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Role of the adverse outcome pathway framework in the validation of predictive biomarkers
Citation:
Villeneuve, Dan. Role of the adverse outcome pathway framework in the validation of predictive biomarkers. Eurotox 2017, 53rd Congress of the European Societies of Toxicology, Bratislava, SLOVAKIA, September 10 - 13, 2017.
Impact/Purpose:
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Description:
Gene expression, enzyme activities, changes in endogenous metabolite or hormone titers, altered histology, etc. are widely used as biomarkers, but rarely, if ever, used for regulatory decision-making or to define management objectives. The disconnect between the measurements commonly used as biomarkers and the endpoints and outcomes that we regulate on has served as one of the major barriers to widespread application of biomarker data. The adverse outcome pathway (AOP) framework was designed specifically to address that barrier. An AOP is a conceptual framework that captures and organizes information concerning the linkage between some direct molecular initiating event, through which a chemical interacts with a molecule in the body of an organism to perturb its biology, and a cascade of measureable biological changes that reflect progression toward and adverse outcome considered relevant to risk assessment and regulatory decision-making. Measureable “key events” along the AOP can serve as biomarkers of exposure and/or effect, while “key even relationships” define the biological basis of the linkage, the empirical support available in the extant literature, the quantitative understanding of how much change in a biomarker signals progression toward adversity, and the biological context (in terms of life-stage, sex, taxa, etc.) in which a particular outcome is likely to be relevant. Application of the AOP framework to validation and application of predictive biomarkers will be demonstrated through case study.