Pathway information on methylation analysis using deep neural network (PROMINENT): An interpretable deep learning method with pathway prior for phenotype prediction using gene-level DNA methylation

DNA methylation is a key epigenetic marker that influences gene expression and phenotype regulation, and is affected by both genetic and environmental factors. Traditional linear regression methods such as elastic nets have been employed to assess the cumulative effects of multiple DNA methylation markers on phenotypes. However, these methods often fail to capture the complex nonlinear nature of the data. Recent deep learning approaches, such as MethylNet, have improved the prediction accuracy but lack interpretability and efficiency. To address these limitations, we introduced P athway Info r mati o n on M ethylat i on Analysis using a Deep Ne ural N e t work (PROMINENT), a novel interpretable deep learning method that integrates gene-level DNA methylation data with biological pathway information for phenotype prediction. PROMINENT enhances interpretability and prediction accuracy by incorporating gene- and pathway-level priors from databases such as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). It employs SHapley Additive exPlanations (SHAP) to prioritize significant genes and pathways. Evaluated across various datasets, childhood asthma, idiopathic pulmonary fibrosis (IPF), and first-episode psychosis (FEP)—PROMINENT consistently outperformed existing methods in terms of prediction accuracy and computational efficiency. PROMINENT also identified crucial genes and pathways involved in disease mechanisms. PROMINENT represents a significant advancement in leveraging DNA methylation data for phenotype prediction, offering both high accuracy and interpretability within reasonable computational time. This method holds promise for elucidating the epigenetic underpinnings of complex diseases and enhancing the utility of DNA methylation data in biomedical research. • PROMINENT outperformed both MethylNet and Elastic Net in prediction accuracy for various phenotypes, including childhood asthma, idiopathic pulmonary fibrosis, and first-episode psychosis. • PROMINENT provided meaningful biological insights by identifying key genes and pathways associated with diseases, contributing to a deeper understanding of disease mechanisms. • The streamlined architecture of PROMINENT allows for efficient parameter tuning and faster computation times, making it highly suitable for DNA methylation data analysis. • We believe that PROMINENT represents a significant advancement in the field of bioinformatics, particularly in the analysis of DNA methylation data. It offers not only improved prediction accuracy but also valuable biological insights, which were previously unattainable with other methods.