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American Journal of Epidemiology Advance Access published online on January 12, 2006
American Journal of Epidemiology, doi:10.1093/aje/kwj062
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.
Received April 18, 2005
Accepted October 13, 2005

SPECIAL ARTICLE

Limits to Causal Inference based on Mendelian Randomization: A Comparison with Randomized Controlled Trials

Dorothea Nitsch 1 *, Mariam Molokhia 1, Liam Smeeth 1, Bianca L. DeStavola 1, John C. Whittaker 1, and David A. Leon 1

1 From the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom

* To whom correspondence should be addressed.
Dorothea Nitsch, E-mail: Dorothea.Nitsch{at}lshtm.ac.uk


  Abstract

"Mendelian randomization" refers to the random assortment of genes transferred from parent to offspring at the time of gamete formation. This process has been compared to a randomized controlled trial of genetic variants. This could greatly aid observational epidemiology by potentially allowing an unbiased estimate of the effects of gene products on disease outcomes. However, studies utilizing Mendelian randomization to estimate effects of gene products on outcomes should be interpreted with caution. In this paper, the authors discuss some of the challenges facing epidemiologists in the analysis and interpretation of Mendelian randomization studies, particularly those that become apparent when the analogy with randomized controlled trials is closely examined. The authors conclude that Mendelian randomization is a powerful addition to etiologic research tools. However, care must be taken, because drawing valid causal inferences from its application depends upon more extensive assumptions than are required in randomized controlled trials.

Keywords: causality; epidemiologic methods; genetics; random allocation; randomized controlled trials.
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