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Power and Sample Size Calculations for Genetic Association Studies in the Presence of Genetic Model Misspecification.
Human Heredity ( IF 1.8 ) Pub Date : 2020-07-28 , DOI: 10.1159/000508558
Camille M Moore 1 , Sean A Jacobson 2 , Tasha E Fingerlin 2
Affiliation  

Introduction: When analyzing data from large-scale genetic association studies, such as targeted or genome-wide resequencing studies, it is common to assume a single genetic model, such as dominant or additive, for all tests of association between a given genetic variant and the phenotype. However, for many variants, the chosen model will result in poor model fit and may lack statistical power due to model misspecification. Objective: We develop power and sample size calculations for tests of gene and gene × environment interaction, allowing for misspecification of the true mode of genetic susceptibility. Methods: The power calculations are based on a likelihood ratio test framework and are implemented in an open-source R package (“genpwr”). Results: We use these methods to develop an analysis plan for a resequencing study in idiopathic pulmonary fibrosis and show that using a 2-degree of freedom test can increase power to detect recessive genetic effects while maintaining power to detect dominant and additive effects. Conclusions: Understanding the impact of model misspecification can aid in study design and developing analysis plans that maximize power to detect a range of true underlying genetic effects. In particular, these calculations help identify when a multiple degree of freedom test or other robust test of association may be advantageous.
Hum Hered


中文翻译:

在存在遗传模型错误指定的情况下进行遗传关联研究的功效和样本大小计算。

简介:在分析大规模遗传关联研究(例如靶向或全基因组重测序研究)的数据时,通常会针对给定遗传变异体与表型。但是,对于许多变体,所选模型将导致模型拟合差,并且由于模型规格不正确而可能缺乏统计功效。目的:我们开发用于计算基因和基因×环境相互作用的能力和样本量计算,以允许对遗传易感性的真实模式进行错误指定。方法:功效计算基于似然比测试框架,并以开源R包(“ genpwr”)实施。结果:我们使用这些方法制定了用于特发性肺纤维化重测序研究的分析计划,并表明使用2自由度测试可以增加检测隐性遗传效应的能力,同时保持检测显性和累加效应的能力。结论:了解模型错误指定的影响可以帮助进行研究设计和制定分析计划,从而最大程度地检测一系列真正的潜在遗传效应。特别地,这些计算帮助识别何时进行多个自由度测试或其他鲁棒的关联测试可能是有利的。
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更新日期:2020-07-28
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