An integrated approach to identify causal network modules of complex diseases with application to colorectal cancer

Zhenshu Wen, Zhi-Ping Liu, Zhengrong Liu, Yan Zhang, Luonan Chen
2013 JAMIA Journal of the American Medical Informatics Association  
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
more » ... ork, we developed a novel networkbased 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. Conclusion Our method can potentially be extended to the study of other complex diseases and the multiclassification problem.
doi:10.1136/amiajnl-2012-001168 pmid:22967703 pmcid:PMC3721155 fatcat:eipl4asyufabro72mlzkn4lv2u