1. Epidemiological studies

2. Experimental studies Scientifically rigorous Considered as natural experiments Costly Sometimes not feasible Enrollment issues Ethical issues Observational studies Investigators is an disinterested observer People expose themselves to the agent Ethical issues mitigated

3. Observational study - Two types Cohort study Cross-sectional study

4. Analytical Studies Introduction: Analytical studies are either: Observational Case-Control Cohort Study Experimental (Intervention): Animal Experiments Human Therapeutic trials Preventive trials

5. Analytic Studies Analytic studies, etiologic studies, are performed to test specific hypothesis about a specific health problem. In general, associations observed in descriptive studies are often the basis for gathering more specific data and testing hypothesis in additional studies.

6. Analytic studies involve the selection and comparison of two or more groups of persons, based on either their exposure or disease status…. WHY? To evaluate an association between exposure and disease. Analytic studies focuses on the magnitude of the association between the exposure and the health problem under the study.

7. Study Design Life’s a journey... We each carry the burden of personal and group risk factors and exposures. As health professionals, we hope to identify those characteristics causing disease.

8. Study Design Life’s a journey... In individuals, the only way to know if a risk factor caused disease would be to find an exact double, living in a parallel universe, identical in every way to the exposed subject--except for the exposure.

9. Study Design Life’s a journey... If only the exposed subject developed disease, we could be certain the exposure was causal.

10. Study Design Life’s a journey... This is called the “counterfactual argument” because exact doubles and parallel universes do not exist. (Stephen Hawking’s opinions notwithstanding...) How to address this problem?

11. Study Design Life’s a journey... The best we can do is compare populations that are similar (not identical) in everything except the risk factor. If we see increased disease only in the group with the risk factor, we can suspect that the risk factor caused the disease.

12. Study Design Life’s a journey... The “study base” is a population of individuals, each carrying the burden of personal and group risk factors. (Rothman and Greenland, Modern Epidemiology, 1998)

13. Cohort Study

15. What is a cohort? From Latin word Cohors, group of soldiers – 6 centuries (100 men) form a cohort, – 10 cohorts form a legion (therefore 6,000 men). A century, then, would correspond to a company, a cohort to a battalion, and a legion to a regiment. – Once a cohort was formed, no new soldier were added. Soldiers remain in the same cohort for rest of service. – Attrition occurred mainly through death

16. What is a cohort in epidemiology? A group of individuals/persons who are followed / traced over a period of time – Sharing a common characteristic or experience Some alternate names – Cohort study – Longitudinal study – Incidence study – Longitudinal study

18. Retrospective (Case-Control) a b d c DISEASE present absent EXPOSUREEXPOSURE present absent casescontrols Total Prospective (Cohort) exposed Not exposed A fourfold table Mausner, 1985

19. The difference between the two types of studies lies in the way the study groups are assembled With either method of study, if there is a positive association between the factor and the disease: Those exposed will tend to develop the disease (group a), Those not exposed will tend not to develop it (group d).

20. The Prospective Approach The general concept of a prospective study is relatively simple. This type of study has been described by a variety of items:-Cohort -Incidence -Longitudinal -Forward looking -Follow-up

21. Prospective Cohort “concurrent” COHORT Study Retrospective Cohort “non-concurrent” Historical prospective

22. The Prospective Approach (cont.) 1. It starts with a group of people (a cohort) all considered to be free of a given disease. Information is obtained to determine persons having a particular characteristic (certain exposure) that is suspected of being related to the development of disease being investigated. 2. These individuals are then followed for a period of time to observe who develops/or dies from that disease 3. Incidence or death rates for the disease are then calculated.

23. The Prospective Approach (cont.) 4. Rates are compared for those with the characteristic and those without it. 5. If the rates (of development of disease) are different, an association can be said to exist between the characteristic (exposure) and the disease. 6. It is important to obtain information on other characteristic of the study groups: age, sex, … to account for an influence of any factors related to the disease.

24. Study Design Exposure (Risk Factor) Disease (Outcome) Disease (Outcome) + ++ + + _ _

25. Cohort Studies Healthy Cohort  Begin with sample  “Healthy Cohort” (i.e., subjects without the outcome yet) Exposure subsequent disease  Start with Exposure status, then compare subsequent disease experience in exposed vs. unexposed.

26. Study Design Exposure (Risk Factor) Disease (Outcome) Disease (Outcome) + ++ + + _ _

27. Case-Control Studies Cases and Controls  Begin with sample of “Cases and Controls” Disease Exposures  Start with Disease status, then assess and compare Exposures in cases vs. controls.

28. Study Design Exposure (Risk Factor) Disease (Outcome) Disease (Outcome) + ++ + + _ _

29. Cross-Sectional Studies Cross-sectional  Begin with “Cross-sectional” sample ExposureDisease  Determine Exposure and Disease at same time

30. What is a cohort ? A cohort is a group of persons who share a common experience within a defined time period. Example: Birth cohort, marriage cohort, occupational cohort

31. Cohort Study (cont.) Essential points: Exposed individuals in the study should be representative of all exposed persons. Unexposed persons should be representative of all unexposed persons in the population.

32. Cohort Study (cont.) Selection of Cohorts: several approaches Accessible group (volunteers) Group with available records/history of exposure Group experiencing some particular exposure (arising during work) Cohorts may be heterogeneous or homogenous

33. Heterogeneous: with respect to some previous exposure as study of lung cancer and smoking. Homogenous in exposure: As study of the frequency of cancer among asbestos workers. The comparison group is the general population values Demonstrate excess in deaths among asbestos workers.

34. Cohort studies Intuitive approach to studying disease incidence and risk factors: 1. Start with a population at risk 2. Measure characteristics at baseline 3. Follow-up the population over time with a) surveillance or b) re-examination 4. Compare event rates in people with and without characteristics of interest

35. Cohort studies Can be large or small Can be long or short Can be simple or elaborate Can be local or multinational For rare outcomes need many people and/or lengthy follow-up May have to decide what characteristics to measure long in advance

36. Community surveillance enhances generalizability of cohort findings 1. Cohort Community: compare incidence rates and characteristics of events in residents who do and who do not participate in cohort 2. Communities Cohort: compare the study community CHD experience with areas in the U.S.

37. COHORT STUDIES Cohort Study – Key Point: – Presence or absence of risk factor is determined before outcome occurs.

38. Cohort Studies Characteristics: follow-up period (prospective; retrospective) Merits: no temporal ambiguity; several outcomes could be studied at the same time; suitable for incidence estimation Limitations (of prospective type): expensive; time- consuming; inefficient for rare diseases; may not be feasible Effect measure: Risk Ratio (Relative Risk)

39. Cohort Design time Study begins here Study population free of disease Factor present Factor absent disease no disease disease no disease present future

40. Timing of cohort study Prospective cohort study Retrospective cohort study Ambidirectional cohort study

41. Timing of cohort study Prospective Cohort Study Exposure Disease

42. COHORT STUDIES 50% 50% 10%90% R.F. (+) (-) (+) (-) Disease Basic Idea: See if those with the risk factor develop more disease than those without the risk factor

43. COHORT STUDIES Basic Approach: Cohort Study – Identify Cohort (s) – Measure exposure and outcome variables – Follow for development of outcomes

44. COHORT STUDIES Fixed Cohort Exposure (+) (-) x x x X = outcome Relative risk = (2/3)/(1/3) = 2.0

45. 30 a 70 b 70 b 3 c 3 c 57 d 57 d SaladSalad (+) (-) (+)(-) Disease = Hepatitis A a + b 100 c + d 60 Risk =a/(a+b) =0.3 Risk =c/(c+d) = 0.05 Rel. risk= COHORT STUDIESa a + b c c + d 0.3/0.05 = 0.3/0.05 =6 Fixed cohort

46. 30 a 70 b 70 b 3 c 3 c 57 d 57 d SaladSalad (+) (-) (+)(-) Disease = Hep A a + b = 100 c + d = 60 Odds Ratio: (a/c)/(b/d)=(a/b)/(c/d) Rel. risk= COHORT STUDIESa a + b c c + d 0.3/0.05 = 0.3/0.05 =6 (30/3)/(70/57)= 8.14

47. COHORT STUDIES Dynamic Cohort Exposure (+) (-) Rel. Risk = 2/3 / 2/3 =1 or 2/5 py / 2/10 py = 2.0 Years X X X X

48. COHORT STUDIES Cohort : 16, 936 Harvard grads Measure: Question re: activity level Follow: “Sedentary”: 24 CHD deaths per 10,000 person-years vs. “Active”: 16 CHD deaths per 10,000 person-years Relative risk = 24/16 = 1.5

49. COHORT STUDIES Questions: Findings due to confounding? Could subclinical disease have affected the risk factor (activity)?

50. COHORT STUDIES Take-Home Message: The best measure of effect is the “relative risk.” For a fixed cohort, this will be the ratio of the cumulative incidences. For a dynamic cohort, this will be the ratio of the incidence rates. The odds ratio can be used for fixed cohorts comparing cumulative incidences. It will be close to the relative risk for rare diseases.

51. COHORT STUDIES Variations on a theme: Retrospective (Historical) Cohort

52. COHORT STUDIES Prospective: Outcomes have not yet occurred as study begins. Example: Women’s Health Study. Retrospective: Outcomes have already occurred as the study begins. Example: finding a trove of medical records allowing you to follow a cohort born in 1880 to death.

53. COHORT STUDIES Utility and Strengths Incidence and natural history Temporal sequence Avoid survivor bias Avoid reporting bias Look at multiple outcomes

54. Purpose of cohort study Descriptive – To describe the incidence of certain outcome overtime Analytical – To analyze association between risk factors and outcomes

55. Two basic types of cohort study Prospective cohort Retrospective cohort

56. Types of population studied 3 types of population – Open or dynamic – Fixed – Closed TypeDefined byFollow upMeasure of disease Open or dynamicChangeable characteristic Members come and go, losses can occur Incidence rate FixedIrrevocable eventNo gain in member, loses may occur Incidence rate ClosedIrrevocable eventNo gain in member, no loses occur Cumulative incidence

57. Open/ dynamic population Membership criteria is changeable – Smoking – Alcohol drinking – Certain occupation – People living in a geographic area Consider / account for in- and out- migration

58. Examples: Open/ dynamicpopulation Cancer incidence among never-married men aged 15-54 yrs and resided in San Francisco – Period of FU 1973-1990 – Changeable characteristics- marriage, age, place of residence – FU of 1,930,000 person years – incidence of NHL increased by 20 times, but rectal cancer remained same

59. Fixed population Membership criteria is irrevocable / fixed – Giving birth to a baby – Undergoing a medical procedure – Eating contaminated food – Joining military – Presence during a disaster Exposures do not change over time Followed for a fixed period Loss of members may occur

60. Examples: Fixed population World war II- Hiroshima & Nagasaki nuclear bombing – Biological effects of radiation exposure – Monitoring of mortality and cancer incidence among 94000 residents who were in the city and 27000 residents who were outside the city during bombing – Follow up for disease incidence

61. Closed population Same as fixed cohort – Membership criteria is irrevocable / fixed Giving birth to a baby Undergoing a medical procedure Eating contaminated food Joining military Presence during a disaster – Exposures do not change over time – Followed for a fixed period But NO Loss of members occur

62. Examples: Closed population To examine risk of GI infection during one week after an eating of certain type of food among people attending a party – Assuming the symptoms would start relatively fast and will end by 7 days – Everybody who attended the party is a member – Follow up starts at the end of the party and continues till one week – No loss of member, as period of observation is short – Estimate cumulative incidence

63. Exposure Event that has bearing on the outcome of interest

64. Cohort Study (Prospective Design) Passive smoking & respiratory infections in children Is passive exposure to tobacco smoke associated with increased respiratory infections in children ? Design: Children exposed and not exposed tobacco smoke in their homes Follow them in time for disease occurrence.

65. Children (<12 yrs) 1000 Family smoker 500 children Exposed Family non-smoker 500 children Not exposed 1 year Diseased 300 Not diseased 200 Diseased 120 Not diseased 380 OutcomeStart

66. Rate: Incidence rate Incidence of Resp. Infection among exposed children: 300 500 = 60% Incidence of Resp. Infect. Among non exposed children: 120 500 = 24%

67. Cohort Study (cont.) Relative Risk : Incidence rate among exposed Risk Ratio Incidence rate in non exposed. 60 24 = 2.5 Relative Risk is a direct measure of risk (to assess the etiologic role of a factor in disease occurrence). 300 x 500 500 120

68. Cohort Study (cont.) Relative Risk : Smoking -Lung Cancer mortality: RR=18.57 -Myocardial infarction mortality: RR=1.35 It measures the strength of association

69. Cohort Study (cont.) Attributable Risk : The absolute difference in Incidence rates among groups. “Risk Difference” RD 60 - 24 = 36% The extent to which the incidence of disease can be attributed to the risk factor Smoking -Lung cancer mortality: RD=1.23 -Myocardial infarction mortality RD=1.25

70. Annual Death Rates / 100,000 personsExposure Category Lung Cancer Coronary Heart D. 166 599 7 422 166 / 7 = 23.7 599 / 422 = 1.4 166 – 7 =159 599 – 422 = 177 Heavy smokers Nonsmokers Measures of Excess Risk Relative Risk: Attributable risk: Doll and Hill study : Mortality of British doctors cited from Mausner, 1985

71. The previous table suggests that prevention of coronary heart disease would require alteration of other factors in addition to smoking. The population attributable risk: relates both relative risk and frequency of the factor in the population i.e. a large proportion of the deaths from lung cancer in the total population are due to smoking not only because of the high RR associated with smoking, but also bec large proportion of the pop that smoke.

74. Examples from the literature Framingham Heart Study initiated in 1948 by US Public Health Services: to study the relationship of a variety of factors to the subsequent development of heart disease Group of persons 30 – 62yrs 6,500 Both sexes 20 years follow up Information: S. cholest.level Bl.pressure, weight Cig. Smoking outcome

75. Occupation Based Studies to study effect of exposures Benzene workers and Leukemia Coke-oven workers and lung cancer Asbestos workers and lung cancer Radium dial painters and oral cancer

76. Males Females (45-54y) (45-54) Initial Serum Cholesterol Level RR 1.35 1.3 1.48 1.43 2.85 2.57 3.25 2.89 200 - < 220 220 - < 240 320 - < 340 340 - < 970 There is an increasing risk of CHD with increasing initial Serum cholest. Levels in the 45-54 age group from a relative Risk of 1.13-3.25 M, 1.13-2.89 F

77. 1/9/2007Cohort studies 77 Relating risk factors to health outcomes – questions Is this health condition associated with this exposure? – Association not = causation but may reflect it How strongly are these two factors related? – Strong association more likely causal How much of a disease can be attributed to a causative factor?

78. 9/27/2004Cohort studies 78 What is an association? Factors are associated if: the distribution of one factor is different for different values of another. knowing the value of one factor gives information about the distribution of the other.

79. 9/20/2000 79 Example – oral contraceptives and CHD

80. 9/27/2004 80 Example – oral contraceptives and CHD (positive association) 30% (30/100) of controls OC, overall 60% (30/50) of CHD cases used OC

81. 9/27/2000 81 Example – oral contraceptives and breast cancer

82. 9/27/2004 82 Example – oral contraceptives and breast cancer (no association) 30% (30/100) of noncases used OC 30% (15/50) of cases used OC

83. 6/9/2002Cohort studies 83 Measures of association Can compare incidences (rate or proportion), prevalences Look at differences (e.g., “incidence difference”) (retains units) Look at ratios (e.g., “incidence ratio”) (no units)

84. 2/21/2006Cohort studies 84 Translating measures of association If incidence ratio for runners / non-runners = 3.0: – “Incidence in runners was 3 times that in non- runners.” – “Incidence in runners was 3 times as great as in non-runners.” – “Incidence in runners was 200% greater than incidence in non-runners.” [(3.0 – 1.0) / 1.0 = 200%]

85. 10/1/2001Cohort studies 85 Translating measures of association “Incidence in runners was 3 times greater than incidence in non-runners” is ambiguous Does it mean incidence ratio = 3.0 ? Does it mean incidence ratio = 4.0 ?

86. 10/1/2001Cohort studies 86 Translating measures of association If incidence for runners / non-runners = 0.30: – “Incidence in runners was 0.30 times that in non-runners.” – “Incidence in runners was 30% of that in non- runners.” – “Incidence in runners was 70% lower [or “less”] than incidence in non-runners.” [(1.0 – 0.30) / 1.0 = 0.70 = 70%]

87. 10/1/2001Cohort studies 87 Translating measures of association Or, can say “Incidence in non-runners was 3.3 times as great as incidence in runners”.

88. 2/21/2006Cohort studies 88 Measures of impact Concept of attributable risk – How much of a disease can be attributed to a causative factor? – What is the potential benefit from intervening to modify the factor? Important for – Public health policy – Legal liability – Clinical/individual decisions

89. 10/1/2001Cohort studies 89 Example questions – Now that I am 35 years old, my CHD risk from taking oral contraceptives is twice as great as when I was 25. But how much more risk do I have due to taking the pill? – How much of the risk of heterosexual transmission of HIV might be eliminated through eliminating bacterial sexually transmitted diseases?

90. 10/1/2001Cohort studies 90 Example questions How many cases of asthma are due to ambient sulfur dioxide? What proportion of motor vehicular deaths can be prevented by mandatory seat belt use. What proportion of perinatal HIV transmission has been prevented through the use of prenatal, intrapartum, and neonatal zidovudine (AZT)?

91. 10/1/2001Cohort studies 91 Simplifying assumptions 1. “Exposure” either causes or prevents the outcome, but not both (no two-edged swords) 2. “Exposed” and “unexposed” groups are alike in all other respects (no confounding) 3. No other causes “compete” with the exposure

92. 10/1/2001Cohort studies 92 Several concepts Concepts “Absolute” versus “relative” Exposed versus total population Disease caused, disease prevented

93. 10/1/2001Cohort studies 93 Many terms, many meanings E.g., “attributable risk” can mean: – Risk difference – Population attributable risk percent – Concept of assessing impact

94. 10/1/2001Cohort studies 94 “Absolute” perspective How much risk? – In exposed persons: risk difference (I 1 – I 0 ) – In the total population: (I 1 – I 0 ) x exposure prevalence (P 1 ) How many cases? (I 1 – I 0 ) x # of exposed persons (n 1 )

95. 10/1/2001Cohort studies 95 Relative perspective What proportion of the risk is attributable? (What proportion of cases could be eliminated?) In exposed persons: (I 1 – I 0 ) / I 1 = (IR–1) / IR (Relative strength of association) In the population: (I – I 0 ) / I (Strength of association and prevalence)

96. 10/6/2009Cohort studies 96 How much risk? What %? How many cases? What %?

97. 10/6/2009Cohort studies 97 How much risk? What %? How many cases? What %?

98. 6/9/2002Cohort studies 98 Attributable risk diagram Attributable cases

99. 6/9/2002Cohort studies 99 Prevented fraction diagram Prevented cases

100. Advantages of Cohort Study Correct classification of exposure before disease develops. Permits calculation of incidence rates thus, a direct measure of relative risk, and attributable risk. Many possible outcomes to the same exposure can be studied. No chick egg dilema Accurate

101. Disadvantages of Cohort Study Large number of people are needed (large scale). Time consuming (follow up) Losing people in follow up (Attrition) Expensive Status of subjects may be changed leading to error in classification of exposure eg. Change in habit, occupation. Administrative problems: loss of staff, funding, high costs of the extensive record keeping

102. Non concurrent studies Retrospective Cohort The period of observation starts from some date in the past.past. They usually involve specially exposed groups or industrial populations. Done by using company records of past & present employees: Information: - date of employment - date of departure - duration, degree of exposure - status: living/dead

103. Nested case control studies