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Biomedical Informatics 1 Expanding the SPL Model Beyond Indexing to Include Annotations Richard D. Boyce, PhD University of Pittsburgh 2014 DailyMed Jamboree Public Workshop September, 18 th 2014 Department of Biomedical Informatics

Pharmacogenomics annotation in drug structured product labeling for clinical decision support

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Prof. Boyce presents work on a semantic model for clinical pharmacogenomics statements in structured product labeling (SPLs) and how it can be integrated into clinical decision support. See a video of the talk starting at 32:04 at the following link: http://videocast.nih.gov/summary.asp?Live=14776&bhcp=1

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Page 1: Pharmacogenomics annotation in drug structured product labeling for clinical decision support

Biomedical Informatics1

Expanding the SPL Model Beyond Indexing to Include Annotations

Richard D. Boyce, PhD University of Pittsburgh

2014 DailyMed Jamboree Public WorkshopSeptember, 18th 2014

Department of Biomedical Informatics

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What is annotation?• “Annotation” involves turning unstructured

text descriptions into a normalized data structure– Different from “indexing” which simply tags

mentioned entities

“Drug X indicated for condition Y”– Indexing: tags Drug X and Condition Y to aid

information retrieval • does not retain the relationship “indicated for”

– Annotation: retains the relationship

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“Take home” point• Annotation of specific content written into

SPLs will enable innovative downstream uses– Decision support

– Drug safety

– Drug discovery / repositioning

• Pharmacogenomics will be used as a case study– Other potentially relevant kinds of information

exist

• drug-drug interactions, adverse drug reactions

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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.pdf2. http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm3. http://dailymed.nlm.nih.gov/dailymed/downloadLabels.cfm

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NLM DailyMedSPL database

Pharma contributes

SPLs to FDA

Active and inactive ingredients

Represented organization

Route of administration

SPL identification (setid, version, effective date)

Names (trade name and generic)

LOINC-coded sections

Clinical Studies

Boxed Warnings

Clinical pharmacology

Drug interactions

Adverse Reactions

…other sections…

FDA indexing(pharmacologic class and billing

unit)

Unstructured textand HTML tables

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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 HLA-B*5701

• Lauren wants to quickly know what the implications are for each drug that her patient is taking

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What does she need to know?For each drug ?d taken by her patient, who carries the HLA-B*5701 genotype, what is the… …potential impact

– pharmacokinetic / pharmacodynamic

...patient specific risk factors– Concomitant medications

– Medical conditions

…recommendations– dosage, drug administration, alternatives,

monitoring, and tests

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FDA’s goals for pharmacogenomics and product labeling [1]

“Inform prescribers about the impact, or lack of impact, of genotype on phenotype”

“Indicate whether a genomic test is available and if so, whether testing should be considered, recommended, or necessary.”1. FDA. Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical Studies.

Rockville, MD: Federal Drug Administration; 2011.

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Example label pharmgx statements

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The current status of pharmgx statements in labeling• August 18, 2014 [1]:

– 138 drugs, 43 biomarkers

– 11 drug/biomarker pairs with boxed warning or warning and precaution mentions

– 19 drug therapeutic areas

1. FDA. Table of Pharmacogenomic Biomarkers in Drug Labels. 2014. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm. Last accessed 09/15/2014

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Pharmgx information within SPLs

Unstructured text statements in various sections

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Finding label pharmgx information (current)

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

Four clicks from here to a PDF version of the label

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Annotation vs indexing

• The FDA biomarker table basically indexes pharmacogenomics information – This information could be provided as

supplementary SPL files

– Some basic kinds of queries would be supported• But, many clinician use cases would not be met

• What about extending the SPL to include annotations?

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Expanding SPLs to include annotationsThe Open Annotation (OA) Data model: An extensible and interoperable framework for annotations [1]

1. http://www.openannotation.org/spec/core/

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Example pharmgx recommendation

Predicate Object

drug abacavir

biomarker HLA-B*5701

drug-selection-recommendation

do-not-restart

Predicate Object

hasSource URL to product label

Exact-text “For HLA-B*5701…”

Preceding-text

Post-text …

ex:body-1 ex:target-1

ex:annotation-1

about

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One annotation for many labels

Once created, annotations can be rendered in an OA client for any label where the statement is written the same way.

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More on the general annotation model

Predicate Object

drug abacavir

biomarker HLA-B*5701

drug-selection-recommendation

do-not-restart

Predicate Object

hasSource URL to product label

Exact-text “For HLA-B*5701…”

Preceding-text

Post-text …

ex:body-1 ex:target-1

ex:annotation-1

about

The use of standard terminologies enables interoperability

Text selection is not dependent on a specific document

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Our multidisciplinary approach• Work with pharmacists to:

– Understand their information needs

– Develop a semantic model for pharmacogenomics statements

– Train them on how to annotate the statements• using a custom plugin for a web annotation tool

(Domeo [1])

• Develop a prototype decision support tool [2]

1. Ciccarese P, Ocana M, Clark T. Open semantic annotation of scientific publications using DOMEO. J Biomed Semantics. 2012 Apr 24;3 Suppl 1:S1. doi: 10.1186/2041-1480-3-S1-S1.

2. Boyce, RD., Freimuth, RR., Romagnoli, KM., Pummer, T., Hochheiser, H., Empey, PE. Toward semantic modeling of pharmacogenomic knowledge for clinical and translational decision support. AMIA Summits Transl Sci Proc. Mar 18 2013:28-32. PMCID: PMC3814496

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Progress• Semi-structured interviews

– 14 completed with different types of pharmacists

– Their information needs are informing a prototype

• Pharmacist annotations on labels for 16 drugs– To date 8 pharmacist have participated

– Consensus annotations completed for 10 drugs

• Annotations published as an annotation web service– in OA at the “LinkedSPLs” RDF endpoint

– more to say about this later today

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Revisiting how to find label pharmgx information

Video of the concept: https://www.youtube.com/watch?v=Te546vOiruo

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Video of the concept: https://www.youtube.com/watch?v=Te546vOiruo

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Video of the concept: https://www.youtube.com/watch?v=Te546vOiruo

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Some lessons learned while annotating• Which labels to annotate?

– Innovator labels chosen. Further work needed to determine consistency of content across labels

• Tables should also be annotated– e.g., warfarin dosing

• Some annotations are actually on dynamically generated sections– the "Highlights" section is generated by an SPL

stylesheet

– We decided to annotate within the text and code special (42229-5 SPL UNCLASSIFIED SECTION)

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Future work• Determining the stability of

annotations – across labels

– over time

• Task based usability studies– How well are information needs being

met

– What problems do clinicians have with understanding the information

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Want more information?• Proof-of-concept:

– https://www.youtube.com/watch?v=Te546vOiruo

• Code project– LinkedSPLs : https://code.google.com/p/swat-4-med-safety/

– Domeo Pharmgx and drug-drug interaction plugins: https://github.com/rkboyce/DomeoClient

• Open Data Anotation– http://www.openannotation.org/spec/core/

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Research Team

University of Pittsburgh Department of Biomedical Informatics:•Harry Hochheiser, Katrina M. Romagnoli, Yifan Ning, Andres Hernandez

University of Pittsburgh School of Pharmacy •Philip E. Empey, Solomon Adams

Harvard/Mass General (Domeo and the OA standard)•Paolo Ciccarese, Tim Clark

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Acknowledgements• Annotators (U of Pitt School of Pharmacy):

– Solomon Adams, Allison Doherty, Jocelyn Hatfield, Alex R. Cockerham, Linda Huang, Michael Diduch, William Wilson, Fengyee Zhou

• Grant funding for the research:– National Library of Medicine (R01LM011838-01), The National

Institute of Aging (K01 AG044433-01), NIH/NCATS (KL2TR000146), NIH/NIGMS (U19 GM61388; the Pharmacogenomic Research Network), NIH/NLM (T15 LM007059-24)

– Fogarty International Center of Global Health of the National Institutes of Health under the grant No. 1D43TW008443-0

– Agency for Healthcare Research and Quality (K12HS019461).

– U of Pitt Institute for Personalized Medicine (PreCISE-Rx: Pharmacogenomics-guided Care to Improve the Safety and Effectiveness of Medications)

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Discussion/questions