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ACAT: A Fast and Powerful p Value Combination Method for Rare-Variant Analysis in Sequencing Studies.

Authors :
Liu Y
Chen S
Li Z
Morrison AC
Boerwinkle E
Lin X
Source :
American journal of human genetics [Am J Hum Genet] 2019 Mar 07; Vol. 104 (3), pp. 410-421.
Publication Year :
2019

Abstract

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.<br /> (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1537-6605
Volume :
104
Issue :
3
Database :
MEDLINE
Journal :
American journal of human genetics
Publication Type :
Academic Journal
Accession number :
30849328
Full Text :
https://doi.org/10.1016/j.ajhg.2019.01.002