Statistics in Health Care Management: Assignment Week 1

Chapter 2

Study Designs

Learning Objectives

• List and define the components of a good

study design

• Compare and contrast observational and

experimental study designs

• Summarize the advantages and disadvantages

of alternative study designs

Learning Objectives

• Describe the key features of a randomized

controlled trial

• Identify the study designs used in public health

and medical studies

Study Designs

• Observational Studies

– Case-series study

– Cross-sectional (prevalence) survey

– Case-control study

– Cohort study

• Experimental Studies

– Randomized Controlled (Clinical) Trial

Inferences

• Observational studies – inferences limited to descriptions

and associations; with carefully designed analysis can

make stronger inferences (statistical adjustment)

• Experimental studies – cause and effect

In ALL studies – need careful definition of disease

(outcome) and exposure (risk factor)

Which Design is Best

• Depends on the study question

• What is current knowledge on topic

• How common is disease (and risk factors)

• How long would study take, what are costs

• Ethical issues

Case Report/Case Series

• Observational study

• Case report: Detailed report of specific features of case

• Case series: Systematic review of common features of a small number of cases

• Advantage: Cost-efficient

• Disadvantages: No comparison group, no specific research question

Case-Series

• Simplest design – description of interesting

observations in a small number of individuals

• Usually case-series do not involve control patients

(i.e., patients free of disease)

• Usually lead to generation of hypotheses for more

formal testing

• Criticisms: not planned – no research hypotheses

Case-Series

• Gottleib (1981) studied 5 young homosexual men with rare form of pneumonia and other unusual infections

• Initial report was followed by more series (26 cases in NY and CA; “cluster” in southern CA; 34 cases among Haitians, etc.)

• Condition termed AIDS in 1982

Cross-Sectional Survey

• Observational study conducted at a point in

time

• Advantages: Cost-efficient, easy to implement,

ethical

• Disadvantages: No temporal information, non-

response bias

Cross-Sectional Survey

• Is there an association between diabetes and

cardiovascular disease (CVD)?

Patients with

Diabetes

Patients without Diabetes

Patients with CVD

Prospective Cohort Study

• Observational study involving a group (cohort) of individuals who meet inclusion criteria followed prospectively in time for risk factor and outcome information

• Advantages: Can assess temporal relationships

• Disadvantages: Need large numbers for rare outcomes, confounding

Cohort Study

• Is there an association between hypertension and cardiovascular disease?

CVD Hypertension

No CVD

Cohort

CVD

No Hypertension

No CVD

Study Start Time

Cohort Studies

• Identify a group of individuals that meet

inclusion criteria

• Follow prospectively in time

• Assess exposure

• Evaluate outcome status

Cohort Studies

• Include persons exposed and not exposed to risk

factor at outset - usually persons are disease free

• Can assess temporal relationship

• Problem if disease is rare (small numbers)

• Bias is less of an issue than in Case-Control

• Confounding may be a problem

The Framingham Heart Study

• 5000+ men and women enrolled in 1948

• Longitudinal cohort study

• Exams every 2 years for cardiovascular risk factors -

surveillance

• Ancillary studies – hearing, exercise, nutrition,

neurological studies

• 5000+ offspring & spouses enrolled in 1976

• Third generation enrolled in 2002

Boston University Biostatistics

Selection of Study Sample

Exposure Group

• Common risk factors – general population (e.g.,

Framingham Study)

• Rare risk factors – special exposure cohort (e.g., soldiers

exposed to agent orange)

Comparison Group

• Similar on all other factors that might affect outcome

Case-Control Study

• Observational study involving individuals with

(cases) and without (controls) outcome of

interest

• Advantages: Cost and time efficient for rare

outcomes

• Disadvantages: Need careful selection of cases

and controls, bias

Case-Control Study

• Is there an association between sleep position and sudden infant death syndrome (SIDS)?

Sleep prone

SIDS

Other

Sleep prone

No SIDS

Other

Study Start Time

Case-Control Studies

• Select subjects on the basis of outcome:

Cases have disease

Controls are free of disease

• Compare groups with respect to proportions with a

history of exposure (possible cause)

• Investigation is retrospective in time

Sampling

• Selection of Cases

– Need explicit definition to make cases as homogeneous as possible

– Debate over whether cases should represent all persons with disease or specific subgroup (limit inferences)

• Selection of Controls

– Should be comparable to cases (same exclusions)

– They represent non-diseased persons who would have been included as cases if they had disease

Features

• Retrospective design

• Cost and time efficient

• Can get sufficient number of cases (useful for

rare conditions)

• Can investigate array of exposures

• Best for diseases with long latency

Issues

• Ascertainment of exposure and disease status

– Both exposure and disease have occurred – hard to establish temporal relationship

• Bias

– Selection bias – select cases or controls and some drop out – leaving groups not comparable

– Observation bias – knowledge of disease might influence reporting of exposure (overreporting among cases)

– Recall bias – retrospective (long term)

Randomized Control Trial

• Experimental study where patients are randomized to receive one of several comparison treatments

• Advantages: Gold standard from a statistical point of view, minimizes bias and confounding

• Disadvantages: Expensive, requires extensive monitoring, inclusion criteria can limit generalizability

Randomized Control Trial

• Is new drug effective in reducing hyperlipidemia (high total serum cholesterol)?

Hyperlipidemia Drug

No Hyperlipidemia

Sample RANDOMIZE

Hyperlipidemia

Placebo

No Hyperlipidemia

Study Start Time

Randomized Controlled Trial

(Clinical Trial)

• Subjects are randomized to one of two (or more) treatments, one of which may be a control treatment.

• In the long run treatment groups will be balanced in known and unknown prognostic factors.

• Important that the treatments are concurrent - that the active and control treatments occur in the same period of time.

• Single- versus multi-center.

Features

• If possible a study should be double blinded - neither the investigator nor the participant being aware of what treatment the participant is undergoing.

• Sometimes it is impossible to blind the participants, for example when the treatments being compared are medical Vs surgical - but often it is possible to ensure that the people evaluating the outcome are unaware of the treatment.

Phase I – Safety

• First time in humans; main objective to assess

toxicity and safety in humans – pharmacokinetics

• Usually involves 10-15 patients

• Subjects usually healthy

• Some are placebo-controlled

Phase II – Feasibility Study

• Focus still on safety

• Side effects and adverse events

• Efficacy is important – goal is to determine

optimal dosage

• Involve a control group and subjects are

randomized

Phase III – Clinical Trial

• Focus is efficacy

• Data are collected to monitor safety

• Involve a control group (placebo, active

control)

• Usually involve 200-500 subjects

• Subjects are randomized

• At least 2 centers

Phase IV – Post Marketing

• After approval by FDA (based on efficacy

proven statistically in 2+ studies – New Drug

Application (NDA) reviewed within 1 year)

• Focus is effectiveness

Critical Components of RCT

• Randomization

• Control Group – Ethical Issues

• Monitoring

– Interim Analysis

– Data and Safety Monitoring Board

• Data Management

• Reporting