A data-adaptive method for investigating effect heterogeneity with high-dimensional covariates in Mendelian randomization

Abstract

Background Mendelian randomization is a popular method for causal inference with observational data that uses genetic variants as instrumental variables. Similarly to a randomized trial, a standard Mendelian randomization analysis estimates the population-averaged effect of an exposure on an outcome. Dividing the population into subgroups can reveal effect heterogeneity to inform who would most benefit from intervention on the exposure. However, as covariates are measured post-“randomization”, naive stratification typically induces collider bias in stratum-specific estimates. Method We extend a previously proposed stratification method (the “doubly-ranked method”) to form strata based on a single covariate, and introduce a data-adaptive random forest method to calculate stratum-specific estimates that are robust to collider bias based on a high-dimensional covariate set. We also propose measures based on the Q statistic to assess heterogeneity between stratum-specific estimates (to understand whether estimates are more variable than expected due to chance alone) and variable importance (to identify the key drivers of effect heterogeneity). Result We show that the effect of body mass index (BMI) on lung function is heterogeneous, depending most strongly on hip circumference and weight. While for most individuals, the predicted effect of increasing BMI on lung function is negative, it is positive for some individuals and strongly negative for others. Conclusion Our data-adaptive approach allows for the exploration of effect heterogeneity in the relationship between an exposure and an outcome within a Mendelian randomization framework. This can yield valuable insights into disease aetiology and help identify specific groups of individuals who would derive the greatest benefit from targeted interventions on the exposure.

Causal relationship between telomere length and sepsis: a bidirectional Mendelian randomization study

“…Participants have provided written informed consent, granting permission for the utilization of their medical records and samples for research purposes related to health. The consent statement can be found at https://www.ukbiobank.ac.uk/media/05ldg1ez/consent-form-uk-biobank.pdf 23 . Additionally, this study strictly adheres to the fundamental principles outlined in the STROBE-MR (Strengthening the Reporting of Observational Studies in Epidemiology—Mendelian Randomization), aimed at gaining a more accurate and in-depth understanding of this specific field 24 ( Supplementary Materials ).…”

“…uk/ media/ 05ldg 1ez/ conse nt-form-uk-bioba nk. pdf 23 . Additionally, this study strictly adheres to the fundamental principles outlined in the STROBE-MR (Strengthening the Reporting of Observational Studies in Epidemiology-Mendelian Randomization), aimed at gaining a more accurate and in-depth understanding of this specific field 24 (Supplementary Materials).…”