ACAT: A Fast and Powerful p Value Combination Method for Rare-Variant Analysis in Sequencing Studies
ACAT: A Fast and Powerful p Value Combination Method for Rare-Variant Analysis in Sequencing Studies
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DOI：
10.1016/j.ajhg.2019.01.002
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发表时间：
2019-03-07
影响因子：
9.8
通讯作者：
Lin, Xihong
中科院分区：
文献类型：
--
作者：
Liu, Yaowu;Chen, Sixing;Lin, Xihong
基于集合的分析联合测试组中变体的关联性，已成为分析测序研究中罕见和低频变体的流行工具。现有的基于集合的测试可以遭受显着的功率损失时，只有一小部分的变量是因果关系，和他们的权力可以是敏感的数量，效果大小，效果方向的因果变量和权重的选择。在这里，我们提出了一个聚合柯西关联检验（ACAT），一个通用的，功能强大的，计算效率高的p值组合方法，以提高功率测序研究。首先，通过组合变量水平的p值，我们使用ACAT来构建基于集合的测试（ACAT-V），该测试在变量集中仅存在少量因果变量的情况下特别强大。其次，通过结合不同的变量集水平p值，我们使用ACAT构建了一个综合检验（ACAT-O），该检验结合了多个互补的基于集的检验的强度，包括负担检验，序列核关联检验（SKAT）和ACAT-V。通过分析广泛的模拟数据和来自社区动脉粥样硬化风险（ARIC）研究的全基因组测序数据，我们证明ACAT-V是对SKAT和负担测试的补充，并且ACAT-O比替代测试具有更强大、更高的功效。
Set-based analysis that jointly tests the association of variants in a group has emerged as a popular tool for analyzing rare and low-frequency variants in sequencing studies. The existing set-based tests can suffer significant power loss when only a small proportion of variants are causal, and their powers can be sensitive to the number, effect sizes, and effect directions of the causal variants and the choices of weights. Here we propose an aggregated Cauchy association test (ACAT), a general, powerful, and computationally efficient p value combination method for boosting power in sequencing studies. First, by combining variant-level p values, we use ACAT to construct a set-based test (ACAT-V) that is particularly powerful in the presence of only a small number of causal variants in a variant set. Second, by combining different variant-set-level p values, we use ACAT to construct an omnibus test (ACAT-O) that combines the strength of multiple complimentary set-based tests, including the burden test, sequence kernel association test (SKAT), and ACAT-V. Through analysis of extensively simulated data and the whole-genome sequencing data from the Atherosclerosis Risk in Communities (ARIC) study, we demonstrate that ACAT-V complements the SKAT and the burden test, and that ACAT-O has a substantially more robust and higher power than those of the alternative tests.