title: PhenoPredict: A disease phenome-wide drug repositioning approach towards schizophrenia drug discovery.
abstract: Schizophrenia (SCZ) is a common complex disorder with poorly understood mechanisms and no effective drug treatments. Despite the high prevalence and vast unmet medical need represented by the disease, many drug companies have moved away from the development of drugs for SCZ. Therefore, alternative strategies are needed for the discovery of truly innovative drug treatments for SCZ. Here, we present a disease phenome-driven computational drug repositioning approach for SCZ. We developed a novel drug repositioning system, PhenoPredict, by inferring drug treatments for SCZ from diseases that are phenotypically related to SCZ. The key to PhenoPredict is the availability of a comprehensive drug treatment knowledge base that we recently constructed. PhenoPredict retrieved all 18 FDA-approved SCZ drugs and ranked them highly (recall=1.0, and average ranking of 8.49%). When compared to PREDICT, one of the most comprehensive drug repositioning systems currently available, in novel predictions, PhenoPredict represented clear improvements over PREDICT in Precision-Recall (PR) curves, with a significant 98.8% improvement in the area under curve (AUC) of the PR curves. In addition, we discovered many drug candidates with mechanisms of action fundamentally different from traditional antipsychotics, some of which had published literature evidence indicating their treatment benefits in SCZ patients. In summary, although the fundamental pathophysiological mechanisms of SCZ remain unknown, integrated systems approaches to studying phenotypic connections among diseases may facilitate the discovery of innovative SCZ drugs.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States. Electronic address: rxx@case.edu.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: ThinTek, LLC, Palo Alto, CA 94306, United States. Electronic address: qwang@thintek.com.
authors.forename: QuanQiu
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000465:Algorithms; D014150:Antipsychotic Agents / Q000627:therapeutic use; D019540:Area Under Curve; D019295:Computational Biology / Q000379:methods; D016208:Databases, Factual; D016503:Drug Delivery Systems; D055808:Drug Discovery / Q000295:instrumentation* / Q000379:methods; D058492:Drug Repositioning; D051188:Knowledge Bases; D010641:Phenotype; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000175:diagnosis*; D012984:Software; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D014150:Antipsychotic Agents
keywords: Disease phenotype; Drug discovery; Drug repositioning; Schizophrenia; Systems biology