ACAT: A Fast and Powerful P-value Combination Method for Rare-variant Analysis in Sequencing Studies

By Yaowu Liu, Sixing Chen, Zilin Li, A. Morrison, Eric Boerwinkle, Xihong Lin. bioRxiv, 2018

385 citations recorded by the source corpus.

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 to boost 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 casual 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 burden test, and that ACAT-O has a substantially more robust and higher power than the alternative tests.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c592384802c2a69304f9e21cb03039be80b7bfac

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In Genetics

1. Zhili Zheng
2. Longda Jiang
3. Hailing Fang
4. Jian Yang
5. Alkes L Price

In Molecular Biology

1. Jian Yang
2. Zhili Zheng

Citations in the corpus

• A generalized linear mixed model association tool for biobank-scale data (2021, methodology): “We have implemented an efficient version of ACAT-V in GCTA by C/C ++ code.”