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

1. Design and Analysis of Clinical Study 6. Case-control Study Dr. Tuan V. Nguyen Garvan Institute of Medical Research Sydney, Australia

2. 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”

3. 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.

4. Case-Control Study Yes Cases No Yes Controls No Population at risk

5. Case-Control Study Aspirin use Cases No Aspirin use Aspirin use Controls No Aspirin use Population at risk

6. 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?

7. 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?

8. 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.

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

10. Results of a Case-Control Study N1 and N2 are fixed numbers

11. 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

12. Matched Case-Control Studies Cases All cases or random sample cases Controls Random sample of non-cases Non-cases Cases All cases or random sample cases Controls Matched controls Non-cases

13. 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

14. 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

15. 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 YESNOTOTALYESNOTOTAL YES 85 462 547 38 34 72 NO 116 1511 1627 113 117 230 TOTAL 201 1973 2174 151 151 302 ODDS RATIO = 2.40 ODDS RATIO = 1.16

16. Sample Size Calculation • Power :  probability of detecting a real effect (eg b = 0.20) • Alpha level : probability of detecting a false effect (eg a = 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

17. Sample Size Calculation • The estimated sample size is:

18. Website for Sample Size Calculation http://www.sph.emory.edu/~cdckms/sample%20size%202%20grps%20case%20control.html

19. Relatively cheap compared to cohort studies Relatively quick Useful for study of rare diseases. No ethical problems Useful for diseases with long latent period. Advantages and Disadvantages of Case-control Studies Advantages Disadvantages • Estimate of disease incidence cannot be done • At times difficult to measure exposure accurately • Open to selection bias. • Difficult to interpret.

20. 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.