title: An integrated approach to identify causal network modules of complex diseases with application to colorectal cancer.
abstract: BACKGROUND
  Many methods have been developed to identify disease genes and further module biomarkers of complex diseases based on gene expression data. It is generally difficult to distinguish whether the variations in gene expression are causative or merely the effect of a disease. The limitation of relying on gene expression data alone highlights the need to develop new approaches that can explore various data to reflect the casual relationship between network modules and disease traits.
  
  
  METHODS
  In this work, we developed a novel network-based approach to identify putative causal module biomarkers of complex diseases by integrating heterogeneous information, for example, epigenomic data, gene expression data, and protein-protein interaction network. We first formulated the identification of modules as a mathematical programming problem, which can be solved efficiently and effectively in an accurate manner. Then, we applied our approach to colorectal cancer (CRC) and identified several network modules that can serve as potential module biomarkers for characterizing CRC. Further validations using three additional gene expression datasets verified their candidate biomarker properties and the effectiveness of the method. Functional enrichment analysis also revealed that the identified modules are strongly related to hallmarks of cancer, and the enriched functions, such as inflammatory response, receptor and signaling pathways, are specific to CRC.
  
  
  RESULTS
  Through constructing a transcription factor (TF)-module network, we found that aberrant DNA methylation of genes encoding TF considerably contributes to the activity change of some genes, which may function as causal genes of CRC, and that can also be exploited to develop efficient therapies or effective drugs.
  
  
  CONCLUSIONS
  Our method can potentially be extended to the study of other complex diseases and the multiclassification problem.
authors.affiliation: Key Laboratory of Systems Biology, SIBS-Novo Nordisk Translational Research Centre for PreDiabetes, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhenshu
authors.initials: Z
authors.lastname: Wen
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Liu
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Luonan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000465:Algorithms; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D015870:Gene Expression; D053263:Gene Regulatory Networks; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D008957:Models, Genetic; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D005819:Genetic Markers; D014157:Transcription Factors