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Beyond Mendelian randomization: how to interpret evidence of shared genetic predictors

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journal contribution
posted on 29.10.2015, 11:59 by S. Burgess, A. S. Butterworth, John R. Thompson
OBJECTIVE: Mendelian randomization is a popular technique for assessing and estimating the causal effects of risk factors. If genetic variants which are instrumental variables for a risk factor are shown to be additionally associated with a disease outcome, then the risk factor is a cause of the disease. However, in many cases, the instrumental variable assumptions are not plausible, or are in doubt. In this paper, we provide a theoretical classification of scenarios in which a causal conclusion is justified or not justified, and discuss the interpretation of causal effect estimates. RESULTS: A list of guidelines based on the 'Bradford Hill criteria' for judging the plausibility of a causal finding from an applied Mendelian randomization study is provided. We also give a framework for performing and interpreting investigations performed in the style of Mendelian randomization, but where the choice of genetic variants is statistically, rather than biologically motivated. Such analyses should not be assigned the same evidential weight as a Mendelian randomization investigation. CONCLUSION: We discuss the role of such investigations (in the style of Mendelian randomization), and what they add to our understanding of potential causal mechanisms. If the genetic variants are selected solely according to statistical criteria, and the biological roles of genetic variants are not investigated, this may be little more than what can be learned from a well-designed classical observational study.

Funding

Open Access funded by Wellcome Trust

History

Citation

Journal of Clinical Epidemiology, 2015 (In press)

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Health Sciences

Version

VoR (Version of Record)

Published in

Journal of Clinical Epidemiology

Publisher

Elsevier

eissn

1878-5921

Acceptance date

07/08/2015

Copyright date

2015

Available date

29/10/2015

Publisher version

http://www.sciencedirect.com/science/article/pii/S0895435615003765

Language

en