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Optimal Threshold Determination for Interpreting Semantic Similarity and Particularity: Application to the Comparison of Gene Sets and Metabolic Pathways Using GO and ChEBI

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  • Charles Bettembourg
  • Christian Diot
  • Olivier Dameron

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. Conclusion: 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.

Suggested Citation

  • Charles Bettembourg & Christian Diot & Olivier Dameron, 2015. "Optimal Threshold Determination for Interpreting Semantic Similarity and Particularity: Application to the Comparison of Gene Sets and Metabolic Pathways Using GO and ChEBI," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-30, July.
    • Handle: RePEc:plo:pone00:0133579
    DOI: 10.1371/journal.pone.0133579
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    References listed on IDEAS

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    1. Graeme D. Ruxton, 2006. "The unequal variance t-test is an underused alternative to Student's t-test and the Mann--Whitney U test," Behavioral Ecology, International Society for Behavioral Ecology, vol. 17(4), pages 688-690, July.
    2. Catia Pesquita & Daniel Faria & André O Falcão & Phillip Lord & Francisco M Couto, 2009. "Semantic Similarity in Biomedical Ontologies," PLOS Computational Biology, Public Library of Science, vol. 5(7), pages 1-12, July.
    3. Xiaomei Wu & Erli Pang & Kui Lin & Zhen-Ming Pei, 2013. "Improving the Measurement of Semantic Similarity between Gene Ontology Terms and Gene Products: Insights from an Edge- and IC-Based Hybrid Method," PLOS ONE, Public Library of Science, vol. 8(5), pages 1-11, May.
    4. Charles Bettembourg & Christian Diot & Olivier Dameron, 2014. "Semantic Particularity Measure for Functional Characterization of Gene Sets Using Gene Ontology," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-11, January.
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