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GuiltyTargets: Prioritization of Novel Therapeutic Targets with Deep Network Representation Learning

By Özlem Muslu, Charles Tapley Hoyt, Martin Hofmann-Apitius, Yong Li

Posted 16 Jan 2019
bioRxiv DOI: 10.1101/521161

The majority of clinical trial failures are caused by low efficacy of investigated drugs, often due to a poor choice of target protein. Computational prioritization approaches aim to support target selection by ranking candidate targets in the context of a given disease. We propose a novel target prioritization approach, GuiltyTargets, which relies on deep network representation learning of a genome-wide protein-protein interaction network annotated with disease-specific differential gene expression and uses positive-unlabeled machine learning for candidate ranking. We evaluated our approach on six diseases of different types (cancer, metabolic, neurodegenerative) within a 10 times repeated 5-fold stratified cross-validation and achieved AUROC values between 0.92 - 0.94, significantly outperforming a previous approach, which relies on manually engineered topological features. Moreover, we showed that GuiltyTargets allows for target repositioning across related disease areas. Applying GuiltyTargets to Alzheimer's disease resulted into a number of highly ranked candidates that are currently discussed as targets in the literature. Interestingly, one (COMT) is also the target of an approved drug (Tolcapone) for Parkinson's disease, highlighting the potential for target repositioning of our method. Availability: The GuiltyTargets Python package is available on PyPI and all code used for analysis can be found under the MIT License at https://github.com/GuiltyTargets.

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