Modeling the pharmacogenomics of depression

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Modeling the pharmacogenomics of depression

• Michel Dumontier, Muhammad Faizan,
• Joseph Obeng, Natalia Villanueva-Rosales
• Carleton University

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• 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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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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• 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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• 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

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• Pharmacogenomics Ontology simpler knowledge
  representation
• Pharmacogenomics of Depression explicit
  knowledge representation

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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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• 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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• 2a SEVEN ESSENTIAL CONCEPTS (out of 20)

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2b N-ARY MODELING
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3 ONTOLOGY

• English name (rdfslabel)
• Clear and precise definition (rdfscomment).
• 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 SOPHARMs measures
• - differences in values different from values

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5 RELATIONS

• 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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• 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 14
WatsonStrand 14
Frequency 847
DatabaseSource 1
Total 4266
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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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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
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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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Michel Dumontier

• michel_dumontier_at_carleton.ca
• http//dumontierlab.com