Challenges Representing Phenotype in Pharmacogenomics
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Transcript of Challenges Representing Phenotype in Pharmacogenomics
Challenges Representing Phenotype in Pharmacogenomics
Tina Hernandez-Boussard
PharmGKB
www.pharmGkB.org
PharmacogenomicsUnderstanding how genetic
variation leads to variation in responses to drugs
A promise from the Genome Project
Personalized Medicine– Making drug use effective and safe
based on a person’s specific genotype
Pharmacogenomics Flow
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PharmGKB: Capturing knowledge to Capturing knowledge to to catalyze pharmacogenomics researchto catalyze pharmacogenomics research
PharmGKB Core Contents
Mission: aggregate, integrate & annotate pharmacogenomic data and knowledge
PharmGKB Knowledge
VIPs– Structured textual summaries of Very Important
Pharmacogenes and their key variants Pathways
– Graphical pathway representations built by consensus, associated with literature evidence and links to PharmGKB genes, drugs, phenotypes.
Literature Annotations– PharmGKB curators create data entries that
associate genes with drugs and phenotypes, based on an interpretation of the literature. They encode with controlled vocabularies.
Genetic Variation Complexity Genetic variation and its relation to proteins is
complicated “Gene” exists in the genome “Gene variations” specify the existence of
polymorphism:– E.g. “There is A/C SNP at Golden Path X.”– Haplotype variations = collection of simple variations
“Gene alleles” are specific variation options– E.g. “One allele of the A/C SNP is A at GP X…”– Haplotype alleles = collection of simple alleles
Genotypes are diploid alleles = “diplotypes” ASSOCIATIONS can be described to all of
these
Genotype-Phenotype Relations
Knowledge about gene-drug-pheno interactions comes at different levels of granularity:1. Product of Gene X interacts with Drug Y (in pheno
Z)--in a physical sense
2. Variant of Gene X makes a difference in pheno Z for Drug Y--in an association sense (can also be a physical interaction, but that is with product)
3. Specific Allele of Variant of Gene X has a particular effect on pheno Z for Drug Y--also in an association sense
Mosaic Challenge: Throughput & Redundancy Limited curatorial staff has many duties Need methods to quickly identify
important knowledge and capture it in computable form ONCE for multiple uses
With computable knowledge, can generate displays appropriate for user interests: pathways, VIP summaries, literature summaries.
Goals for Representing Knowledge in PharmGKB
Common platform for entering & curating Pharmacogenomic knowledge = Protégé-based– Pathways– Very important pharmacogenes + variants– Gene+variant-drug-phenotype associations
Structured entry for computability– Standard vocabularies– Automated linkages to existing data
• Genes, drugs, external resources
– Clear semantics Extensible
– Usable SOON– Expandable ALWAYS
Vocabularies Currently Used HGNC for genes
– Gene families? MEDDRA for adverse events
– Medical dictionary MESH for disease, symptoms
– Vocabulary Gene Ontology for cellular location, molecular
function, cellular biological process ASSUMESASSUMES:
– Cell type vocabulary (MESH for now)– chemical & drug vocabulary (MESH for now)
• Switch to chEBI for chemicals?• Building drug dictionary @ PharmGKB
Knowledge Templates
Ingredients– Controlled vocabulary of objects– Logical representation of relationships– Statement of key “slots” to be filled using objects,
according to logic. EXAMPLE: Pathway Knowledge
– Pathway Overview template, points to “Steps”– Pathway Step templates for
• Metabolism step (PK)• Transport step (PK)• Inhibition step (PD!)• Downstream phenotype step (PK & PD)
Sample metabolism step
Sample Drug Interaction
Sample Phenotype Association
Conclusions PharmGKB integrates, aggregates and
annotates data and knowledge to serve the PGx research community
Deep, high quality genotype data Phenotype data--mostly small studies, some
large ones in the pipeline. Knowledge services include literature
curations, pathways, VIP gene summaries Research efforts focus on creating pipeline to
improve efficiency and precision of curated information
PharmGKB Team
Questions? Thanks.