Retrospective & Prospective Studies

Case Studies

ICRI Delhi

Hierarchy of Evidence

1. Anecdotal case reports2. Case series without controls3. Series with literature control4. Analyses using computer databases5. Case control studies6. Cohort studies7. Randomized control trials (RCTs)8. Meta-analysis with original data

Evidence PyramidEvidence Pyramid

Study DesignStudy Design

• Experimental Study

(Controlled Controlled AssignmentAssignment)• RCT (randomized

person assignment)

• Cluster trial (randomized cluster assignment)

• Observational Study

(Uncontrolled Assignment)• Cohort studies (sampling

with regard to exposure)• Cross-Sectional• Case-Control (sampling

with regard to disease or effect)

Study Designs

Experimental Observational

DescriptiveAnalytical

Case-Control Cohort

+ cross-sectional & ecologic

(RCTs)

Descriptive studiesDescriptive studies

Examine patterns of disease

Analytical studiesAnalytical studies

Studies of suspected causes of diseases

Experimental studiesExperimental studies

Compare treatment modalities

Purpose of Studies

Algorithm for classification

of types of clinical

research

ObservationalObservational Studies Studies(no control over the circumstances)

- Descriptive: Most basic demographic studies

- Analytical: Comparative studies testing an hypothesis

* Cross-sectional (a snapshot; no idea on cause-and-effect

relationship) * Cohort (prospective; cause-and-effect relationship can be

inferred) * Case-control (retrospective; cause-and-effect relationship can be

inferred)

•Descriptive studies do not feature a comparison (control) group.

•Descriptive studies are often the first foray into a new area of medicine.

•They describe the frequency, natural history, and possible determinants of a condition.

•Hypothesis generation about the cause ot the

disease.

Types of clinical research

Case report Case-series reports

Good descriptive reporting answers the five basic

W questions:

Who, what, why, when, where

Descriptive studies

Case report

Case-series reports

Surveillance studies / Surveys / Cross-sectional studies

And a sixth: so what ?

Who has the disease in question ? What is the condition or disease being studied ? Why did the condition or disease arise ? When and Where does or does not the disease or condition arise ?

Case reports and series

• Case report: describes an observation in a single patient.– “I had a patient with a cold who drank lots of

orange juice and got better. Therefore, orange juice may cure colds.”

• Case series: same thing as a case report, only with more people in it.– “I had 10 patients with a cold who drank

orange juice….”

Value of case reports/series

• May generate a hypothesis: “maybe orange juice cures colds….”

• Weakness: cannot test the hypothesis– no control group– often too few people to make generalizations

Analytical Studies

Retrospective & Prospective Studies

AnalyticalAnalytical Studies Studies

(comparative studies testing an hypothesis)

* Cohort (prospective)

Begins with an exposure (smokers and non-smokers)

* Case-control (retrospective)

Begins with outcome (cancer cases and healthy controls)

* Cross-sectional (concurrent)

Exposure & outcome co-exist

Cross-sectional Study

Exposure

Outcome

300 men MI Next door neighbour

Mean S-cholesterol Mean S-cholesterol

256 mg/dl 202 mg/dl

at the same time

Cross-Sectional Study

•Ask each person about both exposure and disease at that point in time.

•Investigator gathers data only at that one point in time.

•Disease rate in exposed group is compared to disease rate in unexposed group.

•Select a study sample.

Data Gathering Approaches

-Person-to-person interviews or surveys, mailed questionnaires, telephone interviews etc.

Cross-Sectional StudyAdvantages

•One stop, one time•Less expensive

•Useful for planning services

•Shows relative distribution of conditions

•Shows interrelatedness of attributes and conditions•Does not rely on individuals who present for medical treatment •No one exposed to harmful causal agent because of study

Cross-Sectional Study

Disadvantages

•Only representative of participants

•Not effective if disease is rare

•May not be representative of all cases

•Cause and effect uncertain because exposure and disease are measured simultaneously

• Cannot be used for hypothesis testing

Ovarian cancer

Use of oral contraceptives

Control group

Case Control & Cohort Studies

Case-control study

Study Population

Cases

Controls

Exposed

Non-exposed

Exposed

Non-exposed

Schematic diagram of a case control study design

Bias in Case-Control studies

• Selection bias

• Confounding bias

• Berkesonian bias

• Observation bias

• Recall Bias: Cases are more likely to remember exposure than controls

• Non response

Question

• In a study on the association between smoking and CHD, 200 CHD patients were selected from a hospital OPD and 400 similar controls were enrolled. History of patients revealed that there were 112 smokers in the CHD group as compared to 176 in the control (non CHD) group. Comment on the association between smoking and CHD.

400200Total

22488Non-smoker

176112SmokerExposure Status

No CHD

(Controls)

CHD cases

(Cases)

Disease Status

Calculating the Odds Ratio

Odds Ratio = =AD

BC

112 x 224

176 x 88= 1.62

Interpreting the Odds Ratio

or

The odds of exposure for cases are 1.62 times the odds of exposure for controls.

Those with CHD are 1.62 times more likely to be smokers than those without CHD

or

Those with CHD are 62% more likely to be smokers than those without CHD

Cohort study / Follow-up study

Study population

Exposed

Non-exposed

Disease +

Disease +

Disease -

Disease -

Cohort StudiesCohort Studies

time

Exposure Study startsDisease

occurrence

Prospective cohort studyProspective cohort study

time

ExposureStudy startsDisease

occurrence

Radiation Leak in Nuclear Plant

12 workers on site at time of the leak

24 workers off duty at home at time of the leak

Cohort Workers1969

Workers disease status1999

4 with leukemia

8 no leukemia

4 with leukemia

20 not leukemia

Exposed

Unexposed

Retrospective cohort studiesRetrospective cohort studies

Exposure

time

Diseaseoccurrence Study starts

Radiation Leak in Nuclear Plant

12 workers on site at time of the leak

24 workers off duty at home at time of the leak

Cohort of Workers 1999 collect info from1969

Workers disease status1999

4 with leukemia

8 no leukemia

4 with leukemia

20 not leukemia

Exposed

Unexposed

Nested case-control studies

• Cases and controls come from a well-defined population.

• Combine many of the strengths of retrospective cohort and case-control studies.

Prospective vs. Retrospective Cohort Studies

• Prospective Cohort Studies– Time consuming, expensive– More valid information on exposure– Measurements on potential confounders

• Retrospective Cohort Studies– Quick, cheap– Appropriate for examining outcomes with long

latency periods– Difficult to obtain information of exposure– Risk of confounding

The Framingham Study

• Since 1948, samples of residents of

Framingham, Massachusetts, have

been subjects of investigations of risk

factors in relation to the occurrence of

heart disease and other outcomes

The Framingham Study• Hypotheses:

– Persons with hypertension develop CHD at a greater rate than those who are normotensive.

– Elevated blood cholesterol levels are associated with an increased risk of CHD.

– Tobacco smoking and habitual use of alcohol are associated with an increased incidence of CHD.

– Increased physical activity is associated with a decrease in development of CHD.

– An increase in body weight predisposes a person to CHD.

The Framingham Study

• Study population consisted of 5,127 men and

women between ages 30 and 62 years and were at

the time of entry free of cardiovascular disease

(1948-1952)

• Cohort was examined every 2 years and by daily

surveillance of hospitalizations at Framingham

Hospital

The Framingham Study• Exposures included:

– Smoking

– Alcohol use

– Obesity

– Elevated blood pressure

– Elevated cholesterol levels

– Low levels of physical activity, etc.

Comparison (Control) Groups• With a one-sample (population-based) cohort,

exposure is unknown until after the first period of observation

– Example: • Select the cohort (all residents of Framingham) • All members of the cohort are given questionnaires,

and/or clinical examinations, and/or testing to determine exposure status

• The cohort is then divided into exposure categories based on those results

Comparison (Control) Groups

• The nonexposed become the internal controls

• For continuous variables, such as caloric intake or amount of exercise, multiple levels of exposure are constructed

• It is common to break exposure into quantiles (equally ordered subgroups) and to use the extremes as the comparison (referent) group

Question

How does the design of a cohort study change if everybody in the cohort is exposed (special exposure cohort)?

Example: All persons exposed to radiation from the Chernobyl accident.

Answer

• You need to select a separate control cohort people as similar as possible to the exposed cohort (income, age, gender, employment) but with no exposure

• If you cannot find a comparison group, you may use available population incidence rates under certain circumstances

Question

• In a study on association between smoking and CHD, 288 smokers and 312 nonsmokers, i.e a total of 600 subjects were enrolled. selected from a hospital OPD and 400 similar controls were enrolled. The subjects were followed up and 112 smokers developed CHD while 88 nonsmokers also developed CHD. Comment on the association between smoking and CHD.

224

176

No CHD

31288Non-smoker

288112SmokerExposure Status

TOTALCHD

Disease Status

Example: Calculating the Relative Risk

Relative Risk = =A/(A+B)

B/(C+D)

112 / 28888 / 312

= 1.38

Example: Interpreting the Relative Risk

Relative Risk = 1.38

The risk of developing CHD is 38% higher for a smoker than for a nonsmoker.

The risk of developing CHD is 1.38 times higher for a smoker than for a nonsmoker.

or