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SourceSet: A graphical model approach to identify primary genes in perturbed biological pathways

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  • Elisa Salviato
  • Vera Djordjilović
  • Monica Chiogna
  • Chiara Romualdi

Abstract

Topological gene-set analysis has emerged as a powerful means for omic data interpretation. Although numerous methods for identifying dysregulated genes have been proposed, few of them aim to distinguish genes that are the real source of perturbation from those that merely respond to the signal dysregulation. Here, we propose a new method, called SourceSet, able to distinguish between the primary and the secondary dysregulation within a Gaussian graphical model context. The proposed method compares gene expression profiles in the control and in the perturbed condition and detects the differences in both the mean and the covariance parameters with a series of likelihood ratio tests. The resulting evidence is used to infer the primary and the secondary set, i.e. the genes responsible for the primary dysregulation, and the genes affected by the perturbation through network propagation. The proposed method demonstrates high specificity and sensitivity in different simulated scenarios and on several real biological case studies. In order to fit into the more traditional pathway analysis framework, SourceSet R package also extends the analysis from a single to multiple pathways and provides several graphical outputs, including Cytoscape visualization to browse the results.Author summary: The rapid increase in omic studies has created a need to understand the biological implications of their results. Gene-set analysis has emerged as a powerful means for gaining such understanding, evolving in the last decade from the classical enrichment analysis to the more powerful topological approaches. Although numerous methods for identifying dysregulated genes have been proposed, few of them aim to distinguish genes that are the real source of perturbation from those that merely respond to the signal dysregulation. This distinction is crucial for network medicine, where the prioritization of the effect of biological perturbations may help in the molecular understanding of drug treatments and diseases. Here we propose a new method, called SourceSet, able to distinguish between primary and secondary dysregulation within a graphical model context, demonstrating a high specificity and sensitivity in different simulated scenarios and on real biological case studies.

Suggested Citation

  • Elisa Salviato & Vera Djordjilović & Monica Chiogna & Chiara Romualdi, 2019. "SourceSet: A graphical model approach to identify primary genes in perturbed biological pathways," PLOS Computational Biology, Public Library of Science, vol. 15(10), pages 1-28, October.
    • Handle: RePEc:plo:pcbi00:1007357
    DOI: 10.1371/journal.pcbi.1007357
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