Power and Sample Size Calculations for Genetic Association Studies in the Presence of Genetic Model Misspecification.

IF 1.1 4区 生物学 Q4 GENETICS & HEREDITY Human Heredity Pub Date : 2019-01-01 Epub Date: 2020-07-28 DOI:10.1159/000508558
Camille M Moore, Sean A Jacobson, Tasha E Fingerlin
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引用次数: 36

Abstract

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.

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存在遗传模型错配的遗传关联研究的功率和样本量计算。
在分析大规模遗传关联研究的数据时,如靶向或全基因组重测序研究,通常假设单一遗传模型,如显性或加性,用于给定遗传变异与表型之间的所有关联测试。然而,对于许多变体,所选择的模型将导致较差的模型拟合,并可能由于模型错误规范而缺乏统计能力。目的:我们开发了基因和基因与环境相互作用测试的功率和样本量计算,允许对遗传易感性的真实模式进行错误说明。方法:功率计算基于似然比测试框架,并在开源R包(“genpwr”)中实现。结果:我们使用这些方法制定了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加性效应的能力。结论:了解模型错配的影响有助于研究设计和制定分析计划,最大限度地检测一系列真正潜在的遗传效应。特别是,这些计算有助于确定何时多自由度检验或其他稳健的关联检验可能是有利的。
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来源期刊
Human Heredity
Human Heredity 生物-遗传学
CiteScore
2.50
自引率
0.00%
发文量
12
审稿时长
>12 weeks
期刊介绍: Gathering original research reports and short communications from all over the world, ''Human Heredity'' is devoted to methodological and applied research on the genetics of human populations, association and linkage analysis, genetic mechanisms of disease, and new methods for statistical genetics, for example, analysis of rare variants and results from next generation sequencing. The value of this information to many branches of medicine is shown by the number of citations the journal receives in fields ranging from immunology and hematology to epidemiology and public health planning, and the fact that at least 50% of all ''Human Heredity'' papers are still cited more than 8 years after publication (according to ISI Journal Citation Reports). Special issues on methodological topics (such as ‘Consanguinity and Genomics’ in 2014; ‘Analyzing Rare Variants in Complex Diseases’ in 2012) or reviews of advances in particular fields (‘Genetic Diversity in European Populations: Evolutionary Evidence and Medical Implications’ in 2014; ‘Genes and the Environment in Obesity’ in 2013) are published every year. Renowned experts in the field are invited to contribute to these special issues.
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