Multistage Genetic Association Studies

The practice of individualized medicine for therapy or prevention could be informed by studies of genetic modifiers of treatment effects. This special case of gene–environment interaction studies offers several unique opportunities by exploiting random assignment of treatments. Two basic approaches are possible, one based on genetic studies added to a preexisting randomized controlled trial, the other based on targeted intervention studies added to a preexisting genetic cohort study. We focus in particular on multistage sampling designs that exploit the prior information from the parent study to improve the statistical efficiency of the study of genetic modifiers of treatment effects. In particular, we discuss different contexts in which either design might be used—a study of a single candidate gene, an entire pathway, or a genome-wide association scan. Keywords: pharmacogenetics; genetic association; gene-environment interaction; multistage study design

治疗或预防的个体化医疗实践可从治疗效果的遗传修饰因子研究中获取信息。这种基因 - 环境相互作用研究的特殊情况通过利用治疗的随机分配提供了一些独特的机会。两种基本方法是可行的，一种是在已有的随机对照试验基础上增加遗传学研究，另一种是在已有的遗传队列研究基础上增加靶向干预研究。我们特别关注多阶段抽样设计，这种设计利用来自母体研究的先验信息来提高治疗效果遗传修饰因子研究的统计效率。特别是，我们讨论了可能使用这两种设计的不同情况——对单个候选基因、整个通路或全基因组关联扫描的研究。 关键词： 药物遗传学； 遗传关联； 基因 - 环境相互作用； 多阶段研究设计