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Jon D. Duke, MD NLM Medical Informatics Fellow Regenstrief Institute Indiana University

Illuminating the Fine Print: Visualizing Medication Side-Effects in Complex Multi-drug Regimens. Jon D. Duke, MD NLM Medical Informatics Fellow Regenstrief Institute Indiana University. The QuARK Project. Quantitative Adverse R eaction Knowledgebase. The Tao of QuARK. The Concept

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Jon D. Duke, MD NLM Medical Informatics Fellow Regenstrief Institute Indiana University

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  1. Illuminating the Fine Print: Visualizing Medication Side-Effects in Complex Multi-drug Regimens Jon D. Duke, MD NLM Medical Informatics Fellow RegenstriefInstitute Indiana University

  2. The QuARK Project Quantitative Adverse Reaction Knowledgebase

  3. The Tao of QuARK • The Concept • Building the Knowledgebase • Clinical Applications • Testing the Model • Future Directions and Research QuARK: Quantitative Adverse Reactions Knowledgebase

  4. Part I:The Concept

  5. QuARK: What is it good for? The primary goal of QuARK is to simplify the process of assessing adverse drug reactions in patients taking multiple medications. QuARK: Quantitative Adverse Reactions Knowledgebase

  6. Polypharmacy

  7. Polypharmacy Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;287: 337-44.

  8. Polypharmacy • Has increased significantly over past 20 years • Increases risk for adverse drug reactions • Known risk factor for overall morbidity and mortality • Estimated cost $76B annually 1 2 1 3 Hajjar ER, Cafiero AC, Hanlon JT. Polypharmacy in elderly patients. Am J GeriatrPharmacother 2007;5: 345-51. 2. Nguyen JK, Fouts MM, Kotabe SE, Lo E. Polypharmacy as a risk factor for adverse drug reactions in geriatric nursing home residents. Am J GeriatrPharmacother 2006;4: 36-41. 3. Tam-McDevitt J. Polypharmacy, Aging, and Cancer: Growing Risks. Oncology 2008;9.

  9. Side-Effect Complexity

  10. X Number of Drugs SE Complexity Physician Time = The Problem

  11. Side-Effects Interactions

  12. Current Solutions

  13. Goals • Look up multiple medications simultaneously • Rapidly get to side-effect of interest • Show the relative strength of association between a drug and its side-effects • Well-integrated into clinical workflow

  14. Origins of QuARK

  15. Hmmmmm…. Zocor Metformin Norvasc Lisinoprol/HCTZ Azithromycin Nausea Dizziness Edema Fatigue Cough Palpitations

  16. Part II:Building the Knowledgebase

  17. Which Medications to Include? • By prescribing volume • By formulary QuARK Wishard Top 500 Clarian Top 500 U.S. Top 300

  18. Coding the Medications • RxNorm • UNI • NDC • Regenstrief Dictionary QuARK RI Dictionary RxNorm

  19. Sources of Adverse Reaction Data • FDA Label • MedWatch / AERS • Clinical Repository (eg. RMRS) • Social Networks (eg. patientslikeme.com) QuARK FDA Label

  20. Coding the Side-Effects • MedDRA • CTCAE • SNOMED-CT • ICD-9 • UMLS CUI QuARK MedDRA UMLS CUI SNOMED-CT

  21. Which Side-Effects to Include? Must select a singleunique representation of each medication / side-effect pair

  22. Which Side-Effect Data to Include? • Which treatment indication? • Which dose? • Which trial duration? • Pre- / Post-marketing data? QuARK If duplicate data: Most common indication preferred Aggregate dose data preferred, otherwise most common dose Larger trials with longer duration preferred Post-marketing data included if not present in trials

  23. Side-Effect Quantification The assignment of a numericscore to represent the relative frequency at which a particular medication causes a particular side-effect.

  24. Types of Frequency Data • Drug vs Placebo • 34% of Neurontin patients experienced nausea vs 12% of placebo patients • Frequency Range • Between 3% and 9% of patients taking Lipitor experienced dizziness • Qualitative Frequency Descriptor • Diarrhea occurredinfrequently in patients taking Lisinopril • Statement of Occurrence • Thrombocytopenia was reported in patients taking Norvasc.

  25. Drug vs Placebo eg. 34% of Neurontin pts experienced nausea vs 12% of placebo pts • Optimal data format • Applied “Absolute Risk Reduction” approach (ie. treatment incidence – placebo incidence) • ex. Score = 34 - 12 = 22 • Database would include both the original raw data in addition to the calculated score QuARK Drug vs Placebo Score = Treatment Incidence - Placebo Incidence

  26. Frequency Range eg. Between 3% and 9% of Lipitor patients experienced dizziness • No placebo data given • Study size and duration not available • Patient population unknown • Conservative score calculation: Score = x+(y-x)/3 = 3+(9-3)/3 = 5 • Original data range preserved in database QuARK Frequency Range Scoring Between X% and Y% of patients taking {drug} experienced {effect} Score = X+(Y-X)/3

  27. Qualitative Frequency Descriptor • eg. Diarrhea occurred infrequently in patients taking Lisinopril • No placebo or population data • Wide range of terms used (eg. rarely, occasionally, often) • Quantitative mappings may be provided (Rarely = “< 1/100”) • Where mappings unavailable, conservative scores assigned based on interpretation of terms (sometimes = occasionally > infrequently) QuARK Qualitative Scoring Occasionally 0.75 Infrequently 0.5 Rarely 0.3

  28. Statement of Occurrence • eg. Thrombocytopenia was reported in patients taking Norvasc. • No frequency information • No placebo or population data • Commonly seen with post-marketing reports or class effects • Conservative scoring applied • “Post-Marketing” status noted in database QuARK Occurrence Scoring Occurs in drug 0.8 Occurs in class 0.7 Occurs more often in placebo 0.1

  29. QuARK Part III:Applications

  30. Rxplore • Interactive visualization of QuARK data • Allows quick retrieval of most common side-effects of complex drug regimens • Highlights potential causal agents in the setting of an adverse drug event • Allows “virtual swapping” of a medication to assess impact on patient’s side-effect profile

  31. QuARK & Gopher • Goal: Allow QuARK visualizations to be retrieved directly from Gopher order entry • Created prototype running on Gopher Dev • Auto-populates medication list directly from Gopher patient chart

  32. QuARK Bubble Map

  33. Medication Heat Map Adverse Effects by Organ System Dizziness 24% vs 3% Headache 11% vs 2% Insomnia 6% vs 3% Diazepam Highly Affected Minimally Affected

  34. QuARK & Clinical Reminders • Chief Complaint-driven • Trigger Event-driven

  35. QuARK & Clinical Reminders • Chief Complaint-driven • Which of a patient’s medications are associated with the Chief Complaint? • At what frequency? “ The patient’s complaint of Dizziness has been associated with use of: Gabapentin (28% vs. 7% Placebo) Atenolol (13% vs 6% Placebo) Omeprazole (Less than 1%) ”

  36. QuARK & Clinical Reminders • Trigger Event-driven • Laboratory / EKG change generates reminder • Offers suggestions for possible causal agents “ Neutropenia (WBC 1.4 10/22/08) has been associated with use of: Valsartan (1.9% vs 0.8% placebo) Amiodarone (Has been reported) Lisinopril (Occurs rarely) ”

  37. QuARK Part IV: Testing the Model

  38. Garbage In / Garbage Out? • Limitations of the Data • Algorithmic Considerations • Does a Gold Standard exist? • An Approach to Validation

  39. Comparison with AERS • Adverse Event Reporting System • Captures over 400,000 reports a year • Allows for listing of multiple medications • Records Adverse Reaction and Suspected Cause • Subset includes “Dechallenge” Data

  40. QuARKvs AERS • Dechallenge data from 2008 Q2 • Evaluated reports of four common reactions (nausea, edema, insomnia, hyponatremia ) • Limited to cases where patient was taking at least 5 medications • Compared the QuARK “suspected drug” with actual reported cause

  41. Accuracy of QuARK Ranking for AERS Reports Q2 2008 % Accuracy n=21 n=14 n=25 n=31 Reported Adverse Reaction

  42. Sources of Error • <10% missed cases due to algorithm error • >90% missed cases due to complete absence of the adverse reaction from the drug label • Delays in drug label updating • Reflects nature of adverse event reporting • Known side-effects often not reported • New drug mandatory reporting predominates AERS

  43. QuARK Part V:Future Directions and Research

  44. Evaluation Studies • Laboratory study of “decision velocity” • Survey of User Satisfaction / Efficiency

  45. Clinical Reminder Study • Generate QuARK-based reminders for laboratory triggers (eg. LFT’s) • Intervention group receives reminder noting potential causal agents / frequency data • Compare drug discontinuation rates as well as time between trigger and discontinuation

  46. Build a Better QuARK • Additional medications • Expansion of AERS-QuARK analysis • Optimization of scoring algorithm • Additional visualization methods • Potential use in consumer health

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