Robust Mendelian randomization in the presence of residual population stratification, batch effects and horizontal pleiotropy.

Mendelian Randomization (MR) studies are threatened by population stratification, batch effects, and horizontal pleiotropy. Although a variety of methods have been proposed to mitigate those problems, residual biases may still remain, leading to highly statistically significant false positives in large databases. Here we describe a suite of sensitivity analysis tools that enables investigators to quantify the robustness of their findings against such validity threats.

Generalizing experimental results by leveraging knowledge of mechanisms.

We show how experimental results can be generalized across diverse populations by leveraging knowledge of local mechanisms that produce the outcome of interest, only some of which may differ in the target domain. We use structural causal models and a refined version of selection diagrams to represent such knowledge, and to decide whether it entails the invariance of probabilities of causation across populations, which then enables generalization. We further provide: (i) bounds for the target effect when some of these conditions are violated; (ii) new identification results for probabilities of causation and the transported causal effect when trials from multiple source domains are available; as well as (iii) a Bayesian approach for estimating the transported causal effect from finite samples.