Mediation analysis in longitudinal study with high-dimensional methylation mediators

Abstract Mediation analysis has been widely utilized to identify potential pathways connecting exposures and outcomes. However, there remains a lack of analytical methods for high-dimensional mediation analysis in longitudinal data. To tackle this concern, we proposed an effective and novel approach with variable selection and the indirect effect (IE) assessment based on both linear mixed-effect model and generalized estimating equation. Initially, we employ sure independence screening to reduce the dimension of candidate mediators. Subsequently, we implement the Sobel test with the Bonferroni correction for IE hypothesis testing. Through extensive simulation studies, we demonstrate the performance of our proposed procedure with a higher F$_{1}$ score (0.8056 and 0.9983 at sample sizes of 150 and 500, respectively) compared with the linear method (0.7779 and 0.9642 at the same sample sizes), along with more accurate parameter estimation and a significantly lower false discovery rate. Moreover, we apply our methodology to explore the mediation mechanisms involving over 730 000 DNA methylation sites with potential effects between the paternal body mass index (BMI) and offspring growing BMI in the Shanghai sleeping birth cohort data, leading to the identification of two previously undiscovered mediating CpG sites.