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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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!