Integrated quantile rank test (iQRAT) for gene-level associations

DOI10.1214/21-AOAS1548zbMATH Open1498.62265arXiv1910.10102OpenAlexW3112412569MaRDI QIDQ2170394FDOQ2170394

Authors: Tianying Wang, Iuliana Ionita-Laza, Ying Wei 

Publication date: 5 September 2022

Published in: The Annals of Applied Statistics (Search for Journal in Brave)

Abstract: Gene-based testing is a commonly employed strategy in many genetic association studies. Gene-trait associations can be complex due to underlying population heterogeneity, gene-environment interactions, and various other reasons. Existing gene-based tests, such as Burden and Sequence Kernel Association Tests (SKAT), are based on detecting differences in a single summary statistic, such as the mean or the variance, and may miss or underestimate higher-order associations that could be scientifically interesting. In this paper, we propose a new family of gene-level association tests which integrate quantile rank score processes to better accommodate complex associations. The resulting test statistics have multiple advantages: (1) they are almost as efficient as the best existing tests when the associations are homogeneous across quantile levels, and have improved efficiency for complex and heterogeneous associations, (2) they provide useful insights on risk stratification, (3) the test statistics are distribution-free, and could hence accommodate a wide range of underlying distributions, and (4) they are computationally efficient. We established the asymptotic properties of the proposed tests under the null and alternative hypothesis and conducted large scale simulation studies to investigate their finite sample performance. We applied the proposed tests to the Metabochip data to identify genetic associations with lipid traits and compared the results with those of the Burden and SKAT tests.

Full work available at URL: https://arxiv.org/abs/1910.10102

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zbMATH Keywords

quantile processrank score testgene-set associations

Mathematics Subject Classification ID

Nonparametric hypothesis testing (62G10) Applications of statistics to biology and medical sciences; meta analysis (62P10)

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Cited In (1)

• Operating characteristics of the rank‐based inverse normal transformation for quantitative trait analysis in genome‐wide association studies

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