Illuminating the Fine Print: Visualizing Medication Side-Effects in Complex Multi-drug
Regimens
Jon D. Duke, MDNLM Medical Informatics Fellow
Regenstrief InstituteIndiana University
The QuARK Project
Quantitative Adverse Reaction Knowledgebase
The Tao of QuARK
• The Concept• Building the
Knowledgebase• Clinical Applications• Testing the Model• Future Directions and
Research
QuARK: Quantitative Adverse Reactions Knowledgebase
Part I:The Concept
The primary goal of QuARK is to simplify the process of assessing
adverse drug reactions in patients taking multiple medications.
QuARK: What is it good for?
QuARK: Quantitative Adverse Reactions Knowledgebase
Polypharmacy
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.
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. Hajjar ER, Cafiero AC, Hanlon JT. Polypharmacy in elderly patients. Am J Geriatr Pharmacother 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 Geriatr Pharmacother 2006;4: 36-41.3. Tam-McDevitt J. Polypharmacy, Aging, and Cancer: Growing Risks. Oncology 2008;9.
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Side-Effect Complexity
Number of Drugs SE ComplexityX
Physician Time
= The Problem
Side-Effects Interactions
Current Solutions
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
Origins of QuARK
Hmmmmm….
Zocor
Metformin
Norvasc
Lisinoprol/HCTZ
Azithromycin
Nausea Dizziness Edema Fatigue Cough Palpitations
Part II:Building the Knowledgebase
Which Medications to Include?
• By prescribing volume• By formulary
QuARK
Wishard Top 500Clarian Top 500U.S. Top 300
Coding the Medications
• RxNorm• UNI• NDC• Regenstrief Dictionary
QuARK
RI Dictionary
RxNorm
Sources of Adverse Reaction Data
• FDA Label• MedWatch / AERS• Clinical Repository (eg. RMRS)• Social Networks (eg. patientslikeme.com)
QuARK
FDA Label
Coding the Side-Effects
• MedDRA• CTCAE• SNOMED-CT• ICD-9• UMLS CUI
QuARK
MedDRA
UMLS CUI
SNOMED-CT
Which Side-Effects to Include?
Must select a single unique representation of each
medication / side-effect pair
Which Side-Effect Data to Include?
• Which treatment indication?• Which dose?• Which trial duration?• Pre- / Post-marketing data?
QuARK
Most common indication preferred
Aggregate dosedata preferred, otherwise mostcommon dose
Larger trials withlonger durationpreferred
If duplicate data:
Post-marketingdata included ifnot present in trials
Side-Effect Quantification
The assignment of a numeric score to represent the relative frequency at which a particular medication causes a particular side-effect.
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 occurred infrequently in patients taking Lisinopril
• Statement of Occurrence– Thrombocytopenia was reported in patients taking Norvasc.
Drug vs Placebo
• 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
eg. 34% of Neurontin pts experienced nausea vs 12% of placebo pts
Frequency Range
• 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
eg. Between 3% and 9% of Lipitor patients experienced dizziness
Frequency RangeScoring
Between X% and Y% of patients taking {drug} experienced
{effect}
Score =X+(Y-X)/3
Qualitative Frequency Descriptor
• 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
eg. Diarrhea occurred infrequently in patients taking Lisinopril
QualitativeScoring
Occasionally 0.75Infrequently 0.5Rarely 0.3
Statement of Occurrence
• 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
eg. Thrombocytopenia was reported in patients taking Norvasc.
OccurrenceScoring
Occurs in drug 0.8
Occurs in class 0.7
Occurs more often in placebo 0.1
RI Term IngredientName Effect Drug Placebo Score Code18175 Sertraline HCl Nausea 25 11 14 CALC18175 Sertraline HCl Ejaculation Disorders 14 1 13 CALC18175 Sertraline HCl Diarrhea 20 10 10 CALC18175 Sertraline HCl Insomnia 21 11 10 CALC18175 Sertraline HCl Dry Mouth 14 8 6 CALC18175 Sertraline HCl Nervousness 6 0 6 CALC18175 Sertraline HCl Somnolence 13 7 6 CALC18175 Sertraline HCl Tremor 8 2 6 CALC18175 Sertraline HCl Dizziness 12 7 5 CALC18175 Sertraline HCl Fatigue 12 7 5 CALC18175 Sertraline HCl Dyspepsia 8 4 4 CALC18175 Sertraline HCl Decreased Libido 6 2 4 CALC18175 Sertraline HCl Anorexia 6 2 4 CALC18175 Sertraline HCl Flatulence 3 0 3 CALC18175 Sertraline HCl Paresthesias 3 0 3 CALC18175 Sertraline HCl Vomiting 4 2 2 CALC18175 Sertraline HCl Suicidal Ideation 4 2 2 CALC18175 Sertraline HCl Flushing 2 0 2 CALC18175 Sertraline HCl Headache 25 23 2 CALC18175 Sertraline HCl Agitation 5 3 2 CALC
QuARK Part III:Applications
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
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
QuARK Bubble Map
Medication Heat MapAdverse Effects by Organ System Dizziness 24% vs 3%
Headache 11% vs 2%Insomnia 6% vs 3%
Highly Affected
Minimally Affected
Diazepam
QuARK & Clinical Reminders
• Chief Complaint-driven• Trigger Event-driven
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%) ”
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) ”
QuARK Part IV:Testing the Model
Garbage In / Garbage Out?
• Limitations of the Data• Algorithmic Considerations• Does a Gold Standard exist?• An Approach to Validation
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
QuARK vs 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
Nausea Edema Insomnia Hyponatremia0
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20
30
40
50
60
70
80
90
Exact MatchTop Two%
Acc
urac
y
Reported Adverse Reaction
Accuracy of QuARK Ranking for AERS Reports Q2 2008
n=31 n=21 n=14 n=25
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
QuARK Part V:Future Directions and Research
Evaluation Studies
• Laboratory study of “decision velocity”• Survey of User Satisfaction / Efficiency
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
Build a Better QuARK
• Additional medications• Expansion of AERS-QuARK analysis• Optimization of scoring algorithm• Additional visualization methods• Potential use in consumer health
Summary
• QuARK is a knowledgebase containing quantitative frequency data for adverse drug reactions
• Potential applications include:– visualization of side-effect data– simplified lookup of multidrug regimens – clinical reminders targeted at adverse drug events
• Opportunities for research collaboration
Thanks!
NLM, Steve Downs, Mike McCoy, Marc Overhage, Shaun Grannis, Gunther Schadow, Siu Hui, Martin Were, Marc Rosenmann, Linas Simonatis, Atif Zafar, Paul Dexter, Mike Weiner, Paul Biondich, Burke Mamlin, Anne Belsito
Pop the QuARK!
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