DR.DEGMON: self-explainable deep neural network for drug-induced cell viability prediction incorporating differentially expressed genes and gene ontology

Abstract

Accurate prediction of cancer drug responses is essential for advancing cancer treatment strategies and drug development. With the increasing availability of large-scale pharmacogenomic datasets, many deep learning models have been proposed to predict cancer drug responses. However, many existing models lack the capacity to offer critical biomedical insights, such as providing interpretability regarding the potential mechanism of action. We propose DR.DEGMON (Drug Response prediction using Differentially Expressed Genes with Multi-layer perceptron integrating gene Ontology Network), a self-explainable deep neural network designed to predict the viability of pan-cancer cell lines in response to drug treatments by utilizing differentially expressed genes. DR.DEGMON leverages prior biological knowledge by incorporating Gene Ontology (GO) into the hierarchical structure of a multi-layer perceptron. The architecture of DR.DEGMON highlights key genes and GO terms that contribute to drug responses through layer-wise relevance propagation (LRP), suggesting potential biological pathways associated with specific drugs. DR.DEGMON achieved a Pearson correlation coefficient of 0.8568 for cell viability prediction, outperforming all baseline models. The model also showed robust generalization performance on external datasets, including GDSC, PRISM, and CCLE. In addition, we employed layer-wise relevance propagation (LRP) to obtain relevance scores for input genes and nodes representing GO terms. DR.DEGMON shows high performance in predicting drug responses and provides interpretable results. The integration of GO and LRP enabled the model to suggest the underlying biological processes involved in drug responses, making it a valuable tool for predicting outcomes and discovering new biomedical knowledge in cancer pharmacogenomics. This approach offers both practical utility in drug development and a method for improving the understanding of cancer biology.