title: Optimal Threshold Determination for Interpreting Semantic Similarity and Particularity: Application to the Comparison of Gene Sets and Metabolic Pathways Using GO and ChEBI.
abstract: BACKGROUND
  The analysis of gene annotations referencing back to Gene Ontology plays an important role in the interpretation of high-throughput experiments results. This analysis typically involves semantic similarity and particularity measures that quantify the importance of the Gene Ontology annotations. However, there is currently no sound method supporting the interpretation of the similarity and particularity values in order to determine whether two genes are similar or whether one gene has some significant particular function. Interpretation is frequently based either on an implicit threshold, or an arbitrary one (typically 0.5). Here we investigate a method for determining thresholds supporting the interpretation of the results of a semantic comparison.
  
  
  RESULTS
  We propose a method for determining the optimal similarity threshold by minimizing the proportions of false-positive and false-negative similarity matches. We compared the distributions of the similarity values of pairs of similar genes and pairs of non-similar genes. These comparisons were performed separately for all three branches of the Gene Ontology. In all situations, we found overlap between the similar and the non-similar distributions, indicating that some similar genes had a similarity value lower than the similarity value of some non-similar genes. We then extend this method to the semantic particularity measure and to a similarity measure applied to the ChEBI ontology. Thresholds were evaluated over the whole HomoloGene database. For each group of homologous genes, we computed all the similarity and particularity values between pairs of genes. Finally, we focused on the PPAR multigene family to show that the similarity and particularity patterns obtained with our thresholds were better at discriminating orthologs and paralogs than those obtained using default thresholds.
  
  
  CONCLUSIONS
  We developed a method for determining optimal semantic similarity and particularity thresholds. We applied this method on the GO and ChEBI ontologies. Qualitative analysis using the thresholds on the PPAR multigene family yielded biologically-relevant patterns.
authors.affiliation: Université de Rennes 1, Rennes, France; INRA, UMR1348 PEGASE, Saint-Gilles, France; Agrocampus OUEST, UMR1348 PEGASE, Rennes, France; IRISA, Campus de Beaulieu, Rennes, France; INRIA, Rennes, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Bettembourg
authors.affiliation: INRA, UMR1348 PEGASE, Saint-Gilles, France; Agrocampus OUEST, UMR1348 PEGASE, Rennes, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Diot
authors.affiliation: Université de Rennes 1, Rennes, France; IRISA, Campus de Beaulieu, Rennes, France; INRIA, Rennes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dameron
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods; D063990:Gene Ontology; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D058977:Molecular Sequence Annotation / Q000379:methods; D005810:Multigene Family / Q000235:genetics; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics; D012660:Semantics
chemical_list: D047492:Peroxisome Proliferator-Activated Receptors