2. S. Mazloomzadeh MD, PhD COHORT STUDIES

3. Learning Objectives To develop an understanding of: - What is a cohort study? - What types of cohort studies are available? - When to conduct a cohort study? - The value of such studies - The basic methodology

4. Epidemiological study designs Observational studies Observational studies 1- Descriptive Patterns and frequency of disease Patterns and frequency of disease 2- Analytical Determinants and risk of disease Determinants and risk of disease Interventional studies Interventional studies

5. Cohort study - An analytical observational study - Prospective study - Longitudinal - Incidence study The most powerful observational study

6. What is a cohort? a group of people who share a common characteristic or experience within a defined time period. A birth cohort A cohort of smokers A cohort of vegetarians

7. Purpose: To measure and usually to compare the incidence of disease in one or more study cohorts. Starts with people free of disease Starts with people free of disease Assesses exposure at baseline Assesses exposure at baseline Assesses disease status at follow-up Assesses disease status at follow-up Cohort study

8. مواجهه یافتهمواجهه نیافته بیمار غیر بیمار Cohort study

9. Population without disease Sample Time No Disease Exposure to Disease Risk Factor Exposed Not Exposed Yes No Yes No Cohort study

10. Types of cohort studies Prospective (Concurrent) Prospective (Concurrent) Retrospective (Historical cohort) Retrospective (Historical cohort) Retrospective- Prospective Retrospective- Prospective In both studies, subjects are classified on the basis of presence or absence of exposure. In both studies, subjects are classified on the basis of presence or absence of exposure.

11. Prospective cohort At the time of study, the relevant exposures may or may not have occurred, but the outcome have certainly not yet occurred. At the time of study, the relevant exposures may or may not have occurred, but the outcome have certainly not yet occurred. Example: Framingham study Example: Framingham study Massachusetts, 1948 Massachusetts, 1948

12. All the relevant events (both the exposures and outcomes of interest) have already occurred when the study is initiated. All the relevant events (both the exposures and outcomes of interest) have already occurred when the study is initiated. Example: Atomic bomb blast survivors Example: Atomic bomb blast survivors Retrospective cohort

13. Cohort Study Design Define Population Non-randomizing Exposed Non-Exposed Disease No Disease Disease No Disease 2015 2005 Concurrent 1995 Retrospect 1975 1985 1995

14. Retrospective- Prospective Initiated in the past and extended into the future. Initiated in the past and extended into the future. Most useful for exposures having both short- term and long-term effects. Most useful for exposures having both short- term and long-term effects. Example: a chemical that may increase the risk of birth defects within a few years of exposure as well as cancer risk after one or two decades. Example: a chemical that may increase the risk of birth defects within a few years of exposure as well as cancer risk after one or two decades.

15. Prospective vs. Retrospective Cost Cost Latency of disease Latency of disease Availability and quality of data Availability and quality of data

16. Nested case-control study Nested case-control study Inserting a new case-control study into a cohort study Inserting a new case-control study into a cohort study Example: to examine the association between serum levels of micronutrients and cancer risk Example: to examine the association between serum levels of micronutrients and cancer risk Baseline: blood sample taken and stored Baseline: blood sample taken and stored Analysis when sufficient number of cancer accrued Analysis when sufficient number of cancer accrued Types of cohort studies

17. Indications When there is good evidence of exposure and disease. When there is good evidence of exposure and disease. When exposure is rare but incidence of disease is higher among exposed When exposure is rare but incidence of disease is higher among exposed When follow-up is easy, cohort is stable When follow-up is easy, cohort is stable When ample funds are available When ample funds are available

19. Issues in the Design Selection of the Exposed Population Selection of the Exposed Population Selection of the Comparison Group Selection of the Comparison Group Source of Data Source of Data Follow up Follow up

20. Selection of the Exposed Population General population General population Whole population in an area A representative sample Special group of population Special group of population occupation group professional group

21. Selection of the Comparison Group Internal comparison Internal comparison –Only one cohort involved in study –Sub classified and internal comparison done External comparison External comparison –More than one cohort in the study for the purpose of comparison –e.g. Cohort of radiologist compared with ophthalmologists

22. Selection of the Comparison Group Comparison with general population rates Comparison with general population rates –Cancer rate of uranium miners with cancer in general population –“ Healthy worker ” effect

23. Source of Data Data on exposure Data on exposure Personal interviews / mailed questionnaire Personal interviews / mailed questionnaire Reviews of medical or employment records Reviews of medical or employment records –Dose of drug, radiation, type of surgery Medical examination or special test Medical examination or special test –Blood pressure, serum cholesterol

24. Source of Data Outcome Data (morbidity or death) Outcome Data (morbidity or death) Death certificates Death certificates Medical records Medical records Questionnaires Questionnaires Physical examinations Physical examinations

25. Follow up Follow up is the most critical part of the study Some loss to follow up is inevitable due to death, change of address, migration, change of occupation. Some loss to follow up is inevitable due to death, change of address, migration, change of occupation. Loss to follow-up is one of the draw- back of the cohort study. Loss to follow-up is one of the draw- back of the cohort study.

26. Bias Major issue in any epidemiologic study design Deviation of results from “truth” Systemic error in the design, conduct, or analysis of a study that results in a mistaken estimate of the association between an exposure and outcome

27. Important biases in Cohort Studies Selection bias Information bias/misclassification Degree of accuracy of classification of exposure, confounders and disease status Loss to follow-up (affects validity) Nonresponse (limits generalizability, not validity) Confounding

28. Selection bias In retrospective cohort, both the exposure and outcome have occurred at the start and knowledge of the disease may affect the selection or classification of exposed and non- exposed groups. In retrospective cohort, both the exposure and outcome have occurred at the start and knowledge of the disease may affect the selection or classification of exposed and non- exposed groups.

29. Misclassification Random Random misclassification Increase the similarity between the exposed and non-exposed groups, so true association will be underestimated. Non-random Non-random misclassification Can result in a biased risk estimate

30. Loss to follow-up To the extent that losses To the extent that losses to follow-up are correlated with both exposure and disease – e.g., that smokers are more likely to leave the study area if they develop lung cancer than if a nonsmoker develops that disease- a biased estimate may result.

31. Nonparticipation Those who agree to participate are likely to differ from nonparticipants in motivation and attitudes towards health and risk factor status. Those who agree to participate are likely to differ from nonparticipants in motivation and attitudes towards health and risk factor status. This may limit the ability to generalize the study results, it will not usually affect their validity. This may limit the ability to generalize the study results, it will not usually affect their validity.

32. Minimize Confounding Matching Restriction Adjustment in analysis

33. Strengths Efficient for rare exposures Can examine multiple effects of a single exposure Can examine multiple effects of a single exposure Can elucidate temporal relationship between exposure and disease Can elucidate temporal relationship between exposure and disease If prospective, minimizes bias in ascertainment of exposure Allows direct measurement of incidence of disease in exposed and nonexposed groups

34. Limitations inefficient for the evaluation of rare diseases If prospective, extremely expensive and time consuming If retrospective, requires the availability of adequate records Validity of the results can be seriously affected by losses to follow-up

35. Measures of Disease Occurrence Cumulative Incidence = No. of new cases of disease during a period of time No. persons at risk of developing the disease during same time period Cumulative Incidence No. of new cases of disease during a period of time No. persons at risk of developing the disease during same time period

37. Cumulative Incidence Proportion with no units Probability of developing disease Measure of risk Can be measured only in closed population Assumes all subjects followed until develop disease or observation period ends

38. Who is “ at risk ” ? Persons are at risk if they do not have the disease of interest and are capable of developing the disease Examples: Study of statin use and ovarian cancer risk Exclude women with prior oophorectomy

39. Measures of Disease Occurrence Incidence Rate No. of new cases of disease during a period of time Person-time of observation among persons at risk during same time period =

40. Incidence Rate Average rate at which disease develops in a population Actual rate with units of time Accounts for differing rates of follow- up so don ’ t need closed population Also referred to as incidence density, hazard rate, and mortality rate

41. Person-time = sum, over all individuals, of time at risk until the date of the event of interest or date of censoring (i.e., death, end of follow-up, disenrollment from health plan, dropout) Example: 8 year follow-up study

42. Subject 1 Event 2 Die 3 Disenroll 3 Disenroll 4 End follow-up 5 Event Person-time 0 8 Years

43. Person-time DisenrollDiedEvent Years follow up Subject 0012.01 0105.22 1003.53 0008.04 0015.95 Person-time= 24.6 years

44. Incidence rate = 2 events / 24.6 person-years 0.08 per py =80 per 1000 py Person-time

45. Analysis a+bba c+ddc Nb+da+c Disease status exposure status Yes No Yes NoTotal Relative risk = incidence of disease in exposed Compared to the incidence of disease in unexposed = (a/a+b) (c/c+d)

46. Relative risk (Risk ratio) Ratio of disease incidence among exposed to disease incidence among non-exposed Quantifies magnitude of the association between exposure and disease Varies from 0 to infinity RR=1: no association RR>1: exposure is a risk factor for disease; increases risk for disease RR<1: exposure decreases the risk for disease Example: RR=2.0 can be interpreted as two fold increase in risk RR=0.7 can be interpreted as 30% decrease in risk

47. Attributable risk (AR) The excess risk of disease in those exposed compared with those nonexposed The excess risk of disease in those exposed compared with those nonexposed AR= I e – I o AR= I e – I o AR%= AR%= PAR= I T – I o PAR= I T – I o AR Ie X 100