1. Case-Control Studies Afshin Ostovar Bushehr University of Medical Sciences Bushehr, 2011 3/14/20161

2. 2 Epidemiological Studies Descriptive Case ReportCase-seriesEcologic Cross- sectional Analytical Observational Cross- Sectional Case- Control Cohort Interventional Clinical trials Field Trials Community Trials

3. The sophisticated use and understanding of case-control studies is the most outstanding methodologic development of modern epidemiology. (Rothman 1986, p. 62) A primary goal is to reach the same conclusions in a retrospective study as would have been obtained from a forward study, if one had been done. (Mantel and Haenszel 1959, p. 722) 3/14/20163

4. Key advantages Statistically efficient for rare conditions Logistically efficient for prolonged induction or latency diseases Can examine many exposures in one study Ethical - cannot affect onset of disease 3/14/20164

5. Case-Control Studies Examines the association between disease and potential risk factors by taking separate samples of diseased cases and of controls at risk of developing disease. Information may be collected for both cases and controls on genetic, social, behavioral, environmental or other determinants of disease risk. 3/14/20165

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7. Odds Ratio (cross-product ratio) 3/14/20167

8. The initial interpretation of the case-control study was the comparison of exposure histories for a group of diseased cases with those for non-diseased controls. The critics argued that such comparisons provided no information about the quantities of true epidemiologic interest, namely the disease rates. Cornfield (1951) corrected this misconception by demonstrating that the exposure odds ratio for cases vs. controls was equal to the disease odds ratio for exposed vs. non-exposed. 3/14/20168

9. Selection of cases and controls Matching Case-control studies based on a defined cohort 3/14/20169

10. Selection of cases Sources for cases Problems in case selection Incident or Prevalent Cases 3/14/201610

11. Sources for cases Hospitals Physicians— practices, or clinics Registries 3/14/201611

12. Problems in case selection If cases are selected from a single hospital, any risk factors that are identified may be unique to that hospital as a result of referral patterns or other factors, and the results may not be generalizable to all patients with the disease. Furthermore, if the hospital from which the cases are drawn is a tertiary care facility, which selectively admits severely ill patients, any risk factors identified in the study may be risk factors only in persons with severe forms of the disease. 3/14/201612

13. Incident or Prevalent Cases Number of cases available Survival bias 3/14/201613

14. Principles of Control Selection The “study-base” Principle The Deconfounding Principle The Comparable Accuracy Principle 3/14/201614

15. The “study-base” Principle Controls be randomly selected from disease-free members of the underlying cohort, also known as the source population or study-base at the times that cases are being ascertained When controls are in fact selected later, it sometimes mandates the random selection of a reference date for each control so that the distributions of the case diagnosis dates and control reference dates are comparable. 3/14/201615

16. The “study-base” Principle. Cont. Only exposures occurring prior to the reference|diagnosis date would be taken into account. This principle also implies that whatever exclusion criteria have been applied to the cases must also be applied equally to the controls. 3/14/201616

17. The Deconfounding Principle This principle underlies the stratified sampling of controls to render possible, or improve the efficiency of, an adjusted analysis designed to control confounding 3/14/201617

18. The Comparable Accuracy Principle Controls be selected so that the errors of measurement of their exposures and covariates are comparable to the measurement errors of the cases. 3/14/201618

19. Selection of Controls Sources of Controls Non-hospitalized Persons Hospitalized Patients 3/14/201619

20. Non-hospitalized Persons Probability sample of the total population School rosters Selective service lists Insurance company lists Neighborhood controls Random-digit dialing Best friend control Spouse or sibling 3/14/201620

21. Hospitalized Patients as Controls “captive population” = more economical Ill-defined reference population “All other patients admitted to the hospital” Vs “a specific “other diagnosis” 3/14/201621

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23. How Many Controls per Case? For a fixed number of study subjects, statistical power for testing the null hypothesis is optimized by having equal numbers of cases and controls. When the disease is extremely rare or acquisition of cases particularly expensive, however, it may be important and cost- effective to increase the numbers of controls. 3/14/201623

24. How Many Controls per Case? In order to have the same statistical power (to reject the null hypothesis of no exposure effect against local alternatives) as a design with equal numbers of cases and controls, a design with M controls per case would need only (M+1)|2M as many cases. For a fixed number of cases, the relative efficiency of a design with M controls per case relative to one that uses an unlimited number of controls is therefore only M|(M + 1). 3/14/2016 24

25. How Many Control Groups? multiple control groups were recommended by Dorn (1959) to improve the case-control study so that it would “provide a more valid basis for generalization”. If a whole series of control groups, e.g., of patients with different diseases, gives much the same answer and only the one affected group differs, the evidence is clearly much stronger than if the affected group differs from merely one other group.” 3/14/201625

26. How Many Control Groups? Failure to detect a difference among control groups may give a false sense of security unless they were deliberately selected to differ with respect to unmeasured potential confounders. Recent reviews of case-control methods have tended to shy away from the use of multiple control groups. They argue that there is usually a single “best” control group, and that since the discovery of an adjusted exposure difference with other control groups will force these to be discarded, the effort involved will have been wasted. 3/14/201626

27. Case-Control Types Primary-based Vs Secondary-based Population-based Vs Hospital-based 3/14/201627

28. Matching Group Matching (frequency matching) Individual Matching (matched pairs) 3/14/201628

29. Problems with matching Practical Problems Conceptual Problems 3/14/201629

30. Problem of Recall Limitations in Recall Recall Bias 3/14/201630

31. Case-control studies based on a defined cohort Nested Case-Control Studies Case-Cohort Studies 3/14/201631

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36. advantages of conducting a case- control study in a defined cohort 1. No recall 2. Temporality is established 3. Efficiency 4. Compariblity 3/14/201636

37. Case-Crossover Design Primarily used for studying the etiology of acute outcomes such as myocardial infarctions or deaths from acute events in situations where the suspected exposure is transient and its effect occurs over a short time. The question being asked is: Was there any difference in exposure between the time period immediately preceding the outcome and a time period in the more remote past which was not immediately followed by any adverse health effect? 3/14/201637