Reconsidering association testing methods using single-variant test statistics as alternatives to pooling tests for sequence data with rare variants.

PloS One
Daniel D KinnamonEden R Martin

Abstract

Association tests that pool minor alleles into a measure of burden at a locus have been proposed for case-control studies using sequence data containing rare variants. However, such pooling tests are not robust to the inclusion of neutral and protective variants, which can mask the association signal from risk variants. Early studies proposing pooling tests dismissed methods for locus-wide inference using nonnegative single-variant test statistics based on unrealistic comparisons. However, such methods are robust to the inclusion of neutral and protective variants and therefore may be more useful than previously appreciated. In fact, some recently proposed methods derived within different frameworks are equivalent to performing inference on weighted sums of squared single-variant score statistics. In this study, we compared two existing methods for locus-wide inference using nonnegative single-variant test statistics to two widely cited pooling tests under more realistic conditions. We established analytic results for a simple model with one rare risk and one rare neutral variant, which demonstrated that pooling tests were less powerful than even Bonferroni-corrected single-variant tests in most realistic situations. We also pe...Continue Reading

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Citations

Jan 30, 2013·PLoS Genetics·Yun-Ching ChenRachel Karchin
Feb 26, 2013·PloS One·Petra Bůžková
Aug 27, 2013·Current Opinion in Allergy and Clinical Immunology·Kelly Burkett, Celia Greenwood
Jul 30, 2014·Genetic Epidemiology·Qiuying Sha, Shuanglin Zhang
Apr 12, 2014·Genetic Epidemiology·Daniel D Kinnamon, Eden R Martin
Sep 23, 2014·PloS One·Olga A VsevolozhskayaQing Lu
Jun 21, 2013·BMC Bioinformatics·Ren-Hua Chung, Chung-Chin Shih
Jun 14, 2013·PLoS Computational Biology·Nanye LongAndrew S Allen
Jul 15, 2016·Journal of Human Genetics·Degang ZhuShili Lin
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Jul 13, 2012·Current Protocols in Human Genetics·Dana B Hancock, William K Scott
Feb 20, 2019·PLoS Computational Biology·Rachel Marceau WestJung-Ying Tzeng
Jun 30, 2016·PLoS Computational Biology·Xinge Jessie JengJung-Ying Tzeng
Mar 17, 2017·Genetic Epidemiology·Asuman Turkmen, Shili Lin
May 14, 2021·Circulation Research·Ray E HershbergerDaniel D Kinnamon

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