Knowledge Graphs and Explainable AI for Drug Repurposing on Rare Diseases

Abstract

Artificial Intelligence (AI)-based drug repurposing is an emerging strategy to identify drug candidates to treat rare diseases. However, cutting-edge algorithms based on Deep Learning (DL) typically dont provide a human understandable explanation supporting their predictions. This is a problem because it hampers the biologists ability to decide which predictions are the most plausible drug candidates to test in costly lab experiments. In this study, we propose rd-explainer a novel AI drug repurposing method for rare diseases which obtains possible drug candidates together with human understandable explanations. The method is based on Graph Neural Network (GNN) technology and explanations were generated as semantic graphs using state-of-the-art eXplainable AI (XAI). The model learns features from current background knowledge on the target rare disease structured as a Knowledge Graph (KG), which integrates curated facts and their evidence on different biomedical entities such as symptoms, drugs, genes and ortholog genes. Our experiments demonstrate that our method has excellent performance that is superior to state-of-the-art models. We investigated the application of XAI on drug repurposing for rare diseases and we prove our method is capable of discovering plausible drug candidates based on testable explanations. The data and code are publicly available at https://github.com/PPerdomoQ/rare-disease-explainer. HighlightsO_LIWe demonstrated the use of graph-based explainable AI for drug repurposing on rare diseases to accelerate sound discovery of new therapies for this underrepresented group. C_LIO_LIWe developed rd-explainer for rare disease specific drug research for faster translation. It predicts drugs to treat symptoms/phenotypes, it is highly performant and novel candidates are plausible according to evidence in the scientific literature and clinical trials. Key is that it learns a GNN model that is trained on a knowledge graph built specifically for a rare disease. We provide rd-explainer code freely available for the community. C_LIO_LIrd-explainer is researcher-centric interpretable ML for hypothesis generation and lab-in-the-loop drug research. Explanations of predictions are semantic graphs in line with human reasoning. C_LIO_LIWe detected an effect of knowledge graph topology on explainability. This highlights the importance of knowledge representation for the drug repurposing task. C_LI