Lecture 6

Study Design II:

Cohort and Case-Control Studies

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 Learning Objectives
• Characterize a cohort study, including pros and
cons
• Distinguish among different types of cohort
studies: prospective, retrospective, and
ambidirectional
• Characterize a case-control study, including pros
and cons
• Discuss the relationship between cohort and
case-control studies
• Estimate the odds ratio and understand its
relationship to the risk ratio
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 Observational studies
• RCTs are rigorous but often infeasible due to
pragmatic and ethical reasons.
• Observational studies take advantage of the
fact that people may expose themselves to
harmful or healthy exposures through
personal habits, occupation, place of
residence, or other reasons.

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 Types of observational studies
• Two principal types:
• Cohort study: subjects are defined according
to their exposure levels and followed over
time to determine disease occurrence.
• Case-control study: subjects are defined as
cases and controls and exposure histories are
compared.

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 Cross-sectional study
• Before we go into the cohort study and case-
control study in more detail, a quick note on a
third type of observational study
• Cross-sectional study: examines the
relationship between exposure and disease
prevalence at a single point in time

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Cohort study

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 Cohort: Definition
• “Cohort” comes from the Latin word cohors,
meaning a group of soldiers (ancient Rome).
• Today we use the word cohort to
– characterize “any designated group of people who
are followed over a period of time.”
– describe a group of individuals with a common
characteristic or experience.

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 Cohort: Types of populations studied
• Open/dynamic:
– Members come and go; losses may occur
• Fixed: 不可改变的

– Defined by irrevocable event

– Does not gain members; losses may occur
• Closed:
– Defined by irrevocable event
– Does not gain members; no losses occur

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 Cohort study: Design
与RCT的不同，没有randomized
RR（risk ratio） Defined population
RD（risk difference）
sample
NON-RANDOMIZED

E+ E-

D+ D- D+ D-
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 First identify…

Total
Exposed a+b

Unexposed c+d

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Then follow to measure disease…

Not
Diseased Total
Diseased
Exposed a b a+b

Unexposed c d c+d

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 Then calculate risk ratio
Not
Diseased Total
Diseased
Exposed a b a+b

Unexposed c d c+d

Numerator a
Risk of disease in exposed a+b
=
Denominator c
Risk of disease in unexposed c+d
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 Risk ratio interpretation
• Ratios > 1.0 indicate risk is higher among
exposed than unexposed
• Ratios = 1.0 indicate no association
• Ratios < 1.0 indicate risk is lower among
exposed than unexposed

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 Risk ratio vs. rate ratio
• Risk ratios are ideal when there is little or no loss
to follow-up.
• Most studies have substantial loss to follow-up.
• Rate ratios more accurately represent the
strength of the association when loss to follow-up
is an issue.

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Rate ratio

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 Rate ratio

Numerator a
Rate of disease in exposed person years exposed
= c
Denominator
Rate of disease in unexposed person years unexposed

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 Rate ratio interpretation
Similar to risk ratio
• Ratios > 1.0 indicate rate is higher among
exposed than unexposed
• Ratios = 1.0 indicate no association
• Ratios < 1.0 indicate rate is lower among
exposed than unexposed

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 Risk difference

Difference between two risks =

• Interpretation: Excess risk due to the exposure

• Example: If the risk of disease is 10 per
100,000 in the unexposed and 15 per 100,000
in the exposed, then 5 per 100,000 cases are
associated with the exposure of interest.

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 Example: Nutrition and obesity
Research question: Are nutrition classes in middle
school associated with the development of obesity in
adolescence?
Sample:
 Middle school A, 400 students, receives nutrition
class (intervention)
 Middle school B, 300 students, in neighboring
district, does not receive nutrition class
Measures: Schools collect students’ height and weight
yearly for 5 years
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Example: Risk difference

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 Example: Risk difference
• Incidence proportion (or risk) of obesity among those
who had nutrition class = 0.175 or 17.5%
• Incidence proportion (or risk) of obesity among those
who did not have nutrition class = 0.33 or 33%
• Risk difference
 Incidence proportion of exposed – incidence proportion of unexposed
 0.175 – 0.33= - 0.155
• Interpretation: There are approximately 15.5 fewer
cases of obesity during adolescence for every 100
adolescents associated with nutrition class in middle
school.
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 Rate difference
• Difference between two rates:

• Interpretation: Similar to risk difference; excess rate

due to the exposure
• Example: If the rate of disease is 8 per 100,000
person-years in the exposed and 4 per 100,000
person-years in the unexposed, then 4 excess cases
per 100,000 person-years of exposure are associated
with the exposure of interest.

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 Types of cohort studies
• Prospective cohort study
– Concurrent cohort study or longitudinal study
• Retrospective cohort study
– Non-concurrent cohort or historical cohort
• Ambidirectional cohort study
– Incorporates aspects of both

Depends on where the investigator sits!

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Prospective cohort study
done in 2015
Defined population 2015

NON-RANDOMIZED

E+ E-

D+ D- D+ D- 2025
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Retrospective cohort study
done in 2015
Defined population 2000

NON-RANDOMIZED

E+ E-

D+ D- D+ D- 2015

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Ambidirectional cohort study
done in 2015
Defined population

NON-RANDOMIZED

2015
E+ E-

D+ D- D+ D-
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 Keys to all cohort studies

• Comparison groups are defined as

exposed (E+) vs. unexposed (E-)
• Subjects must be disease-free (i.e., at risk
of the outcome) at the beginning of the
study

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 Example A:
Multivitamins and memory loss
• Sample of 80 men at age 65 with no evidence
of memory loss
• Measure daily multivitamin use
• Follow groups for ten years
• Count men who develop memory loss
• Assume no losses to follow-up

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 Example A:
Multivitamins and memory loss
Memory No loss
Total
loss
Daily use 8 32 40
No daily use
16 24 40
Total 24 56 80
8/40 Interpretation: The risk of memory loss
Risk Ratio = = 0.5 among those who use a multivitamin is
16/40 50% less than the risk of memory loss
among those who do not use a
multivitamin over 10 years.
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 Cohort study: Advantages
针对rare exposures的

• Temporality
• Can look at changes in exposure over time
• Can study multiple exposures
• Possible to estimate all measures of incidence
and effect
• Efficient for rare exposures

2019习题第17题

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 Cohort study: Disadvantages
• Usually requires large investments in
resources
• Requires large sample sizes
• Not easy to reproduce
• Not efficient for rare outcomes

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Case-control study

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 Case-control study
• Case-control studies start with the
identification of persons with the disease and
a suitable control group of persons without
the disease.
• Controls may be selected in a variety of ways;
e.g., from the same underlying cohort as the
cases or from a similar population to that
which gave rise to the cases.
• Key: comparison groups are defined as
diseased (D+) vs. non-diseased (D-)
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 How do we ensure that cases and
controls come from the same source
population?

The “would criterion”:

• Would your cases have been selected to be
controls had they not gotten disease?
• Would your controls have been selected to be
cases had they gotten disease?

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When to conduct a case-control study
• The disease is rare
• Exposure data are difficult or expensive to
obtain
• The disease has a long induction/latent period
• Little is known about the disease
• The underlying population is dynamic

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 Case-control study: Design
odd ratio

E+ E- E+ E-

D+ D-
“Cases” “Controls”

population
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 First select…

Cases Controls
(with (without
disease) disease)
Exposed

Unexposed

Total a+c b+d

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Then measure past exposure…

Cases Controls
(with (without
disease) disease)
Exposed a b

Unexposed c d

Total a+c b+d

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Then calculate odds ratio
Cases Controls
(with (without
disease) disease)
Exposed a b

Unexposed c d

ad
Odds Ratio =
bc

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 Why do we calculate an odds ratio?
• We cannot estimate the risk of disease directly
when we sample people based on whether they
have the disease or not (case-control study).
• We can estimate the proportion exposed among
diseased and non-diseased.
– Estimate odds ratio for exposure
– Odds ratio for exposure = Odds ratio for disease
• If the disease is rare in the population, the odds
ratio approximates the risk ratio from a
prospective study.
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 What is an odds?
a
a+c
Cases a
1–
(with a+c
disease)
a
Exposed a a+c
=
a+c a
–
Unexposed c a+c a+c

a
=
c

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 The exposure odds ratio
a
Cases Controls a+c
(with (without a
disease) disease) 1–
a+c
Exposed a b b
b+d
Unexposed c d b
1–
b+d
a
c ad
Simplifies to: =
b bc
d
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Let’s compare a cohort study
and a case-control study

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 Example B: Maternal smoking during
pregnancy and ADHD
Research question: Is smoking cigarettes during
pregnancy a potential cause of offspring attention-
deficit hyperactivity disorder (ADHD)?
Sample:
• Recruit 5,000 women during pregnancy who are
smokers and 5,000 women during pregnancy who are
not smokers
• Prospective cohort study
• Assume no loss to follow-up
Measures: Follow offspring at age 10 and determine
which children developed ADHD and which did not
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 Risk ratio
ADHD No ADHD Total
Smoking 300 4700 5000

No Smoking 200 4800 5000

Total 500 9500 10,000

300/5000
Risk Ratio = = 1.5
200/5000

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 Interpretation of risk ratio
• Offspring of women who smoked in pregnancy
have 1.5 times the risk of developing ADHD
over 10 years compared to offspring of
women who did not smoke in pregnancy.

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 Example C: Maternal smoking during
pregnancy and ADHD
Research question: Is smoking cigarettes during pregnancy
a potential cause of offspring attention-deficit hyperactivity
disorder (ADHD)?
Sample:
• 500 10-year-old children who are seeking care for ADHD
• For each child we find with ADHD, we select two children
of the same age from the same physician offices who
present for routine well visits (do not have ADHD)
• Case-control study
Measures: Mothers respond to questions, including
whether they smoked cigarettes while they were pregnant
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 Odds ratio
ADHD No ADHD Total
Smoking 300 503 803

No Smoking 200 497 697

Total 500 1000 1500

300*497
Odds Ratio = = 1.48
200*503

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 Interpretation of odds ratio
• The odds of exposure (mother smoking in
pregnancy) among those with ADHD are 1.48
times the odds of exposure among those
without ADHD over 10 years.

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 Let’s compare
• Risk ratio in cohort study = 1.5
• Odds ratio in case-control study = 1.48

• This odds ratio is approximately equivalent to

the risk ratio because the disease is rare
(prevalence = 500 out of 10,000 or 5% in our
cohort study).

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 When does the OR do a good job of
approximating the RR?

OR
or
RR

Prevalence of disease

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 Selection of cases
• Create a case definition
• Begin identifying and enrolling cases
– Hospital or clinic patient rosters
– Death certificates
– Special surveys (NHANES)
– Reporting systems (cancer registries)

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 Selection of controls
• Controls should be a sample of the population
that gave rise to the cases. population source
• The purpose of the control group is to provide
information on the exposure distribution in
the source population.
• Controls should be sampled independently of
exposure status. 2019习题第20题

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 Case-control study: Advantages
• Relatively short duration and less expensive
• Efficient for rare diseases
• Require smaller sample sizes
• Can study multiple risk factors (exposures) for
one disease
• Easily reproduced in different populations by
different investigators

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 Case-control study: Disadvantages
• Temporality hard to establish
• Relies on recall
• Difficult to identify appropriate control group
• Does not provide estimate of risks so cannot
calculate risk ratios and risk differences
• Inefficient for rare exposures

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Let’s look at two studies of
smoking and lung cancer

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 Study 1: Cohort study
 In October 1951, a questionnaire was sent to
59,600 doctors in the United Kingdom about
their smoking habits
 40,564 valid responses
 Deaths ascertained with death certificates
 After 10 years of follow-up, 4,597 deaths, of
which 212 were due to lung cancer

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 British doctors

Smokers Non
smokers
Follow-up

% died of lung % died of lung

cancer cancer
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 Lung cancer death
 Between November 1st, 1951, and October 31st,
1961
 Risk period = 10 years

Doll R, Hill AB. (1964) Mortality in relation to smoking: Ten years’ observations of British Doctors. BMJ1:1399-1410

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 Smoking and lung cancer in the
British Doctor’s Study
Smoking status Deaths from LC N Person-years

 Never smokers 3 5,439 42,800

 Ever smokers* 143 27,769 149,000

 Other (pipe, cigar, mixed) 66

* As of Nov 1, 1951, > 1cig/day for a year

Doll & Hill, 1964

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 Smoking and lung cancer in the
British Doctor’s Study

Deaths Person- Death rate

from LC years (per 1000 py)
Ever smokers
143 149,000 0.96
(E+)
Never smokers
3 42,800 0.07
(E-)

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 Rate ratio

Rate ratio (IRR)

IRR = IR(E+) = 0.96 = 13.7
IR(E-) 0.07

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 Interpretation of rate ratio
• Doctors who smoked had 13.7 times the rate
of lung cancer death compared with doctors
who did not smoke.

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 Study 2: Case-control study
• Cases: incident lung cancer in 20 hospitals of
London
• Controls: Age-hospital matched patients
admitted for diseases other than cancer
• Exposure: questionnaire on duration, dates of
starting and stopping of smoking, amount
smoked, type of tobacco

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Lung cancer Controls
cases free of
lung cancer

RECALL

% smokers % smokers

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 Case-Control Design

Lung cancer Controls free

cases of lung cancer
(649) (649)

Ever Never Ever Never

smokers smokers smokers smokers
(647) (2) (622) (27)

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Odds ratio of ever smoking

Cases Controls
Ever smokers 647 622

Never smokers 2 27

647*27
Odds Ratio = = 14.0
2*622

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 Interpretation of odds ratio
• Lung cancer cases had 14.0 times the odds of
smoking history compared with cancer
controls without lung cancer.

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 In summary:
• The conditional risk of disease given exposure is not
very meaningful in a case-control study, therefore
the risk ratio and risk difference in a case control
study is not meaningful.
• However, the exposure odds ratio (the odds of
exposure given disease) is very useful, for 2 reasons:
1. The exposure odds ratio is mathematically equivalent to
the disease odds ratio
2. If the disease is rare, the disease odds ratio approximates
the disease risk ratio.
• Therefore, we can get a pretty accurate estimate of
the exposure risk ratio with the disease odds ratio!
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 Comparing the cohort study
and case-control study
• Cohort study
– Doctors who smoked had 13.7 times the rate of
lung cancer compared with doctors who did not
smoke.
• Case-control study
– Lung cancer cases had 14.0 times the odds of
smoking history compared with cancer controls
without lung cancer.

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 Odds ratios as proxies for risk ratios
• When the disease is rare, the odds ratio will
approximate the risk ratio you would have
gotten had you done a cohort study.

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 What have we learned?
• Characterize a cohort study, including pros and
cons
• Distinguish among different types of cohort
studies: prospective, retrospective, and
ambidirectional
• Characterize a case-control study, including pros
and cons
• Discuss the relationship between cohort and
case-control studies
• Estimate the odds ratio and understand its
relationship to the risk ratio
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Questions?

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Thank you!

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