Instrumental variable-based high-dimensional mediation analysis with unmeasured confounders for survival data in the observational epigenetic study

Abstract

Background: High dimensional mediation analysis is frequently conducted to explore the role of epigenetic modifiers between exposure and health outcome. However, the issue of high dimensional mediation analysis with unmeasured confounders for survival analysis in observational study has not been well solved.Methods: In this study, we proposed an instrumental variable based approach for high dimensional mediation analysis with unmeasured confounders in survival analysis for epigenetic study. We used the Sobel‘s test, the Joint test, and the Bootstrap method to test the mediation effect. A comprehensive simulation study was conducted to decide the best test strategy. An empirical study based on DNA methylation data of lung cancer patients was conducted to illustrate the performance of the proposed method.Results: Simulation study suggested that the proposed method performed well in the identifying mediating factors. The estimation of the mediation effect by the proposed approach is also reliable with less bias compared with the classical approach. In the empirical study, we identified two DNA methylation signatures including cg21926276 and cg26387355 with a mediation effect of 0.226 (95%CI: 0.108-0.344) and 0.158 (95%CI: 0.065-0.251) between smoking and lung cancer using the proposed approach.Conclusion: The proposed method obtained good performance in simulation and empirical studies, it could be an effective statistical tool for high dimensional mediation analysis.