title: Gene Sets Net Correlations Analysis (GSNCA): a multivariate differential coexpression test for gene sets.
abstract: BACKGROUND
  To date, gene set analysis approaches primarily focus on identifying differentially expressed gene sets (pathways). Methods for identifying differentially coexpressed pathways also exist but are mostly based on aggregated pairwise correlations or other pairwise measures of coexpression. Instead, we propose Gene Sets Net Correlations Analysis (GSNCA), a multivariate differential coexpression test that accounts for the complete correlation structure between genes.
  
  
  RESULTS
  In GSNCA, weight factors are assigned to genes in proportion to the genes' cross-correlations (intergene correlations). The problem of finding the weight vectors is formulated as an eigenvector problem with a unique solution. GSNCA tests the null hypothesis that for a gene set there is no difference in the weight vectors of the genes between two conditions. In simulation studies and the analyses of experimental data, we demonstrate that GSNCA captures changes in the structure of genes' cross-correlations rather than differences in the averaged pairwise correlations. Thus, GSNCA infers differences in coexpression networks, however, bypassing method-dependent steps of network inference. As an additional result from GSNCA, we define hub genes as genes with the largest weights and show that these genes correspond frequently to major and specific pathway regulators, as well as to genes that are most affected by the biological difference between two conditions. In summary, GSNCA is a new approach for the analysis of differentially coexpressed pathways that also evaluates the importance of the genes in the pathways, thus providing unique information that may result in the generation of novel biological hypotheses.
  
  
  METHODS
  Implementation of the GSNCA test in R is available upon request from the authors.
authors.affiliation: Division of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA and Computational Biology and Machine Learning Laboratory, Center for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7BL, UK.
authors.forename: Yasir
authors.initials: Y
authors.lastname: Rahmatallah
authors.forename: Frank
authors.initials: F
authors.lastname: Emmert-Streib
authors.forename: Galina
authors.initials: G
authors.lastname: Glazko
mesh_terms: D045744:Cell Line, Tumor; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks; D016158:Genes, p53; D006801:Humans; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis