Toward semantic modeling ofpharmacogenomic knowledgefor clinical and translationaldecision supportRichard Boyce*, Universi...
Scenario• Lauren is a physician in an outpatient  clinic. She receives a pharmacogenomics  test result for one of her fema...
What does she need to know?For each drug ?d taken by her patient,who carries the CYP2D6*2X2 genotype,what is the……potentia...
Where can she look?• Local clinical setting  – Institution/clinic specific information  – Likely to be very few in number•...
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 genotyp...
The current status of pharmgxstatements in labeling• March 2013 [1]:      – 38 biomarkers      – 107 active ingredients   ...
Examples“For HLA-B*5701-positivepatients, initiating orreinitiating treatment with anabacavir-containing regimenis not rec...
Examples               “Nursing mothers who are               ultra-rapid metabolizers may               also experience o...
Examples“Patients with low or absentTPMT activity are at anincreased risk of developingsevere, life-threateningmyelotoxici...
Examples            “There is no relevant effect of            genetic variation in CYP2B6,            CYP2C9, CYP2C19, or...
Problem statementPharmacogenomics knowledge written in productlabeling is important for clinical use cases andcomplements ...
Our approach• Work with pharmacists to:    – Develop a semantic model for      pharmacogenomics statements    – Train them...
What is “Open Annotation”   • An extensible and interoperable     framework for expressing annotations     [1]1. http://ww...
Open Data Annotation example  “Nursing mothers who are ultra-rapid metabolizers may  also experience overdose symptoms suc...
Semantic model - descriptions                16       Biomedical Informatics
Description example  “Nursing mothers who are ultra-rapid metabolizers may  also experience overdose symptoms such as extr...
Semantic model - recommendations               18       Biomedical Informatics
Recommendation example  ““For HLA-B*5701-positive patients, initiating or reinitiating  treatment with an abacavir-contain...
Semantic model - references                20       Biomedical Informatics
Progress• Since September 2012:   • Further annotation training      • Improved agreement   • Finalizing first-round annot...
Want more information?• Proof-of-concept:   – Dataset (RDF/XML): http://goo.gl/Spd0p   – Example queries: http://goo.gl/3p...
Acknowledgements• Agency for Healthcare Research and  Quality (K12HS019461).• NIH/NCATS (KL2TR000146),• NIH/NIGMS (U19 GM6...
Backup Slides                24   Biomedical Informatics
Structured Product Labels (SPLs)• All package inserts for currently marketed  drugs are available in this format [1-3]    ...
More about SPLs                  26   Biomedical Informatics
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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 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

    1. 1. 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
    2. 2. 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
    3. 3. 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
    4. 4. 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
    5. 5. This talk is going focus on productlabeling… 5 Biomedical Informatics
    6. 6. 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
    7. 7. 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
    8. 8. Examples“For HLA-B*5701-positivepatients, initiating orreinitiating treatment with anabacavir-containing regimenis not recommended” 8 Biomedical Informatics
    9. 9. Examples “Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing.” 9 Biomedical Informatics
    10. 10. Examples“Patients with low or absentTPMT activity are at anincreased risk of developingsevere, life-threateningmyelotoxicity if receivingconventional doses ofazathioprine.” 10 Biomedical Informatics
    11. 11. 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
    12. 12. 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
    13. 13. 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
    14. 14. What is “Open Annotation” • An extensible and interoperable framework for expressing annotations [1]1. http://www.openannotation.org/spec/core/ 14 Biomedical Informatics
    15. 15. 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
    16. 16. Semantic model - descriptions 16 Biomedical Informatics
    17. 17. 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
    18. 18. Semantic model - recommendations 18 Biomedical Informatics
    19. 19. 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
    20. 20. Semantic model - references 20 Biomedical Informatics
    21. 21. Progress• Since September 2012: • Further annotation training • Improved agreement • Finalizing first-round annotations (~140) • Proof-of-concept dataset 21 Biomedical Informatics
    22. 22. 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
    23. 23. 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
    24. 24. Backup Slides 24 Biomedical Informatics
    25. 25. 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
    26. 26. More about SPLs 26 Biomedical Informatics
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