New proposal to address mediation analysis interrogations by using genetic variants as instrumental variables.

The application of causal mediation analysis (CMA) considering the mediation effect of a third variable is increasing in epidemiological studies; however, this requires fitting strong assumptions on confounding bias. To address this limitation, we propose an extension of CMA combining it with Mendelian randomization (MRinCMA). We applied the new approach to analyse the causal effect of obesity and diabetes on pancreatic cancer, considering each factor as potential mediator. To check the performance of MRinCMA under several conditions/scenarios, we used it in different simulated data sets and compared it with structural equation models. For continuous variables, MRinCMA and structural equation models performed similarly, suggesting that both approaches are valid to obtain unbiased estimates. When noncontinuous variables were considered, MRinCMA presented, overall, lower bias than structural equation models. By applying MRinCMA, we did not find any evidence of causality of obesity or diabetes on pancreatic cancer. With this new methodology, researchers would be able to address CMA hypotheses by appropriately accounting for the confounding bias assumption regardless of the conditions used in their studies in different settings.