PINT: Pathway-pathway interactions for predicting interpretable clinical outcomes from gene expression

<jats:p>Motivation: Disease mechanisms emerge from the coordinated activity of multiple biological pathways, rather than from individual pathways acting in isolation. Existing pathway-based deep learning models, however, treat pathways as independent entities, aggregating their representations through fully connected layers that disregard inter-pathway relationships. This architectural limitation overlooks an important dimension of disease biology, potentially constraining both predictive performance and the capacity to generate biologically meaningful interpretations. Results: We introduce a pathway-based attentive interpretability model, named PINT, that models interactions among pathways through a selfattention mechanism from gene expression data. An attention-based pooling layer further identifies patient-specific pathway contributions to the final prediction. Evaluation across five TCGA cancer datasets demonstrated that PINT consistently outperformed benchmark models in survival analysis. More importantly, PINT identifies pathways significantly associated with survival as well as reveals biologically meaningful interactions among pathways. In the BRCA dataset, PINT identified significant pathways, pathway-pathway interactions, and gene-level contributions within pathways for individual patients, most of which were supported by existing literature. Specifically, the RAS signaling pathway emerged as significantly associated with patient survival, and the learned interaction scores recovered known relationships between RAS signaling and several regulatory pathways, including cAMP, TNF, and Rap1 signaling. Availability and implementation: The source code and data are available at https://github.com/datax-lab/PINT.</jats:p>