Department of Statistical Sciences, Faculty of Arts and Science, University of Toronto, Toronto, Canada.
Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
Biometrics. 2022 Jun;78(2):487-498. doi: 10.1111/biom.13456. Epub 2021 May 4.
The allele-based association test, comparing allele frequency difference between case and control groups, is locally most powerful. However, application of the classical allelic test is limited in practice, because the method is sensitive to the Hardy-Weinberg equilibrium (HWE) assumption, not applicable to continuous traits, and not easy to account for covariate effect or sample correlation. To develop a generalized robust allelic test, we propose a new allele-based regression model with individual allele as the response variable. We show that the score test statistic derived from this robust and unifying regression framework contains a correction factor that explicitly adjusts for potential departure from HWE and encompasses the classical allelic test as a special case. When the trait of interest is continuous, the corresponding allelic test evaluates a weighted difference between individual-level allele frequency estimate and sample estimate where the weight is proportional to an individual's trait value, and the test remains valid under Y-dependent sampling. Finally, the proposed allele-based method can analyze multiple (continuous or binary) phenotypes simultaneously and multiallelic genetic markers, while accounting for covariate effect, sample correlation, and population heterogeneity. To support our analytical findings, we provide empirical evidence from both simulation and application studies.
基于等位基因的关联检验比较病例和对照组之间等位基因频率的差异，是局部最有效的。然而，经典等位基因检验的应用在实践中受到限制，因为该方法对 Hardy-Weinberg 平衡（HWE）假设敏感，不适用于连续性状，也不容易考虑协变量效应或样本相关性。为了开发广义稳健的等位基因检验，我们提出了一种新的基于个体等位基因作为响应变量的等位基因回归模型。我们表明，从这个稳健统一的回归框架中得出的得分检验统计量包含一个校正因子，该因子明确调整了潜在的偏离 Hardy-Weinberg 平衡的情况，并将经典的等位基因检验作为一个特例包含在内。当感兴趣的性状是连续的时，相应的等位基因检验评估个体水平等位基因频率估计值和样本估计值之间的加权差异，其中权重与个体的性状值成正比，并且在 Y 相关抽样下检验仍然有效。最后，所提出的基于等位基因的方法可以同时分析多个（连续或二分类）表型和多等位基因遗传标记，同时考虑协变量效应、样本相关性和群体异质性。为了支持我们的分析结果，我们从模拟和应用研究中提供了经验证据。
