Design and Analysis of Clinical Study 6. Case-control Study

Dr. Tuan V. Nguyen

Garvan Institute of Medical Research

Sydney, Australia

What is Case-Control ?

• Traditional view: compare - people who get the disease - people who do not get the disease

• “Controls” a misnomer, derived from faulty analogy to controls in experiment

• Modern conceptualization: controls are a “window” into the “study base”

Case – Control Study

• Grouping studied: "cases" vs. "Control" group(s).

• Measurements analyzed: past "exposures.“

• Case-selection usually clinic- or hospital-based.

• Controls may also be clinic- or hospital-based, or population-sampled.

• Controls may be unmatched, group-matched, or individually matched.

Case-Control Study

Cases

Controls

Population at risk

Yes

No

Yes

No

Case-Control Study

Cases

Controls

Population at risk

Aspirin use

No Aspirin use

Aspirin use

No Aspirin use

Steps in Designing Case-control Studies

• Selection of cases

– Precise definition of ‘case’.

– Inclusion / Exclusion criteria.

– Are cases to be ‘incident’ or ‘prevalent’?

– How are cases to be identified? How recruited?

Steps in Designing Case-control Studies

• Selection of Controls

– Source ( hospital patients without disease; neighbourhood controls; random sample of population; sibs).

– Inclusion / exclusion criteria.

– Match to cases?

Steps in Designing Case-control Studies

• Collection of information

– Identify risk factor of interest

– Method of collection of information ( questionnaire; medical records; employment records)

– Same procedure to be used for cases and controls

– Interviewer should be unaware who is a case and who a control.

Two Methods of Selection

• Select new cases (i.e.incident) as they come up. Controls are selected from those in the same setting at the same time.

• Select existing cases (prevalent) from a defined population. From the same population a larger number of controls are identified.

The Incident type of case-control study is stronger because diagnosis of cases and ascertainment of exposure is being done by the researcher.

Results of a Case-Control Study

Risk factorDisease

Yes (cases) No (controls)

Aspirin Use a c

No Aspirin Use b d

Total N1 N2

N1 and N2 are fixed numbers

Nested Case-Control Study

• Case-control studies within a cohort study

• In ARIC (Atherosclerosis Risk in Communities) study, a cohort of 16 thousand men, all men provided serum samples at the outset which were saved.

• The cohort is observed for CHD.

• After 5 years we have 246 cases of CHD.

• We randomly choose 500 participants to be controls.

• We only measure Chlamydia antibody in the stored sera from these 246 + 500 subjects.

• We compare the cases (CHD) to the controls (no CHD) with regard to the presence of exposure (Chlamydia) which preceded the outcome

Matched Case-Control Studies

cases

Non-cases

cases

Non-cases

All cases or random sample

Cases

Random sample of non-cases

Cases All cases or random sample

Controls

Controls

Matched controls

Effects of Beta-blocker on Hip Fracture

• Select a hip fracture case

• Note the patient’s age, sex, weight, bone mineral density (BMD)

• Select a sample of controls

• Randomly selected k controls who have the same age, weight, and BMD as the case

Potential Biases

• A knowledge of the patient's disease status may influence: – Both the intensity and outcome of a search for

exposure to the putative cause

• A late look at those exposed (or affected) early will miss: – Fatal and other short episodes, plus mild or silent

cases and cases in which evidence of exposure disappears with disease onset

COHORT VS. CASE-CONTROL STUDIES OF CHD VS. CHOLESTEREMIA AMONG MEN

UPPER QUARTILE SERUM CHOLESTEROL

COHORT STUDY CASE-CONTROL STUDY

CHD BY EXAM 6 CHD BY EXAM 6 YES NO TOTAL YES NO TOTAL

YES 85 462 547 38 34 72NO 116 1511 1627 113 117 230TOTAL 201 1973 2174 151 151 302

ODDS RATIO = 2.40 ODDS RATIO = 1.16

Sample Size Calculation

• Power :  probability of detecting a real effect (eg = 0.20)• Alpha level : probability of detecting a false effect (eg =

0.05)

• P0 :  probability of exposure in controls

• P1 :  probability of exposure in case subjects

• R  : odds ratio of exposures between cases and controls• m : number of control subjects per case subject

Sample Size Calculation

• The estimated sample size is:

Website for Sample Size Calculation

http://www.sph.emory.edu/~cdckms/sample%20size%202%20grps%20case%20control.html

Advantages and Disadvantages of Case-control Studies

• Relatively cheap compared to cohort studies

• Relatively quick• Useful for study of rare

diseases.• No ethical problems• Useful for diseases with long

latent period.

• Estimate of disease incidence cannot be done

• At times difficult to measure exposure accurately

• Open to selection bias.• Difficult to interpret.

Advantages Disadvantages

Self-evaluation Questions

• Q2: Suppose that in a case-control study using incident cases of colon cancer you found that 80% of the cases were married. Does this demonstrate that being married increases the risk of developing cancer?

• Q2: In the same case-control study above, assume that 90% of the control group group are married. If there are 200 cases and 200 controls, estimate the risk of colon cancer for single men. Constuct a 2x2 table and determine and interpret the exposure odds ratio.