1. Module 6: Part One Analytic Epidemiology: Case-control and cohort study designs

2. Analytic observational studies Case-control studies Cohort (prospective and retrospective) studies Clinical trials © 2010 Jones and Bartlett Publishers, LLC

3. 3 Let’s say… You observe two events and want to investigate whether or not their relationship is causal. For example: The observation that women with low saturated fat intake have lower rates of breast cancer than women with high saturated fat intake. Because of ethical considerations and cost, constructing a clinical trial (randomized controlled trial or RCT) to investigate the role of saturated fat intake in breast cancer is not an option.

4. But, if possible, RCT would be the preferred study design because: It is the gold standard of epidemiologic designs It is a special type of cohort study in which self-selection for a particular treatment is eliminated Group exposure status is assigned by the investigator Assignment of the next subject cannot be predicted The therapy a subject receives is not influenced by either conscious or subconscious bias of the investigator 4

5. But, RCT is considered highly unethical in most medical investigations: Hence there is a need to find mechanisms to take advantage of natural experiments in which the breast cancer rate in women with high levels of saturated fat intake are compared to breast cancer rates of women with low saturated fat intake. 5

6. Observational vs. Intervention study designs The term “observational study” refers to the fact that the investigator takes advantage of natural events and studies them. There is no manipulation on the part of the researcher This differs from an intervention study, such as a clinical trial, in which the investigator determines who gets the exposure and who does not. 6

7. 7 There is a difference between things that are “associated” with each other vs. things that are causally related to each other. For example: Consider the association in the figure below showing the relationship between per capita # of telephones and coronary heart disease deaths for 15 countries in the world: Clearly, it is incorrect to assert that telephones cause heart disease. On the other hand, there is a true association depicted here It is simply not causal.

8. 8 Types of Observational Studies: There are two general types of observational studies: descriptive studies and analytic studies. Descriptive epidemiolgical studies attempt to describe patterns of disease and antecedent factors as they occur in “free-range” human populations. They often provide the first clues as to the relationship between exposures and outcomes. Examples include: Fluoride and dental caries Smoking and lung cancer Downs Syndrome and maternal age

9. Analytic epidemiology An analytic study attempts to answer why and how a health-related state or event occurred Tests specific a priori hypotheses Uses a comparison group © 2010 Jones and Bartlett Publishers, LLC

10. 10 Analytic Studies: There are two general types of analytic observational studies: Cohort studies, of which there are both prospective and retrospective types Case-control studies The major differences in these studies relate to: How and when we identify our sample of subjects How and when we measure exposure and outcome.

11. 11 Case-Control Studies: The key concept to grasp: Case control studies begin with the outcome and proceed to look back at the history of exposure. Case-control studies then have the unique advantage of guaranteeing a substantial number of subjects with the disease of interest for study.

12. Design of a Case-Control Study Not Exposed Exposed Not Exposed DiseaseNo Disease “CASES”“CONTROLS” Exposed Marc Schenker M.D., M.P.H Dept. of Public Health Sciences; UC Davis

13. Case-control approach is most often used: When a case ascertainment system in place: a) Population-based cancer registry b) Hospital-based surveillance systems c) Mandated disease reporting systems d) Office records of physicians e) Hospital admission or discharge records f) Pathology department records When funding and time constraints are not compatible with a cohort study.

14. 14 It is important to note that the controls in a case- control study are not like the “controls” in a cohort study: In a prospective cohort study, the controls are the non-exposed group. In a case-control study, the controls are subjects without disease, NOT the group without the exposure.

15. I. Case-control study: The outcome is always identified prior to the exposure 1.Identify cases (persons experiencing a health- related state or event) 2.Identify controls (similar except not cases) 3.Investigate whether the cases are more or less likely than controls to have had similar past experiences, lifestyle behaviors, or exposures

16. Selection of cases May consist of new cases (incidence) that show selected characteristics during a specific time period in a specified population and a particular area. Cases may also consist of existing cases at a point in time (prevalence).

17. Sources of cases Cases come from ▫Records from public health clinics ▫Physician offices ▫Health maintenance organizations ▫Hospitals ▫Industrial and government sources Cases should be representative of all persons with the disease

18. Selection of controls Control subjects should be as similar as possible to the cases with the exception of not having the disease An epidemiologic assumption is that controls are representative of the general population in terms of probability of exposure and that controls have the same possibility of being selected or exposed as the cases © 2010 Jones and Bartlett Publishers, LLC

19. Measuring the association between exposure and outcome variables The appropriate measure of association to use depends on the nature of the data When exposure and outcome variables are dichotomous (two level nominal data) ▫Odds ratio – use with case-control study ▫Risk ratio – use with cohort study

20. 20 Analytic methods: In case-control studies the analytic approach involves assessing the likelihood that someone with the disease (outcome) of interest will report a particular exposure. Since we start with disease and choose a group of control subjects to match these cases, we cannot measure in a meaningful way the incidence of new cases of disease as we can in cohort studies. The measure that is used is call the Odds Ratio

21. Case-Control Studies Typically, compare the proportions of exposure by means of a ratio: Odds ratio (relative odds) OR = Odds for exposure among cases Odds for exposure among controls dcE-E- baE+E+ D-D- D+D+ (a / c) OR =------- (b / d)

22. Odds Ratio Can have a value of zero to infinity If the OR = 1, no association between exposure and the disease If the OR > 1, this indicates a positive relationship between the exposure and disease If the OR < 1, this indicates a negative relationship between the exposure and the disease © 2010 Jones and Bartlett Publishers, LLC

23. Case-Control: Example You have an interest in the association between hearing loss and IPOD use. You undertake a study with 600 young adults with hearing loss (D+) and match these cases with 600 controls (D-). You then determine the presence (or absence) of the exposure (IPOD use symbolized by E+ or E-). What is the odds for exposure among cases? Odds for exposure among controls? Odds Ratio? 23 500400E-E- 100200E+E+ D-D- D+D+

24. Bias Systematic error in the collection or interpretation of epidemiologic data Results in inaccurate (over or under) estimation of the association between exposure and disease Avoiding bias at the design stage of a study is paramount because of the difficulty to identify and account for it thereafter

25. Types of bias in case-control studies Selection Observation ▫Recall ▫Interviewer © 2010 Jones and Bartlett Publishers, LLC

26. Selecting Controls 1. The prevalence of exposure among controls should reflect the prevalence of exposure in the source population. 2. Controls should come from the same source population as cases (e.g. would have been cases if diagnosed with the disease). 3. The time during which a subject is eligible to be a control should be the time in which the individual is also eligible to be a case. If #1, #2, or #3 are not met = Selection Bias

27. Confounding Occurs when an extrinsic factor is associated with a disease outcome and, independent of that association, is also associated with the exposure Exposure Outcome Confounder © 2010 Jones and Bartlett Publishers, LLC

28. Confounding: Example Coffee Heart Disease Smoking © 2010 Jones and Bartlett Publishers, LLC

29. StrengthsWeaknesses  Useful for studying rare outcomes  Short duration  Relatively inexpensive  Relatively small  Yields odds ratio (usually a good approximation of relative risk)  Does not establish sequence of events  Potential bias in measuring exposure variables  Limited to a single outcome variable  Does not yield prevalence, incidence or excess risk  Prone to selection and observation bias Selected strengths and weaknesses of case-control studies

30. Summary: Case-Control Studies Selection of an appropriate comparison group is the most challenging and important aspect of the study design. Advantages: Relatively quick and inexpensive. Well-suited for evaluation of diseases with long induction periods. Optimal for evaluation of rare diseases. Can examine multiple etiologic factors for a single disease.

31. Summary: Case-Control Studies Disadvantages: Inefficient for evaluation of rare exposures unless the disease is common among the exposed. May be difficult to establish the temporal relationship between exposure and disease. Prone to bias compared to other analytic designs, in particular, selection and recall bias.

32. II.Cohort studies Cohorts of persons placed in a group can be studied as a group, forward in time (prospectively) or backward in time (retrospectively) © 2010 Jones and Bartlett Publishers, LLC

33. I. Cohort Studies: Cohort studies come in two types: prospective and retrospective. Studies in which the exposure and outcome have already occurred are termed retrospective Studies in which the outcome has yet to occur are called prospective.

34. The term “cohort” is derived from the fact that, in these studies, one begins with the “exposure” by choosing a cohort of people with an exposure and comparing the number of new cases of disease in this group with the number of new cases in a cohort of non- exposed people

35. Cohort effect Also called generation effect Is the change and variation in the disease or health status of a study population as the study group moves through time Cohort effects include any exposure or influence from environmental effects to societal changes © 2010 Jones and Bartlett Publishers, LLC

36. Measures of association in cohort studies Ratio of attack rates ▫Risk ratio Ratio of person-time rates ▫Rate ratio © 2010 Jones and Bartlett Publishers, LLC

37. Risk ratio (relative risk) It is defined as the incidence of disease in the exposed divided by the incidence in the non- exposed. Incidence in the exposed Relative Risk = ----------------------------- Incidence in the non-exposed 37

38. 38 Hypothesis:The risk of developing emphysema (D+ or D-) is associated with cigarette smoking (E+ or E-) Study design: Cohort study of 465 subjects D+D+ D-D- E+E+ 40180220 E-E- 30215245 70395465 RR = (40 / 220) ÷ (30 / 245) RR = 1.48 Smokers appear to be at 1.48 times higher risk of emphysema compared to non-smokers 38

39. Attributable Risk If relative risk measures the strength of an association, then attributable risk measures the actual amount of illness or disease we can ascribe to a given exposure, i.e. the amount of disease attributable to the exposure. Attributable risk is defined as : AR = Incidence in the exposed (E+) - Incidence in the non-exposed (E-) 39

40. Researchers, wanting to study the relationship between obesity and osteoarthritis (OA) of the knees, recruited 20,000 women to participate in a 15-year follow-up study. Subjects were screened at the beginning of the study for any evidence of existing OA of the knees as well as for obesity. Women with pre-existing OA were eliminated from the study. The subjects were subsequently examined annually for evidence of OA and classified as either “OA +” or “OA –”. Weight was recorded as well. At the conclusion of the study, 240 of the 8,000 women who were classified as obese had been diagnosed as having OA, while only 130 of the normal weight (12,000) women showed evidence of OA of the knees. 40

41. Example: From the OA scenario, the attributable risk of developing OA if one were obese can be defined as:.03 -.01 =.02 (or 20 per 1,000 per 15 years) Interpretation: Approximately 20 cases of OA per 1,000 people diagnosed as obese are the result of the obesity 41

42. Selecting the study cohort From population choose those at risk of becoming a case Exclude: ▫Individuals who already have a disease outcome of interest ▫Those not at risk (e.g., they have had an organ removed such that they cannot become a case) © 2010 Jones and Bartlett Publishers, LLC

43. Bias in cohort studies Selection bias ▫Healthy worker effect ▫Loss to follow-up © 2010 Jones and Bartlett Publishers, LLC

44. Healthy worker effect Occurs in cohort studies when workers represent the exposed group and a sample from the general population represents the unexposed group This is because workers tend to be healthier, on average, than the general population © 2010 Jones and Bartlett Publishers, LLC

45. Loss to follow-up A circumstance where researchers lose contact with study participants, resulting in unavailable outcome data on those people A common problem in cohort studies, increasingly so in cohorts with longer follow-up times Reasons ▫Refusal to participate ▫Unable to locate ▫Unable to be interviewed ▫Death © 2010 Jones and Bartlett Publishers, LLC