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Instrumental variable analysis with a nonlinear exposure-outcome relationship.


Type

Article

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Authors

Davies, Neil M 
Thompson, Simon G 
EPIC-InterAct Consortium 

Abstract

BACKGROUND: Instrumental variable methods can estimate the causal effect of an exposure on an outcome using observational data. Many instrumental variable methods assume that the exposure-outcome relation is linear, but in practice this assumption is often in doubt, or perhaps the shape of the relation is a target for investigation. We investigate this issue in the context of Mendelian randomization, the use of genetic variants as instrumental variables. METHODS: Using simulations, we demonstrate the performance of a simple linear instrumental variable method when the true shape of the exposure-outcome relation is not linear. We also present a novel method for estimating the effect of the exposure on the outcome within strata of the exposure distribution. This enables the estimation of localized average causal effects within quantile groups of the exposure or as a continuous function of the exposure using a sliding window approach. RESULTS: Our simulations suggest that linear instrumental variable estimates approximate a population-averaged causal effect. This is the average difference in the outcome if the exposure for every individual in the population is increased by a fixed amount. Estimates of localized average causal effects reveal the shape of the exposure-outcome relation for a variety of models. These methods are used to investigate the relations between body mass index and a range of cardiovascular risk factors. CONCLUSIONS: Nonlinear exposure-outcome relations should not be a barrier to instrumental variable analyses. When the exposure-outcome relation is not linear, either a population-averaged causal effect or the shape of the exposure-outcome relation can be estimated.

Description

Keywords

Body Mass Index, Cardiovascular Diseases, Causality, Epidemiologic Methods, Europe, Humans, Linear Models, Mendelian Randomization Analysis, Multicenter Studies as Topic, Prospective Studies, Risk Factors

Journal Title

Epidemiology

Conference Name

Journal ISSN

1044-3983
1531-5487

Volume Title

25

Publisher

Ovid Technologies (Wolters Kluwer Health)
Sponsorship
Medical Research Council (MR/L003120/1)
Wellcome Trust (100114/Z/12/Z)
British Heart Foundation (None)
British Heart Foundation (None)
The EPIC-InterAct study received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community).