MOTIVATION: Mediation analysis plays a crucial role in understanding how exposure variables influence health outcomes via intermediate variables, or mediators, in environmental studies. When analyzing a large number of environmental exposures, such as chemical mixtures or pollutants, together with multiple potential mediators such as metabolites, advanced methodologies are necessary to accurately separate direct and indirect effects. This paper proposes a novel mediation analysis method based on Sparse Canonical Correlation Analysis (SCCA), designed specifically for settings where both exposures and mediators are high-dimensional. The effectiveness of the proposed method is evaluated through simulation studies and an application to real-world data.

RESULTS: The proposed SCCA-based mediation framework improved identification of relevant mediators and pathways in simulation studies, particularly in high-dimensional and noisy settings. The two-step screening extension further enhanced feature selection while maintaining stable estimation. In the real-data application, the method identified interpretable exposure-metabolite pathways associated with MELD score, with several pathways showing moderate selection stability and robustness to potential unmeasured confounding.

AVAILABILITY: The R code for implementing the proposed method and the simulation studies is available at https://github.com/MaggieLi2001/HDM-SCCA2.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.