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

  • 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
  • 2007 2008 2009 2010 2011 2012 H apM ap Phase II 1,000 Genom es GW AS catalog SID ER IM PC EN CO D E
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Translational 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.
  • Pharmacogenomics databases
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Ontology Gruber (1993): An ontology is the explicit specification of a conceptualization of a domain. controlled vocabulary provide background knowledge hierarchically organized
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Ontology Ontologies in pharmacogenomics drugs and chemicals: ATC ChEBI MeSH UMLS diseases: HumanDO Human Phenotype Ontology ICD MeSH SNOMED CT UMLS
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Ontology Ontologies alone do not resolve heterogeneity. Euzenat (2007): “[M]erely using ontologies [...] does not reduce heterogeneity: it just raises heterogeneity problems to a higher level.”
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Ontology Data-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
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Aims: 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
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Required: 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
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Approach 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)
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Queries What drugs can be used to treat parasitic infectious diseases (DOID:1398)? Chloroquine Arthemeter ...
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Queries What drugs are effective for diseases affecting the joints (FMA:7490)? Folic acid (for arthritis) Chloroquine (for Chikungunya virus) ...
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Queries What genotypes are related to diseases affecting the joints (FMA:7490)? RSID:rs70991108 (with arthritis) RSID:rs1207421 (Osteoarthritis, Knee) ...
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Queries What genotypes are related to response to steroids (CHEBI:35341)? RSID:rs45566039 (with estrogen) RSID:rs1042713 (with budesonide) ...
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Disease and drug pathways Ontology 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)
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Disease and drug pathways OntoFUNC 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)
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Disease and drug pathways OntoFUNC 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)
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Gene expression and drug response Ongoing 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
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Limitations 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
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Conclusions 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
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Acknowledgements Michel Dumontier George Gkoutos
  • Introduction Integration and querying Discovering disease pathways Outlook and conclusions Thank you!