Modeling the pharmacogenomics of depression Michel Dumontier, Muhammad Faizan, Joseph Obeng, Natalia Villanueva-Rosales Carleton University HCLS2008 @ WWW2008

“If it were not for the great variability among individuals, medicine might as well be a science and not an art” Sir William Osler, 1892 Pharmacogenomics: The application of genomics to the study of human variability in drug response HCLS2008 @ WWW2008

Personalized Medicine The ability to offer The Right Drug To The Right Patient For The Right Disease At The Right Time With The Right Dosage HCLS2008 @ WWW2008

+Role of genes, gene variants , drugs PHARMGKB +Role of genes, gene variants , drugs +pharmacokinetics +pharmacodynamics + clinical outcomes. + Links to publications - Natural language descriptions - Variant details in publications HCLS2008 @ WWW2008

Suggested Ontology for Pharmacogenomics SOPHARM Suggested Ontology for Pharmacogenomics + OWL ontology +/- Ontology reuse High complexity 14 ontologies: ChEBI, PATO, Unit Ontology, Disease Ontology, Mammalian Phenotype Ontology, MEO, Sequence Ontology, SNP-Ontology, Amino-Acid Ontology, Family Bond Ontology, Pharmacogenetics Ontology, Relationship Ontology and CTO/OBI (Ontology of Clinical Investigation) SOPHARM: 70 classes, 56 properties OTHER: 84786 classes, 189 properties - Very expensive to reason with HCLS2008 @ WWW2008

Pharmacogenomics Ontology: simpler knowledge representation Pharmacogenomics of Depression: explicit knowledge representation HCLS2008 @ WWW2008

Define the scope of the ontology from use cases. METHODOLOGY Define the scope of the ontology from use cases. Derive essential concepts. Construct concept taxonomy. Map to an upper level ontology Assign relations between concepts and attributes. Add complex class descriptions. HCLS2008 @ WWW2008

researcher, doctor or patient personalized medicine 1 SCOPE researcher, doctor or patient personalized medicine What is the most effective drug treatment for an individual with a particular genetic profile that suffers from a particular disease? Which gene variants affect therapeutic outcomes? What is the clinical response for treating individuals with a particular drug and having a particular allele? HCLS2008 @ WWW2008

2a SEVEN ESSENTIAL CONCEPTS (out of 20) HCLS2008 @ WWW2008

2b N-ARY MODELING HCLS2008 @ WWW2008

English name (rdfs:label) Clear and precise definition (rdfs:comment). 3 ONTOLOGY English name (rdfs:label) Clear and precise definition (rdfs:comment). Concepts that subsumed each other were hierarchically organized and a child term is differentiable from its parent term. In line with general normalization techniques, all ontological terms are asserted to have but a single parent. Refactored and Expanded SOPHARM’s measures - differences in values different from values HCLS2008 @ WWW2008

Basic Relation Ontology (BRO) 50+ domain independent relations e.g. hasPart Anticipated compatibility with RO huge reuse opportunities Specialized Relations enormous number of possible domain dependent relations isVariantOf set usage with domain / range restrictions. HCLS2008 @ WWW2008

Queried PharmGKB web services, mapped to ontology Ontology Population Queried PharmGKB web services, mapped to ontology Contained generic relationship to other named entities Instance representation Reuse individuals Drug(nortryptiline) reduces KB size Class Instances Gene 1396 SNP 60 IntronicSNP 607 NS-SNP 101 S-SNP 79 Drug 269 Disease 156 Phenotype 75 Publication 71 ClinicalOutcomeMeasure 36 GenotypeMeasure 35 PharmacokineticMeasure 30 PharmacodynamicMeasure 26 Pathway 18 OneDimensionalRegion 417 Chromosome 14 CrickStrand WatsonStrand Frequency 847 DatabaseSource 1 Total 4266 HCLS2008 @ WWW2008

Pharmacogenomics of Depression KNOWLEDGE BASE contains statements from 11/40 relevant publications involving 45 genes / gene variants, 57 drugs annotated with 19 classes of antidepressants, 45 drug treatments, 47 drug-gene interactions, 29 clinical outcomes, 10 drug-induced side-effects, and 8 gene-disease interactions. HCLS2008 @ WWW2008

Querying the PGDKB Nortriptyline treatments for postural hypotension having drug interactions with the ABCB1 gene DrugTreatment that hasPart some (DrugInducedSideEffect that hasParticipant value PosturalHypotension) and hasParticipant value PA450657 and hasParticipant value ABCB1_3435_C Recommended nortriptyline dose for postural hypotension for CYP2D6 heterozygous individuals Dose that isParticipantIn some (DoseRecommendation that hasParticipant value CYP2D6_4 and hasParticipant value CYP2D6_6 and hasParticipant value PA450657) Protégé 4, FaCT++, DL Query Tab HCLS2008 @ WWW2008

Simplified pharmacogenomics / pharmacogenetics KR Conclusions Simplified pharmacogenomics / pharmacogenetics KR Reasoning-capable knowledge base for pharmacogenomics of depression Further extend for pharmacogenomics of other diseases Work with PharmGKB & SOPHARM HCLS2008 @ WWW2008

Michel Dumontier michel_dumontier@carleton.ca http://dumontierlab.com HCLS2008 @ WWW2008