High-dimensional mediation analysis for continuous outcome with confounders using overlap weighting method in observational epigenetic study

Background: Mediation analysis is a powerful tool to identify factors mediating the causal pathway of exposure to health outcomes. Mediation analysis has been extended to study a large number of potential mediators in high-dimensional data settings. The presence of confounding in observational studies is inevitable. Hence, it’s an essential part of high-dimensional mediation analysis (HDMA) to adjust for the potential confounders. Although the propensity score (PS) related method such as propensity score regression adjustment (PSR) and inverse probability weighting (IPW) has been proposed to tackle this problem, the characteristics with extreme propensity score distribution of the PS-based method would result in the biased estimation. Methods: In this article, we integrated the overlapping weighting (OW) technique into HDMA workflow and proposed a concise and powerful high-dimensional mediation analysis procedure consisting of OW confounding adjustment, sure independence screening (SIS), de-biased Lasso penalization, and joint-significance testing underlying the mixture null distribution. We compared the proposed method with the existing method consisting of PS-based confounding adjustment, SIS, minimax concave penalty (MCP) variable selection, and classical joint-significance testing. Results: Simulation studies demonstrate the proposed procedure has the best performance in mediator selection and estimation. The proposed procedure yielded the highest true positive rate, acceptable false discovery proportion level, and lower mean square error. In the empirical study based on the GSE117859 dataset in the Gene Expression Omnibus database using the proposed method, we found that smoking history may lead to the estimated natural killer (NK) cell level reduction through the mediation effect of some methylation markers, mainly including methylation sites cg13917614 in CNP gene and cg16893868 in LILRA2 gene. Conclusions: The proposed method has higher power, sufficient false discovery rate control, and precise mediation effect estimation. Meanwhile, it is feasible to be implemented with the presence of confounders. Hence, our method is worth considering in HDMA studies.