Funder: National Institute for Health Research (GB

Burgess, Stephen

Labrecque, Jeremy A

Swanson, Sonja A

Reverse causation occurs when the outcome variable at an earlier timepoint, or a proximal precursor of the outcome (such as pre-clinical disease), has a causal effect on the risk
factor. This confounding by pre-clinical or prior outcome can lead to bias when trying
to estimate an average causal effect of the risk factor on the outcome. By proposing
genetic variants as instrumental variables, Mendelian randomization can make inferences about the effect of shifting the trajectory of a risk factor on a later-measured
outcome. As genetic variants are fixed at conception, it has been stated that Mendelian
randomization investigations are not affected by reverse causation. While Mendelian
randomization analyses have some protection against bias due to reverse causation, the
claim of complete immunity is a misconception. We provide three plausible scenarios
and accompanying examples of how reverse causation can influence Mendelian randomization estimates: 1) the effect of the genetic variant on the risk factor is mediated (at
least in part) by the outcome, 2) the genetic association with the outcome is distorted
by a feedback mechanism whereby the risk factor and outcome variable both influence
each other over time, and 3) the genetic association with the outcome is distorted by
an effect of the outcome in the parental generation on the outcome in the offspring
generation. In these scenarios, we show that all causal effects typically estimated in
Mendelian randomization analyses will be biased, though hypothesis testing can still
be valid in Scenario 2 and 3 for a sharp causal null hypothesis. This underscores the
general recommendation to view Mendelian randomization as primarily testing a causal
null hypothesis rather than estimating a causal effect

Apollo (Cambridge)

Are Mendelian randomization investigations immune from bias due to reverse causation?

Swanson, Sonja A.

Labrecque, Jeremy A.

NARCIS 

EUR Research Repository

English

https://pure.eur.nl/files/54322633/Are_Mendelian_randomization_investigations_immune_from_bias_due.pdf

Are Mendelian randomization investigations immune from bias due to reverse causation?

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Apollo (Cambridge)

NARCIS

EUR Research Repository

Apollo (Cambridge)

EUR Research Repository