Office of Biostatistics Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA.
Stat Med. 2010 Jan 15;29(1):158-80. doi: 10.1002/sim.3759.
When testing genetic linkage and association, test statistics that follow a normal or Chi-square distributions are often used. These statistics are usually derived under a specific mode of inheritance (genetic model). Common genetic models include, but not limited to, the recessive, additive, multiplicative, and dominant models. For many diseases, their underlying genetic models are often unknown. Instead, a family of scientifically plausible genetic models may be available, which includes the four commonly used models. Hence, the optimal test is not available. Employing a single test statistic which is optimal for one model may suffer from substantial loss of power when the model is misspecified. In this situation efficient robust tests are useful. In this tutorial, we first review several commonly used robust statistics, including maximum efficiency robust tests, maximal tests, and constrained likelihood ratio tests for three common designs in genetic studies: (i) linkage analysis using affected sib-pairs, (ii) association studies using parents-offspring trios, and (iii) case-control association studies (unmatched and matched). Codes in the R statistical language for applying these robust statistics to test for linkage and association are presented with examples. We also provide some comparisons of the performance of the various robust tests via simulation studies. Guidelines for applications are also given for each study design. Finally, applications of robust tests to genome-wide association studies and meta-analysis are discussed.
在测试遗传连锁和关联时，通常使用遵循正态或卡方分布的检验统计量。这些统计量通常是根据特定的遗传模式（遗传模型）得出的。常见的遗传模型包括但不限于隐性、加性、乘法和显性模型。对于许多疾病，其潜在的遗传模型通常是未知的。相反，可能有一系列科学上合理的遗传模型可供选择，其中包括这四种常用模型。因此，不存在最优的检验方法。当模型指定不正确时，使用针对一种模型最优的单个检验统计量可能会导致大量的功效损失。在这种情况下，有效的稳健检验很有用。在本教程中，我们首先回顾了几种常用的稳健统计量，包括最大效率稳健检验、最大检验和受约束似然比检验，用于遗传研究中的三种常见设计：（i）使用受影响的同胞对的连锁分析，（ii）使用父母-子女三对的关联研究，以及（iii）病例-对照关联研究（不匹配和匹配）。我们还提供了通过模拟研究对各种稳健检验性能的一些比较。为每个研究设计提供了应用指南。最后，讨论了稳健检验在全基因组关联研究和荟萃分析中的应用。
