EPI-546 Block I

Lecture 8 Study Design I

XS and Cohort Studies

Mathew J. Reeves BVSc, PhD

Associate Professor, Epidemiology

Mathew J. Reeves, PhD 1

Dept. of Epidemiology, MSU
Objectives - Concepts

Uses of risk factor information

Association vs. causation
Architecture of study designs (Grimes I)
Cross sectional (XS) studies
Cohort studies (Grimes II)
Measures of association RR, PAR, PARF
Selection and confounding bias
Advantages and disadvantages of cohort studies

Mathew J. Reeves, PhD 2

Dept. of Epidemiology, MSU
Objectives - Skills

Recognize different study designs

Define a cohort study
Explain the organization of a cohort study
Distinguish prospective from retrospective
Define, calculate, interpret RR, PAR and PARF
Understand and detect selection and confounding
bias

Mathew J. Reeves, PhD 3

Dept. of Epidemiology, MSU
Risk Factor heard almost daily

Cholesterol and heart disease

HPV infection and cervical CA
Cell phones and brain cancer
TV watching and childhood obesity

However, association does not mean causation!

Mathew J. Reeves, PhD 4

Dept. of Epidemiology, MSU
Why care about risk factors? Fletcher lists the ways
risk factors can be used:

Identifying individuals/groups at-risk

But ability to predict future disease in individual patients is very
limited even for well established risk factors
e.g., cholesterol and CHD
Causation (causative agent vs. marker)
Establish pretest probability (Bayes theorem)
Risk stratification to identify target population
Example: Age > 40 for mammography screening
Prevention
Remove causative agent & prevent disease

Mathew J. Reeves, PhD 5

Dept. of Epidemiology, MSU
Predicting disease in individual patients

Fig. Percentage distribution of serum cholesterol levels (mg/dl) in men aged

50-62 who did or did not subsequently develop coronary heart disease
(Framingham Study)

Mathew J. Reeves, PhD 6

Dept. of Epidemiology, MSU
Causation vs. Association

An association between a risk factor and disease can

be due to:
the risk factor being a cause of the disease (= a causative
agent) OR
the risk factor is NOT a cause but is merely associated with
the disease (= a marker)

Must guard against thinking that A causes B when

really B causes A (reverse causation).
e.g. sedentariness and obesity.

Mathew J. Reeves, PhD 7

Dept. of Epidemiology, MSU
A B C

A B
A B

A B

Mathew J. Reeves, PhD 8

Dept. of Epidemiology, MSU
Prevention

Removing a true cause disease incidence.

Decrease aspirin use Reyes Syndrome
Discourage prone position
Back to Sleep SIDS

Mathew J. Reeves, PhD 9

Dept. of Epidemiology, MSU
Back-To-Sleep Campaign
Began in 1992

Mathew J. Reeves, PhD 10

Dept. of Epidemiology, MSU
Architecture of study designs
Experimental vs. observational

Experimental studies
Randomization?
RCT vs. quasi-randomized or natural experiments

Observational studies
Analytical vs. descriptive
Analytical
XS, Cohort, CCS
Descriptive
Case report, case series

Mathew J. Reeves, PhD 11

Dept. of Epidemiology, MSU
Grimes DA and Schulz KF 2002. An overview of clinical research. Lancet 359:57-61.

Mathew J. Reeves, PhD 12

Dept. of Epidemiology, MSU
Grimes DA and Schulz KF 2002. An overview of clinical research. Lancet 359:57-61.

Mathew J. Reeves, PhD 13

Dept. of Epidemiology, MSU
Cross-sectional studies
Also called a prevalence study

Prevalence measured by conducting a survey of the population

of interest e.g.,
Interview of clinic patients
Random-digit-dialing telephone survey

Mainstay of descriptive epidemiology

patterns of occurrence by time, place and person
estimate disease frequency (prevalence) and time trends

Useful for:
program planning
resource allocation
generate hypotheses

Mathew J. Reeves, PhD 14

Dept. of Epidemiology, MSU
Cross-sectional Studies

Select sample of individual subjects and report

disease prevalence (%)

Can also simultaneously classify subjects

according to exposure and disease status to draw
inferences
Describe association between exposure and disease
prevalence using the Odds Ratio (OR)

Mathew J. Reeves, PhD 15

Dept. of Epidemiology, MSU
Cross-sectional Studies

Examples:
Prevalence of Asthma in School-aged Children in Michigan

Trends and changing epidemiology of hepatitis in Italy

Characteristics of teenage smokers in Michigan

Prevalence of stroke in Olmstead County, MN

Mathew J. Reeves, PhD 16

Dept. of Epidemiology, MSU
 Concept of the Prevalence Pool

New cases

Recovery
Death

Mathew J. Reeves, PhD 17

Dept. of Epidemiology, MSU
Cross-sectional Studies

Advantages:
quick, inexpensive, useful

Disadvantages:
uncertain temporal relationships
survivor effect
low prevalence due to
rare disease
short duration

Mathew J. Reeves, PhD 18

Dept. of Epidemiology, MSU
Cohort Studies
A cohort is a group with something in common e.g., an exposure

Start with disease-free at-risk population

i.e., susceptible to the disease of interest

Determine eligibility and exposure status

Follow-up and count incident events

a.k.a prospective, follow-up, incidence or longitudinal

Similar in many ways to the RCT except that exposures are

chosen by nature rather than by randomization

Mathew J. Reeves, PhD 19

Dept. of Epidemiology, MSU
 Types of Cohort Studies
Population-based (one-sample)
select entire popl (N) or known fraction of popl (n)
p (Exposed) in population can be determined

Multi-sample
select subgroups with known exposures
e.g., smokers and non-smokers
e.g., coal miners and uranium miners
p (Exposed) in population cannot be determined

Mathew J. Reeves, PhD 20

Dept. of Epidemiology, MSU
Prospective Cohort Study Population-
based Design (select entire pop)

Disease
+ -

Exp + a b n1

Exp - c d n0

Mathew J. Reeves, PhD 21

Dept. of Epidemiology, MSU
Prospective Cohort Study Multi-sample
Design (select specific exposure groups)

Disease
+ -

Exp + a b n1 Rate= a/ n 1

Exp - c d n0 Rate= c/ n 0

Mathew J. Reeves, PhD 22

Dept. of Epidemiology, MSU
NOW FUTURE

Disease

Exposed

No disease
Eligible
subjects

Disease
Unexposed

No disease
Mathew J. Reeves, PhD 23
Dept. of Epidemiology, MSU
 Relative Risk Cohort Study

RR = Incidence rate in exposed

Incidence rate in non-exposed

The RR is the standard measure of association for cohort studies

RR describes magnitude and direction of the association

Incidence can be measured as the IDR or CIR

RR = a / ni or a / (a + b)
c / no c / (c + d)

Mathew J. Reeves, PhD 24

Dept. of Epidemiology, MSU
Example - Smoking and Myocardial Infarction (MI)

Study: Desert island, pop= 2,000 people, smoking prevalence= 50%

Population-based cohort study. Followed for one year.
What is the risk of MI among smokers compared to non-smokers?

MI
+ -

Smk + 30 970 Rate = 30 / 1000

Smk - 10 990 Rate = 10 / 1000

RR= 3
Mathew J. Reeves, PhD 25
Dept. of Epidemiology, MSU
 RR - Interpretation
RR = 1.0
indicates the rate (risk) of disease among exposed and non-
exposed (= referent category) are identical (= null value)
RR = 2.0
rate (risk) is twice as high in exposed versus non-exposed
RR = 0.5
rate (risk) in exposed is half that in non-exposed

Mathew J. Reeves, PhD 26

Dept. of Epidemiology, MSU
 RR - Interpretation
RR = > 5.0 or < 0.2
BIG

RR = 2.0 5.0 or 0.5 0.2

MODERATE

RR = <2.0 or >0.5
SMALL

Mathew J. Reeves, PhD 27

Dept. of Epidemiology, MSU
Sources of Cohorts

Geographically defined groups:

Framingham, MA (sampled 6,500 of 28,000, 30-50 yrs of
age)
Tecumseh, MI (8,641 persons, 88% of population)

Special resource groups

Medical plans e.g., Kaiser Permanente
Medical professionals e.g.,
Physicians Health Study, Nurses Health Study
Veterans
College graduates e.g., Harvard Alumni

Mathew J. Reeves, PhD 28

Dept. of Epidemiology, MSU
Sources of Cohorts

Special exposure groups

Occupational exposures
e.g., pb workers, U miners
If everyone exposed then need an external cohort
non-exposed cohort for comparison purposes
e.g., compare pb workers to car assembly workers

Specific risk factor groups

e.g., smokers, IV drug users, HIV+

Mathew J. Reeves, PhD 29

Dept. of Epidemiology, MSU
 Cohort Design Options

variation in timing of E and D measurement

Design Past Present Future

Prospective E D
Retrospective E D
Historical/pros. E E D

Mathew J. Reeves, PhD 30

Dept. of Epidemiology, MSU
Retrospective Cohort Study Design
Go back and determine exposure status based on historical
information and then classify subjects according to their
current disease status
Disease
+ -

Exp + a b n1 Rate= a/ n 1

Exp - c d n0 Rate= c/ n 0

Mathew J. Reeves, PhD 31

Dept. of Epidemiology, MSU
PAST NOW
RECORDS
Disease

Exposed

No disease
Eligible
subjects

Disease
Unexposed

No disease
Mathew J. Reeves, PhD 32
Dept. of Epidemiology, MSU
Examples retrospective cohort

Aware of cases of fibromyalgia in women in a large

HMO. Go back and determine who had silicone
breast implants (past exposure). Compare incidence
of disease in exposed and non-exposed.

Framingham study: use frozen blood bank to

determine baseline level of hs-CRP and then
measure incidence of CHD by risk groups (quartile)

Mathew J. Reeves, PhD 33

Dept. of Epidemiology, MSU
PAR and PARF

Important question for public health

How much can we lower disease incidence if we intervene
to remove this risk factor?
Want to know how much disease an exposure
causes in a population.
PAR and PARF assume that the risk factor in
question is causal
See Lecture 3 course notes

Mathew J. Reeves, PhD 34

Dept. of Epidemiology, MSU
Venous thromboemolic disease (VTE) and oral contraceptives (OC) in woman of

reproductive age

Incidence of VTE:
OC users: 16 per 10,000 person-years
non-OC users: 4 per 10,000 person-years
Total population: 7 per 10,000 person-years

RR = 16/4 = 4

Prevalence of exposure to OC:

25% of woman of reproductive age

Mathew J. Reeves, PhD 35

Dept. of Epidemiology, MSU
Population attributable risk (PAR)

The incidence of disease in a population that is associated with

a risk factor.

Calculated from the Attributable risk (or RD) and the prevalence
(P) of the risk factor in the population
PAR = Attributable risk x P
PAR = (16-4) x 0.25
PAR = 3 per 10,000 person years

Equals the excess incidence of VTE in the population due to OC

use

Mathew J. Reeves, PhD 36

Dept. of Epidemiology, MSU
Population attributable risk fraction (PARF)

The fraction of disease in a population that is attributed to a risk

factor.

PARF = PAR/Total incidence

PARF = 3/7per 10,000 person years
PARF = 43%

Represents the maximum potential impact on disease incidence

if risk factor was removed
So, remove OCs and incidence of VTE drops 43% in women of
repro age (assuming OC is a cause of VTE)

Mathew J. Reeves, PhD 37

Dept. of Epidemiology, MSU
 NOW FUTURE

Disease

Exposed

No disease
Eligible
subjects

Disease
Unexposed

No disease
PARF = - Mathew J. Reeves, PhD 38
Dept. of Epidemiology, MSU
PARF Calculation

PARF = P(RR-1)/ [1 + P(RR-1)]

where:
P = prevalence, RR = relative risk

PARF = 0.25(4-1)/ [1 + 0.25(4-1)]

PARF = 43%

Note that a factor with a small RR but a large P can

cause more disease in a population than a factor with
a big RR and a small P.

Mathew J. Reeves, PhD 39

Dept. of Epidemiology, MSU
Selection Bias

Selection bias can occur at the time the cohort is first

assembled:
Patients assembled for the study differ in ways other than the
exposure under study and these factors may determine the
outcome
e.g., Only the Uranium miners at highest risk of lung cancer (i.e.,
smokers, prior family history) agree to participate
Selection bias can occur during the study
e.g., differential loss to follow-up in exposed and un-exposed
groups (same issue as per RCT design)
Loss to follow-up does not occur at random
To some degree selection bias is almost inevitable.

Mathew J. Reeves, PhD 40

Dept. of Epidemiology, MSU
 Confounding Bias
Confounding bias can occur in cohort studies
because the exposure of interest is not assigned at
random and other risk factors may be associated with
both the exposure and disease.
Example: cohort study of lecture attendance

-
Attendance Exam success

- +
Baseline epi proficiency
Mathew J. Reeves, PhD 41
Dept. of Epidemiology, MSU
Cohort Studies - Advantages

Can measure disease incidence

Can study the natural history
Provides strong evidence of casual association between E
and D (time order is known)
Provides information on time lag between E and D
Multiple diseases can be examined
Good choice if exposure is rare (assemble special exposure
cohort)
Generally less susceptible to bias vs. CCS

Mathew J. Reeves, PhD 42

Dept. of Epidemiology, MSU
Cohort Studies - Disadvantages

Takes time, need large samples, expensive

Complicated to implement and conduct
Not useful for rare diseases/outcomes
Problems of selection bias
At start = assembling the cohort
During study = loss to follow-up
With prolonged time period:
loss-to-follow up
exposures change (misclassification)
Confounding
Exposures not assigned at random

Mathew J. Reeves, PhD 43

Dept. of Epidemiology, MSU
Prognostic Studies - predicting outcomes in those with
disease

Also measured using a cohort design (of

affected individuals)
Factors that predict outcomes among those
with disease are called prognostic factors
and may be different from risk factors.
Discussed further in Epi-547

Mathew J. Reeves, PhD 44

Dept. of Epidemiology, MSU