Ancestry Adjustments in Genome-Wide Association Studies of Randomized Clinical Trials
2014
Genome-wide association studies (GWAS) based on data from large-scale genotyping arrays are sometimes undertaken in the Phase II/III drug development setting to probe for DNA polymorphisms predictive of patient response to investigational drug treatments. Typically, Phase II/III studies are not prospectively designed as pharmacogenomic trials with primary or secondary pharmacogenomics objectives; rather, a GWAS is applied retrospectively using a subset of the original randomized cohort and is only well-powered for very large pharmacogenetic (PGx) effects. In such a setting, the type of statistical modeling used, including the testing approach and auxiliary covariates in the model, is critical to flagging potential PGx biomarkers. Adjusting for ancestry is a well-known strategy used to avoid the confounding influence of population substructure in the context of nonrandomized case-control studies probing the genetic epidemiology of complex disease. However, little has been said about the role and impact of ...
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