Machine learning-integrated molecular subtyping reveals two biologically distinct endometriosis subtypes in the EndometDB database.
Abstract
Background
Endometriosis affects approximately 10% of reproductive-age women, with a diagnostic delay of 7-10 years. Despite clinical heterogeneity, current rASRM staging poorly predicts treatment outcomes. Molecular subtyping may reveal biologically meaningful patient strata that complement anatomical staging.
Objective
To identify molecular subtypes of endometriosis through integrated bioinformatics and construct machine learning (ML)-based diagnostic and prognostic models.
Methods
Gene expression data from EndometDB (GSE141549; 89 endometriosis patients, 41 controls) were processed. Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) networks were integrated to identify core genes. Consensus clustering defined molecular subtypes. ML diagnostic (XGBoost, ensemble) and prognostic (random survival forest) models were constructed and validated by nested cross-validation. An exploratory treatment response model was additionally evaluated.
Results
823 DEGs (496 upregulated, 327 downregulated), 173 core genes, and 2 molecular subtypes were identified. Subtypes showed distinct ssGSEA pathway profiles but no statistically significant differences in rASRM score (p = 0.641) or age, suggesting molecularly-defined rather than clinically-defined heterogeneity. The ensemble diagnostic model achieved AUC= 0.892 (5-fold nested cross-validation). The random survival forest prognostic model, based on a surrogate endpoint, demonstrated an OOB concordance index of 0.751. An exploratory treatment response model performed no better than chance (AUC = 0.492).
Conclusions
Integrating multi-method bioinformatics with ML identified 2 distinct endometriosis molecular subtypes and yielded internally validated diagnostic and prognostic models, providing an analytical framework and candidate molecular targets for future studies of endometriosis heterogeneity.