PathX-CNN: An Enhanced Explainable Convolutional Neural Network for Survival Prediction and Pathway Analysis in Glioblastoma.

Motivation: Convolutional neural networks (CNNs) offer potential for analyzing non-grid structured data, such as biological array data, by converting it into image-like formats using principal component analysis (PCA) of pathway genes. However, PCA-derived principal components (PCs) from the entire dataset capture global variance but fail to extract sub-cohort (class-specific) variances. Consequently, CNNs trained on global PCs perform poorly in survival prediction of glioblastoma multiforme (GBM), and the corresponding explanation of CNN outcomes may not align with disease-relevant pathways. Results: We present PathX-CNN, an explainable CNN framework that addresses these limitations by integrating multi-omics data through pathway-based images derived from sub-cohort-specific PCs. PathX-CNN outperformed existing pathway-based methods in predicting long-term survival (LTS) versus non-LTS in GBM. By leveraging SHAP (SHapley Additive exPlanations), a cooperative game theory-based explainable AI method, PathX-CNN identified biologically plausible pathways associated with GBM survival. Additionally, experiments on other cancer types demonstrated superior performance compared to traditional approaches. PathX-CNN demonstrates the potential of CNNs for multi-omics integration, offering both improved prediction accuracy and pathway-specific insights into disease mechanisms.