title: Gene-Set Local Hierarchical Clustering (GSLHC)--A Gene Set-Based Approach for Characterizing Bioactive Compounds in Terms of Biological Functional Groups.
abstract: Gene-set-based analysis (GSA), which uses the relative importance of functional gene-sets, or molecular signatures, as units for analysis of genome-wide gene expression data, has exhibited major advantages with respect to greater accuracy, robustness, and biological relevance, over individual gene analysis (IGA), which uses log-ratios of individual genes for analysis. Yet IGA remains the dominant mode of analysis of gene expression data. The Connectivity Map (CMap), an extensive database on genomic profiles of effects of drugs and small molecules and widely used for studies related to repurposed drug discovery, has been mostly employed in IGA mode. Here, we constructed a GSA-based version of CMap, Gene-Set Connectivity Map (GSCMap), in which all the genomic profiles in CMap are converted, using gene-sets from the Molecular Signatures Database, to functional profiles. We showed that GSCMap essentially eliminated cell-type dependence, a weakness of CMap in IGA mode, and yielded significantly better performance on sample clustering and drug-target association. As a first application of GSCMap we constructed the platform Gene-Set Local Hierarchical Clustering (GSLHC) for discovering insights on coordinated actions of biological functions and facilitating classification of heterogeneous subtypes on drug-driven responses. GSLHC was shown to tightly clustered drugs of known similar properties. We used GSLHC to identify the therapeutic properties and putative targets of 18 compounds of previously unknown characteristics listed in CMap, eight of which suggest anti-cancer activities. The GSLHC website http://cloudr.ncu.edu.tw/gslhc/ contains 1,857 local hierarchical clusters accessible by querying 555 of the 1,309 drugs and small molecules listed in CMap. We expect GSCMap and GSLHC to be widely useful in providing new insights in the biological effect of bioactive compounds, in drug repurposing, and in function-based classification of complex diseases.
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, 32001, Taiwan; Center for Dynamical Biomarkers and Translational Medicine, National Central University, Zhongli, 32001, Taiwan.
authors.forename: Feng-Hsiang
authors.initials: FH
authors.lastname: Chung
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, 32001, Taiwan.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Jin
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, 32001, Taiwan.
authors.forename: Tzu-Ting
authors.initials: TT
authors.lastname: Hsu
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, 32001, Taiwan.
authors.forename: Chueh-Lin
authors.initials: CL
authors.lastname: Hsu
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, 32001, Taiwan.
authors.forename: Hsueh-Chuan
authors.initials: HC
authors.lastname: Liu
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, 32001, Taiwan; Center for Dynamical Biomarkers and Translational Medicine, National Central University, Zhongli, 32001, Taiwan; Department of Physics, Chung Yuan Christian University, Zhongli, 32023, Taiwan; Physics Division, National Center for Theoretical Sciences, Hsinchu, 30043, Taiwan.
authors.forename: Hoong-Chien
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D030541:Databases, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male
chemical_list: D000970:Antineoplastic Agents