Biologically Interpretable Model for Precise Recurrence Prediction of Non-Small Cell Lung Cancer

The precise prediction of preoperative recurrence in non-small cell lung cancer (NSCLC) that is suitable for clinical application is still an open question. Recent advancements integrating genomic data with deep learning have shown promise in enhancing recurrence analysis in NSCLC patients. However, the lack of interpretability in the decision-making process of DNN models has hindered their clinical trustworthiness. In this paper, we propose a novel Biologically Informed Pathway-Aware Neural Network (BioPAN). By automatically extracting biological prior knowledge to guide the architecture of DNN models, we design a unified architecture of gene-pathway-biological process-disease. This approach endows each neuron with entity meaning and learns a multi-level view of biological pathways and processes related to recurrence for fully interpretable NSCLC recurrence prediction. We demonstrated that the proposed model well explains the molecular mechanisms linking genes to NSCLC recurrence, identifies several genes that significantly promote and inhibit recurrence, and elucidates the pivotal roles of various gene pathways at the biological process level. Moreover, it outperforms classical machine learning methods, provides fully interpretable biological information, and requires fewer parameters. Broadly, BioPAN enables clinical discovery and prediction, and may have general applicability across cancer types.