1. Modeling the pharmacogenomics of depression
Michel Dumontier, Muhammad Faizan,
Joseph Obeng, Natalia Villanueva-Rosales
Carleton University
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2. “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
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4. 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
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5. +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
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6. 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: classes, 189 properties
- Very expensive to reason with
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7. Pharmacogenomics Ontology: simpler knowledge representation
Pharmacogenomics of Depression: explicit knowledge representation
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8. 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.
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9. 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?
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10. 2a SEVEN ESSENTIAL CONCEPTS (out of 20)
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11. 2b N-ARY MODELING
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12. 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
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13. 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.
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14. 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
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15. 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.
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16. 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 PA 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
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17. 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
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18. Michel Dumontier michel_dumontier@carleton.ca http://dumontierlab.com
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