MiracleNet: A Biologically Interpretable Machine Learning Model for Resected Non-small-cell Lung Cancer.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Accurate prediction of relapse is notoriously difficult, posing substantial challenges to patient care and necessitating advanced tools to improve prognostic outcomes. MicroRNA (miRNA) expression profiles hold promise as biomarkers for predicting relapse, yet existing predictive models lack interpretability or sufficient predictive performance. Biologically informed neural networks have emerged as a modeling approach incorporating biological interpretability and predictive accuracy. Here, we introduce MiracleNet, to our knowledge the first visible neural network in which sparse connectivity is structured by the miRNA → target gene → pathway hierarchy for disease-free survival prediction from circulating miRNA in non-small-cell lung cancer and the first to expose interpretable importances jointly at all 3 biological layers, with nodes connected by prior knowledge about miRNA targets and related biological pathways. Our model, which also integrates clinical data, achieves a maximum concordance index of 0.76, demonstrates improved generalization over unconstrained neural networks of the same dimensionality (including both dense and sparse architectures lacking biological knowledge), and provides explicit biological interpretability. Our model also highlights several important biomarkers in the form of predictive miRNAs and connected biological pathways. We additionally evaluate MiracleNet under a nested repeated 80/20 protocol, augmented with patient sex and tumor stage as clinical covariates and combined across circulating free and extracellular-vesicle-associated miRNAs through early and intermediate fusion; these analyses are reported as separate sections.