Optimal Unified Approach for Rare-Variant Association Testing with Application to Small-Sample Case-Control Whole-Exome Sequencing Studies
Optimal Unified Approach for Rare-Variant Association Testing with Application to Small-Sample Case-Control Whole-Exome Sequencing Studies
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DOI：
10.1016/j.ajhg.2012.06.007
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发表时间：
2012-08-10
影响因子：
9.8
通讯作者：
Lin, Xihong
中科院分区：
文献类型：
--
作者：
Lee, Seunggeun;Emond, Mary J.;Lin, Xihong
在本文中，我们提出了一个统一的方法来测试罕见的变异和表型之间的关联测序关联研究。这种方法通过自适应地使用数据来最优地联合收割机负担测试和非负担序列核关联测试（SKAT）来最大化功率。当一个区域中的大多数变异都是因果关系并且影响方向相同时，负荷检验更有效，而当一个区域中的大部分变异是非因果关系或者因果变异的影响方向不同时，SKAT更有效。建议的统一测试在两种情况下都保持了功率。我们表明，统一的测试对应于最佳的测试在一个扩展的家庭的SKAT测试，我们称之为SKAT-O。本文的第二个目标是开发一个小样本调整过程中提出的方法，用于修正保守的SKAT家庭测试的I型错误率时，感兴趣的性状是二分的，样本量小。小样本调整的SKAT和最优统一检验（SKAT-O）都是计算效率高的，可以很容易地应用于全基因组测序关联研究。我们评估有限样本的性能，所提出的方法使用广泛的模拟研究，并说明其应用程序使用急性肺损伤外显子组测序数据的国家心脏，肺，血液研究所外显子组测序项目。
We propose in this paper a unified approach for testing the association between rare variants and phenotypes in sequencing association studies. This approach maximizes power by adaptively using the data to optimally combine the burden test and the nonburden sequence kernel association test (SKAT). Burden tests are more powerful when most variants in a region are causal and the effects are in the same direction, whereas SKAT is more powerful when a large fraction of the variants in a region are noncausal or the effects of causal variants are in different directions. The proposed unified test maintains the power in both scenarios. We show that the unified test corresponds to the optimal test in an extended family of SKAT tests, which we refer to as SKAT-O. The second goal of this paper is to develop a small-sample adjustment procedure for the proposed methods for the correction of conservative type I error rates of SKAT family tests when the trait of interest is dichotomous and the sample size is small. Both small-sample-adjusted SKAT and the optimal unified test (SKAT-O) are computationally efficient and can easily be applied to genome-wide sequencing association studies. We evaluate the finite sample performance of the proposed methods using extensive simulation studies and illustrate their application using the acute-lung-injury exome-sequencing data of the National Heart, Lung, and Blood Institute Exome Sequencing Project.