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American Journal of Epidemiology Advance Access originally published online on January 6, 2009
American Journal of Epidemiology 2009 169(4):505-514; doi:10.1093/aje/kwn359
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American Journal of Epidemiology Published by Oxford University Press 2009.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

PRACTICE OF EPIDEMIOLOGY

Hardy-Weinberg Equilibrium Testing of Biological Ascertainment for Mendelian Randomization Studies

Santiago Rodriguez, Tom R. Gaunt and Ian N. M. Day

Correspondence to Dr. Ian N. M. Day, MRC Centre for Causal Analyses in Translational Epidemiology and Bristol Genetic Epidemiology Laboratories, Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom (e-mail: ian.day{at}bristol.ac.uk).

Received for publication June 24, 2008. Accepted for publication October 13, 2008.

Mendelian randomization (MR) permits causal inference between exposures and a disease. It can be compared with randomized controlled trials. Whereas in a randomized controlled trial the randomization occurs at entry into the trial, in MR the randomization occurs during gamete formation and conception. Several factors, including time since conception and sampling variation, are relevant to the interpretation of an MR test. Particularly important is consideration of the "missingness" of genotypes that can be originated by chance, genotyping errors, or clinical ascertainment. Testing for Hardy-Weinberg equilibrium (HWE) is a genetic approach that permits evaluation of missingness. In this paper, the authors demonstrate evidence of nonconformity with HWE in real data. They also perform simulations to characterize the sensitivity of HWE tests to missingness. Unresolved missingness could lead to a false rejection of causality in an MR investigation of trait-disease association. These results indicate that large-scale studies, very high quality genotyping data, and detailed knowledge of the life-course genetics of the alleles/genotypes studied will largely mitigate this risk. The authors also present a Web program (http://www.oege.org/software/hwe-mr-calc.shtml) for estimating possible missingness and an approach to evaluating missingness under different genetic models.

epidemiologic methods; genetics; Hardy-Weinberg equilibrium; random allocation; research design

Abbreviations: APOE, apolipoprotein E; HWE, Hardy-Weinberg equilibrium; MR, Mendelian randomization; SNP, single nucleotide polymorphism; WTCCC, Wellcome Trust Case Control Consortium


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