title: Predictive integration of gene functional similarity and co-expression defines treatment response of endothelial progenitor cells.
abstract: BACKGROUND
  Endothelial progenitor cells (EPCs) have been implicated in different processes crucial to vasculature repair, which may offer the basis for new therapeutic strategies in cardiovascular disease. Despite advances facilitated by functional genomics, there is a lack of systems-level understanding of treatment response mechanisms of EPCs. In this research we aimed to characterize the EPCs response to adenosine (Ado), a cardioprotective factor, based on the systems-level integration of gene expression data and prior functional knowledge. Specifically, we set out to identify novel biosignatures of Ado-treatment response in EPCs.
  
  
  RESULTS
  The predictive integration of gene expression data and standardized functional similarity information enabled us to identify new treatment response biosignatures. Gene expression data originated from Ado-treated and -untreated EPCs samples, and functional similarity was estimated with Gene Ontology (GO)-based similarity information. These information sources enabled us to implement and evaluate an integrated prediction approach based on the concept of k-nearest neighbours learning (kNN). The method can be executed by expert- and data-driven input queries to guide the search for biologically meaningful biosignatures. The resulting integrated kNN system identified new candidate EPC biosignatures that can offer high classification performance (areas under the operating characteristic curve>0.8). We also showed that the proposed models can outperform those discovered by standard gene expression analysis. Furthermore, we report an initial independent in vitro experimental follow-up, which provides additional evidence of the potential validity of the top biosignature.
  
  
  CONCLUSIONS
  Response to Ado treatment in EPCs can be accurately characterized with a new method based on the combination of gene co-expression data and GO-based similarity information. It also exploits the incorporation of human expert-driven queries as a strategy to guide the automated search for candidate biosignatures. The proposed biosignature improves the systems-level characterization of EPCs. The new integrative predictive modeling approach can also be applied to other phenotype characterization or biomarker discovery problems.
authors: Laboratory of Cardiovascular Research, Centre de Recherche Public-Santé, L-1150, Luxembourg. Francisco.Azuaje@crp-sante.lu
authors: Francisco J
authors: FJ
authors: Azuaje
authors: Haiying
authors: H
authors: Wang
authors: Huiru
authors: H
authors: Zheng
authors: Frédérique
authors: F
authors: Léonard
authors: Magali
authors: M
authors: Rolland-Turner
authors: Lu
authors: L
authors: Zhang
authors: Yvan
authors: Y
authors: Devaux
authors: Daniel R
authors: DR
authors: Wagner
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D053687:Adult Stem Cells / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C111792:CCL18 protein, human; D019742:Chemokines, CC; D014665:Vasodilator Agents; D000241:Adenosine