EP711 COHORT STUDIES

1. EP711 COHORT STUDIES

2. Types of Epidemiologic Studies • Observational Cohort Case-control • Experimental • Randomized controlled trials

3. Cohort Studies Definition: A study in which two or more groups of people that are free of disease and that differ according to the extent of exposure (e.g. exposed and unexposed) are compared with respect to disease incidence Cohort studies are the observational equivalent of experimental studies but The researcher cannot allocate exposure –he/she must locate a natural experiment to observe the relationship between the exposure and disease

4. Randomized Controlled Trials Identify the study population (cohort) Exposed Active Intervention Outcome? Unexposed Comparison • Design: • Investigator randomly assigns exposure (treatment) • Then observe over time for subsequent outcome

5. Cohort Studies Exposed Smokers Identify the cohort Outcome? Unexposed Non-smokers • Design: • Non-diseased subjects grouped based on presence of exposure • Then determine subsequent outcome (e.g.- disease) • Example: Is smoking associated with lung cancer?

6. Temporal sequence between exposure & disease is clear (e.g., smoking preceded cancer) Can directly calculate incidence, RD, PRD Good for looking at rare exposures or unusual risk factors (e.g. agent orange) Can evaluate multiple effects of a single factor Advantages of Cohort Studies

7. Have factor Don’t have factor Start of Study Past Future Retrospective Cohort Study The Cohort Compare Incidence • Cheaper, faster • Efficient with diseases with long latent period • Exposure data may be inadequate (limitation)

8. Have factor Don’t have factor Start of Study Past Future Prospective Cohort Study Compare Incidence The Cohort • More expensive, time consuming • Not efficient for diseases with long latent periods • Better exposure and confounder data • Less vulnerable to bias

9. Have factor Don’t have factor Ambidirectional Cohort Study Retrospective part Prospective part Compare Incidence Compare Incidence Past Start of Study Future Contains elements of both types of studies

10. Types of Cohort Populations • Open or Dynamic • Changeable characteristic • Members come and go • Losses may occur • Fixed • Irrevocable event • Does not add new members • Losses may occur • Closed • Irrevocable event • Does not add new members • No losses occur Never married Residents of Boston Aged 25-54 Baby Boomers, 9/11 survivors, RCT participants Church Picnic or Wedding Attendees

11. Selection of Study Population • Choice depends upon hypothesis under study and feasibility considerations • For common risk factors(obesity, HBP): • A cohort from the general population (e.g., Framingham Heart Study, NHANES) • A special study group, e.g., doctors or nurses (e.g. The Nurse’s Health Study, Black Women’s Health Study) • For unusual risk factors : • A special (rare) exposure group: • (e.g., Agent Orange, Hiroshima, Occupational)

12. The Framingham Heart Study • Initiated by NHLBI • Objective was to identify the common factors or characteristics that contribute to CVD by following healthy individuals • The researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts • Since 1948, the subjects have continued to return to the study every two years for a detailed medical history, physical examination, and laboratory tests • In 1971, the study enrolled a second generation - the original participants' adult children and their spouses • In April 2002 the Study entered a new phase: the enrollment of a third generation of participants, the grandchildren of the original cohort.

13. The Nurse’s Health Study • 2 cohorts; Differ by age • NHS I • Assembled in 1976 • ~122,000 female nurses aged 30-55 years • NHS II • Assembled in 1989 • 117,000 female nurses aged 25-42 years • Biennial postal questionnaires

14. The Nurse’s Health Study • The primary goal to investigate the potential long term consequences of the use of oral contraceptives, in a population of normal women • Primary outcomes include heart disease & cancer (common endpoints) • Examines multiple common risk factors (diet, exercise, obesity, vitamin use) • Subjects able to respond with a high degree of accuracy • Motivated to participate in a long term study • Easy to locate

15. Air Force Ranch Hand Study (“Agent Orange Study”) • The U.S. military sprayed some 11 million gallons of the defoliant over southern and central Vietnam from 1962 to 1971 in an effort to expose enemy supply lines, sanctuaries and bases. • Airmen were exposed during spraying flights, while loading the chemical and while performing maintenance on the aircraft and the spraying equipment. • Agent Orange was named for the orange-striped barrels it was shipped in. It contains dioxin, a cancer-causing byproduct linked to medical ailments in U.S. war veterans and their Vietnamese counterparts.

16. Selection of the Comparison Group • 1)As similar as possible with respect to other factors that could influence outcome • 2) Comparable & accurate information • Counterfactual ideal • The ideal comparison group consists of exactly the same individuals in the exposed group – but without the exposure • Epidemiologists must select different sets of people who are as similar as possible Exposed Unexposed

17. Road Crew/ Asphalt Workers Land- scapers/ Grounds Crew Nurses Rubber Workers General Population General Population General Population General Population Lean Obese vs. vs. vs. Sources of Comparison Group General Population Comparison InternalComparison Comparison Cohort Which of the three comparison groups is best?

18. “Healthy-Worker Effect” • Rates of morbidity and mortality among a working population are lower than those of the general population • Health requirements for workers (especially physical laborers) tend to be stringent • General population consists of both healthy and ill people • Leads to underestimation of risk

19. Sources of Exposure Information • Pre-Existing Records • Advantages • Inexpensive • Recorded before disease occurrence • Disadvantages • Inadequate level of detail • Missing records • Little or no information on confounders

20. Sources of Exposure Information • Questionnaires, Interviews • Advantages • Good for information not routinely recorded • Disadvantages • Potential for recall bias

21. Sources of Exposure Information • Direct Testing • (Physical exams, tests, environmental monitoring) • Advantages • Good for certain exposures • Disadvantages • Expensive • Not feasible in large studies

22. Sources of Outcome Information • Death certificates • Physician, hospital, health plan records • Questionnaires (verify by records) • Medical exams You can use blinding to ensure that there is comparable ascertainment of the outcomes in both groups

23. Follow-up • Goal is to obtain complete follow-up information on all subjects regardless of exposure status • Ascertainment of outcome data involves following all subjects from exposure into the future • Time consuming process • However, high losses to follow-up raise doubts about the validity of the study (bias)

24. Apparent RR = 1.0 Loss to Follow Up If likelihood of loss to follow up is related to the risk factor and the outcome, the estimate of the association will be biased OC Users Non-OC users Example: True incidence of thromboembolism: Subjects lost to follow up: 1,012 1,008 Subjects with TE lost to follow up: Apparent incidence of TE: 20/10,000 10/10,000 12 2 8/8,988 8/8,992 True RR = 2.0 Can occur in prospective cohort studies and in experimental studies Effects: can produce over- or under- estimate of association.

25. Follow-up Resources • Town lists • Telephone books, 411 • Vital records (birth, death, marriage) • Registry of Motor Vehicles (RMV) lists • MD & Hospital records • Internet • Credit bureau • Relatives, friends (“contacts”) • Professional registries (AMA, RN, ABA, etc.)

26. Tuberculosis Treatment and Breast Cancer Study

27. Follow-up Strategies • Begin with an interested group • Collect identifiable information • Full name & Address • DOB, SSN • Contact information • Maintain frequent contact with all respondents • Regular mail (questionnaires, newsletters) • Telephone calls • Personal contact (if possible) • Incentives (gifts, calendars, money)

28. Analysis of Cohort Study • Basic analysis involves calculation of incidence of disease among exposed and unexposed groups • Depending on available data, you can calculate cumulative incidence (CI) or incidence rates (IR) • Recall set up of 2 x 2 tables

29. x= when they got disease Time at Risk 8.3 x 11.0 14.0 14.0 10.2 x 3.0 12.0 7.0 10.0 3.0 9.0 x 6.2 Total time at risk =107.7 Total person-yrs Person-Time In A Prospective Cohort Study Subject A- B- C- D- E- F- G- H- I- J- K- L- D ? ? D P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13 X= when they got disease D= death ? = Lost to follow-up

30. Analysis of a Cohort Study IRE = A/PYE IRU = C/PYU RR = IRE/IRU Interpretation: The RR is the risk of developing the outcome in the exposed relative to the unexposed

31. Nurse’s Health Study Examine the association Between obesity and CHD In a sample of 117,000 RNs w/o cardiovascular disease Have risk factor Don’t have it Compare Incidence of Disease obese lean Follow-up Surveys Start of Study Future

32. Analysis IR1 = 85/99,573 = 8.54/10,000 woman-years IR0 = 41/177,356 = 2.31/10,000 woman-years RR = IR1/IR0 = 3.7 Obese women had 3.7 times the risk of CHD compared to lean women

33. Rate of CHD per 100,000 P-Yrs (incidence) CHD cases Person-years of observation Risk Ratio <21 41 177,356 1.0 21-<23 57 194,243 29.3 23-<25 56 155,717 36.0 25-<29 67 148,541 45.1 >29 85 99,573 3.7 Risk Ratio In The Nurses Health Study ? Rate of CHD Obesity BMI: 23.1 85.4 Risk Ratio = 85.4/100,000 / 23.1/100,000 = 3.7

34. rate of CHD per 100,000 P-Yrs (incidence) CHD cases person-years of observation Risk Difference <21 41 177,356 23.1 0.0 21-<23 57 194,243 29.3 23-<25 56 155,717 36.0 25-<29 67 148,541 45.1 >29 85 99,573 85.4 62.3 Risk Difference In The Nurses Health Study ? Rate of CHD Obesity BMI: Risk Difference = 85.4/100,000 - 23.1/100,000 = 62.3 excess cases per 100,000 P-Yrs in heaviest group

35. Strengths of Cohort Studies • Efficient for rare exposures • Usually good information on exposures • Can evaluate multiple effects of an exposure

36. A Cohort Study Can Look at Multiple Outcomes Orthopedic Problems Breast Cancer Yes No Cardiovascular Disease Yes No Reproductive Problems Yes Yes No 139 Obesity 119 Yes P-Yrs 169 217 310,820 No 239 3 98 138 227 320,807

37. Disadvantages to Cohort Studies(especially prospective) • May need large numbers of subjects for long periods of time • Can be expensive and time consuming • Not good for rare diseases or those with long latency • Loss to follow up undermines validity

38. When Reading A Cohort Study, Ask… • How were the study groups selected or • defined? • Did they differ in other ways that could • influence the outcome? • Were the data accurate? • Was data collection comparable for all • study groups? • How complete was the follow-up?

39. The Black Women’s Health Study (BWHS) A Follow-up Study of African-American Women Boston University Slone Epidemiology Center

40. Why Is The BWHS Needed? • Rates of illness and death from many diseases are higher in African-American women • Lack of health research studies involving African-American women, particularly large studies

41. Exposure and Outcome Information • Biennial postal questionnaires • Self-report

42. 1995 Questionnaire Data:Baseline Age Weight Height Waist, hip circumference Use of medical care Occupation Education Medical history (prevalent disease) Reproductive history Drugs (OCs, HRT, vitamins, medications) Cigarette smoking Alcohol use Diet (60 item Block-NCI questionnaire) Physical activity Family care responsibilities

43. 1997-2007 Follow-up Questionnaires Update “exposures” for previous 2-year period: (e.g., OC use, weight, alcohol use, cigarette smoking, physical activity, etc.) Record “outcomes” for previous 2-year period: Incident disease, Births, Deaths Additional questions: Ancestry (race, ethnicity, where born) Lupus symptom list Experiences and perceptions of racism Hair straightener use Family history of disease Exposure to violence Use of herbal remedies Individual health/belief system Depression scale (CESD)* Household Income Education * Diet * Religion/Spirituality Perceived stress and coping Dental health Access to car/transportation Siblings/birth order *Repeat Question

44. 1995 – 2007 Questionnaire Data Prevalent and incident diseases and conditions: Hypertension Cervical cancer Diabetes Rheumatoid arthritis High cholesterol Osteoarthritis Heart attack Gingivitis Angina Depression Stroke Sarcoidosis Clot in lung, leg Asthma Cyst in breast Toxemia/Pre-eclampsia Fibroids Gastric/duodenal ulcer Endometriosis Hydatidiform mole Lupus Polycystic ovary Sickle cell anemia Glaucoma Breast cancer Multiple Sclerosis Lung cancer Kidney Stones Colon/rectal cancer Other - specify

45. Validation • Self-reported data • Important for minimizing bias (misclassification) • Must confirm: • Exposures (when feasible) • Vital status (deaths) • Outcomes

46. Validation: Exposures • Expensive, not feasible in most cohort studies • Not all exposures can be easily validated (subjective measures) • Perceptions and experiences of racism/unfair treatment • Can be accomplished in a sample of the cohort • Anthropometric (height, weight, hip & waist circumference) • Physical Activity • Diet

47. Diet Validation Study • 408 BWHS Participants • Over a 1-year period (quarterly) provided: • 3 telephone 24 hour diet recalls • 1 3-day food diary • Compared nutrient intake estimates • FFQ Data vs. Combined recall & diary data Kumanyika et al., Ann Epidemiol 2003;13:111-118

48. Validation: Outcomes Non-medical cohort: • Symptoms of illness are nonspecific • Participants may not know the diagnosis even if it was made • Direct examinations not feasible in a large cohort study

49. Validation: Outcomes Information requested depends on outcome studied • Breast cancer and other cancers: hospital records, pathology reports, discharge summaries, CA registry data • Coronary heart disease: hospital records, discharge summaries • Lupus, RA, MS, Sarcoidosis: hospital records, physician checklists • Hypertension and Diabetes: self-report plus use of appropriate drug, physician checklists

50. Challenges Medical records • Difficulties in obtaining records • Additional consent process (medical release) • Incomplete records • Records from multiple sources • Physician checklists: a burden on physician • Remedies • Patient checklists • Registry Data (Cancer)