A phenome-guided drug repositioning through a latent variable model

BMC Bioinformatics

Halil Bisgin¹  Zhichao Liu¹  Hong Fang²  Reagan Kelly¹  Xiaowei Xu³  Weida Tong¹ 

[1] Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA

[2] Office of Scientific Coordination, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA

[3] Department of Information Science, University of Arkansas at Little Rock, 2801 S. University Ave., Little Rock, AR 72204-1099, USA

关键词: Indications;    Side effects;    Phenome;    Data mining;    Latent dirichlet allocation;    Bayesian methods;    Drug repositioning;   

Others  :  1087525
DOI  :  10.1186/1471-2105-15-267

 received in 2014-02-26, accepted in 2014-07-21,  发布年份 2014

【 摘 要 】

Background

The phenome represents a distinct set of information in the human population. It has been explored particularly in its relationship with the genome to identify correlations for diseases. The phenome has been also explored for drug repositioning with efforts focusing on the search space for the most similar candidate drugs. For a comprehensive analysis of the phenome, we assumed that all phenotypes (indications and side effects) were inter-connected with a probabilistic distribution and this characteristic may offer an opportunity to identify new therapeutic indications for a given drug. Correspondingly, we employed Latent Dirichlet Allocation (LDA), which introduces latent variables (topics) to govern the phenome distribution.

Results

We developed our model on the phenome information in Side Effect Resource (SIDER). We first developed a LDA model optimized based on its recovery potential through perturbing the drug-phenotype matrix for each of the drug-indication pairs where each drug-indication relationship was switched to “unknown” one at the time and then recovered based on the remaining drug-phenotype pairs. Of the probabilistically significant pairs, 70% was successfully recovered. Next, we applied the model on the whole phenome to narrow down repositioning candidates and suggest alternative indications. We were able to retrieve approved indications of 6 drugs whose indications were not listed in SIDER. For 908 drugs that were present with their indication information, our model suggested alternative treatment options for further investigations. Several of the suggested new uses can be supported with information from the scientific literature.

Conclusions

The results demonstrated that the phenome can be further analyzed by a generative model, which can discover probabilistic associations between drugs and therapeutic uses. In this regard, LDA serves as an enrichment tool to explore new uses of existing drugs by narrowing down the search space.

【 授权许可】

   
2014 Bisgin et al.; licensee BioMed Central Ltd.

【 图 表 】

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