Issues in case-control studies

1. Issues in case-control studies • Internal Medicine Samsung Medical CenterSungkyunkwanUniversity School of MedicineKwangHyuckLeelkhyuck@gmail.com

2. Issues in case-control studies EliseoGuallar, MD, DrPHeguallar@jhsph.edu Juhee Cho, M.A., Ph.D. jcho@samsung.com

3. Case-control study – historical synonyms • Retrospective study • Trohoc study • Case comparison study • Case compeer study • Case history study • Case referent study

4. Case Control Study Control Case

5. 생체 간이식 후 간수치 상승 환자에서 담도 협착의 조기 발견과 관련된 요인 오초롱, 이광혁, 이종균 , 이규택 , 권준혁*,조재원*, 조주희** 성균관대학교 의과대학, 삼성서울병원 소화기내과, 이식외과*, 암교육센터**

6. 연구목적 • 생체간이식(LDLT) 후 발생하는 담도 합병증 • 가장 좋은 치료인 내시경적 치료 성공률 : 50% 전후 • 담도 합병증을 조기에 발견하여 내시경적 배액술을 시행하면 성공률이 높다. • LDLT 후 간 기능 이상 소견을 보이는 환자 중에 담도 합병증을 예측할 수 있는 요인을 찾고자 하였다.

7. 대상 및 방법 • 기간 및 대상 환자 • 2006년1월부터2008년12월 생체간이식을 받은 환자 • 수술 후 회복된 간기능이 다시 악화되었던 환자 • duct to duct 문합 환자만 포함(hepaticojejunostomy 환자는 제외) • 조사한 항목 • 기저질환, 증상 • 간기능 검사 • 수술기록 • 영상의학검사

8. 분석 group • LDLT 후 간수치가 재상승한 환자를 대상으로 group 을 나눔 (상승 기준 :AST>80, ALT>80, ALP>250 or bilirubin>2.2) • Group A • : ERCP가 필요한 환자 Vs ERCP 필요하지 않은 환자 • Group B • : 문합부담도협착 환자 Vs 거부반응 환자 • Group C • : CT 상 협착소견이 없었던 환자 중에 • ERCP가 필요한 환자 Vs 필요하지 않은 환자

9. LDLT patients during 3years : n=213 Patients with LFT elevation : n=120 Analysis group A Analysis group B Analysis group C CT(-) need ERCP : 32 CT(-) not need ERCP : 40

10. Case-Control Study or not?

13. Brock MV, et al. N Engl J Med 2008;358:900-9

14. Conducting case-control studies • Case and Control selection • Exposure measurement • Odds ratio

15. Research • New Question ?? • Method • Clinical study • Translational study • Laboratory study • Clinical study • Observational studies • Case-control study Vs Cohort study • Randomized controlled trial

16. Why case-control studies? • New question of interest • Cohort study with the appropriate outcome or exposure ascertainment does NOT exist • Need to initiate a new study • Do you have the time and/or resources to establish and follow new cohort?

17. Case control study ?? • High cholesterol  Myocardial infarction • MI (+) case • MI (-) control • Cholesterol level • Result • Negative • Positive

18. Impetus for case-control studies : EFFICIENCY • May not have the sufficient duration of time to see the development of diseases with long latency periods. • May not have the sufficiently large cohort to observe outcomes of low incidence. NOTE: Rare outcomes are not necessary for a case-control study, but are often the drive.

20. Efficiency of case-control study • Do maternal exposures to estrogens around time of conception cause an increase in congenital heart defects? • Assume RR = 2, 2-sided α = 0.05, 90% power • Cohort study: If I0 = 8/1000, I1 = 16/1000, would need 3889 exposed and 3889 unexposed mothers • Case-control study: If ~30% of women are exposed to estrogens around time of conception, would need 188 cases and 188 controls Schlesselman, p. 17

21. Strengths of case-control study • Efficient – typically: • Shorter period of time • Not as many individuals needed • Cases are selected, thus particularly good for rare diseases • Informative – may assess multiple exposures and thus hypothesized causal mechanisms

22. Learning objectives • Exposure • Selection of cases and controls • Bias • Selection, Recall, Interviewer, Information • Odds ratios • Matching • Nested studies • Conducting a case-control study DCR Chapter 8

23. Exposure ascertainment – examples • Active methods • Questionnaire (self- or interviewer- administered) • Biomarkers • Passive methods • Medical records • Insurance records • Employment records • School records

24. Exposure ascertainment issues • Establish biologically relevant period • Measurement occurs once at current time • Repeated exposure • Previous exposure • Measure of exposure occurs after outcome has developed • Possibility of information bias • Possibility of reverse causation (outcome influences the measure of exposure)

25. Is it possible in case-control study? – relevant period Yesterday smoking and radiation  Cancer risk

26. Information bias: recall bias Mothers of babies born with congenital malformations more likely to recall (accurately or “over-recall”) events during pregnancy such as illnesses, diet, etc.

27. Possibility of reverse causation • High cholesterol  Myocardial infarction • MI (+) case • MI (-) control • Cholesterol level • Result ? • MI  Cholesterol level decrease • Measure cholesterol after MI

28. Case selection – basic tenets • Eligibility criteria • Characteristics of the target and source population • Diagnostic criteria • Definition of a case: misclassification • Feasibility

29. Source populations – samples • Health providers: clinics, hospitals, insurers • Occupations: work place, unions • Surveillance/screening programs • Laboratories, pathology records • Birth records • Existing cohorts • Special interest groups: disease foundations or organizations

30. Incident versus prevalent cases • Incident cases: All new cases of disease cases (that become diagnosed) in a certain period • Prevalent cases: All current cases regardless of when the case was diagnosed

31. Incident Vs Prevalence • Do the cases represent all incident cases in the target population? • Exposure–disease association Vs Exposure–survival association

32. Prevalence cases • Disease • only A (causal factor) 1-month survival • A+B (protective factor) 1-year survival • A+C (protective factor) 10-year survival • Patient A: A1 1 month • Patient B: A1+B 1 year • Patient C: A1+C 10 years Prevalence cases  A1,B,C : Causes intervention of B or C ↓↓Survival

33. Disease severity • Whichstage is chosen for a case? • Early stage only Progression not always • Late stage only Influence of severity • Increase sample size for stratification

34. Early stage only • Case selection was done in prevalent cases of thyroid cancer • Case: small thyroid cancer • Control: normal population • Determined the differences • Clinical meaning of this study if there is no difference of survival between them

35. Late stage only – difficult diagnosis • Pancreatic cancer Vs. Weight • Cases: late stage pancreatic cancer • Low weight due to Cancer progression • Conclusion • low weight  pancreatic cancer Increase sample size for stratification

36. Selection bias • Selection of cases independent of exposure status • Related to severity • Related to hospitalization or visiting

37. Example selection bias (1) • Hypothesis • Common cold  Asthma • Setting • Patients in Hospital • Truth • Common cold: aggravating factor not causal factor • No different incidence of asthma according to common cold • Common cold (+)  aggravation hospital visit • Common cold (-)  no symptoms  no visit

38. Example selection bias (2) Odds ratio = (1X49)/(4X1)

39. Case and Control selection Study population Source population Target population Same distribution of risk factors ??

40. Guallar E, et al. N Engl J Med 2002;347:1747-54

41. Selection of controls – basic tenets • Same target population of cases • Confirmation of lack of outcome/disease • Selection needs to be independent of exposure

42. Controls in case-control studies • Should have the same proportion of exposed to non-exposed persons as the underlying cohort (source population) • Should answer yes to: If developed disease of interest during study period, would they have been included as a case?

43. Selecting controls – Same as case source Characteristics • Convenient • Most likely same target population • Rule out outcome – avoids misclassification • Similar factors leading to inclusion into source population • Sometimes impractical • Examples • Breast cancer screening program • Confirmed breast cancer – cases • No breast cancer – controls • Same hospital as case series • Similar referral pattern – examine by illness types • Pediatric clinics • Geographic population • Other special populations (e.g., occupational setting)

44. Source for controls • Geographic population • Roster needed • Probability sampling • Neighborhood controls • Random sample of the neighborhood • Friends and family members • Hospital-based control

45. Selection of controls: Friends or family members • Friends or family members • Ask each case for list of possible friends who meet eligibility criteria • Randomly select among list • Type of matching - will be addressed later • Concerns: • May inadvertently select on exposure status, that is, friends because of engaging in similar activities or having similar characteristics/culture/tastes • “over-matching”

46. Am J Epidemiol 2004;159:915-21

47. Selection of controls Hospital or clinic-based • Strengths • Ease and accessibility • Avoid recall bias • Concerns • Section bias: exposure related to the hospitalization • A mixture of the best defensible control • Referralpattern • Same • Or not

48. Diet pattern: Colon cancer • 소화기 암 전문 병원 (GI referral center)에서 연구를 수행함 • Case : 소화기 클리닉의대장암 (+) • Control : 호흡기 클리닉의대장암 (-) • 소화기 클리닉: 대기실 소화기 암 관련 음식 정보 • 호흡기 클리닉 • 두 군 간에 차이는 질환의차이가 아니라 클리닉의차이를 반영할 수도 있다. • Control:소화기클리닉의 위암 (+)

49. Guallar E, et al. N Engl J Med 2002;347:1747-54

50. Weakness of Case-Control Studies • Timeperiod from which the cases arose • Survival factor, Reverse causation • Biologically relevant period • Only one outcome measured • Susceptibility to bias • Separate sampling of the cases and controls • Retrospective measurement of the predictor variables