Healthcare Statistics

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Chapter 2

Study Designs

Learning Objectives (1 of 2)

  • 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 (1 of 2)

  • 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 report/case series
  • 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 (1 of 2)

  • 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 (2 of 2)

  • Gottleib (1981) studied five 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 (1 of 2)

  • 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 (2 of 2)

  • 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 (1 of 3)

  • Is there an association between hypertension and cardiovascular disease?

CVD Hypertension

  No CVD

 Cohort

CVD

No Hypertension

No CVD

Study Start Time

Cohort Study (2 of 3)

  • Identify a group of individuals that meet inclusion criteria.
  • Follow prospectively in time.
  • Assess exposure.
  • Evaluate outcome status.

Cohort Study (3 of 3)

  • Includes 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 and spouses enrolled in 1976
  • Third generation enrolled in 2002

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 (1 of 3)

  • 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 (2 of 3)

  • 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 Study (3 of 3)

  • 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)
  • Controls 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 (over-reporting among cases)
  • Recall bias—retrospective (long term)

Randomized Control Trial (1 of 2)

  • 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 (2 of 2)

  • 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 multicenter

Features

  • If possible, a study should be double blinded—neither the investigator nor the participant are 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 versus 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 to 15 patients
  • Subjects are 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.
  • Involves a control group, and subjects are randomized.

Phase III: Clinical Trial

  • Focus is efficacy.
  • Data are collected to monitor safety.
  • Involves a control group (placebo, active control)
  • Usually involves 200 to 500 subjects
  • Subjects are randomized.
  • At least two centers

Phase IV: Post-Marketing

  • After approval by FDA (based on efficacy proven statistically in two or more 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