1. Prospective Studies (cohort, longitudinal, incidence studies) Sue Lindsay, Ph.D., MSW, MPH Division of Epidemiology and Biostatistics Institute for Public Health San Diego State University

2. Prospective Study Design Develop disease Do not develop disease Develop disease Do not develop disease ExposedNot Exposed Population (does not have disease) select

3. Design Considerations These investigations are oriented to exposure status The objective is to find exposures that lead to disease. How well can you identify exposed individuals? How long should your follow-up be? How frequently do you need to measure exposure? Can you ensure that study subjects do not have the disease at the beginning of the study?

4. Design Considerations Baseline characteristics of exposed and not exposed subjects should not differ. Use comparable source populations with equivalent information. Both groups should be equally available for follow-up. The degree of surveillance for disease should be equal in both groups. Those assessing for disease should be blind to risk factor group.

5. Cohort Study Analysis Incidence rate Relative Risk with Confidence Intervals Risk Difference Attributable Risk Population Attributable Risk

6. The 2 X 2 Table for Cohort Studies a Disease Develops No Disease Exposed (+) Not Exposed (-) b cd Totals a + b c + d First Select

7. Incidence Rate Incidence Per 1,000 = No. of New Cases of Disease In a Population No. of Persons at Risk of Developing Disease During a Specified Period of Time

8. Relative Risk Risk of disease among exposed Risk of disease among the not exposed OR Risk (exposed) Incidence (exposed) Risk (unexposed) Incidence (unexposed)

9. Relative Risk in a 2 X2 Table a DiseaseNo Disease Exposed (+) Not Exposed (-) b cd Risk a c a + b c + d Relative Risk = a/(a+b) c/(c+d)

10. Relative Risk Relative risk measures the strength of an association The larger the relative risk, the stronger the association between the risk factor and the disease Relative risk does not tell you about the actual risk of the disease (this is measured with incidence)

11. Etiologic Objective If exposure is associated with disease, the incidence rate in the exposed group will be greater than in the not exposed group. a a + b >>> c c + d Exposed Not exposed

12. Hypothetical Example: Maternal stress and preterm birth 110 Preterm birth Full term birth Stressed Not stressed 2,890 874,913 Risk 110 3,000 87 5,000 Relative Risk = 110/3000 87/5000 = 2.18 = 0.037 = 0.017

13. RR = 1: There is no association between the risk factor and the disease. RR > 1: There is a positive association between the risk factor and the disease. The risk factor may be a cause of disease. Possible range 1 to infinity. RR < 1: There is a negative association between the risk factor and the disease. The risk factor may be protective against the disease. Possible range 0-1. Interpretation of Relative Risk

14. The Health Risk of Passive Smoking Hirayama et al. 1981 Study Objective: To assess the health effects of passive cigarette smoking Japan 1965 - Data collected in 6 prefectures Studied the smoking habits of the spouses of: 91,540 non-smoking wives 20,289 non-smoking husbands

15. IDENTIFY NEW CASES OF LUNG CANCER Not exposed to second hand smoke 1965 1979 PASSIVE SMOKING IN JAPAN 14 YEAR FOLLOW-UP (Death Certificates) Population: Non-smoking spouses Exposed to second hand smoke

16. Mortality In Non-Smoking Wives Shows increasing risk of mortality with increasing number of cigarettes smoked by spouse Dose-response relationship Relative Risk

17. Mortality in Non-Smoking Husbands Shows increasing risk of mortality with increasing number of cigarettes smoked by spouse Relative Risk

18. Exposure to Second Hand Smoke Number Cancers Incidence 15+ cigarettes/day 1,000 20 20/1,000 10-15 cigarettes/day 1,000 10 10/1,000 5-10 cigarettes/day 1,000 8 8/1,000 <5/day 1,000 5 5/1,000 occasional (not daily) 1,000 4 4/1,000 quitter 1,000 4 4/1,000 never smoked 1,000 2 2/1,000 TOTAL 7,000 53 7.6/1,000 Ever smoked 6,000 51 8.5/1,000 occasional,quitter,never 3,000 10 3.3/1,000 Relative Risk is Relative: Hypothetical Example Relative Risks: 15+ cigarettes/never smoked: 20/2 = 10.00 Ever smoked/never smoked: 8.5/2 = 4.25 Daily/occasional,quitter,never: 10.8/3.3 = 3.25

19. The Royal College of General Practitioners (RCGP) Oral Contraception Study England: Is oral contraceptive use a risk factor for cardiovascular disease? May 1968 - July 1969 23,000 oral contraceptive users identified and recruited by physicians Equal number of non-users identified, matched for marital status and age

20. The RCGP Oral Contraceptive Study 1968 - 1969 23,000 OC Users 23,000 Non- Users 1974 1977 1981 Morbidity and Mortality Follow-up

21. RCGP Oral Contraceptive Study: Relative Risks for Cardiovascular Disease Heart Disease Hypertension Ischemic Heart Disease Subarachnoid Hemorrhage Stroke

22. The Hepatitis B Virus Cohort Study Taiwan: November 1975 – June 1978 Is Hepatitis B etiologically associated with primary hepatocellular cancer? 21,227 male Taiwanese government civil servants recruited

23. The Hepatitis B Cohort Study Recruit 22,707 Taiwanese Men 1975- 1978 3,454 Hepatitis B + 1986 161 new cases of primary hepatocellular cancer 19,253 Hepatitis B -

24. The Hepatitis B Cohort Study 152 Cancer No Cancer HBsAg (+) HBsAg (-) 3302 919244 Risk 152 3454 9 19,253 Relative Risk = 152/3454 9/19,253 = 98.1

25. Potential Bias in Cohort Studies Bias in Ascertainment of Outcome Staff responsible for the identification of disease are aware of exposure status or hypotheses Diagnostic suspicion bias

26. Potential Bias in Cohort Studies Information Bias Occurs when the extent or quality of the information obtained is different for exposed and not exposed study subjects.

27. Potential Bias in Cohort Studies Non-response and Loss to Follow-up Occurs if non-response or loss is different for exposed compared to non- exposed study subjects.

28. Risk Difference Risk (exposed) Incidence (exposed) Risk (unexposed ) Incidence (unexposed) __

29. Maternal Stress and Preterm Birth: Risk Difference 110 Preterm birthFull term Stressed Not stressed 2,890 874,913 Risk 110 3,000 87 5,000 Risk difference = 0.037-0.017 = 0.020 = 0.037 = 0.017 The risk of preterm birth is increased by 0.020 for women who are stressed in their pregnancies

30. Attributable Risk Percent Risk (exposed) Risk (not exposed ) __ What percent of the risk in the exposed population is due to the exposure? Risk (exposed) X 100

31. Maternal stress and preterm birth: Attributable risk percent 110 Preterm birthFull term Stressed Not stressed 2,890 874,913 Risk 110 3,000 87 5,000 Attributable risk = 0.037- 0.017 X 100 54% = 0.037 = 0.017 54% of the total risk for preterm birth among stressed pregnant women is their stress 0.037 =

32. Population Attributable Risk Percent (PARP, Etiologic Fraction) Incidence (total population) Incidence (not exposed) __ The reduction in the incidence of the disease that can be expected if we eliminate the risk factor. X 100 Incidence (total population)

33. Population Attributable Risk Percent (PARP, Etiologic Fraction) This statistic is influenced by two things: Prevalence of the risk factor in the population The strength of the association between risk factor and disease

34. Population Attributable Risk Percent (PARP, Etiologic Fraction) Prevalence of the risk factor in the population

35. Incidence of lung cancer 20% 15% 10% 5% Smokers (25%) Non-smokers (75%) 17% 4% What is the incidence of lung cancer in this population? (17 *.25) + ( 4 *.75) = 7.25% Population Attributable Risk Percent

36. Incidence of lung cancer 20% 15% 10% 5% Smokers (25%) Non-smokers (75%) 17% 4% Incidence in total pop = 7.25% Among the total population, what is the reduction in incidence that we could expect if we eliminated smoking (exposure) from the population? 7.25 - 4 PAR% = 7.25 X 100 = 44.8% Population Attributable Risk Percent 44.8% of incidence could be reduced if smoking is eliminated

37. Incidence of lung cancer 20% 15% 10% 5% Smokers (75%) Non-smokers (25%) 17% 4% What if there were far more smokers in the population? Incidence of lung cancer in this population = (17*.75) + (4*.25) = 13.75% PAR% = 13.75 - 4 13.75 X 100 = 70.9% Population Attributable Risk Percent 70.9% of incidence could be reduced if smoking is eliminated

38. Population Attributable Risk Percent (PARP, Etiologic Fraction) The strength of the association between the risk factor and the disease

39. Incidence of lung cancer 20% 15% 10% 5% Smokers (75%) Non-smokers (25%) 10% 4% What if there were just as many smokers but they smoked less? (only 2 cigarettes per day each) Incidence of lung cancer in this population = (10*.75) + (4*.25) = 8.5% PAR% = 8.5 - 4 8.5 X 100 = 52.9% Population Attributable Risk Percent 52.9% of incidence could be reduced if smoking is eliminated

40. Population Attributable Risk Percent: A comparison of three populations PARP = Incidence in population - incidence in not exposed (incidence of lung cancer in not Incidence in population exposed is 4%) Pop #1: Total population incidence = (.25*17) + (.75*4) = 7.25% 25% smokers PARP = 7.25 – 4 = 44.8% 17% cancer incidence 7.25 Pop #2: Total population incidence = (.75*17) + (.25*4) = 13.75% 75% smokers PARP = 13.75 – 4 = 70.9% 17% cancer incidence 13.75 Pop #3: Total population incidence = (.75*10) + (.25*4) = 8.5% 75% smokers PARP = 8.5 – 4 = 52.9% Only 2 a day 8.5 10% cancer incidence