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A two-tiered unsupervised clustering approach for drug repositioning through heterogeneous data integration.

ABSTRACT: 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.

SUBMITTER: Hameed PN

PROVIDER: S-EPMC5896044 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other

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A two-tiered unsupervised clustering approach for drug repositioning through heterogeneous data integration.

Hameed Pathima Nusrath PN Verspoor Karin K Kusljic Snezana S Halgamuge Saman S

BMC bioinformatics 20180411 1

<h4>Background</h4>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 ...[more]

PMID: 29642848

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Project description:Drug repurposing has broad importance in planetary health for therapeutics innovation in infectious diseases as well as common or rare chronic human diseases. Drug repurposing has also proved important to develop interventions against the COVID-19 pandemic. We propose a new approach for drug repurposing involving two-stage prediction and machine learning. First, diseases are clustered by gene expression on the premise that similar patterns of altered gene expression imply critical pathways shared in different disease conditions. Next, drug efficacy is assessed by the reversibility of abnormal gene expression, and results are clustered to identify repurposing targets. To cluster similar diseases, gene expression data from 262 cases of 31 diseases and 268 controls were analyzed by Uniform Manifold Approximation and Projection for Dimension Reduction followed by k-means to optimize the number of clusters. For evaluation, we examined disease-specific gene expression data for inclusion, body myositis, polymyositis, and dermatomyositis (DM), and used LINCS L1000 characteristic direction signatures search engine (L1000CDS2) to obtain lists of small-molecule compounds that reversed the expression patterns of these specifically altered genes as candidates for drug repurposing. Finally, the functions of affected genes were analyzed by Gene Set Enrichment Analysis to examine consistency with expected drug efficacy. Consequently, we found disease-specific gene expression, and importantly, identified 20 drugs such as BMS-387032, phorbol-12-myristate-13-acetate, mitoxantrone, alvocidib, and vorinostat as candidates for repurposing. These were previously noted to be effective against two of the three diseases, and have a high probability of being effective against the other. That is, inclusion body myositis and DM. The two-stage prediction approach to drug repurposing presented here offers innovation to inform future drug discovery and clinical trials in a variety of human diseases.

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A two-tiered unsupervised clustering approach for drug repositioning through heterogeneous data integration.

Publications

A two-tiered unsupervised clustering approach for drug repositioning through heterogeneous data integration.

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