1 Clinical Investigation and Outcomes Research Health Outcomes Research Marcia A. Testa, MPH, PhD Department of Biostatistics Harvard School of Public

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Clinical Investigation and Outcomes Research

Health Outcomes Research

Marcia A. Testa, MPH, PhD

Department of Biostatistics

Harvard School of Public Health

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The Discipline of Health The Discipline of Health Outcomes ResearchOutcomes Research

• Scientific inquiry evaluating the results of medical interventions and health care services.

• Outcomes data are direct measures of whether medical treatments are beneficial

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How Are Outcomes Results Used?

• “Outcomes research seeks to understand the end results of particular health care practices and interventions.

• Used to provide information on the quality of care so that it can be improved by determining– which health care services influence the probability of

optimal patient outcomes – which produce optimal improvement in the patient's

physiologic status, physical function, emotional and intellectual performance and comfort (comparative effectiveness research)

1. Outcomes Research Resource Guide, 1996/97 Edition, American Medical Association

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Measuring Outcomes

• Outcomes are a function of – baseline health status – patient clinical characteristics – patient demographics– psychosocial characteristics – treatment – health care setting

• The GOAL of health outcomes research analysis is to isolate the relationship between outcomes and treatment.

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Outcome Measures

• Mortality – Survival time, Death event• Morbidity – Time to an Occurrence of a Clinical

Events (e.g., Stroke, MI, Cancer)• Health Status – Physical, Mental and Emotional

Health Functioning• Quality of Life – Health Status as Perceived by the

Individual• Patient Satisfaction – Distance between Quality of

Life and Individual Expectations • Health Economic Outcomes – Cost utility, cost

effectiveness

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Hematologic Malignancies & Anemia Comparative Effectiveness Trial

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Hb Changes

Figure 2. Mean hemoglobin (Hb) change (intent-to-treat; n = 269). aP < .0001 early versus late group. Postrandomization Months 1, 2, 3, and 4 values correspond with mean Hb between Weeks 0 (baseline) to Weeks 4, 5-9, 10-14, and 15-20, respectively.

a P < 0.0001

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Treatment, Fatigue, Symptoms

bP < .01 late vs. early treatment. cP < .05 late vs. early treatment.

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Treatment and Health Status


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Treatment and QOL


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Measuring Outcomes

Death Full Health Outcome

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Measuring Outcomes, Measuring Performance

Measurement

Improving Process (how we perform)

Improving Outcomes (the results of our performance)

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Clinical

Economic

The Consequences of Health Care and Medical Intervention

PatientCentered

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Clinical

The Consequences of Health Care and Medical Intervention –Types of Outcomes

Labs, Clinical Events, Physician Assessments

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PatientCentered

The Consequences of Health Care and Medical Intervention –Types of Outcomes

Symptom reports, health status, quality of life, patient satisfaction

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Well-beingWell-being

Mental andMental and

EmotionalEmotional

Physical/Physical/

SymptomsSymptoms

Work/SocialWork/Social

CognitiveCognitive

GeneralGeneral

PerceivedPerceived

HealthHealth

Multi-faceted QOL Domains

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Outcomes Research - 1996QOL is Recognized as Important

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Outcome MeasuresFunctional Health Coverage

• Generic health instruments are address larger health constructs and hence their causal links to specific treatment events may be more difficult to detect

• Condition-specific instruments will vary with the condition being treated, and hence are typically more sensitive to treatment effects

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Outcome MeasuresFormat Influencing Coverage

• Fixed-Length or “Static” – number of questions is fixed – greater coverage requires greater number of questions

• Dynamic instruments - use computer adaptive testing to restrict items based upon a Bayesian approach which selects the next question based upon the answer to the previous question

• Combines the practicality of short form instruments with the sensitivity and target coverage of condition-specific instruments

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Questionnaires and SurveysGeneric Instruments

• Some outcomes survey questions, commonly referred to as “instruments”, focus on describing how individuals rate their health overall – or generic instruments

• General health surveys such as the SF-36 are now used in research studies, population surveys, and some health plans to assess patients' overall level of functioning.

• Translation of SF-36 into Arabic and the translation methods references are given in the Additional Resources Section of the Website.

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Questionnaires and Surveys Condition-Specific Instruments

• Developing outcome instruments for specific diseases has been an especially prolific research area

• Such instruments are more likely than general health survey measures to be able to detect changes in the disease due to treatment

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Steps in Designing an Outcome Research Study

• Define a researchable question• Develop a conceptual model• Identify the critical dependent and independent

variables• Identify appropriate measures for each• Develop an analysis plan• Indicate what is believed to cause the outcome• Identify critical pathways and what other factors are

likely to affect the outcome• Identify which variables (in the outcomes function

equation) are relevant to your hypothesis

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The Conceptual Health Model

Environmental Behavioral, Social•Income•Social Support•Education•Health Access•Lifestyle

Patient Factors•Age•Gender•Occupation

Medical Interventions•Specific medications•Surgery•Diet and Exercise•Case Management

Outcome Measures•Lab values•Symptoms•Functioning•Quality of life•Employment/Work

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The Outcomes Model

Patient Characteristics

Structure (Setting)

Process (Treatment)

OUTCOME

Change

Change

Risk Adjustment

Measurement

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Outcomes Research - 1998Health Economic Benefits

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Diabetes Outcomes Model

Clinical Factors•Severity•Duration•Etiology•Comorbidity

Patient Factors•Age•Race•Gender•Occupation

Treatment•Specific medications•Diet•Exercise•Case Management

Outcomes•HbA1c•Symptoms•Function•Complications•Quality of life•Employment/Work

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Understanding Causal Pathways

EFFICACY

• Clinical 1c

QUALITY OF LIFE

• Functional status• Physical, Mental,Cognitive, Social

SIDE EFFECTS

•Adverse reactions

REGIMEN BURDEN

• Pain, Life-style,discomfort

HEALTH STATUS

• Self-ReportedSymptom distress

HEALTH ECONOMICS

• Productivity

• Health Care UtilizationTreatment Satisfaction

Adherence

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Study Design

62 sites in the United StatesGlipizide GITS + diet vs Placebo + diet16-week multicenter, randomized, double-blind, placebo-controlled, parallel titration study

• 1-week washout• 3-week single-blindplacebo• 4-week dose titration• 8-week maintenance

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Testa MA, Simonson DC. JAMA 1998; 280:1490-1496.

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Study Design

Screening / washout

Single-blind placebo

Dose titration 5-20 mg

Maintenance

Week -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Maintenance

Randomization to placebo & diet orGlipizide GITS & diet (1:2)

Clinical and Laboratory Assessment

Health Economic Assessment

■


■ ■ ■ ■

■

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Multicenter, Random ized C linical Trial

W eek 4 ,8 ,n = 1 7 8 ,1 6 9

E arly W ith d raw a l

W eek 1 2n = 1 5 8

C om p le te rs

D ie t & P laceb oIn e lig . Q O L : n = 9

E lig ib le Q O L : n = 1 9 2

W eek 4 ,8n = 3 4 9 ,3 4 0

E arly W ith d raw a l

W eeK 1 2n = 3 3 3

C om p le te rs

D ie t an d G L ip iz id e G ITSIn e lig Q O L : n = 1 6E lig ib le : n = 3 7 7

S c reen ed /P laceb o W ashN = 1 0 0 7

E lig ib le fo r C lin ica l S tu d yn = 5 9 4

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Patient Population

Baseline Clinical Characteristics

Placebo Glipizide GITS

Number of Patients 201 393

Gender (M / F) (%) 60 / 40 55 / 45

Race (W / B / O) (%) 70 / 18 / 12 70 / 18 / 12

Emp / Ret / Unemp(%) 50 / 38 / 12 48 / 40 / 12

Age (yrs) 58 ± 12 59 ± 11

Duration DM (yrs) 5 ± 5 6 ± 6

FPG (mg / dL) 231 ± 66 218 ± 62

HbA1c (%) 8.7 ± 1.4 8.5 ± 1.5


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Clinical Results

End of Week 15

Placebo Glipizide GITS P-Value

FPG (mg / dL) 224 ± 66 161 ± 41 < 0.001

HbA1c (%) 9.3 ± 1.9 7.5 ± 1.2 < 0.001

Hypoglycemic Symptoms (%)

4.8 6 NS

Glucose < 55mg / dL (%)

0 0 NS


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HbA1c and Symptom Distress

HEALTH STATUS

• Self-Reported Symptom distress

EFFICACY

• HbA1c

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Pharmacological SideEffects and Symptom Distress

HEALTH STATUS

• Self-reported Symptom distress

EFFICACY

• HbA1c

SIDE EFFECTS


35SD UnitsSD Units

Mean HbAMean HbA1c1c: 9.3 : 9.3 1.9% 7.5 1.9% 7.5 1.2%1.2%TremblingTrembling

Low blood sugar reactionLow blood sugar reactionFast pulse, rapid heartbeat, palpitationsFast pulse, rapid heartbeat, palpitations

HeartburnHeartburnWheezing or difficulty breathingWheezing or difficulty breathing

Gaining weightGaining weightCold hands or feetCold hands or feetFeeling overweightFeeling overweight

ConstipationConstipationSwelling of feet or anklesSwelling of feet or ankles

Abdominal crampsAbdominal crampsSkin rashSkin rash

Decrease in appetiteDecrease in appetiteMood swingsMood swingsLosing weightLosing weight

Flushing, sensation of heatFlushing, sensation of heatShortness of breath or breathing hardShortness of breath or breathing hard

Increase in hungerIncrease in hungerInability to sleep, insomniaInability to sleep, insomnia

Pains in legs or calvesPains in legs or calvesLightheadednessLightheadedness

Lethargy, no energy to do thingsLethargy, no energy to do thingsNumbness or tingling of hands or feetNumbness or tingling of hands or feet

VomitingVomitingNauseous, queasy, sick to stomachNauseous, queasy, sick to stomach

DiarrheaDiarrheaItching, scratchingItching, scratching

Heart pounding, beating hardHeart pounding, beating hardNightmaresNightmaresHeadachesHeadaches

Impaired or worsening visionImpaired or worsening visionTired, feeling wearyTired, feeling weary

Muscle crampsMuscle crampsVertigo, sensation of spinningVertigo, sensation of spinning

Dizziness when standing upDizziness when standing upTightness,pain in chest Tightness,pain in chest

Drowsy or sleepyDrowsy or sleepyCold sweat, clammy skinCold sweat, clammy skin

Sugar in urineSugar in urineFoot cramps, foot painFoot cramps, foot pain

Sweating, perspiringSweating, perspiringConfusionConfusion

General weakness or fatigueGeneral weakness or fatigueNumbness of lips or mouthNumbness of lips or mouth

Blurred or double visionBlurred or double visionCrabby, short-temperedCrabby, short-tempered

Getting up often during the night to urinateGetting up often during the night to urinateBeing ThirstyBeing Thirsty

Having to urinate frequentlyHaving to urinate frequentlySweet taste in mouthSweet taste in mouthDrinking a lot of fluidsDrinking a lot of fluids

Dryness of mouth, eyes or noseDryness of mouth, eyes or noseHigh blood sugarHigh blood sugar

00 0.20.2 0.40.4 0.60.6 0.80.8 11-0.2-0.2

P < .05P < .05

P < .001P < .001

P < .01P < .01

P = N.S.P = N.S.

Symptom Worsening Symptom Worsening With Glucose With Glucose LoweringLowering

Symptom Symptom Improvement With Improvement With Glucose LoweringGlucose Lowering


Hypoglycemic Hypoglycemic symptoms, weight gain,symptoms, weight gain, feeling overweightfeeling overweight

Hyperglycemic Hyperglycemic symptoms,symptoms,thirst, nocturia, thirst, nocturia, blurred vision, blurred vision, fatiguefatigue

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EFFICACY

• HbA1c HEALTH STATUS

• Self- Reported Symptom distress

QUALITY OF LIFE

• Functional status• Physical, Mental, Cognitive, Social

Impact on Quality of Life

SIDE EFFECTS

• Adverse reactions

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Change In QOL Scales With Therapy in Type 2 Diabetes

-0.3-0.3

-0.2-0.2

-0.1-0.1

00

0.10.1

0.20.2

0.30.3

0.40.4

PlaceboPlacebo Glipizide GITSGlipizide GITS

QO

L S

core

(S

D u

nit

s)Q

OL

Sco

re (

SD

un

its)

Overall RatingOverall RatingMental HealthMental HealthCognitive FunctionCognitive FunctionPerceived HealthPerceived HealthSymptom DistressSymptom Distress

* P < 0.05** P < 0.01*** P < 0.001

*****

***


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Change in HbA1c and QOL

In Patients with NIDDM

*

0

0.2

-0.2

-0.4

-0.6

-0.8 QO

L G

loba

l Ou

tco

me

(Z

-sco

re)

>1.5 1.5 to .5 .5 to -.5 -.5 to -1.5 <-1.5ImprovedHbA1c

WorsenedHbA1c HbA 1 c (%) Change from Baseline

log-linear regression, r = .95, p < .01

Favorable QOL Response

Unfavorable QOL Response

No Change in HbA1c*

** *

No Change in QOL


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Understanding Causal Pathways

EFFICACY

• Clinical 1c

QUALITY OF LIFE

• Functional status• Physical, Mental,Cognitive, Social

SIDE EFFECTS


REGIMEN BURDEN

• Pain, Life-style,discomfort

HEALTH STATUS

• Self-ReportedSymptom distress

HEALTH ECONOMICS

• Productivity

• Health Care UtilizationTreatment Satisfaction

Adherence

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$ Loss$ Loss

$ Savings$ Savings

Production Losses

PlaceboPlacebo GlipizideGlipizideGITSGITS

00

22

44

-2-2

P = 0.01

Restricted Activity DaysRestricted Activity Days(US $ / 1000 person days)(US $ / 1000 person days)

$1000's$1000's

PlaceboPlacebo

00

500500

10001000

-500-500

P = 0.05

Bed DaysBed Days(US $ / 1000 person days)(US $ / 1000 person days)

GlipizideGlipizideGITSGITS

PlaceboPlacebo

00

5050

100100

-50-50

P < 0.001

AbsenteeismAbsenteeism(US $ / worker / month)(US $ / worker / month)

Ch

ang

e (

Wee

k 1

5 –

Bas

elin

e)C

han

ge

(W

eek

15

– B

asel

ine)

GlipizideGlipizideGITSGITS

Testa MA, Simonson DC. JAMA; 1998;280:1490-1496.

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BaselineBaseline Week 15Week 152020

3030

4040

PP = NS = NS

Pe

rcen

t o

f P

ati

ents

Pe

rcen

t o

f P

ati

ents

BaselineBaseline Week 15Week 152020

3030

4040

P = 0.002

Percent of Patients Reporting 1 or More Non-study-Percent of Patients Reporting 1 or More Non-study-related Ambulatory Visits (clinic, ER, physician office) related Ambulatory Visits (clinic, ER, physician office)

per Monthper Month

Estimated savings = $11 per patient per month (assuming cost of $66 per ambulatory visit)Estimated savings = $11 per patient per month (assuming cost of $66 per ambulatory visit)

PlaceboPlacebo Glipizide GITSGlipizide GITS

Health Care Utilization

Testa MA, Simonson DC. JAMA; 1998;280:1490-1496.

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Summary

• Use Outcomes Research to – Improve the quality of health care by changing

treatment and services and by promoting preventive strategies

• Outcomes are “probability statements”– Multifaceted– Requires integrating and consolidating many

different components of health functioning

• Outcomes may take time to develop, use intermediate outcomes if necessary

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Summary

• Use Outcomes Research to – Improve the quality of health care by changing

treatment and services and by promoting preventive strategies

• Outcomes are “probability statements”– Multifaceted– Requires integrating and consolidating many

different components of health functioning

• Outcomes may take time to develop, use an intermediate outcomes

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Additional Resources and References

• Online Questionnaires: SF12, LASA, EQ-5D. • SF-36 translated into Arabic by Saud Abdulaziz bin Al

Abdulmoshin, 1997• Coons SJ, Reliability of an Arabic Version of the

RAND-36 Health Survey and Its Equivalence to the US English Version

• Testa and Simonson, NEJM, 1996• Testa and Simonson, JAMA, 1998• Straus, Testa, Sarokhan et al., Cancer 2006

http://www.zoomerang.com/Survey/WEB22AJ253TA3T

Documents

1 Clinical Investigation and Outcomes Research Health Outcomes Research Marcia A. Testa, MPH, PhD Department of Biostatistics Harvard School of Public