Accessibility issues or difficulties with this website?
Call 919-962-2073 or email hchsadministration@unc.edu.

BinomiRare: A robust test of the association of a rare variant with a disease for pooled analysis and meta-analysis, with application to the HCHS/SOL.

TitleBinomiRare: A robust test of the association of a rare variant with a disease for pooled analysis and meta-analysis, with application to the HCHS/SOL.
Publication TypePublication
Year2017
AuthorsSofer T
JournalGenet Epidemiol
Volume41
Issue5
Pagination388-395
Date Published2017 07
ISSN1098-2272
KeywordsAlgorithms, asthma, calibration, Case-Control Studies, Computer Simulation, Genetic Variation, Hispanic Americans, Humans, Models, Genetic, Probability
Abstract

Most regression-based tests of the association between a low-count variant and a binary outcome do not protect type 1 error, especially when tests are rejected based on a very low significance threshold. Noted exception is the Firth test. However, it was recently shown that in meta-analyzing multiple studies all asymptotic, regression-based tests, including the Firth, may not control type 1 error in some settings, and the Firth test may suffer a substantial loss of power. The problem is exacerbated when the case-control proportions differ between studies. I propose the BinomiRare exact test that circumvents the calibration problems of regression-based estimators. It quantifies the strength of association between the variant and the disease outcome based on the departure of the number of diseased individuals carrying the variant from the expected distribution of disease probability, under the null hypothesis of no association between the disease outcome and the rare variant. I provide a meta-analytic strategy to combine tests across multiple cohorts, which requires that each cohort provides the disease probabilities of all carriers of the variant in question, and the number of diseased individuals among the carriers. I show that BinomiRare controls type 1 error in meta-analysis even when the case-control proportions differ between the studies, and does not lose power compared to pooled analysis. I demonstrate the test in studying the association of rare variants with asthma in the Hispanic Community Health Study/Study of Latinos.

DOI10.1002/gepi.22044
Alternate JournalGenet Epidemiol
PubMed ID28393384
PubMed Central IDPMC5510891
Grant ListHHSN268201300005C / HL / NHLBI NIH HHS / United States
N01HC65236 / HL / NHLBI NIH HHS / United States
N01HC65235 / HL / NHLBI NIH HHS / United States
N01HC65234 / HL / NHLBI NIH HHS / United States
N01HC65233 / HL / NHLBI NIH HHS / United States
N01HC65237 / HL / NHLBI NIH HHS / United States
MS#: 
0487
Manuscript Lead/Corresponding Author Affiliation: 
HCHS/SOL Genetic Analysis Center - University of Washington, Seattle
ECI: 
Manuscript Status: 
Published and Public