. The calculated molar mass, hydrogen-to-carbon (H/C) ratio and RON of Surrogate 4 and distillation based one are close to those of FACE I.