title: Development and application of an interaction network ontology for literature mining of vaccine-associated gene-gene interactions.
abstract: BACKGROUND
  Literature mining of gene-gene interactions has been enhanced by ontology-based name classifications. However, in biomedical literature mining, interaction keywords have not been carefully studied and used beyond a collection of keywords.
  
  
  METHODS
  In this study, we report the development of a new Interaction Network Ontology (INO) that classifies >800 interaction keywords and incorporates interaction terms from the PSI Molecular Interactions (PSI-MI) and Gene Ontology (GO). Using INO-based literature mining results, a modified Fisher's exact test was established to analyze significantly over- and under-represented enriched gene-gene interaction types within a specific area. Such a strategy was applied to study the vaccine-mediated gene-gene interactions using all PubMed abstracts. The Vaccine Ontology (VO) and INO were used to support the retrieval of vaccine terms and interaction keywords from the literature.
  
  
  RESULTS
  INO is aligned with the Basic Formal Ontology (BFO) and imports terms from 10 other existing ontologies. Current INO includes 540 terms. In terms of interaction-related terms, INO imports and aligns PSI-MI and GO interaction terms and includes over 100 newly generated ontology terms with 'INO_' prefix. A new annotation property, 'has literature mining keywords', was generated to allow the listing of different keywords mapping to the interaction types in INO. Using all PubMed documents published as of 12/31/2013, approximately 266,000 vaccine-associated documents were identified, and a total of 6,116 gene-pairs were associated with at least one INO term. Out of 78 INO interaction terms associated with at least five gene-pairs of the vaccine-associated sub-network, 14 terms were significantly over-represented (i.e., more frequently used) and 17 under-represented based on our modified Fisher's exact test. These over-represented and under-represented terms share some common top-level terms but are distinct at the bottom levels of the INO hierarchy. The analysis of these interaction types and their associated gene-gene pairs uncovered many scientific insights.
  
  
  CONCLUSIONS
  INO provides a novel approach for defining hierarchical interaction types and related keywords for literature mining. The ontology-based literature mining, in combination with an INO-based statistical interaction enrichment test, provides a new platform for efficient mining and analysis of topic-specific gene interaction networks.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109 USA.
authors.forename: Junguk
authors.initials: J
authors.lastname: Hur
authors.affiliation: Department of Computer Engineering, Bogazici University, 34342 Istanbul, Turkey.
authors.forename: Arzucan
authors.initials: A
authors.lastname: Özgür
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109 USA.
authors.forename: Zuoshuang
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109 USA ; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109 USA ; Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109 USA ; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109 USA.
authors.forename: Yongqun
authors.initials: Y
authors.lastname: He
keywords: Biomedical ontology; Gene-gene interaction; Interaction enrichment; Interaction network ontology; Literature mining