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Ma, C.* ; Blackwell, T.* ; Boehnke, M.* ; Scott, L.J.* ; GoT2D Consortium (Gieger, C. ; Grallert, H. ; Hrabě de Angelis, M. ; Huth, C. ; Kriebel, J. ; Meisinger, C. ; Meitinger, T. ; Müller-Nurasyid, M. ; Peters, A. ; Rathmann, W. ; Ried, J.S. ; Strauch, K. ; Strom, T.M.)

Recommended joint and meta-analysis strategies for case-control association testing of single low-count variants.

Genet. Epidemiol. 37, 539-550 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
In genome-wide association studies of binary traits, investigators typically use logistic regression to test common variants for disease association within studies, and combine association results across studies using meta-analysis. For common variants, logistic regression tests are well calibrated, and meta-analysis of study-specific association results is only slightly less powerful than joint analysis of the combined individual-level data. In recent sequencing and dense chip based association studies, investigators increasingly test low-frequency variants for disease association. In this paper, we seek to (1) identify the association test with maximal power among tests with well controlled type I error rate and (2) compare the relative power of joint and meta-analysis tests. We use analytic calculation and simulation to compare the empirical type I error rate and power of four logistic regression based tests: Wald, score, likelihood ratio, and Firth bias-corrected. We demonstrate for low-count variants (roughly minor allele count [MAC] < 400) that: (1) for joint analysis, the Firth test has the best combination of type I error and power; (2) for meta-analysis of balanced studies (equal numbers of cases and controls), the score test is best, but is less powerful than Firth test based joint analysis; and (3) for meta-analysis of sufficiently unbalanced studies, all four tests can be anti-conservative, particularly the score test. We also establish MAC as the key parameter determining test calibration for joint and meta-analysis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Joint Analysis ; Low-frequency Variants ; Meta-analysis ; Single Nucleotide Polymorphisms ; Single Variant Tests
ISSN (print) / ISBN 0741-0395
e-ISSN 1098-2272
Journal Genetic Epidemiology
Quellenangaben Volume: 37, Issue: 6, Pages: 539-550 Article Number: , Supplement: ,
Publisher Wiley
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Experimental Genetics (IEG)
Institute of Human Genetics (IHG)
Institute of Epidemiology (EPI)