High-Dimensional Mediation Analysis With Confounders in Survival Models

Zhangsheng Yu; Yidan Cui; Ting Wei; Yanran Ma; Chengwen Luo

doi:10.3389/fgene.2021.688871

High-Dimensional Mediation Analysis With Confounders in Survival Models

Front Genet. 2021 Jun 28:12:688871. doi: 10.3389/fgene.2021.688871. eCollection 2021.

Authors

Zhangsheng Yu^{1

2

3}, Yidan Cui^{1

2}, Ting Wei^{1

2}, Yanran Ma^{1

2}, Chengwen Luo^{1

2}

Affiliations

¹ Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
² SJTU-Yale Joint Center for Biostatistics, Shanghai Jiao Tong University, Shanghai, China.
³ Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Mediation analysis is a common statistical method for investigating the mechanism of environmental exposures on health outcomes. Previous studies have extended mediation models with a single mediator to high-dimensional mediators selection. It is often assumed that there are no confounders that influence the relations among the exposure, mediator, and outcome. This is not realistic for the observational studies. To accommodate the potential confounders, we propose a concise and efficient high-dimensional mediation analysis procedure using the propensity score for adjustment. Results from simulation studies demonstrate the proposed procedure has good performance in mediator selection and effect estimation compared with methods that ignore all confounders. Of note, as the sample size increases, the performance of variable selection and mediation effect estimation is as well as the results shown in the method which include all confounders as covariates in the mediation model. By applying this procedure to a TCGA lung cancer data set, we find that lung cancer patients who had serious smoking history have increased the risk of death via the methylation markers cg21926276 and cg20707991 with significant hazard ratios of 1.2093 (95% CI: 1.2019-1.2167) and 1.1388 (95% CI: 1.1339-1.1438), respectively.

Keywords: confounders; high-dimensional mediators; mediation analysis; propensity score; survival model.