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Toward semantic modeling of pharmacogenomic knowledge for clinical and translational decision support
 

Toward semantic modeling of pharmacogenomic knowledge for clinical and translational decision support

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A project update describing the semantic annotation of pharmacogenomics statements in drug product labeling. An innovative aspect of the work is the use of the W3C Open Annotation standard for ...

A project update describing the semantic annotation of pharmacogenomics statements in drug product labeling. An innovative aspect of the work is the use of the W3C Open Annotation standard for publishing semantic annotations.

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  • Manufacturers write recommendations into the product label In 2011 FDA introduced the “pharmacogenomics” section for detailed information [1] Other sections used to convey relevant information in summary form
  • Discuss the shortcomings of Structured Product Labels published by FDA

Toward semantic modeling of pharmacogenomic knowledge for clinical and translational decision support Toward semantic modeling of pharmacogenomic knowledge for clinical and translational decision support Presentation Transcript

  • Toward semantic modeling ofpharmacogenomic knowledgefor clinical and translationaldecision supportRichard Boyce*, University of PittsburghRobert Freimuth, Mayo ClinicKatrina M. Romagnoli, University of PittsburghTara Pummer, University of PittsburghHarry Hochheiser, University of PittsburghPhilip E. Empey, University of Pittsburgh 1 Biomedical InformaticsDepartment of Biomedical Informatics
  • Scenario• Lauren is a physician in an outpatient clinic. She receives a pharmacogenomics test result for one of her female patients.• The result states that the patient has the genotype CYP2D6*2X2.• Lauren wants to quickly know what the implications are for each drug that her patient is taking 2 Biomedical Informatics
  • What does she need to know?For each drug ?d taken by her patient,who carries the CYP2D6*2X2 genotype,what is the……potential impact – pharmacokinetic / pharmacodynamic...patient specific risk factors – Concomitant medications – Medical conditions…recommendations – dosage, drug administration, alternatives, monitoring, and tests 3 Biomedical Informatics
  • Where can she look?• Local clinical setting – Institution/clinic specific information – Likely to be very few in number• Scientific literature – CPIC and Dutch pharmacogenomics working group guidelines – High quality but may be infrequently updated – Available in PharmGKB, does she know that?• Product Labeling – Concise, clinically oriented information – Possibly the first place many clinicians look 4 Biomedical Informatics
  • This talk is going focus on productlabeling… 5 Biomedical Informatics
  • FDA’s goals for pharmacogenomicsand product labeling [1]“Inform prescribers about the impact,or lack of impact, of genotype onphenotype”“Indicate whether a genomic test isavailable and if so, whether testingshould be considered, recommended,or necessary.”1. FDA. Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical Studies. Rockville, MD: Federal Drug Administration; 2011. 6 Biomedical Informatics
  • The current status of pharmgxstatements in labeling• March 2013 [1]: – 38 biomarkers – 107 active ingredients • > 1000 products – 19 indications1. FDA. Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical Studies. Rockville, MD: Federal Drug Administration; 2011.2. FDA. Table of Pharmacogenomic Biomarkers in Drug Labels. 2012. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm. 7 Biomedical Informatics
  • Examples“For HLA-B*5701-positivepatients, initiating orreinitiating treatment with anabacavir-containing regimenis not recommended” 8 Biomedical Informatics
  • Examples “Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing.” 9 Biomedical Informatics
  • Examples“Patients with low or absentTPMT activity are at anincreased risk of developingsevere, life-threateningmyelotoxicity if receivingconventional doses ofazathioprine.” 10 Biomedical Informatics
  • Examples “There is no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrels active metabolite or its inhibition” 11 Biomedical Informatics
  • Problem statementPharmacogenomics knowledge written in productlabeling is important for clinical use cases andcomplements other resources.However, this knowledge is currentlyunstructured which presents barriers to itsefficient acquisition and use in the clinical setting 12 Biomedical Informatics
  • Our approach• Work with pharmacists to: – Develop a semantic model for pharmacogenomics statements – Train them on how to annotate the statements• Publish annotated statements using the Open Annotation standard [1]• Integrate the annotated statements with other sources of pharmgx information – an interactive prototype1. http://www.openannotation.org/spec/core/ 13 Biomedical Informatics
  • What is “Open Annotation” • An extensible and interoperable framework for expressing annotations [1]1. http://www.openannotation.org/spec/core/ 14 Biomedical Informatics
  • Open Data Annotation example “Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing.” ex:annotation-1 ex:body-1 ex:target-1 aboutPredicate Object Predicate Objectdrug CODEINE hasSource URL to product labelbiomarker CYP2D6 Exact-text “Nursing mothers…”variant Ultra-rapid Preceding- … metabolizer textPharmacokinetic Metabolism-increase Post-text …effectPharmacodynamic Drug-toxicity-risk-effect increase 15 Biomedical Informatics
  • Semantic model - descriptions 16 Biomedical Informatics
  • Description example “Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing.” ex:annotation-1 ex:body-1 ex:target-1 aboutPredicate Object Predicate Objectdrug CODEINE hasSource URL to product labelbiomarker CYP2D6 Exact-text “Nursing mothers…”variant Ultra-rapid Preceding- … metabolizer textPharmacokinetic Metabolism- Post-text …effect increasePharmacodynamic Drug-toxicity-risk-effect increase 17 Biomedical Informatics
  • Semantic model - recommendations 18 Biomedical Informatics
  • Recommendation example ““For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended” ex:annotation-1 ex:body-1 ex:target-1 aboutPredicate Object Predicate Objectdrug codeine hasSource URL to product labelbiomarker HLA-B*5701 Exact-text “For HLA-B*5701…”variant HLA-B*5701 Preceding- …drug-selection- do-not-restart textrecommendation Post-text … 19 Biomedical Informatics
  • Semantic model - references 20 Biomedical Informatics
  • Progress• Since September 2012: • Further annotation training • Improved agreement • Finalizing first-round annotations (~140) • Proof-of-concept dataset 21 Biomedical Informatics
  • Want more information?• Proof-of-concept: – Dataset (RDF/XML): http://goo.gl/Spd0p – Example queries: http://goo.gl/3pQ8q (under GRAPH: http://purl.org/net/nlprepository/spl-pharmgx-annotation-poc) – Integration with W3C Genomic-CDS: https://genomic- cds.googlecode.com/svn• Google code project – code.google.com/p/swat-4-med-safety/• Open Data Anotation – http://www.openannotation.org/spec/core/• Semantic Science Integrated Ontology – http://code.google.com/p/semanticscience/ 22 Biomedical Informatics
  • Acknowledgements• Agency for Healthcare Research and Quality (K12HS019461).• NIH/NCATS (KL2TR000146),• NIH/NIGMS (U19 GM61388; the Pharmacogenomic Research Network)• NIH/NLM (T15 LM007059-24) 23 Biomedical Informatics
  • Backup Slides 24 Biomedical Informatics
  • Structured Product Labels (SPLs)• All package inserts for currently marketed drugs are available in this format [1-3] 1. http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2005-N-0464-gdl.pdf 2. http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm 3. http://dailymed.nlm.nih.gov/dailymed/downloadLabels.cfm 25 Biomedical Informatics
  • More about SPLs 26 Biomedical Informatics