Case-Control Studies

Lecture 7
June 20, 2005
K. Schwartzman MD
Case Control Studies

Readings

• Fletcher, chapter 10

• Walker, chapter 6 [Case-Control Studies] from

Observation and Inference, 1991 [course pack]
Case-Control Studies - Slide 1

Objectives

Students will be able to:

1. Define the term “case-control study”

2. Explain the relationship between case-control

and cohort studies

3. Understand the difference between

cumulative incidence and incidence density designs
Case-Control Studies - Slide 2

Objectives

4. Calculate parameters which may be validly obtained

from case-control studies, namely:
a. Odds parameters:
- odds of exposure in cases
- odds of exposure in controls
- odds ratio
b. Risk parameters:
- approximation of relative risk
- attributable fraction
c. Incidence rate parameters:
- incidence rate ratio
- attributable fraction among the exposed
- attributable fraction for the population
Case-Control Studies - Slide 3

Objectives

5. Indicate situations in which case-control studies

permit estimation of rate differences between
exposure groups

6. Highlight advantages and disadvantages of

case-control studies, including key biases

7. List possible sources of controls in

case-control studies

8. Identify biases which may result from

different types of control selection
Case Control Studies - Slide 4

Case-Control Studies

Fletcher, p. 213:
“Patients who have the disease and a group of
otherwise similar people who do not have the
disease are selected. The researchers then look
backward in time to determine the frequency of
exposure in the two groups.”

In other words, a study population is first assembled

based on a determination as to whether subjects
have or have not developed an outcome of interest.

Subjects (or person-time) are then classified as to

whether an exposure of interest took place.
Data on other variables (e.g. potential confounders)
is also obtained.
Case-Control Studies - Slide 5

Walker, 1991:
“Case-control studies constitute the
major advance in epidemiologic methods
of our time”

Classic example:
Doll & Hill, relationship between lung cancer
and cigarette smoking (1950)
Case-Control Studies - Slide 6

Advantages
Useful for study of conditions that are rare
and/or characterized by a long latency
between exposure(s) and outcomes of interest.
May be useful in evaluating the impact of
multiple types of exposure.

Disadvantages

May be particularly vulnerable to biases arising from

selection of subjects (most often of the control group),
and measurement (estimation) of exposure
Case-Control Studies - Slide 7

In case-control studies, data about exposure status is

calculated after first determining outcome status.

However, subjects may be recruited “prospectively”

(concurrently), e.g.:

- All persons aged 30-50 who are diagnosed with

hypertension on the island of Montreal during 2005,
within 2 weeks of diagnosis.

- Controls recruited among persons of the same age

who are newly diagnosed with appendicitis in
Montreal during the same time period.
Case Control Studies - Slide 8

Often, outcome status is already available for all subjects

(“historical”) at the time of initiation, e.g.:

- During 2005, a researcher identifies all women

aged 40-50 who were diagnosed with breast cancer
on the island of Montreal in 2004.

- In 2005, she recruits a control group among

women of the same age who had negative
screening mammograms in Montreal in 2004.
Case-Control Studies - Slide 9

Note that the terms

“prospective” and “retrospective”
are not very useful
with respect to case-control studies,
since data about exposure status
is always retrospective (by definition).
Case-Control Studies - Slide 10

Cohort and Case-Control Studies

Every case control study corresponds to an underlying cohort study,

which is (ordinarily) hypothetical.

Example (from Doll & Hill, 1950):

_____________________________________________________
Women diagnosed with lung cancer vs other diseases
at 20 London hospitals

Smokers Non-Smokers Total

Lung cancer cases 41 19 60
No lung cancer (controls) 28 32 60
Total 69 51 120
_________________________________________________________

Crude odds ratio = odds of exposure in cases/odds of exposure in controls

= (a/b)/(c/d)
= ad/bc = (41x32) / (19x28) = 2.5
Case-Control Studies - Slide 11

In the corresponding cohort study,

women from the same geographic area
would be recruited and classified as to
smoking status, then followed for the
development vs non-development of lung cancer.
Case-Control Studies - Slide 12

Assuming all cases of lung cancer during the period of interest

were detected,

one possible 2x2 table

would be
Smokers Non-Smokers Total
Lung cancer 41 19 60
No lung cancer (controls) 859 981 1,840
Total 900 1000 1,900
OR = 2.5

but it could also be:

Smokers Non-Smokers Total
Lung cancer 41 19 60
No lung cancer (controls) 70 81 151
Total 111 100 211
OR = 2.5
Case-Control Studies - Slide 13

• The cases diagnosed and included, and the

controls sampled, relate to the exposure experience
of an underlying source population.

• In each scenario, the estimated odds of cigarette

smoking among cases are 2.5 times those
among controls.

• In each scenario, all cases of lung cancer were

included. The size of the source population
(and hence the number of non-cases) was varied.
Case-Control Studies - Slide 14

Cumulative incidence case-control studies

Goal is to
derive estimate of relative risks
(relative cumulative incidences)
of outcomes among
exposed vs. unexposed

Design:

- Cases are ascertained during a defined

observation period

- Controls are persons who did not become cases

during the period of observation.

- The underlying cohort is a fixed one

(not open or dynamic).
Case-Control Studies - Slide 15

Doll and Hill, 1950

Assume that the source population was as follows:
900 smokers & 1000 non smokers - followed 5 years
Then the 2x2 table would be:
Smokers Non-Smokers Total
Cancer + 41 19 60
Cancer - 859 981 1,840
Total 900 1,000 2,000
________________________________________________

Risk of cancer in smokers: 41/900 = 0.046

Risk of cancer in non smokers: 19/1000 = 0.019
Risk ratio: 0.046/0.019 = 2.4

Odds of smoking in women with cancer: 41/19 = 2.2

Odds of smoking in women without cancer: 859/981 = 0.88
Odds ratio = 2.5
Case-Control Studies - Slide 16

In the corresponding case control study we take 100% of cases, but

sample the controls (60/1840 or 3.3% of all potential controls - those
who happened to be admitted to hospital for some other reason).

Hence the new table is:

Smokers Non smokers Total

Cancer + 100% x 41 = 41 100% x 19 = 19 60
Cancer - 3.3% x 859 = 28 3.3% x 981 = 32 60
Total 69 51 120
_________________________________________________________

“Risk” of cancer in smokers: 41/69 = 0.59 INVALID

“Risk” of cancer in non smokers: 19/51 = 0.37 INVALID

The “risk ratio” from this 2x2 table is also invalid

Odds of smoking among cases: 41/19 = 2.2 (as before)

Odds of smoking among controls: 28/32 = 0.88 (as before)
Odds ratio: 2.2/0.88 = 2.5 (as before)
Case-Control Studies - Slide 17

General Form: Cumulative incidence case-control studies

exposure + exposure -
outcome + a b | total cases
outcome - c
___________ d
_____________ || total controls
total exposed total unexposed | total subjects

Odds of exposure in cases = a/b

Odds of exposure in controls = c/d
Odds ratio = odds of exposure in cases
______________________ = a/b
___ = ad
__
odds of exposure in controls c/d bc
but:

Odds of disease among exposed = a/c

Odds of disease among unexposed = b/d
Odds ratio = odds of disease among exposed
___________________________ = a/c
___ = ad
__
odds of disease among unexposed b/d bc
Case-Control Studies - Slide 18

Risk parameter estimation

in cumulative incidence case-control studies:

Recall that relative risk = risk of disease in exposed

______________________
risk of disease in unexposed

 From our 2x2 table, this is: a/(a+c)

_______ = a(b+d)
______
b/(b+d) b(a+c)

 If the disease is rare,

then a<<c and b<<d among the source population
then a+c ~ c and b+d ~ d
then a(b+d)
______ ~ ad
__
b(a+c) bc
Case-Control Studies - Slide 19

In a case-control study, it is then possible to estimate

the attributable risk (fraction) among the exposed,
even if the risk for the population is unknown.

In a cohort study, the attributable risk fraction is:

Rexp - Runexp
__________
Rexp

= (Rexp/Runexp) - (Runexp/Runexp)
_______________________
Rexp/Runexp
= RR-1
_____
RR

In a case-control study, this is estimated by (OR-1)/OR

Case-Control Studies - Slide 20

Hence, from Doll and Hill (1950),

the estimated fraction of
lung cancer among female smokers
which is attributable to smoking is:

2.5 -1
______ = 0.6 or 60%
2.5
Case-Control Studies - Slide 21

Incidence Density Case-Control Studies

The incidence density case-control study involves the

implicit comparison of the person-time experience
of cases and controls with respect to the exposure(s)
of interest.

The absolute quantity of person-time sampled - and

hence the sampling fraction - is unknown. This is
analogous to the situation with respect to persons in a
cumulative incidence case-control study.
Case-Control Studies - Slide 22

Hence the underlying (hypothetical) cohort is an open

or dynamic one.
Persons considered controls at one point in time
may then become cases; they can then appear twice
in the 2x2 table.
For this cohort, the general form of the 2x2 table is:
exposure + exposure -
outcome + a b
person-time Pe Po

Where Pe = person-time among exposed

Po = person-time among unexposed

IRe = a/Pe and IRo = b/Po

IRR = aPo
____
bPe
Case-Control Studies - Slide 23

Suppose that all cases are counted, but the

controls are sampled with respect to person-time,
with sampling fraction ”f” generating the incidence
density case-control study.

Then the 2x2 table is:

exposure + exposure -
outcome + a b
outcome - c = fPe d = fPo

Then OR = ad = afPo = aPo

___ _____ ____
bc bfPe bPe

which is equivalent to the IRR above.

Case-Control Studies - Slide 24

Note that this formulation does not involve any

assumptions about disease rarity.

It requires that the likelihood of being sampled from the

source “population” of person-time varies as
a proportion of the person-time potentially “contributed”
by each individual.

For example:

A potential control subject who was absent from

the geographic area of interest during most of the
accrual period should have less chance of being selected
than a potential subject who was present throughout.

As with the cumulative incidence design, validity hinges

on the assumption that f (the sampling fraction)
does not vary with exposure status.
Case-Control Studies - Slide 25

An example of an incidence density case-control study:

• A researcher wishes to evaluate the association

between the use of nonsteroidal anti-inflammatory
drugs (NSAIDS) and ventricular tachycardia (VT)

• In an open cohort study lasting 2 years,

subjects are recruited and classified as to
exposure status (NSAID use), then followed for
development of VT

• In principle, it is possible to document periods

of exposure and non-exposure for individuals,
e.g. months on/off medication, as long as
exposure is somehow reassessed
Case-Control Studies - Slide 26

Then for the cohort,

incidence rates and an incidence rate ratio can be calculated for
the exposed vs unexposed person-time experience, e.g.

NSAID No NSAID Total

VT, cases 80 40 120
Person-years 800 1200 2000
Incidence 0.1/p-y 0.033/p-y 0.06/p-y

The estimated incidence rate ratio is:

80/800
_______
40/1200
=3

So, assuming no confounding, we estimate that the

incidence of ventricular tachycardia among NSAID users
is 3 times that among non-users
Case-Control Studies - Slide 27

Suppose we instead devise a case-control study.

Here, cases will be defined by a first diagnosis

of VT at Montreal hospitals, and
controls will be recruited among persons who
visit the eye clinics of the same hospitals:
both over a 2-year accrual period.
They will be compared with respect to use of
NSAIDS within the last 24 hours prior to presentation.

 If sampling is done correctly (e.g. the probability

of selection is unrelated to NSAID use) then
the controls should represent the
person-time experience of the source population
Case-Control Studies - Slide 28

• If a possible control spent half the accrual period

on NSAIDS, and half off, he has a 50% chance
of contributing to the “exposed” group and a
50% chance of contributing to the “unexposed” group

• This individual will contribute one or the other,

depending on the date of the visit chosen as control;
but in a larger group of people,
the control days sampled will reflect the proportion
of exposed person-time

• A person can be a control early in the accrual period

and a case later

• In principle, a single person can also be sampled

repeatedly as a control if the time window for
exposure definition is short (more complicated in
terms of analysis)
Case-Control Studies - Slide 29

Suppose that the case-control study includes all cases which

would have been detected with the open cohort design.
Two controls are recruited per case. This (unbeknownst
to the researchers) corresponds to a sampling fraction
for controls of 0.12 person-day sampled per person-year
of follow-up that would have occurred in the open cohort.

Then the 2x2 table is:

NSAID No NSAID Total
VT, cases 80 40 120
No VT(controls) 800*0.12 1200*0.12 2000*0.12
= 96 = 144 = 240
_____________________________________________
Total 176 184 360

OR = (80x144)/(40x96) = 3.0  same as earlier IRR

Case-Control Studies - Slide 30

Another example of an incidence density design:

• Bronchodilators are used for the treatment of asthma

• There is concern that overuse may be associated with

an increased risk of adverse events, including death

• Side effects can include arrhythmias, which may lead

to sudden death

• Suissa et al conducted a case-control study using

the Saskatchewan health insurance database

• They identified 30 persons prescribed anti-asthma

medications who died of cardiovascular events,
rather than of asthma; the date of death was
termed the index date
Case-Control Studies - Slide 31

• 4080 control days were then sampled randomly

from the 574,103 person-months of follow-up
for the entire asthmatic group; each such day
was also an index date

• Cases and controls were then compared as to

use of theophylline and beta-agonists during the
3 months preceding the index date

• These were the main exposures of concern

Case-Control Studies - Slide 32

Questions for discussion:

• Why do you think the researchers chose

this study design?

• What would have been the corresponding

cohort study?
Case-Control Studies - Slide 33

With respect to the relationship between theophylline use and

sudden cardiac death, the authors found the following:

Theophylline in last 3 months

Yes No | Total
Cardiac Death Yes 17 13 | 30
No 956 3124 | 4080

Note that numbers in table refer to

person-days (not to persons)

OR (crude) = ad
__ = 17 x 3124
________ = 4.3 (2.1 - 8.8)
bc 13 x 956

IRR (crude) = 4.3 (2.1 - 8.8)

Case-Control Studies - Slide 34

The odds of recent theophylline use among persons

aged 5-54 years prescribed anti-asthma drugs
who died of cardiovascular events were
4.3 times those among other persons in the same age
range who were also prescribed anti-asthma drugs,
but did not die.

“Asthmatics” aged 5-54 who are prescribed theophylline

have an estimated 4.3 fold increase in incidence of
fatal cardiovascular events, compared with
“asthmatics” who are not prescribed theophylline.
Case-Control Studies - Slide 35

As with the cumulative incidence design, an attributable rate

fraction can be estimated for exposed persons:

It is: I____
e-Io, where Ie = incidence among exposed and
Ie Io = incidence among the unexposed

= IRR -1 =
______ OR -1
_____
IRR OR

For the Saskatchewan study, the estimated attributable

rate fraction among “asthmatics” who were prescribed
theophylline is:
4.3 - 1 = 0.77
______
4.3

Among “asthmatics” aged 5-54 prescribed theophylline,

an estimated 77% of fatal cardiovascular events
were related to its prescription.
Case-Control Studies - Slide 36

It is also possible to estimate the attributable rate fraction

for the entire population (PAR%)

In a cohort study, this is simply

I_____
t - Io, where It = incidence among the total population
It Io = incidence among the unexposed

For the corresponding incidence density case-control study,

the population attributable rate fraction is

IRR
____- 1 x proportion of cases who were exposed,
IRR
estimated as OR -1 x
_____ a
____
OR a+b

Similar parameters involving risk can be generated for

the cumulative incidence design
Case-Control Studies - Slide 37

For the Saskatchewan study, recall the 2 x 2 table

Theophylline in last 3 months

Yes No | Total
Cardiac death Yes 17 13 | 30
No 956 3124 | 4080

OR = 4.3
Pexp |case = 17/30 = 0.57

then PAR fraction = OR -1 x Pexp |case

_____
OR

= 4.3 - 1 x 0.57 = 0.44

______
4.3

Among Saskatchewan “asthmatics” aged 5-54, an estimated

44% of cardiovascular deaths relate to theophylline prescriptions.
Case-Control Studies - Slide 38

Attributable rates (rate difference)

The absolute rate difference (i.e., the absolute

rate of disease attributable to exposure) is Ie - Io

Data from a standard case-control study alone

cannot validly be used to estimate
absolute rates of disease.

Even if case ascertainment is complete,

the controls represent an unknown and
arbitrary fraction of the true person-time at risk.

Hence the rate difference cannot be estimated.

Case-Control Studies - Slide 39

However, incidence rates can be estimated if there is

additional knowledge about the amount of person-time at risk

Exposure
(+) (-)
Disease (+) a b
Disease (-) c = f x  x Pt d = f x (1- ) x Pt

Then Ie = a
_____ = ___________
a
 x Pt [c/(c+d)] x Pt

Then Io = b
_________ =___________
b
(1- ) x Pt [d/(c+d)] x Pt

and the rate difference is Ie-Io

where  = proportion of person-time which is exposed
Case-Control Studies - Slide 40

Example:

In this nested case-control study,

the researchers knew that in the source cohort
(Saskatchewan “asthmatics” aged 5-54), there were
47,842 person-years at risk during the study period

The 2x2 table was:

Theophylline in last 3 months
Yes No | Total
Cardiac death Yes 17 13 | 30
No 956 3124 | 4080
Case-Control Studies - Slide 41

Then the estimated incidence of cardiac death in “asthmatics”

prescribed theophylline (Ie) is:
a
___________ = ________________
17 = 0.0015 per person-year
[c/(c+d)] x Pt 956/4080 x 47,842

And in “asthmatics” who were not prescribed theophylline the

estimated incidence (Io) is:
b
___________ = 13
_________________ = 0.00035 per person-year
[d/(c+d)] x Pt 3124/4080 x 47,842

The estimated rate difference is therefore

0.0015-0.00035 = 0.00115 per person-year.

Note that the IRR computed as Ie/Io remains 4.3

Case-Control Studies - Slide 42

Ie and Io may also be estimated if It is known for the source population

Recall that It = (Ie x ) + [Io x (1- )]

But Ie = Io x OR

Then It = Io [(OR x ) + (1- )]

So Io = It = It
______________ ________________________
(OR x ) + (1- ) {OR x [c/(c+d)]} + [d/(c+d)]

Then use Ie = Io x OR

Then RD = Ie - Io as usual [= Io (OR-1)]

Case-Control Studies - Slide 43

Example:
The total incidence (It) of cardiovascular death
in the Saskatchewan cohort was
30 deaths/47,842 person-years
= 0.00063 per person-year.

Then Io = 0.00063
___________________________ = 0.00035
[4.3 x (956/4080)] + (3124/4080)

and Ie = 0.00036 x 4.3 = 0.0015

RD = 0.0015 - 0.00035 = 0.00115

Case-Control Studies - Slide 44

Additional points

 Corresponding estimates of attributable risks and

risk differences can be made for cumulative incidence
case-control studies, if the corresponding additional data
is available

 Estimates of absolute risks/incidence rates and

risk/rate differences can be made only if the
total amount of persons/person-time at risk is known,
or at least one absolute risk/incidence rate is known
(i.e. for the total population, the exposed, or
the unexposed)

 Nested case-control studies are a special type of study

where cases and controls are explicitly drawn from
a defined larger cohort (as in the Saskatchewan
asthma study)
Case-Control Studies - Slide 45

Case-Control Studies: Strengths and Limitations

Advantages of case-control studies:

 Efficiency - much less expensive/intensive

than cohort studies.

 Very useful for outcomes that are rare

or occur after a long latency period.

 Most outcomes are relatively rare over

short-term follow-up.
 Permit evaluation of multiple exposures.

 Can rapidly “accrue” person-time experience.

 Avoid losses to follow-up inherent in cohort studies.

Case-Control Studies - Slide 46

Disadvantages

• Not useful/efficient for very rare exposures

(may not be present in either cases or controls).

• Cannot directly compute incidence rates.

• Cannot usually evaluate more than one outcome.

• Temporality may be lost or distorted.

• Potential for considerable bias, i.e. loss of validity.

Bias relates to:

- Measurement of exposure status
- Selection of subjects (usually controls)
Case-Control Studies - Slide 47

With respect to measurement,

exposure ascertainment must be consistent
for cases and controls.

There may be potential for misclassification of

exposure in relation to disease status
Case-Control Studies - Slide 48

Example 1

Differential recall of exposures among cases

vs controls

e.g. medication use and congenital malformations

- particularly if mothers “attuned” to
study hypothesis.

If cases more likely to recall exposure,

results will be biased toward a
positive association between exposure and outcome.

The more objective the source of exposure data,

the better.
Case-Control Studies - Slide 49

Example 2

Different sources of information about exposure

e.g. family members asked about
alcohol consumption of persons
who died of gastric cancer,
vs Direct questioning of control subjects.

If family members tend to underestimate cases’

alcohol consumption, results will be biased
against finding a positive association between
alcohol and gastric cancer.
Case-Control Studies - Slide 50

Example 3

Exposure status changes as a consequence of

the outcome
e.g. patients with symptoms of lung cancer
stop smoking

If patients with newly diagnosed lung cancer are

compared to controls with respect to current
or recent smoking, results may be biased, i.e.,
the association between smoking and lung cancer
will be underestimated.

Data collection must reflect relevant person-time

experience and temporality of exposure and outcome.
Case-Control Studies - Slide 51

Association may also be missed

if the exposure of interest is poorly documented
(an example of non-differential misclassification)

Example: mesothelioma
It can be caused by brief, intense exposures
to asbestos, with a very long latency period
(>30 years).

In a case control study,

both cases and controls may recall such exposures
very poorly, thereby leading to an underestimate
of the true association.
Case-Control Studies - Slide 52

Control selection in case-control studies

Recall that the validity of case-control studies

hinges on the assumption that the
sampling fraction for cases (which may be 100%)
and that for controls (usually unknown)
does not vary by exposure status.

In other words, controls should represent the

source population from which the cases arose,
with respect to exposure experience.
Case-Control Studies - Slide 53

Example 1
A researcher wishes to test the hypothesis that
use of nonsteroidal anti-inflammatory drugs (NSAIDs)
is associated with development of gastric cancer.

She plans a case-control study comparing gastric cancer

patients (cases) with patients seen at the same hospital
for peptic ulcer disease (controls).
- NSAID use is a known risk factor for ulcers.

What will be the effect on her findings:

a) if NSAID use is truly a risk factor for gastric cancer?

b) if NSAID use is truly unassociated with gastric cancer?

Case-Control Studies - Slide 54

Hence, controls should not differ systematically

from the population of interest
with respect to exposure experience.

Sometimes the bias may be less obvious,

i.e. unrelated to explicit criteria for
control selection.
Case-Control Studies - Slide 55

Example 2

A researcher wishes to evaluate the association between

cellular phone use and brain tumours
using a case-control design.

 Cases are recruited from the brain tumour clinic at the

Royal General Hospital, a neurosurgery referral centre.

 Controls are recruited from the family medicine clinic

at the same hospital. This clinic primarily serves a
low-income population from the area adjacent to
the hospital.

 This control group is less likely than the general population

to own cellular phones.

Result:
The study will be biased toward detecting an
association between brain tumours and cell phone use.
Case-Control Studies - Slide 56

Controls should be at risk for developing the outcome of interest

- otherwise they do not contribute useful data to the study
(inefficient)
- inclusion of individuals not at risk may
also distort the results if the reason they are not at risk
relates to the exposure under study. This may not be obvious.

Example:
Sleep apnea (exposure) and risk of traffic accidents (outcome)

Cases: Drivers involved in car accidents.

Including non-drivers in the control group would be
a waste of time
- it could bias the results if
persons with severe apnea have chosen not to drive
and are over-represented in the control group.
Case-Control Studies - Slide 57

Controls should be persons who,

had they developed the outcome of interest,
would have had the same opportunity as
the actual cases to be included as such.

Similarly, cases should have

had the same opportunity as actual controls
to be included, had they
not developed the outcome of interest.

If this is not the case, controls may not properly

represent the source population.
e.g., study of brain tumours and cell phone use
discussed above
Case-Control Studies - Slide 58

Types of controls in case-control studies

1. Population Controls

 Suitable if cases are a representative sample

(or all cases) arising from a well-defined
source population.

 Controls are then randomly sampled

from the same population.

 With the incidence-density design,

the probability of being sampled should
vary with an individual’s person-time at risk.

 Often, it is not easy to define the

precise source population.
Case-Control Studies - Slide 59

2. Neighbourhood Controls

 May match controls to individual cases

with respect to neighbourhood of residence.

 If cases are from a hospital, their neighbours

may or may not be equally likely to be
treated at the same hospital should
they develop the disease in question.

Example:
A hospital which caters to a particular group
within society.
Case-Control Studies - Slide 60

3. Family members or friends as controls

 May share exposure characteristics with cases

as opposed to broader source population
(e.g. tobacco and alcohol use, dietary intake,
use of household products).
This can obscure relevant associations.

 Depends on information provided by cases;

investigator loses control over factors leading
to selection.

 Cases’ friends may overlap, leading to

disproportionate probabilities of selection
of certain individuals as controls.
Case-Control Studies - Slide 61

4. Hospital/clinic based controls

 Often used when cases accrued at specific

hospital(s)/clinic(s).

 Controls are recruited among persons seen

at the same hospitals/clinics for
other reasons or conditions.

 To avoid bias, the basis for control selection

cannot be related to the exposure under study.

 The incidence of the “control” condition(s)

determines the sampling fraction.
Case-Control Studies - Slide 62

Example:
A researcher wishes to examine the relationship
between anti-hypertensive medication use
and car accidents.

What will happen if controls are recruited

in the cardiology clinic?
Case-Control Studies - Slide 63

The best hospital controls are

persons with acute conditions that
consistently require hospital care but
are not related to the exposure of interest.

Example:

In a case control study of smoking as a

risk factor for colon cancer, a researcher
recruits controls who undergo appendectomy,
prostatectomy, or hysterectomy at
the same hospital as the cases.
Supplemental Material - Slide 1

Derivation of formula - Part 1

For the cohort study, the 2 x2 table is:

exposed unexposed total

Cases a b a+b
Person-time Pe Po Pe + Po = Pt

IRR = Ie = a/Pe = aPo

___ _____ ____
Io b/Po bPe

= a(Pt - Pe)
_______ = a (1 - Pe/Pt)
_________
bPe b (Pe/Pt)
= a
_ x (1-)
____
b 

Where  = Pe/Pt = the proportion of person-years with

exposure among total person-years
in the source population
Supplemental Material - Slide 2

Furthermore,

a
_ = a/(a+b)
_______ = Pexp|case
__________
b b/(a+b) = 1- Pexp|case

where Pexp|case = proportion of cases exposed

Then IRR = Pexp|case (1- )

_____________ Equation 1
 (1-Pexp|case)
Supplemental Material - Slide 3

Derivation of formula - Part 2

if  = proportion of person-years with exposure

then 1- = proportion of person-years without exposure
and It = Ie  + Io (1- )

i.e. a weighted average of incidence rates

among exposed and unexposed persons
Supplemental Material - Slide 4

Then the PAR fraction is:

I_____
t - Io = (I e ) + [(Io (1- )] - Io
____________________
It (Ie ) + [Io (1- )]

=  (Ie/Io) + (1- ) (Io/Io) - Io/Io

______________________________________
 (Ie/Io) + (Io/Io) (1- )

=  (IRR) + 1 -  - 1
________________
 (IRR) + 1 - 

=  (IRR - 1)
____________
 (IRR - 1) + 1
Supplemental Material - Slide 5

Derivation - Part 3

= IRR -1
_____________
IRR + (1/ ) - 1

= IRR -1
____________
IRR + (______
1-  )


= IRR -1
______________
IRR + IRR (1- )
_________
IRR ()
Supplemental Material - Slide 6

Substituting equation 1 for IRR, this is

IRR -1
____________________________
IRR + _______________________
IRR (1- ) () (1 - Pexp |case)
() (Pexp |case) (1- )

= IRR -1
__________________
IRR + _____________
IRR (1-Pexp |case)
Pexp case

= IRR -1
______________________________
IRR (Pexp |case) + IRR - IRR (Pexp |case)
______________________________
Pexp case

= IRR -1 x
______ Pexp |case = OR -1 x Pexp |case
____
IRR OR