title: Linking rare and common disease: mapping clinical disease-phenotypes to ontologies in therapeutic target validation.
abstract: BACKGROUND
  The Centre for Therapeutic Target Validation (CTTV - https://www.targetvalidation.org/) was established to generate therapeutic target evidence from genome-scale experiments and analyses. CTTV aims to support the validity of therapeutic targets by integrating existing and newly-generated data. Data integration has been achieved in some resources by mapping metadata such as disease and phenotypes to the Experimental Factor Ontology (EFO). Additionally, the relationship between ontology descriptions of rare and common diseases and their phenotypes can offer insights into shared biological mechanisms and potential drug targets. Ontologies are not ideal for representing the sometimes associated type relationship required. This work addresses two challenges; annotation of diverse big data, and representation of complex, sometimes associated relationships between concepts.
  
  
  METHODS
  Semantic mapping uses a combination of custom scripting, our annotation tool 'Zooma', and expert curation. Disease-phenotype associations were generated using literature mining on Europe PubMed Central abstracts, which were manually verified by experts for validity. Representation of the disease-phenotype association was achieved by the Ontology of Biomedical AssociatioN (OBAN), a generic association representation model. OBAN represents associations between a subject and object i.e., disease and its associated phenotypes and the source of evidence for that association. The indirect disease-to-disease associations are exposed through shared phenotypes. This was applied to the use case of linking rare to common diseases at the CTTV.
  
  
  RESULTS
  EFO yields an average of over 80% of mapping coverage in all data sources. A 42% precision is obtained from the manual verification of the text-mined disease-phenotype associations. This results in 1452 and 2810 disease-phenotype pairs for IBD and autoimmune disease and contributes towards 11,338 rare diseases associations (merged with existing published work [Am J Hum Genet 97:111-24, 2015]). An OBAN result file is downloadable at http://sourceforge.net/p/efo/code/HEAD/tree/trunk/src/efoassociations/. Twenty common diseases are linked to 85 rare diseases by shared phenotypes. A generalizable OBAN model for association representation is presented in this study.
  
  
  CONCLUSIONS
  Here we present solutions to large-scale annotation-ontology mapping in the CTTV knowledge base, a process for disease-phenotype mining, and propose a generic association model, 'OBAN', as a means to integrate disease using shared phenotypes.
  
  
  BACKGROUND
  EFO is released monthly and available for download at http://www.ebi.ac.uk/efo/.
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
authors.forename: Sirarat
authors.identifier: 0000-0002-2548-641X
authors.initials: S
authors.lastname: Sarntivijai
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
authors.forename: Drashtti
authors.initials: D
authors.lastname: Vasant
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Jupp
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Saunders
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
authors.forename: A Patrícia
authors.initials: AP
authors.lastname: Bento
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; GSK, Medicine Research Centre, Stevenage, SG1 2NY UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Betts
authors.affiliation: Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; GSK, Medicine Research Centre, Stevenage, SG1 2NY UK.
authors.forename: Samiul
authors.initials: S
authors.lastname: Hasan
authors.affiliation: Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; GSK, Medicine Research Centre, Stevenage, SG1 2NY UK.
authors.forename: Gautier
authors.initials: G
authors.lastname: Koscielny
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Dunham
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Parkinson
authors.affiliation: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK ; Centre for Therapeutic Target Validation, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
authors.forename: James
authors.initials: J
authors.lastname: Malone
mesh_terms: D064229:Biological Ontologies; D057225:Data Mining; D016208:Databases, Factual; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D058990:Molecular Targeted Therapy; D010641:Phenotype; D035583:Rare Diseases / Q000188:drug therapy*; D015203:Reproducibility of Results
keywords: CTTV; EFO; OBAN; Phenotype disease associations; Rare disease