1. Epidemiology – Cohort studies I March 2010
Jan Wohlfahrt
Afdeling for Epidemiologisk Forskning
Statens Serum Institut

2. EPIDEMIOLOGY COHORT STUDIES I March 2009 (modified)
Søren Friis
Institut for Epidemiologisk Kræftforskning
Kræftens Bekæmpelse 2

3. Sherlock Holmes: The Sign of four
”While the individual man is an insoluble puzzle, in the aggregate he becomes a mathematical certainty. You can, for example, never foretell what any one man will do, but you can say with precision what an average number will be up to”
Arthur Conan Doyle
Sherlock Holmes: The Sign of four

4. Ideal study of a causal effect
”The experience of exposed people is compared with their experience when not exposed, while everything else is held constant”
Kenneth Rothman, Modern Epidemiology, 1998

5. Assignment of exposure
Analytic epidemiological studies
Assignment of exposure
Yes No
Non-experimental
studies
Non-experimental
studies
Experimental studies
Sampling according
to exposure status
Sampling according to outcome status
Random allocation no
yes
Community intervention trials
Randomised/
intervention trials
Cohort studies
Case-control
studies

6. Cohort studies Classical definition
”The delineation of a group of persons who are distinguished in some specific way from the majority of the population and observation of them for long enough to allow any unusual morbidity or mortality to be recognised”
Richard Doll 1964

8. Cohort studies Recent definition
Experiments
Randomised clinical trials
two (or multiple)-arm, cross-over
Field trials
intervention on single-person level
Community intervention trials
intervention on community level
Non-experimental cohort studies

9. Udfald + Population at risk - + - Past Present Future Follow-up
Exposed
Censored
Population
at risk - +
Non-exposed
Censored -
Past Present Future
Identify study subjects and assess exposure characteristics
Follow-up

10. Population at risk
Individuals at risk of developing the outcome(s) of interest
Basis for computation of measures of diseases frequency and effect measures
Classified according to exposure characteristics
At baseline
During follow-up
Censoring at
First outcome (typically)
Death
Migration
Upper age limit, if age restriction
Other criteria, e.g. exposure shift

11. Cohort
”Any designated group of individuals who are followed or traced over a period of time”
Kenneth Rothman, Modern Epidemiology, 1998
Can be divided into closed and open populations

12. Closed and Open Populations
Closed population
A population that adds no new members over time
Open/dynamic population
A population that may gain members over time or lose members who are still alive
e.g. drug users within a specific observation period

13. Closed population limitations
Loss to follow-up (censoring)
Decreasing cohort size
Aging of cohort members
Depletion of susceptibles

14. Selection of the exposed population
General population
Diet, Cancer & Health cohort, Danish Cancer Society
Individuals aged 50 to 64 years, follow-up from (n  57,000)
Occupational exposure groups
Nurses Health Study, USA
Nurses aged 30 to 55 years, follow-up from 1976 (n  120,000)
Exposure
”Special exposure groups”
Ex.: Workers at the Thule base, Epileptics at Dianalund, individuals exposed to thorotrast
Drug users
Registers
General Practice Research Database, UK
Danish health and administrative registers

15. Selection of the comparison group
Ideally identical to the exposed group with respect to all other factors that may be related to the disease except the outcome(s) under study
”Internal” comparison
general population/large occupational cohort
frequent exposure
”External” comparison
General population (rates)
Standardised incidence rate ratio (SIR)
Standardised mortality rate ratio (SMR)

16. Data sources Outcome Registers Clinical examination
Information from study subjects
interview
questionnaire
Information from next-of-kin
Mortality data
Exposure
Existing data
registers
medical records
bio-banks
Questionnaires
interview
self-administered
Ad hoc measurements
clinical parametes
biological samples

17. Cohort studies Advantages
Can examine
multiple effects of a single exposure
rare exposures
Exposures with certainty precede outcomes (if prospective)
Allows direct measurement of incidence (IR, IP) of outcomes
Can elucidate temporal relationship between exposure and outcome
Allow study subjects to contribute person-time to multiple exposure categories
Biological material can be collected prior to outcome
If prospective, minimizes bias in the ascertainment of exposure

18. Cohort studies Disadvantages
If prospective, cannot provide quick answers
If retrospective, precise classification of exposure and outcome may be difficult
Validity of the results can be seriously affected by losses to follow-up
Is inefficient for the evaluation of rare diseases
If prospective, can be very expensive and time consuming
If retrospective, requires the availability of adequate records for both exposure and outcome

19. Methods for reduction of costs and time
Cohort studies
Methods for reduction of costs and time
Historical cohort studies
Comparison with general population (rates)
Nested case-control studies
Register studies

20. Register studies in DK

21. Register studies in DK
Frank L. Science 2000;287:

22. Register studies in DK CPR Register Cancer Registry
National Death Files
CPR Register
IDA Register
(socioeconomic
variables)
Birth Register
National Hospital
Register
Prescription
Databases

23. Register studies Registers are highly valuable data sources, BUT
Difficulties in interpretation due to incomplete data on competing risk factors
Life-style factors, socioeconomic factors, comorbidity, medical treatment
Other potential biases
Misclassification, non-compliance, etc.

24. Measures of disease frequency
Definitions
What is the case?
What is the study period?
What is the population at risk?

25. Measures of disease frequency, summary
Incidence proportion (IP)
Proportion of population that develops the outcome of interest during a specified time
Can be measured only in closed populations
”Average risk” for a population
Incidence rate (IR)
Number of new cases of the outcome of interest divided by the amount of person-time in the base population
Can be measured in both open and closed populations
Most often restricted to include a maximum of one event per person
Prevalence proportion (PP)
Proportion of population that has the outcome of interest at given instant

26. Effect measures in cohort studies
IP+ = a/a+b
IP- = c/c+d
RR = IP+/IP-
Attributable risk (AR) = IP+ - IP-
Attributable proportion (AP) = AR/IP+ = (RR-1)/RR

27. Incidence proportion Conditions
All persons should be followed-up from start of study (t0) until end of study with respect to the outcome(s) of interest
Problems:
Open/dynamic population (t0?)
Competing risks of death
Censoring
Is usually not directly observable, solution:
Computation of incidence rates

28. Relation between rate (IR) og risk (IP)
IP = 1 - exp(-IR x t) (IR constant)
IP = 1 - exp(- IRí x tí ) (IR variable)
IR small and/or short t:
IP  IR x t

29. Time dimension Person-time in study
cases
Non-exposed
Exposed
cases
Person-time in study
Problem: Exposure status changes over time (episodical, sporadical)
Solution: Allow persons to contribute person-time to multiple exposure categories

30. Y Age Ex Calendar time X Non-X
30-year-old man is enrolled in a cohort study of drug X in relation to disease Y in 1970 and followed free of Y through 1995 55 50 Y 45 40 35
35-year-old man is enrolled in 1970 and followed until occurrence of Y in 1983 30
1970
1975
1980
1985
1990
1995
Calendar time X
Non-X

31. Effect measures in cohort studies
Cases
Person-time
cases
Exposure A PY
Non-exposed
Yes
Exposed C PY No
cases
A = Exposed cases
C = Non-exposed cases
Person-time in study
Incidence rate = cases / person-time
Incidens Rate Ratio (IRR) = IR+ / IR-

32. Effect measures in cohort studies
IR+ = a/PY+
IR- = c/PY-
Incidence rate ratio (IRR) = IR+/IR-
Incidence rate difference = IRD (≈AR) = IR+ - IR-
AP = IRD/IR+ = (IR+-IR-)/IR+ = (IRR-1)/IRR

33. ”Relative risk” vs. incidence rate ratio
Given IP  IR x t (IR small)
”Relative risk” is equivalent with the ratio of two incidence rates when the disease is rare

34. Effect measures in cohort studies
Indirect Standardisation
Do more outcomes occur in the studied population than would be expected if the risk prevailing was the same as in the general population?
Estimation of expected number of outcomes
Number of person-years at risk x incidence rate
PYage,period,sex x incidenceage,period,sex
Observed number/expected number ≈ RR
Standardised incidence ratio (SIR)

35. Calendar time SIR = Observed number of outcomes/
expected number of outcomes
= Obs/IRpop x PYexp
= (Obs/PYexp) / IRpop
= IRexp / IRpop
≈ IRexp / IR0
= IRR (RR)
Calendar time

36. Risk window
Exposure
Often unknown

37. Relevant exposure? Ex Ex Ex 1-3 days? Ex Ex Ex 10-15 days? Ex Ex Ex
years?

38. Hazard function
Outcome
Theoretical association
Exposure

39. Hazard functions
Outcome
Exposure

40. NSAID cohort study Ex
Population: Saskatchewan – province in Canada with appr. 1.1 mill. inhabitants
A study of the association between use of NSAIDs and risk of gastrointestinal (GI) bleeding included all 228,392 individuals who had redeemed one og more prescriptions for NSAIDs. The study subjects were followed during the period for hospitalization due to upper GI bleeding
From the paper: .. Entered our cohort upon the first receipt of a prescription for diclofenac, indomethacin, naproxen, piroxicam or sulindac. Person-time contributed by this person continued until the earliest of: 1) hospitalization due to UGB, 2) death, 3) departure from Saskatchewan or 4) end of study
Note!: No control group of ’non-exposed’
Garcia Rodriguez et al. NSAIDs and GI-hospitalizations in Saskatchewan: A cohort study. Epidemiology 1992;3:337-42

41. Ex
The person time of the study subjects was categorized according to time since last prescription
1. Rx
Current user
Recent past user
Old past user
Non-user
# 1
Day
Current user
Current user
Current user
Current user
Recent past user
# 2
Day
1.Rx
2.Rx
3.Rx
4.Rx

42. Ex
Modified from Garcia Rodriguez et al. NSAIDS and GI-hospitalizations in Saskatchewan: A cohort study. Epidemiology 1992;3:337-42

43. Absolute vs. relative disease measures
Avoid confusing measures of frequency with measures of association (effect measures)
Ex:
A RR=10 is described as a high risk, or a population for whom RR=10 is said to be at higher risk than a population in which RR=5
A RR=10 may be described as a high relative risk

44. Ex
Risk of deep vein thrombosis (DVT) Third vs. second generation oral contraceptives
RR  1.7 ( )
AR  1.5 per person-years
Mortality of DVT  3%
Kemmeren et al. BMJ 2001; 323: 131-4

45. Vioxx (rofecoxib) and cardiovascular disease APPROVe trialEx
Vioxx (rofecoxib) and cardiovascular disease APPROVe trial
2,586 patients randomised to rofecoxib (Vioxx) (25 mg daily; n=1287) or placebo (n=1299) during a 3-year study period
1.50 CVE per 100 py (46 events; 3,059 py) vs.
0.78 CVE per 100 py (26 events; 3,327 py)
RR = 1.92 ( )
AR  72 pr py
Bresalier et al. N Engl J Med 2005; 352:

46. Attributable proportions
What proportion of the disease among the exposed is attributable to the exposure (APexp)?
APexp = IR+-IR0 / IR+ = AR / IR+ = (RR-1)/RR
What proportion of the disease in the total study population of exposed and non-exposed individuals is attributable to the exposure (APpop)?
APpop = IRpop-IR0 / IRpop
= AR x pe / IRpop (pe = exp. prevalence in population)
= APexp x pc (pc = exp. prevalence among cases)
= [(RR-1) x pe] / [(RR-1) x pe - 1]

47. Ex
Attributable proportion Incidence rates of head and neck cancer per 100,000 py
”Non-smoker”
”Smoker”
”Non-drinker” 1 4
”Drinker” 3 12
Among drinking smokers, what proportion of head and neck cancer is caused by smoking?
Among drinking smokers, what proportion of head and neck cancer is caused by drinking?

48. Ex
Attributable proportion Incidence rates of head and neck cancer per 100,000 py
”Non-smoker”
”Smoker”
”Non-drinker” 1 4
”Drinker” 3 12
Among drinking smokers, what proportion of HNC is caused by smoking?
AP = IRD/IR+S+A = (IR+S+A-IR-S+A)/IR+S+A = (12-3)/12 = 75%

49. Ex
Attributable proportion Incidence rates of head and neck cancer per 100,000 py
”Non-smoker”
”Smoker”
”Non-drinker” 1 4
”Drinker” 3 12
Among drinking smokers, what proportion of HNC is caused by drinking?
AP = IRD/IR+S+A = (IR+S+A-IR+S-A)/IR+S+A = (12-4)/12 ≈ 67%

50. Study population N GI bleeding NSAID users 20,000 100Ex
A hypothetical population consists of users of non-steroid anti-inflammatory drugs (NSAIDs) og non-users of NSAID. The study subjects are followed for one year for the occurrence of upper gastrointestinal (GI) bleeding
Study population N
GI bleeding
NSAID users
20,000
100
Non-users of NSAID
100,000
In total
120,000
200
Please calculate the following measures of frequency and risk:
1. Incidence rate (IR) for GI bleeding in each exposure group
2. Incidence rate ratio (IRR) for the association between NSAID and upper GI bleeding
3. Incidence rate difference (IRD≈AR) between NSAID users and non-users
4. Attributable proportion (APexp) among users of NSAIDs
5. Attributable proportion (APpop) in the total population
(Censoring in the risk population should be ignored)

51. Study population N GI bleeding NSAID users 20,000 100Ex
Study population N
GI bleeding
NSAID users
20,000
100
Non-users of NSAID
100,000
In total
120,000
200
IRNSAID = 100/ = = 5 per 1000 person-years
IRo = / = = 1 per 1000 person-years
IRpop = / = = 1.67 per 1000 person-years
IRR = IRNSAID/IRo = 5/1 = 5
AR = IRD = IRNSAID–IRo = 5-1 = 4 per 1000 person-years
APexp = AR/IRNSAID = 4 per 1000/5 per 1000 = 0.80 or 80%
ARpop = IRpop–IRo = 1.67 – 1 = 0.67 per 1000 person-years
APpop = ARpop /IRpop = 0.67/1.67  0.40 or 40%