title: Knowledge-driven genomic interactions: an application in ovarian cancer.
abstract: BACKGROUND
  Effective cancer clinical outcome prediction for understanding of the mechanism of various types of cancer has been pursued using molecular-based data such as gene expression profiles, an approach that has promise for providing better diagnostics and supporting further therapies. However, clinical outcome prediction based on gene expression profiles varies between independent data sets. Further, single-gene expression outcome prediction is limited for cancer evaluation since genes do not act in isolation, but rather interact with other genes in complex signaling or regulatory networks. In addition, since pathways are more likely to co-operate together, it would be desirable to incorporate expert knowledge to combine pathways in a useful and informative manner.
  
  
  METHODS
  Thus, we propose a novel approach for identifying knowledge-driven genomic interactions and applying it to discover models associated with cancer clinical phenotypes using grammatical evolution neural networks (GENN). In order to demonstrate the utility of the proposed approach, an ovarian cancer data from the Cancer Genome Atlas (TCGA) was used for predicting clinical stage as a pilot project.
  
  
  RESULTS
  We identified knowledge-driven genomic interactions associated with cancer stage from single knowledge bases such as sources of pathway-pathway interaction, but also knowledge-driven genomic interactions across different sets of knowledge bases such as pathway-protein family interactions by integrating different types of information. Notably, an integration model from different sources of biological knowledge achieved 78.82% balanced accuracy and outperformed the top models with gene expression or single knowledge-based data types alone. Furthermore, the results from the models are more interpretable because they are framed in the context of specific biological pathways or other expert knowledge.
  
  
  CONCLUSIONS
  The success of the pilot study we have presented herein will allow us to pursue further identification of models predictive of clinical cancer survival and recurrence. Understanding the underlying tumorigenesis and progression in ovarian cancer through the global view of interactions within/between different biological knowledge sources has the potential for providing more effective screening strategies and therapeutic targets for many types of cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Dokyoon
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Ruowang
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dudek
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Alex T
authors.initials: AT
authors.lastname: Frase
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Pendergrass
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
keywords: Clinical outcome prediction; Grammatical evolution neural network; Integrative analysis; Knowledge-driven genomic interaction; Ovarian cancer