1. Cohort study

2. What is a cohort? One of 10 divisions of a Roman legion
Group of individuals
sharing same experience
followed up for specified period of time
Examples
birth cohort
cohort of guests
occupational cohort of chemical plant workers

3. follow-up period

4. Calculate measure of frequency:
Cumulative incidence
Incidence proportion
Attack rate (outbreak)
Incidence density
end of follow-up

5. Cohort studies Purpose Cohort membership
Study if an exposure is associated with outcome(s)?
Estimate risk of outcome in exposed and unexposed cohort
Compare risk of outcome in two cohorts
Cohort membership
Being at risk of outcome(s) studied
Being alive and free of outcome at start of follow-up

6. Cohort studies
unexposed
exposed

7. Incidence among unexposed
Cohort studies
exposed
Incidence among
exposed
Incidence among unexposed
unexposed

8. Prospective cohort study
Disease
occurrence
Exposure
Study starts
time

9. Retrospective cohort studies
Exposure
Disease
occurrence
time
Study starts

10. Disease occurrence Exposure Study starts time
Case study Salmonella in Belfast

11. Cohort Study Design Directionality
Longitudinal
1990
2000
2010
Prospective
Retrospective
Retrospective
Cohort Study
Prospective
Cohort Study

12. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Time
Healthy People - E DZ
Cohort Study

13. Cohort studies
4/19/2017
B.Shakiba

14. Cohort Study Design (+) Exposed T Study PAR Group S Unexposed
Outcome
Outcome (-)
(+) T
PAR = Population at Risk
S = Sampling design
T = Elapsed time

15. Recipe: Cohort study Identify group of
exposed subjects
unexposed subjects
Follow up for disease occurrence
Measure incidence of disease
Compare incidence between exposed and unexposed group

16. Study Population Define Population at Risk using inclusion criteria
Individuals with outcome of interest at time of screening and enrollment are not eligible for study
Sub-clinical presentation of diseases may be present challenges in defining the cohort

17. Our objective is to compare:
An incidence rate in an exposed population
to the rate that would have been observed
in the same population, at the same time
if it had not been exposed

18. Prospective Cohort Study
Measures of association
Relative risk (ratio of proportions)
Odds ratio

19. Study Design: Prospective Cohort Study
Relation between oral contraceptive use and circulatory disease
Study design:
Identify 23,000 users and 23,000 nonusers of oral contraceptives
Follow and ascertain presence or absence of circulatory disease

20. Cohort Study Design
An epidemiologic design in which the incidence of a disease (or condition) is estimated and compared among exposed and unexposed individuals.

21. Cohort Study Design Rationale
Cohort study designs evolved because of the need for information on the length of survival and the natural history of disease
Clinical and public health interest

22. Cohort Study Design History
Prospective cohort studies
Chronic Disease Cohorts (20th Century)
Framingham study of cardiovascular disease, 1948
Japanese atomic bomb survivors, 1946
British physician study, 1950s
Colorado Plateau uranium miners, 1950s
Retrospective cohort studies
Aniline-dye occupational cohort, 1954

23. Framingham Study Cohort Assembly
No. Men
No. Women
Total
Random Sample
3,074
3,433
6,507
Respondents
2,024
2,445
4,469
Volunteers
312
428
740
Respondents free of CHD
1975
2,418
4,393
Volunteers free of CHD
307
427
734
Total free of CHD
2,282
2,845
5,127

24. Measuring Exposure
Measuring exposure is one of the fundamental activities of a cohort study
Exposure measurement must be comparable for all members of the cohort
Carefully defined in advance of study
Specific attention should be given to the accuracy and precision of proposed measurements
Pilot studies often needed

25. Determining the Exposure
Valid means of determining exposure include:
Questionnaires (e.g., age, smoking history)
Laboratory tests (e.g., cholesterol, hemoglobin)
Physical measurements (e.g., blood pressure, height)
Special procedures (e.g., electrocardiogram,
x-rays)
Medical records

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

27. Comparison (Control) Groups for Cohort Studies
Internal controls
With a one-sample (population-based) cohort, exposure is unknown until after the first period of observation
Example:
Select the cohort (such as all residents of a given neighborhood)
All members of the cohort are then given first round questionnaires, and/or clinical examinations, and/or testing to determine exposure
The cohort is then divided into exposure categories based on those results

28. Comparison (Control) Groups for Cohort Studies (cont.)
External controls
If everyone in a cohort is exposed (such as workers in an industry), a separate cohort as similar as possible to the exposed in terms of income, education, geography, and age should be sought
Example:
Workers in a neighboring but unexposed industry

29. Comparison (Control) Groups for Cohort Studies (cont.)
Known population rates
If a comparison group cannot be assembled, known population rates of outcomes may be acceptable under some circumstances, if they are adjusted for the variables of interest
For lung cancer, however, rates are based on the population and are not adjusted for smoking
They are not, therefore, instructive to compare to populations with high smoking rates, such as miners

30. Outcome Definition
Primary outcome - the main event that will be related to the exposure
Failure-time outcomes
Death
Disease occurrence
Repeated measures
Secondary outcomes - other events that are of interest and may corroborate the findings of the main outcome

31. Follow-up Completeness and non-participation
90% rule of thumb
All subjects must have an equal likelihood for detecting the outcome
Disease ascertainment must be comparable between the exposed and unexposed subjects
Number of visits
Reasons for additional evaluations
Follow-up mechanisms
Active
Passive

32. Follow-up Passive Surveillance Active surveillance Hospitals
Disease Registries
Clinics or physician offices
Surveillance systems, e.g., National Death Index, CDC reportable conditions
Active surveillance
Systematic evaluations for outcome of interest
Regular time intervals
In all study subjects

33. Cohort Study Design Types of Cohorts
Fixed Cohort
A group of individuals recruited and enrolled at a uniform point in the natural history of a disease or by some defining event
Cohort does not take on new members after it is assembled
Examples
Patients admitted to the ER with acute MI
Survivors of Hiroshima bombings
Children born to HIV-infected mothers

34. Cohort Study Design Type of Cohorts
Open cohort
A group of individuals recruited and enrolled through a mechanism that allows for in and out migration of people
Defined by characteristic other than disease, e.g., geographic location, administrative unit
Dynamic population
Examples
Framingham Study

35. Cohort studies
Fixed Cohort
X = outcome x
(+) x
Exposure
(-) x

36. Cohort studies
X = outcome
Dynamic X X
(+)
Exposure X X
(-)
Years

37. Cohort studies Fixed Cohort Loss to follow-up Deaths Open Cohort Out -
In -
Migrations
Out -
Time

38. Cohort Studies
Also called follow-up studies, incidence studies, panel studies, or prospective studies
Begin with a group of individuals free of the disease(s) of interest
Determine the incidence rate (or mortality rate) among the exposed and the unexposed
In a prospective cohort study, you collect exposure information at the time the study begins and follow the cohort for disease status that may occur in the future
In a retrospective cohort study, you collect exposure information from some time in the past and construct disease incidence (or mortality) from then until the present
You may also begin with a retrospective cohort and follow it prospectively (sometimes referred to as an ambicohort study)

39. Advantages
and
disadvantages

40. Cohort Study Design Potential Biases
Nonparticipation (selection bias)
Selective participation of persons
loss to follow-up
Information bias
The quality of information is different between exposed and unexposed subjects
Detection bias
Subjects with exposure are more (or less) closely evaluated for outcome
Blinding to exposure status

41. The cohort study is the gold-standard of analytical epidemiology
Cohort studies
Advantages:
The cohort study is the gold-standard of analytical epidemiology
ascertain incidence and natural history
investigation of multiple outcomes
assessment of many outcomes
Useful for rare exposures
Temporal relationship between exposure and outcome
Ascertainment bias minimized
Less subject to selection biases
outcome not known (prospective)
Can directly measure
incidence in exposed and unexposed groups
true relative risk
Can examine multiple effects for a single exposure
4/19/2017

42. Cohort studies Disadvantages: Selection bias Loss to follow up
Requires excellent follow-up
Large sample size
Latency period
Time consuming
Inefficient for rare diseases
Expensive
Ethical considerations
Exposure can change
4/19/2017

43. Effects

44. Cohort studies
Rate
Rate difference
Rate Ratio (strength of association)
Case control studies
No calculation of rates
Proportion of exposure

45. Measures of Association: Prospective Cohort Study
Relative risk
Also know as risk ratio
Ratio of the proportion of cases in exposed group compare to proportion in unexposed group

46. Relative Risk General interpretation of relative risk (RR)
If RR > 1 Positive association between disease and risk factor
= 1 No association
< 1 Negative association
The “reference group” is in the denominator
Reference group generally chosen as the “unexposed” group

47. Odds Ratios
The odds of a disease is defined as
or equivalently:

48. Odds Ratios
For example, if the risk of having disease A were .20, the odds of having disease A would be .20/.80 = .25 (or 1 in 4)
Notice, the odds is not the risk but is a “function” of the risk
Just as we can compare risk via the risk ratio, we can compare odds via the odds ratio
Odds ratio is very easy to calculate from a 2 x 2 table!

49. Bottom line:
Only cohort studies (including clinical trials) can yield incidence and relative risk.
The odds ratio, (e.g., from a case-control study) will always be greater than the relative risk. For rare diseases, the odds ratio will be close to the relative risk.

50. A cohort study allows to calculate indicators which have a clear, precise meaning.
The results are immediately understandable.

51. Presentation of cohort data: Population at risk
Does HIV infection increase risk of developing TB among a population of drug users?
Population Cases
(f/u 2 years)
HIV
HIV
Source: Selwyn et al., New York, 1989

52. Presentation of cohort data: Person-years at risk
Tobacco smoking and lung cancer, England & Wales, 1951
Person-years Cases
Smoke ,
Do not smoke ,
Source: Doll & Hill

53. Presentation of data: Various exposure levels

54. Effect measures in cohort studies
Absolute measures
Risk difference (RD) Ie - Iue
Relative measures
Relative risk (RR)
Rate ratio
Risk ratio Ie
Iue
Ie = incidence in exposed
Iue= incidence in unexposed

55. Does HIV infection increase risk of developing TB among drug users?

56. Vaccine efficacy (VE)
VE = 1 - RR =
= 72%

57. Cohort study: Tobacco smoking and lung cancer, England & Wales, 1951
Source: Doll & Hill

58. Source population
Cases
Pop. E a P1
I1 = a / P1 c P0 E
I0 = c /P0

59. Source population E a P1 I1 = a / P1 c P0 E I0 = c /P0 E a b c d E
Cases
Pop. E a P1
I1 = a / P1 c P0 E
I0 = c /P0
= sample
Cases
Controls E a b
P1 b
= ----
P0 d c d E

60. } Source population E a P1 I1 = a / P1 c P0 E I0 = c /P0 E a b c d E
Cases
Pop. E a P1
I1 = a / P1 } c P0 E
I0 = c /P0
a/P a . P0 a . d
I1 / I0 = = = =
c/P0 c . P1 c . b
a / c
------
b / d
= sample
Cases
Controls E
Since d/b = P0 / P1 a b
P1 b
= ----
P0 d c d E

61. Source population E 30 100 Case control Cohort 10 100 E E 30 20 10 20
Cases
Pop. E 30
100
Case
control
Cohort 10
100 E
30/ /10
I1 / I = = = 3
10/ /20
Cases E 30 20 10 20 E

62. Case control study design
Cases
Controls
Odds ratio E a b
a b a x d =
c d b x c c d E