2. Epidemiological studies Two types Observation Experiment

3. Exposed Not exposed Disease occurrence Unethical to perform experiments on people if exposure is harmful Exposure assigned

4. Randomised Controlled Trial Blinded Doses Time period Risk - effect No bias If exposure not harmful Treatment Preventive measure (vaccination) If RCT not possible Left with observation of experiments designed by Nature Cohort studies Case control studies

6. Cohort studies marching towards outcomes

7. What is a cohort? One of 10 divisions of a Roman legion Group of individuals - sharing same experience - followed up for specified period of time Examples - birth cohort - cohort of guests at barbecue - occupational cohort of chemical plant workers - EPIET cohort 12

8. follow-up period

9. Calculate measure of frequency Cumulative incidence - Incidence proportion - Attack rate (outbreak) Incidence density end of follow-up

10. Cohort studies Purpose - Study if an exposure is associated with outcome(s)? - Estimate risk of outcome in exposed and unexposed cohort - Compare risk of outcome in two cohorts Cohort membership - Being at risk of outcome(s) studied - Being alive and - Being free of outcome at start of follow-up

11. unexposed exposed Cohort studies

12. unexposed exposed Incidence among exposed Incidence among unexposed Cohort studies

13. ate ham did not eat ham illnot ill 49 49 98 4 6 10 Presentation of cohort data: 2x2 table

14. Population Cases (f/u 2 years) HIV + 215 8 HIV - 289 1 Presentation of cohort data: Population at risk Does HIV infection increase risk of developing TB among a population of drug users? Source: Selwyn et al., New York, 1989

15. Person-yearsCases Smoke 102,600 133 Do not smoke 42,800 3 Presentation of cohort data: Person-years at risk Tobacco smoking and lung cancer, England & Wales, 1951 Source: Doll & Hill

16. Presentation of data: Various exposure levels

17. time ExposureStudy starts Disease occurrence Prospective cohort study time ExposureStudy starts Disease occurrence

18. Retrospective cohort study Exposure time Disease occurrence Study starts

19. Recipe: Cohort study Identify group of - exposed subjects - unexposed subjects Follow up for disease occurrence Measure incidence of disease Compare incidence between exposed and unexposed group

22. Our objective is to compare the incidence rate in the exposed population to the rate that would have been observed in the same population, at the same time if it had not been exposed

23. Principle of case control studies

24. Exposed Unexposed Source population

25. Cases Exposed Unexposed Source population

26. Cases Exposed Unexposed Source population Sample Controls

27. Cases Exposed Unexposed Source population Controls: Sample of the denominator Representative with regard to exposure Controls Sample

28. Intuitively if the frequency of exposure is higher among cases than controls then the incidence rate will probably be higher among exposed than non-exposed

29. Case control study Disease Controls Exposure ???? Retrospective nature

30. CasesControls Exposeda b Not exposedc d Totala + c b + d % exposeda/(a+c) b/(b+d) Distribution of cases and controls according to exposure in a case control study

31. Oral Myocardial contraceptivesInfarction Controls Yes 693 320 No 307 680 Total10001000 % exposed69.3% 32% Distribution of myocardial infarction by oral contraceptive use in cases and controls

32. PhysicalMyocardial activityInfarction Controls >= 2500 Kcal190230 < 2500 Kcal176136 Total366366 % exposed51.9%62.8% Distribution of myocardial infarction by amount of physical activity in cases and controls

33. WaterCases Controls Consumption YES 150 ? NO 50 ? Total 200 200 Volvo factory, Sweden, 3000 employees, Cohort study 200 cases of gastroenteritis

34. Two types of case control studies Exploratory New disease New risk factors Several exposures "Fishing expedition" Analytical Define a single hypothesis Dose response

36. So, uh, well… case-control studies are just fishing expeditions!

37. unexposed exposed Incidence among exposed Incidence among unexposed Cohort studies

38. Absolute measures - Risk difference (RD) I e - I ue Relative measures - Relative risk (RR) Rate ratio Risk ratio Effect measures in cohort studies I e I ue I e = incidence in exposed I ue = incidence in unexposed

39. ate ham did not eat ham illnot ill Incidence 49 49 98 50 % 4 6 10 40 % Risk difference 50% - 40% = 10% Relative risk 50% / 40% = 1.25

40. Does HIV infection increase risk of developing TB among drug users?

41. Vaccine efficacy (VE) VE = 1 - RR = 1 - 0.28 = 72%

42. Population Cases Incidence a1a1 High N1N1 I 1 c Unexposed N ne I ue at risk Exposure level a2a2 Medium N2N2 I 2 a3a3 Low N3N3 I 3 Various exposure levels

43. Population Cases Incidence RR a1a1 High N1N1 I 1 c Unexposed N ne I ue at risk Exposure level a2a2 Medium N2N2 I 2 a3a3 Low N3N3 I 3 RR 1 RR 2 RR 3 Reference Various exposure levels

44. Cohort study: Tobacco smoking and lung cancer, England & Wales, 1951 Source: Doll & Hill

45. A cohort study allows to calculate indicators which have a clear, precise meaning. The results are immediately understandable.

47. Cohort studies Rate Rate difference Rate Ratio (strength of association) No calculation of rates Proportion of exposure Case control studies Any way of estimating Rate ratio ?

48. I 1 = a / P 1 I 0 = c /P 0 E E a c P1P1 P0P0 Population denominator Cases E E a c P 1 /10 P 0 /10 Population sample Cases a/P 1 I 1 / I 0 = ------ c/P 0 } a I 1 = -------- P 1 / 10 c I 0 = -------- P 0 /10 } a/P 1 I 1 / I 0 = ------ c/P 0

49. I 1 = a / P 1 I 0 = c /P 0 CasesControls E E a b cd E E a c P1P1 P0P0 Source population Pop.Cases P 1 b --- = ---- P 0 d = sample a/P 1 I 1 / I 0 = ------ c/P 0 }

50. I 1 = a / P 1 I 0 = c /P 0 Cases = sample E E a b cd Since d/b = P 0 / P 1 E E a c P1P1 P0P0 Source population Pop.Cases a/P 1 a. P 0 a. d I 1 / I 0 = ------ = ------- = ----- = c/P 0 c. P 1 c. b } Controls P 1 b --- = ---- P 0 d a / c ------ b / d

51. Case control study design CasesControls E E a b c d ab a x d ---- ---=--- ---- cdb x c Odds ratio

52. Oral Myocardial contraceptivesInfarctionControlsOR Yes 693 3204.8 No 307 680Ref. Total10001000 % exposed69.3% 32% Distribution of myocardial infarction by recent oral contraceptive use in cases and controls

53. PhysicalMyocardial activityInfarctionControlsOR >= 2500 Kcal1902300.64 < 2500 Kcal176136Ref. Total366366 % exposed51.9%62.8% Distribution of myocardial infarction by amount of physical activity in cases and controls

54. Distribution of cases of endometrial cancer by oestrogen use in cases and controls Oestrogen useCasesControlsOdds ratio High a1b1a1d/b1c Low a2b2a2d/b2c None cdReference

55. Relation of hepatocellular adenoma to duration of oral contraceptive use in 79 cases and 220 controls Months of OC useCasesControlsOdds ratio 0-12 7121Ref. 13-3611 49 3.9 37-6020 2315.0 61-8421 2018.1 >= 8520 749.7 Total79220 Source: Rooks et al. 1979

57. Limitations of case-control studies Cannot compute directly relative risk Not suitable for rare exposure Temporal relationship exposure-disease difficult to establish Biases +++ - control selection - recall biases when collecting data Loss of precision due to sampling

59. Disadvantages of cohort studies Large sample size Latency period Cost Time-consuming Loss to follow-up Exposure can change Multiple exposure = difficult Ethical considerations

60. Advantages of case control studies Rare diseases Several exposures Long latency Rapidity Low cost Small sample size Available data No ethical problem

62. Strengths of cohort studies Can directly measure - incidence in exposed and unexposed groups - true relative risk Well suited for rare exposure Temporal relationship exposure-disease is clear Less subject to selection biases - outcome not known (prospective)

63. Can examine multiple effects for a single exposure PopulationOutcome 1Outcome 2Outcome 3 exposedN e I e1 I e2 I e3 unexposedN ne I ue1 I ue2 I ue3 RR 1 RR 2 RR 3 Strengths of cohort studies

64. The cohort study is the gold standard of analytical epidemiology CASE-CONTROL STUDIES HAVE THEIR PLACE IN EPIDEMIOLOGY but if cohort study possible, do not settle for second best