Disease comorbidity-guided drug repositioning: a case study in schizophrenia.

The key to any computational drug repositioning is the availability of relevant data in machine-understandable format. While large amount of genetic, genomic and chemical data are publicly available, large-scale higher-level disease and drug phenotypic data are limited. We recently constructed a large-scale disease-comorbidity relationship knowledge base (dCombKB) and a comprehensive drug-treatment relationship knowledge base (TreatKB) from 21 million biomedical research articles and other resources. In this study, we demonstrated the potential of dCombKB and TreatKB in drug repositioning for schizophrenia, one of the top ten illnesses contributing to the global burden of disease. dCombKB contains 121,359 unique disease-disease comorbidity pairs for 23,041 diseases. TreatKB contains 208,330 unique drug-disease treatment pairs for 2,484 drugs and 24,511 diseases. We constructed a phenotypic comorbidity disease network (PDN) of 14,645 disease nodes and 101,275 edges based on dCombKB. We applied standard network-based ranking algorithm to find diseases that are phenotypically related to SCZ. We developed a drug prioritization system, PhenoPredict-CDN, to systematically reposition drugs for SCZ from diseases phenotypically related to SCZ. PhenoPredict-CDN found all 18 FDA-approved SCZ drugs and ranked them highly as tested in a de-novo validation setting (recall: 1.0, mean ranking: top 6.05%, median ranking: top 1.65%). When compared to PREDICT, a comprehensive drug repositioning system, for novel predictions, Pheno-Predict-CDN outperformed PREDICT in Precision-Recall (PR) curves across three different evaluation datasets. Compared to PREDICT, PhenoPredict-CDN showed a significant 110.0-230.0% improvements in mean average precision. In summary, large-scale higher-level disease-comorbidity relationships data extracted from biomedical literature has potential in drug discovery for SCZ, a complex disease with unknown pathophysiological mechanisms. All the data are publicly available: dCombKB at http://nlp. CASE: edu/public/data/dCombKB, TreatKB at http://nlp. CASE: edu/public/data/treatKB/, and predictions for SCZ at http://nlp. CASE: edu/public/data/SCZ_CDN/.