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A Literature-Based Knowledge Graph Embedding Method for Identifying Drug Repurposing Opportunities in Rare Diseases

By Daniel N. Sosa, Alexander Derry, Margaret Guo, Eric Wei, Connor Brinton, Russ B. Altman

Posted 07 Aug 2019
bioRxiv DOI: 10.1101/727925

One in ten people are affected by rare diseases, and three out of ten children with rare diseases will not live past age five. However, the small market size of individual rare diseases, combined with the time and capital requirements of pharmaceutical R&D, have hindered the development of new drugs for these cases. A promising alternative is drug repurposing, whereby existing FDA-approved drugs might be used to treat diseases different from their original indications. In order to generate drug repurposing hypotheses in a systematic and comprehensive fashion, it is essential to integrate information from across the literature of pharmacology, genetics, and pathology. To this end, we leverage a newly developed knowledge graph, the Global Network of Biomedical Relationships (GNBR). GNBR is a large, heterogeneous knowledge graph comprising drug, disease, and gene (or protein) entities linked by a small set of semantic themes derived from the abstracts of biomedical literature. We apply a knowledge graph embedding method that explicitly models the uncertainty associated with literature-derived relationships and uses link prediction to generate drug repurposing hypotheses. This approach achieves high performance on a gold-standard test set of known drug indications (AUROC = 0.89) and is capable of generating novel repurposing hypotheses, which we independently validate using external literature sources and protein interaction networks. Finally, we demonstrate the ability of our model to produce explanations of its predictions.

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