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Drug repositioning by integrating target information through a heterogeneous network model.

ABSTRACT: The emergence of network medicine not only offers more opportunities for better and more complete understanding of the molecular complexities of diseases, but also serves as a promising tool for identifying new drug targets and establishing new relationships among diseases that enable drug repositioning. Computational approaches for drug repositioning by integrating information from multiple sources and multiple levels have the potential to provide great insights to the complex relationships among drugs, targets, disease genes and diseases at a system level.In this article, we have proposed a computational framework based on a heterogeneous network model and applied the approach on drug repositioning by using existing omics data about diseases, drugs and drug targets. The novelty of the framework lies in the fact that the strength between a disease-drug pair is calculated through an iterative algorithm on the heterogeneous graph that also incorporates drug-target information. Comprehensive experimental results show that the proposed approach significantly outperforms several recent approaches. Case studies further illustrate its practical usefulness.http://cbc.case.edujingli@cwru.eduSupplementary data are available at Bioinformatics online.

SUBMITTER: Wang W

PROVIDER: S-EPMC4184255 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Drug repositioning by integrating target information through a heterogeneous network model.

Wang Wenhui W Yang Sen S Zhang Xiang X Li Jing J

Bioinformatics (Oxford, England) 20140627 20

<h4>Motivation</h4>The emergence of network medicine not only offers more opportunities for better and more complete understanding of the molecular complexities of diseases, but also serves as a promising tool for identifying new drug targets and establishing new relationships among diseases that enable drug repositioning. Computational approaches for drug repositioning by integrating information from multiple sources and multiple levels have the potential to provide great insights to the comple ...[more]

PMID: 24974205

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Project description:Drug repositioning is the process of identifying new uses for existing drugs. Computational drug repositioning methods can reduce the time, costs and risks of drug development by automating the analysis of the relationships in pharmacology networks. Pharmacology networks are large and heterogeneous. Clustering drugs into small groups can simplify large pharmacology networks, these subgroups can also be used as a starting point for repositioning drugs. In this paper, we propose a two-tiered drug-centric unsupervised clustering approach for drug repositioning, integrating heterogeneous drug data profiles: drug-chemical, drug-disease, drug-gene, drug-protein and drug-side effect relationships.The proposed drug repositioning approach is threefold; (i) clustering drugs based on their homogeneous profiles using the Growing Self Organizing Map (GSOM); (ii) clustering drugs based on drug-drug relation matrices based on the previous step, considering three state-of-the-art graph clustering methods; and (iii) inferring drug repositioning candidates and assigning a confidence value for each identified candidate. In this paper, we compare our two-tiered clustering approach against two existing heterogeneous data integration approaches with reference to the Anatomical Therapeutic Chemical (ATC) classification, using GSOM. Our approach yields Normalized Mutual Information (NMI) and Standardized Mutual Information (SMI) of 0.66 and 36.11, respectively, while the two existing methods yield NMI of 0.60 and 0.64 and SMI of 22.26 and 33.59. Moreover, the two existing approaches failed to produce useful cluster separations when using graph clustering algorithms while our approach is able to identify useful clusters for drug repositioning. Furthermore, we provide clinical evidence for four predicted results (Chlorthalidone, Indomethacin, Metformin and Thioridazine) to support that our proposed approach can be reliably used to infer ATC code and drug repositioning.The proposed two-tiered unsupervised clustering approach is suitable for drug clustering and enables heterogeneous data integration. It also enables identifying reliable repositioning drug candidates with reference to ATC therapeutic classification. The repositioning drug candidates identified consistently by multiple clustering algorithms and with high confidence have a higher possibility of being effective repositioning candidates.

Project description:BACKGROUND:Detection of new drug-target interactions by computational algorithms is of crucial value to both old drug repositioning and new drug discovery. Existing machine-learning methods rely only on experimentally validated drug-target interactions (i.e., positive samples) for the predictions. Their performance is severely impeded by the lack of reliable negative samples. RESULTS:We propose a method to construct highly-reliable negative samples for drug target prediction by a pairwise drug-target similarity measurement and OCSVM with a high-recall constraint. On one hand, we measure the pairwise similarity between every two drug-target interactions by combining the chemical similarity between their drugs and the Gene Ontology-based similarity between their targets. Then we calculate the accumulative similarity with all known drug-target interactions for each unobserved drug-target interaction. On the other hand, we obtain the signed distance from OCSVM learned from the known interactions with high recall (?0.95) for each unobserved drug-target interaction. After normalizing all accumulative similarities and signed distances to the range [0,1], we compute the score for each unobserved drug-target interaction via averaging its accumulative similarity and signed distance. Unobserved interactions with lower scores are preferentially served as reliable negative samples for the classification algorithms. The performance of the proposed method is evaluated on the interaction data between 1094 drugs and 1556 target proteins. Extensive comparison experiments using four classical classifiers and one domain predictive method demonstrate the superior performance of the proposed method. A better decision boundary has been learned from the constructed reliable negative samples. CONCLUSIONS:Proper construction of highly-reliable negative samples can help the classification models learn a clear decision boundary which contributes to the performance improvement.

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Drug repositioning by integrating target information through a heterogeneous network model.

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Drug repositioning by integrating target information through a heterogeneous network model.

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