MELODY: Mediation Analysis in Logistic Regression for High-Dimensional Mediators and a Binary Outcome

Authors

Sunyi Chi
Xingyu Li
Peng Wei
Xuelin Huang

Language

English

Publication Date

2-1-2026

Journal

Genetic Epidemiology

DOI

10.1002/gepi.70033

PMID

41560457

PMCID

PMC12820538

PubMedCentral® Posted Date

1-20-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Mediation analysis is a pivotal tool for elucidating the indirect effect of an environmental factor or treatment on disease through potentially high‐dimensional omics data, such as gene expression profiles. However, traditional mediation analysis methods tailored for binary outcomes often rely on the rare disease assumption in logistic regression and provide inadequate measures of total mediation effect when multiple mediators have effects in different directions. In this paper, we develop a MEdiation analysis framework in LOgistic regression for high‐Dimensional mediators and a binarY outcome (MELODY). It leverages a second‐moment‐based measure analogous to the 𝑅2 for linear models to quantify the total mediation effect. We also develop a variable selection procedure for high‐dimensional data to reduce bias introduced by non‐mediators. Our comprehensive simulations demonstrate the superior performance of MELODY in scenarios with non‐rare disease binary outcomes and high‐dimensional mediators. We apply MELODY to the Framingham Heart Study of over 5000 individuals to analyze the mediation effects of metabolomics and transcriptomics data on the pathways from sex to incident coronary heart disease.

Keywords

Humans, Logistic Models, Male, Mediation Analysis, Female, Computer Simulation, Coronary Disease, Metabolomics, Transcriptome, Gene Expression Profiling, binary outcome, high‐dimensional mediators, mediation analysis, metabolomics, total mediation effect, transcriptomics

Published Open-Access

yes

Recommended Citation

Chi, Sunyi; Li, Xingyu; Wei, Peng; et al., "MELODY: Mediation Analysis in Logistic Regression for High-Dimensional Mediators and a Binary Outcome" (2026). Faculty, Staff and Student Publications. 5876.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5876