Introduction        Integration and querying         Discovering disease pathways   Outlook and conclusions               ...
2007       H           ap                M                 ap2008       1,                   Ph          0                ...
Introduction      Integration and querying   Discovering disease pathways   Outlook and conclusionsTranslational research ...
Pharmacogenomics databases
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsOntology       Gruber...
Introduction         Integration and querying   Discovering disease pathways   Outlook and conclusionsOntologyOntologies i...
Introduction     Integration and querying   Discovering disease pathways   Outlook and conclusionsOntologyOntologies alone...
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsOntologyData-driven a...
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsAims: queries and int...
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsRequired: integration...
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsApproach to data inte...
Introduction         Integration and querying   Discovering disease pathways   Outlook and conclusionsQueries       What d...
Introduction         Integration and querying   Discovering disease pathways   Outlook and conclusionsQueries       What d...
Introduction         Integration and querying   Discovering disease pathways   Outlook and conclusionsQueries       What g...
Introduction         Integration and querying   Discovering disease pathways   Outlook and conclusionsQueries       What g...
Introduction         Integration and querying   Discovering disease pathways   Outlook and conclusionsDisease and drug pat...
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsDisease and drug path...
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsDisease and drug path...
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsGene expression and d...
Introduction         Integration and querying   Discovering disease pathways   Outlook and conclusionsLimitations and futu...
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsConclusions          ...
Introduction        Integration and querying   Discovering disease pathways   Outlook and conclusionsAcknowledgements     ...
Introduction   Integration and querying   Discovering disease pathways   Outlook and conclusions                          ...
Integration of knowledge for personalized medicine: a pharmacogenomics case-study
Integration of knowledge for personalized medicine: a pharmacogenomics case-study
Integration of knowledge for personalized medicine: a pharmacogenomics case-study
Integration of knowledge for personalized medicine: a pharmacogenomics case-study
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Integration of knowledge for personalized medicine: a pharmacogenomics case-study

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Integration of knowledge for personalized medicine: a pharmacogenomics case-study

  1. 1. Introduction Integration and querying Discovering disease pathways Outlook and conclusions Integration of knowledge for personalized medicine: a pharmacogenomics case-study Robert Hoehndorf, Michel Dumontier and George Gkoutos University of Cambridge Carleton University Aberystwyth University 18 September 2012
  2. 2. 2007 H ap M ap2008 1, Ph 0 as 00 e Ge II2009 no GW m2010 AS es ca SI ta D lo ER g2011 IM PC2012 EN CO D E
  3. 3. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsTranslational research National Cancer Institute: Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce [disease] incidence, morbidity, and mortality.
  4. 4. Pharmacogenomics databases
  5. 5. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsOntology Gruber (1993): An ontology is the explicit specification of a conceptualization of a domain. controlled vocabulary provide background knowledge hierarchically organized
  6. 6. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsOntologyOntologies in pharmacogenomics drugs and chemicals: ATC ChEBI MeSH UMLS diseases: HumanDO Human Phenotype Ontology ICD MeSH SNOMED CT UMLS
  7. 7. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsOntologyOntologies alone do not resolve heterogeneity. Euzenat (2007): “[M]erely using ontologies [...] does not reduce heterogeneity: it just raises heterogeneity problems to a higher level.”
  8. 8. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsOntologyData-driven approach to integration data- and question-driven integration of ontologies integration of data and databases through integrated ontologies reduction of complexity background knowledge hierarchical abstraction ontology-based data analysis semantic similarity statistical tests graph-/network-based algorithms data- and question-driven evaluation
  9. 9. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsAims: queries and integrated analysis integrate and query knowledge in pharmacogenomics identify aberrant pathways and patho-physiology underlying disease identify drug pathways (pharmacokinetics and pharmacodynamics) personalized treatment and dosage guidelines based on gene expression profile
  10. 10. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsRequired: integration of multiple data sources drugs and drug targets pathways, genetic interactions, protein interactions, gene regulation drug–disease associations gene–disease associations genotypes–drug response
  11. 11. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsApproach to data integration in pharmacogenomics integration of databases containing drug, gene, genotype, disease and pathway information DrugBank: drugs and drugs targets PharmGKB: genotype and drug response Pathway Interaction Database: biological pathways CTD: toxicogenomics information (chemical–gene–disease)
  12. 12. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsQueries What drugs can be used to treat parasitic infectious diseases (DOID:1398)? Chloroquine Arthemeter ...
  13. 13. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsQueries What drugs are effective for diseases affecting the joints (FMA:7490)? Folic acid (for arthritis) Chloroquine (for Chikungunya virus) ...
  14. 14. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsQueries What genotypes are related to diseases affecting the joints (FMA:7490)? RSID:rs70991108 (with arthritis) RSID:rs1207421 (Osteoarthritis, Knee) ...
  15. 15. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsQueries What genotypes are related to response to steroids (CHEBI:35341)? RSID:rs45566039 (with estrogen) RSID:rs1042713 (with budesonide) ...
  16. 16. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsDisease and drug pathwaysOntology enrichment analysis can identify over-represented ontology classes. ontology-based, statistical approach to identify drug and disease pathways use graph structure of ontology to identify statistically over- and under-represented ontology classes aims: identify over-represented disease classes (in disease ontology) for genes in a pathway (disease pathways) identify over-represented chemical classes (from chemical ontology) for genes in a pathway (drug pathways)
  17. 17. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsDisease and drug pathwaysOntoFUNC enables enrichment analyses over OWL ontologies. OntoFUNC: http://ontofunc.googlecode.com based on FUNC (http://func.eva.mpg.de) supports hypergeometric test Wilcoxon rank test binomial test McDonaldKreitman (2x2 contingency) test correction for multiple testing (FWER, FDR)
  18. 18. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsDisease and drug pathwaysOntoFUNC identifies disease classes that are enriched in pathways. hypergeometric test over Disease Ontology genes participating in pathway P vs. all other genes carcinosarcoma (DOID:4236) and Zidovudine Pathway (PharmGKB:PA165859361) (p < 10−10 ). mood disorder (DOID:3324) and Zidovudine Pathway (PharmGKB:PA165859361) (p < 0.01). (All results at http://pharmgkb-owl.googlecode.com)
  19. 19. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsGene expression and drug responseOngoing research Based on a (differential) gene expression profile, can we find candidate drugs that act (only) on the aberrant pathways? aberrant pathways from (differential) gene expression Wilcoxon signed rank test (types of) drugs acting on these pathways
  20. 20. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsLimitations and future work only works for known pathways extension to interaction networks (experimental) validation include directionality of interactions drug–gene/protein gene regulation protein–protein
  21. 21. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsConclusions knowledge in pharmacogenomics is distributed across multiple databases ontologies can enable data integration and integrated data analysis integration of knowledge is necessary to enable personalized medicine http://pharmgkb-owl.googlecode.com
  22. 22. Introduction Integration and querying Discovering disease pathways Outlook and conclusionsAcknowledgements Michel Dumontier George Gkoutos
  23. 23. Introduction Integration and querying Discovering disease pathways Outlook and conclusions Thank you!

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