Acquiring and representing drug-drug interaction

knowledge and evidence Jodi Schneider and Richard D. Boyce

RWTH AachenFachgruppe Informatik - Knowledge-based Systems GroupAachen, DE2016-04-25

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MEDICATION SAFETY

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Prescribers check for known drug interactions.

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Prescribers consult drug compendia which are maintained by expert pharmacists.

Medscape EpocratesMicromedex 2.0

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Prescribers consult drug compendia which are maintained by expert pharmacists.

Medscape EpocratesMicromedex 2.0

Significant discrepancies on drug interactions!

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Problem

o Thousands of preventable medication errors occur each year.

o Clinicians rely on information in drug compendia (Physician’s Desk Reference, Medscape, Micromedex, Epocrates, …).

o Compendia have information quality problems:• differ significantly in their coverage, accuracy, and

agreement• often fail to provide essential management

recommendations about prescription drugs

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Problem

o Drug compendia synthesize drug interaction evidence into knowledge claims but:• Disagree on whether specific evidence items can

support or refute particular knowledge claims

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Problem

o Drug compendia synthesize drug interaction evidence into knowledge claims but:• Disagree on whether specific evidence items can

support or refute particular knowledge claims• May fail to include important evidence

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Silos: Multiple sources of information

Post-market studies

Reported in

Scientific literature

Pre-market studies Clinical experience

Drug product labels (US Food and Drug

Administration)

Reported in

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“Addressing gaps in clinically useful evidence on drug-drug interactions”

4-year project, U.S. National Library of Medicine R01 grant (PI, Richard Boyce; R01LM011838)o Evidence panel of domain experts: Carol

Collins, Amy Grizzle, Lisa Hines, John R Horn, Phil Empey, Dan Malone

o Informaticists: Jodi Schneider, Harry Hochheiser, Katrina Romagnoli, Samuel Rosko

o Ontologists: Mathias Brochhausen, Bill Hogano Programmers: Yifan Ning, Wen Zhang, Louisa

Zhang

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Goals

o Long-term, provide drug compendia editors with better information and better tools, to create the information clinicians use.

o This talk focuses on how we might efficiently acquire and represent • Knowledge claims about medication safety• And their supporting evidence• In a standard computable format.

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MEDICATION SAFETY DOMAIN

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Existing approaches: RepresentationBradford-Hill criteria (1965)

1. Strength2. Consistency3. Specificity4. Temporality5. Biological gradient6. Plausibility7. Coherence

[Bradford-Hill A. The Environment and Disease: Association or Causation?. Proc R Soc Med. 1965;58:295-300.]

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Existing approaches: Representation

[Horn, J. R., Hansten, P. D., & Chan, L. N. (2007). Proposal for a new tool to evaluate drug interaction cases. Annals of Pharmacotherapy, 41(4), 674-680.]

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Existing approaches: Representation

1. Are there previous credible reports in humans?• If there are case reports or prospective studies that clearly provide

evidence supporting the interaction, answer YES. For case reports, at least one case should have a “possible” DIPS rating (score of 2 or higher).  

• If a study appropriately designed to test for the interaction shows no evidence of an interaction, answer NO.

…5. Did the interaction remit upon de-challenge of the precipitant drug with no change in the object drug?  (if no de-challenge, use Unknown or NA and skip Question 6)• Stopping the precipitant drug should bring about resolution of the

interaction, even if the object drug is continued without change. …• If dechallenge of the precipitant drug without a change in object

drug did not result in remission of the interaction, answer NO.• If no dechallenge occurred, the doses of both drugs were altered,

or no information on dechallenge is provided, answer NA.[Horn et al. 2007] 15

Existing approaches: RepresentationRoyal Dutch Association for the Advancement of Pharmacy (2005)

1. Existence & quality of evidence on the interaction2. Clinical relevance of the potential adverse

reaction resulting from the interaction3. Risk factors identifying patient, medication or

disease characteristics for which the interaction is of special importance

4. The incidence of the adverse reaction

[Van Roon, E.N. et al: Clinical relevance of drug-drug interactions: a structured assessment procedure. Drug Saf. 2005;28(12):1131-9.]

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Existing approaches: Representation

Boyce, DIKB, 2006-present 17

Existing approaches: Acquisition

o Evidence

18Boyce, DIKB, circa 2006

EXAMPLE

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[Hu et al. 2011] 21

22[Hu et al. 2011]

23[Hu et al. 2011]

24[Hu et al. 2011]

[Boyce, DIKB, 2006-present] 25

[Boyce, DIKB, 2006-present] 26

DESIGNING AN EVIDENCE BASE

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Multiple layers of evidence

Medication Safety Studies

Layer

Clinical Studies and Experiments

Scientific Evidence Layer

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[Brochhausen, Schneider, Malone, Empey, Hogan and Boyce “Towards a foundational representation of potential drug-drug interaction knowledge.” First International Workshop on Drug Interaction Knowledge Representation (DIKR-2014) at ICBO.] 29

SCIENTIFIC EVIDENCE LAYER

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Scientific Evidence Layer: Micropublications

[Clark, Ciccarese, Goble (2014) Micropublications: a semantic model for claims, evidence, arguments and annotations in biomedical communications.] 31

Scientific Evidence Layer: Micropublications

[Clark, Ciccarese, Goble (2014) Micropublications: a semantic model for claims, evidence, arguments and annotations in biomedical communications] 32

MODELING NARRATIVE DOCUMENTS AS EVIDENCE

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MP:Claim

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Building up an MP graph

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Building up an MP graph

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Building up an MP graph

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Building up an MP graph

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Building up an MP graph

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Building up an MP graph

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Building up an MP graph

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Building up an MP graph

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Building up an MP graph

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Medication Safety Studies Layer: DIDEO

Brochhausen et al, work in progress, example of Clinical Trial47

DIDEO: Drug-drug Interaction and Drug-drug Interaction Evidence Ontology

https://github.com/DIDEO 48

Definitions

o Drug-drug interaction• A biological process that results in a clinically

meaningful change to the response of at least one co-administrated drug.

o Potential drug-drug interaction• POSSIBILITY of a drug-drug interaction• Data from a clinical/physiological study OR

reasonable extrapolation about drug-drug interaction mechanisms

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HAND ANNOTATION TO CREATE THE EVIDENCE BASE

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Hand-extracting claims and evidence

o Sources• Primary research literature• Case reports• FDA-approved drug labels

o Process• Spreadsheets• PDF annotation

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Work to date

o 410 assertions and 519 evidence items transformed from prior work.

o 609 evidence items (pharmacokinetic potential drug-drug interactions) annotated by hand from 27 FDA-approved drug labels.

o 230 assertions of drug-drug interactions annotated by hand from 158 non-regulatory documents, including full text research articles.

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DIRECTIONS & FUTURE WORK

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We are developing a search/retrieval portal It will:o Integrate across multiple types of source

materials (FDA drug labels, scientific literature, …)

o Systematize search: Enable ALL drug compendium editors to access the same info

o Provide direct access to source materials• E.g. quotes in context

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Quotes in context!

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Evaluation plan for the search/retrieval portalo 20-person user studyo Measures of

• Completeness of information• Level of agreement• Time required• Perceived ease of use

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Generate multiple KBs from the same EB

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Evidence modeling & curation

o Analogous processes could be used in other fields: evidence modeling & curation is a general process.

o Biomedical curation is most mature: structured nature of the evidence interpretation, existing ontologies, trained curators, information extraction and natural language processing pipelines

o Curation pipelines need to be designed with stakeholders in mind.

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Thanks to collaborators & funderso Training grant T15LM007059 from the

National Library of Medicine and the National Institute of Dental and Craniofacial Research

o The entire “Addressing gaps in clinically useful evidence on drug-drug interactions” team from U.S. National Library of Medicine R01 grant (PI, Richard Boyce; R01LM011838) and other collaborators

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Jodi Schneider, Mathias Brochhausen, Samuel Rosko, Paolo Ciccarese, William R. Hogan, Daniel Malone, Yifan Ning, Tim Clark and Richard D. Boyce. “Formalizing knowledge and evidence about potential drug-drug interactions.” International Workshop on Biomedical Data Mining, Modeling, and Semantic Integration: A Promising Approach to Solving Unmet Medical Needs (BDM2I 2015) at ISWC 2015 Bethlehem, Pennsylvania, USA.

Jodi Schneider, Paolo Ciccarese, Tim Clark and Richard D. Boyce. “Using the Micropublications ontology and the Open Annotation Data Model to represent evidence within a drug-drug interaction knowledge base .” 4th Workshop on Linked Science 2014—Making Sense Out of Data (LISC2014) at ISWC 2014 Riva de Garda, Italy.

Mathias Brochhausen, Jodi Schneider, Daniel Malone, Philip E. Empey, William R. Hogan and Richard D. Boyce “Towards a foundational representation of potential drug-drug interaction knowledge .” First International Workshop on Drug Interaction Knowledge Representation (DIKR-2014) at the International Conference on Biomedical Ontologies (ICBO 2014) Houston, Texas, USA.

Richard D. Boyce, John Horn, Oktie Hassanzadeh, Anita de Waard, Jodi Schneider, Joanne S. Luciano, Majid Rastegar-Mojarad, Maria Liakata, “Dynamic Enhancement of Drug Product Labels to Support Drug Safety, Efficacy, and Effectiveness.” Journal of Biomedical Semantics. 4(5), 2013. doi:10.1186/2041-1480-4-5

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Other Implications

o Implications for ontology development.o Implications for improving medication safety.

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o What arguments are used in medication safety?

o How can these arguments be mined/identified?

o What work needs to be done?

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Why is a new data model needed?o Need computer integrationo Want a COMPUTABLE model that can make

inferences

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