Module 2:Fundamentals of Epidemiology

Developed through the APTR Initiative to Enhance Prevention and Population Health Education in collaboration with the Brody School of Medicine at East Carolina University with funding from the Centers for Disease Control and Prevention

Experimental Studies

Acknowledgments

APTR wishes to acknowledge the following individual that developed this module:

Jeffrey Bethel, PhDDepartment of Public HealthBrody School of Medicine at East Carolina University

This education module is made possible through the Centers for Disease Control and Prevention (CDC) and the Association for Prevention Teaching and Research (APTR) Cooperative Agreement, No. 5U50CD300860. The module represents the opinions of the author(s) and does not necessarily represent the views of the Centers for Disease Control and Prevention or the Association for Prevention Teaching and Research.

Presentation Objectives

1. Recognize use of experimental studies as an epidemiologic study design

2. Distinguish between types of experimental studies

3. Describe key features of conducting experimental studies

4. Recognize special considerations of experimental studies

Analytic Study Designs

Experimental studies (experimental) Researcher determines who is exposed

(treatments received)

Cohort studies (observational) Case-control studies (observational) Cross-sectional studies (observational)

Experimental StudiesBackground

Goal of public health and clinical medicine is to modify natural history of disease and improve morbidity and mortality

How do we select the best preventive and therapeutic measures?

Carry out studies to determine value of various measures

Smith, AH. The Epidemiologic Research Sequence. 1984

Experimental Studies

Most closely resemble controlled laboratory experiments

Gold standard of epidemiological research

High status and validity and can pick up small and modest effects

Experimental StudiesScurvy

James Lind identified symptoms of scurvy among sailors at sea after as little as a month

Conducted early experimental study on treatment of scurvy in mid-1700’s among British sailors

Small sample size (6 groups of 2 ill sailors)

Group eating oranges and lemons were fit for duty in 6 days

Experimental Studies Potential Uses

Evaluate new drugs and other treatments for diseases

Evaluate new medical and health care technology

Evaluate new screening programs or techniques

Evaluate new ways of organizing or delivering health services (e.g. home v. hospital care following myocardial infarction)

Experimental Studies Preventive v. Therapeutic

Preventive Does prophylactic agent given to healthy or high-risk

individual to prevent disease?

Therapeutic Does treatment given to diseased individual reduce risk of

recurrence, improve survival, quality of life?

Experimental Studies Individual- v. Community-Based

Individual Do women with stage I breast cancer given a lumpectomy

alone survive as long without recurrence of disease as women given a lumpectomy plus radiation?

Community Does fluoride in the water supply decrease the frequency

of dental caries in a community compared to a similar community without such water treatment?

STUDYPOPULATION

CURRENTTREATMENT

NEWTREATMENT

IMPROVEDO NOT IMPROVE

IMPROVE DO NOTIMPROVE

RANDOM ASSIGNMENT

Experimental Studies Overall Conduct

Hypothesis formed

Participants recruited based on specific criteria and their informed consent is sought

Eligible and willing subjects randomly allocated to receive one of the two or more interventions being compared

Study groups are monitored for outcome under study (recurrence of disease, first occurrence of disease, getting better, side effects)

Rates of the outcome in the various groups are compared

Experimental StudiesHypothesis

Women with stage I breast cancer given a lumpectomy alone will survive as long without recurrence of disease as women given a lumpectomy plus radiation

Water supply with fluoride will decrease the frequency of dental caries in a community compared to a similar community without water treated with fluoride

Experimental StudiesInclusion Criteria for Participants

Who will be in the study? Must be defined specifically before study

begins Remove subjectivity Reproducibility

Experimental StudiesInclusion Criteria for Participants

Women’s Health Study ≥ 45 years No history of coronary heart disease, cerebrovascular

disease, cancer, or other major chronic illness No history of side effects to any of study medications Were not taking any of following meds more than once

per week: aspirin, NSAIDs, supplements of vitamin A, E, or beta-carotene

Were not taking anticoagulants or corticosteroids

NEJM 352;13:1293-1303

Experimental StudiesSample Size

How many participants do we need to enroll in the study?

Programs and tables exist to calculate sample size based on various parameters

TRUTH IN THE POPULATION

CONCLUSION FROM SAMPLE

Ho

(no difference)H1

(there is a difference)

Fail to reject Ho

(no difference)Correct decision Type II error

(Probability = b)

False negative

Reject Ho

(there is a difference)

Type I error(Probability = a)

False positive

Correct decision(Probability = 1- b)

Type I and II errors can be reduced by increasing sample size

Experimental StudiesSample Size Required Parameters

The difference in effect to be detected Estimate of effect in one group Level of significance ( )a

Probability of concluding treatments differ when they do not differ

Level of power desired (1 - β) Probability of concluding treatments differ when

they do differ 1-sided or 2-sided test

Experimental Studies Participant Allocation

Compare the outcome among “exposed” to what the outcome would have been if unexposed

This comparison is counterfactual

Instead, compare the outcome among “exposed” group to the outcome in a “substitute” population

Validity of inference depends on finding a valid substitute population

Experimental StudiesParticipant Allocation

Need to randomly assign participants to one of the intervention groups (test or control)

Randomization Next assignment is unpredictable Coin toss to determine group allocation Random number table, opaque envelopes Computer

Experimental Studies Randomization

Main purpose Reduces selection bias in the allocation of treatment Each participant has an equal chance of being in test or

control group

Secondary purpose If large enough sample size, produce treatment and control

groups with similar baseline characteristics Control for known and unknown factors

Experimental Studies Randomization

Baseline Characteristics in a study of heart disease patients

CharacteristicTest Group(n = 9,599)

Control Group(n = 9,586)

Male (%) 72 72

White (%) 95 95

Current smoker (%) 29 30

Patients with a history of:

Hypertension (%) 52 51

Stable angina (%) 22 22

High cholesterol (%) 41 41

Experimental Studies Randomization

Baseline Characteristics in a study Maternal-Infant HIV Transmission

Characteristic Test Group(n = 239)

Control Group(n = 238)

Median age at entry (yrs) 24 25

White (%) 48 38

Gestational age at entry 29 30

Median (weeks) 26 27

14-26 weeks (%) 52 50

> 26 weeks (%) 48 50

Median CD4 county at entry 41 41

Experimental Studies Data Collection

Treatment Keep track of which treatment group the participant was

assigned Keep track of which therapy received

Baseline data Collect baseline demographic and other risk factor data Compare treatment groups

Experimental Studies Data Collection

Measuring outcome Must be conducted in same fashion for all treatment

groups

Preventive studies▪ Precursors of disease or first occurrence of disease

Therapeutic studies▪ Symptom improvement▪ Length of survival▪ Disease recurrence

Women’s Health Study

Myocardial infarction Symptoms met WHO criteria Abnormal levels of cardiac enzymes or diagnostic

electrocardiograms

Stroke New neurologic deficit of sudden onset that persisted for at

least 24 hours

Death from cardiovascular disease Examination of autopsy reports, death certificates, medical

records, and information obtained from the next of kin or other family members

Experimental Studies Data Collection

Masking (Blinding) Prevents conscious and subconscious bias in research

Use placebo to mask

Single blind: participants do not know which treatment they are receiving

Double blind: participants and observers (data collectors) do not know participant treatment status

Experimental StudiesParallel v. Crossover

Parallel Participants in each group simultaneously receive one

study treatment Treatment and comparison groups consist of different

participants

Crossover Planned reversal of intervention and control groups Each participant can serve as his/her own control

STUDYPOPULATION

NEW TREATMENT CURRENT TREATMENT

RANDOMLY ASSIGNED

Group 1

Group 1

Group 2

Group 2

Group 2

Group 2

Group 1

Group 1

Observe and Measure Effects

Observe and Measure Effects

Experimental StudiesSimple v. Factorial

Simple Each group receives a treatment consisting of one

component (e.g. one drug)

Factorial Use same study population to compare 2 or more

treatments 2 x 2 factorial design Similar to 3 arms (drug A, drug B, and placebo) with fewer

participants

Experimental StudiesFactorial

Drug A

Drug B Yes No Efficacy of B

YesBoth

A and B(cell a)

B only(cell b) a+b

v.c+d

No A only(cell c)

Neither(cell d)

Efficacyof A a+c v. b+d

Aspirin

Beta-carotene

Yes NoEfficacy of

Beta-Carotene

YesAspirin and

Beta-carotene(cell a)

Beta-carotene only

(cell b) a+bv.

c+dNo Aspirin only

(cell c)Neither(cell d)

Efficacyof Aspirin a+c v. b+d

Experimental StudiesFactorial

Experimental StudiesNoncompliance

Overt Notify investigators he/she is dropping out of study Drop outs

Covert Stop taking assigned treatment without telling investigators Need to build compliance checks in to the study (e.g. test

urine, count pills, etc.)

Experimental StudiesExpressing Results

Efficacy Reduction in risk Calculate risk of death, developing disease,

complications in each group

Vaccine example

= (Rate in placebo group) – (Rate in vaccine group) Rate in placebo group

Experimental StudiesExpressing Results

Relative risk Kaplan-Meier plot Hazard ratio Number of patients who would need to be treated

(NNT) to prevent 1 adverse event Number needed to harm (NNH) indicates number

patients treated to cause harm in 1 patient who would not otherwise have been harmed

Experimental StudiesValidity of Results

Internal validity Extent to which the study groups are comparable Comparability Reflected by selection/randomization

External validity Extent to which the results of a study can be applied to

people not in it Generalizability Representativeness

STUDYPOPULATION

CURRENTTREATMENT

NEWTREATMENT

RANDOMLY ASSIGNED

REFERENCEPOPULATION

ExternalValidity

Internal Validity

Experimental StudiesValidity of Results

Items affecting internal validity Loss to follow-up Lack of randomization

Items affecting external validity Loss to follow-up Low response rate Narrow inclusion criteria

Experimental StudiesEthical Considerations

Randomization There must be genuine uncertainty about which treatment

is better

Informed consent Some trials enroll participants immediately after diagnosis

When to stop the study? Harmful or beneficial effects of one treatment arm Outside board monitors study

Experimental StudiesDisadvantages

Expensive and time-consuming Ethical concerns may arise A large number of participants may be required Participant exclusion may limit generalizability Compliance may be an issue Influence of sponsorship

Experimental StudiesAdvantages

Randomization tends to balance risk factors across study groups

Blinding of participants can reduce bias in assessment of outcomes

Prospective design Eliminate bias by comparing two otherwise identical

groups Detailed information collected at baseline and

throughout study period

Summary

Experimental studies top epidemiologic study design hierarchy in terms of validity

Investigators assign treatment to participants (experimental)

Randomization reduces selection bias in treatment allocation

Data collection must be conducted systematically Noncompliance and drop-outs must be minimized to

increase validity of results

Collaborating Institutions

Center for Public Health Continuing EducationUniversity at Albany School of Public Health

Department of Community & Family MedicineDuke University School of Medicine

Advisory Committee

Mike Barry, CAELorrie Basnight, MDNancy Bennett, MD, MSRuth Gaare Bernheim, JD, MPHAmber Berrian, MPHJames Cawley, MPH, PA-CJack Dillenberg, DDS, MPHKristine Gebbie, RN, DrPHAsim Jani, MD, MPH, FACP

Denise Koo, MD, MPHSuzanne Lazorick, MD, MPHRika Maeshiro, MD, MPHDan Mareck, MDSteve McCurdy, MD, MPHSusan M. Meyer, PhDSallie Rixey, MD, MEdNawraz Shawir, MBBS

APTR

Sharon Hull, MD, MPHPresident

Allison L. LewisExecutive Director

O. Kent Nordvig, MEdProject Representative