EPID 600; Class 6

Case control studies

University of Michigan School of Public Health

Drug Abuse: A workshop on behavioral and economic research

October 18-20, 2004
1
 Three key dimensions to epidemiologic
studies
Measures of association
Relative measures (relative risks, rates, and odds)
Absolute measures (risk and rate differences)
Study design
Observational
Cohort
Case-control
Cross-sectional
Experimental
Randomized trial
Field trials
Group randomized trials
Units of analysis
Individual
Group
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 Three key dimensions to epidemiologic
studies
Measures of association
Relative measures (relative risks, rates, and odds)
Absolute measures (risk and rate differences)
Study design
Observational
Cohort
Case-control
Cross-sectional
Experimental
Randomized trial
Field trials
Group randomized trials
Units of analysis
Individual
Group
3
 The world

persons “exposed” persons “unexposed”

4
 The case control study

persons with disease persons without disease

5
 The case control study

persons “exposed” with disease persons “unexposed” with disease

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 Case control studies

E+
Disease
E-
E+
No disease
E-

7
 Case control studies

E+
Disease
E-
E+
No disease
E- Disease No
disease
Exposed a b
Not Exposed c d

8
 Case control studies

E+
Disease
E-
E+
No disease
E- Disease No
disease
Exposed a b
Not Exposed c d

9
 Case control studies

E+
Disease
E-
E+
No disease
E- Disease No
disease
Exposed a b
Not Exposed c d

10
 Case control studies

E+
Disease
E-
E+
No disease
E- Disease No
disease
Exposed a b
Not Exposed c d

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 Case control studies

E+
Disease
E-
E+
No disease
E-
Disease No
disease
Exposed a b
Not Exposed c d

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 Case control studies

E+
Disease
E-
E+
No disease
E- Disease No
disease
Exposed a b
Not Exposed c d

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 Principles of case control studies

A case control study is conceptually the same as a cohort

study but is more efficient
The overriding principle is that we select controls that are
representative of the population at risk that gave rise to the
study cases
Cases are more exposed if exposure increases the risk of
disease; less exposed if exposure is protective

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 Case control study design

The sample size, number of cases and number of controls

(i.e., persons who are not diseased) is determined by the
study design
However, the exposure has to be assessed retrospectively
and the proportions of cases and controls who are exposed
are unknown at the beginning of the study

15
 Issues in selecting cases

Cases should preferably be new, i.e., incident cases, not

existing, i.e., prevalent, ones
Remember...Prevalence=Incidence*duration
Therefore, factors that influence prevalence influence
both whether disease occurs (i.e., incidence) and how
long it lasts (i.e., duration)
So, if we select prevalent cases, we will not be able to
distinguish relative between contribution of factors
(exposures) to relative occurrence of new disease and its
duration

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 Aside...about prevalent cases

Prevalent cases may be ok if exposure causes rapidly

lethal form of disease
Of course, in this case there will be very few prevalent
cases to choose and this is quite inefficient

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 Where do cases come from?

Population-based cases
Complete sample of all cases arising in a well-defined
population (time and place)

Hospital-based cases
Patients admitted to one of several hospitals within a given
population or area

Other sources
Patients of a medical group, persons enrolled through a
screening program, etc.

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 Issues in selecting controls

Controls must belong to the population of origin of the cases

The “world” is called the source population
However, we are interested in the population at risk
Controls must represent the population at risk from which
the cases came; this is called the base population
If controls are selected correctly, a similar proportion of
controls would have developed the disease if they had been
exposed to the same exposure as were the cases

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 Where do controls come from?

Population-based controls
A random sample of all the disease-free population from
where cases came
If cases are within subgroups, then that subgroup is the
population from where controls must come
Neighborhood controls
Similar to cases on some, perhaps not other, factors
Dead people
Problematic if exposure in any way leads to death (i.e.,
exposure associated with control selection)

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 Special case: hospitalized controls
Patients hospitalized for disease unrelated to exposure of interest
Only valid if cases/controls come from same population
(demographically and geographically)
e.g., if controls are patients with myocardial infarction, do not select
controls from pathologies (e.g., bronchitis) that may also be associated
with smoking
Problem is that sometimes we do not know that a particular disease is
associated with outcome; hence frequent use of orthopedic cases
Advantages of hospital-based controls: convenient, may be
representative of population from which cases are selected, may be
assessed in much the same way as cases

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 Advantages of case control studies

Efficient for rare diseases

Relatively efficient in terms of time and money
Can study diseases with long latency period
Allow for the evaluation of multiple exposures that
may increase risk for a specific disease

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 Disadvantages of case control studies

Cannot directly compute incidence of disease in exposed

and non-exposed persons
Temporal relationship between exposure and disease may
be difficult to establish with certainty
Are more prone to errors in selection of cases/controls an
in errors pertaining to the collection of information (bias—
will be discussed later)
Not optimal for rare exposures

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 An example

Is smoking associated with brain cancer?

Cases: All incident cases of brain cancer in Ann Arbor

Controls: A random sample of residents of Ann Arbor
Exposure assessment: questionnaire about ever smoked
Note: exposure assessed independently of case/control status

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 Study findings

140
E+
Disease 180
E- 40

E+ 370
No disease 604
E- 234

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 2x2 table

Brain cancer No cancer Total

Smoking 140 370 510

No smoking 40 234 274

Total 180 604 784

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 What measure of associations can we
calculate?
We cannot calculate either risks or rates since we do not
have a complete population to be denominator for risk nor a
complete person time population for rate calculation
But we can calculate odds; calculation of odds depends
only on numbers of cases and numbers of controls

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 And...

140
Odds of brain cancer among smokers =
370
40
Odds of brain cancer among non − smokers =
234
140* 234
Odds ratio of brain cancer = = 2.2
370* 40
Therefore, the odds of brain cancer is 2.2 times higher
among smokers vs. non - smokers

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 Cell phones and cancer: hype or
hazard?
There has been persistent concern about the potential carcinogenic
effects of electromagnetic radiofrequency fields emitted by cellular
phones
The vast majority of studies do not show an association between cell
phone use and development of tumors
Most studies neglect to look at long term users
A research group in Israel published results of a population-based
case control study to describe the association between cell phone use
and parotid gland tumors

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Sadetzki et al. Cellular phone use and risk of benign and malignant parotid gland tumors-a nationwide case-control study. Am J Epidemiol. 2007; 167:457-467
 Cell phone study: set up

3) 2001-2003: Go back in time and

Cell phone use determine of cell phone use patterns
patterns? for PTG cases and controls

1) 2001-2003: Detected new PTG

cases of (malignant or benign) in
Israel through review of records at all
relevant medical institutions in Israel

2) 2001-2003: Controls randomly

selected from the National Population
Sadetzki et al. Cellular phone use and risk of benign and
Registry; matched to individual cases
malignant parotid gland tumors-a nationwide case-control 30
study. Am J Epidemiol. 2007; 167:457-467
 Cell phone study: cases and controls

Cases: People who were confirmed to have PTG through

medical records and verification by a single physician

Controls: People who do not have PTG and are listed in the
National Population Registry in Israel

31
Sadetzki et al. Cellular phone use and risk of benign and malignant parotid gland tumors-a nationwide case-control study. Am J Epidemiol. 2007; 167:457-467
 Cell phone study: measuring exposure

• Number of calls?
• Duration of calls?
• Use of headsets?
Regular User • Which side of the
(exposed) head was phone held
FOR CASES AND on?
CONTROLS: • Urban or rural
location?
Has the participant
used a cell phone
more than 1x/week
for at least 6 months
(ever)? Not a regular
user
(unexposed)

32
Sadetzki et al. Cellular phone use and risk of benign and malignant parotid gland tumors-a nationwide case-control study. Am J Epidemiol. 2007; 167:457-467
 Cell phone study: findings

For the entire group, no increased chance of PGT was

observed for ever having been a regular cell phone user
(OR=0.87)
However, analysis of regular users showed consistently
elevated probability of PGT

Cumulative call time Adjusted Odds Ratio

(hours) with no hands-
free device
Non Users 1.0 (reference)
<=266.3 0.72
266.4-1034.9 1.57
>=1035 1.96

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Sadetzki et al. Cellular phone use and risk of benign and malignant parotid gland tumors-a nationwide case-control study. Am J Epidemiol. 2007; 167:457-467
 It is helpful to think of all case control studies as
nested within a population cohort

All case control studies are sampling from a base

population, which is the persons at risk in the source
population
Different forms of control sampling then have implications
for how the case control study mimics the underlying cohort
“Incidence density sampling” selects from the risk set
during the same follow-up period in which cases are
identified; that is, the probability of selection is proportional
to the time at risk

34
 Cell phone study: set up

3) 2001-2003: Go back in time and

Cell phone use determine of cell phone use patterns
patterns? for PTG cases and controls

1) 2001-2003: Detected new PTG

cases of (malignant or benign) in
Israel through review of records at all
relevant medical institutions in Israel

2) 2001-2003: Controls randomly

selected from the National Population
Sadetzki et al. Cellular phone use and risk of benign and
Registry; matched to individual cases
malignant parotid gland tumors-a nationwide case-control 35
study. Am J Epidemiol. 2007; 167:457-467
The “underlying cohort”

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Disease cases

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 Incidence density sampling

For every case we select a control from the population risk set during
the same follow-up period in which the cases are identified
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 Therefore, in incidence density sampling

a c Disease Time

IRexp = and IRun exp =

PT1 PT0 Exposed a T1

Not Exposed c To
aim is to select controls so that
Total a+c T1+To
if b is exposed and d is unexposed
b PT1 b d d PT0
= or = or =
d PT0 PT1 PT0 b PT1 so, OR is an unbiased
estimate of the IRR in
therefore
incidence density sampling
a
PT1 a PT0 a d
IRR = = * = * = OR
c c PT1 c b
PT0
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 Case-cohort sampling

For every case we select a control who is a member of the population

at risk; all cases contribute to both numerator and denominator. Note
that it is possible that after a person is selected as a control, that
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person may later become a case
 Therefore, in case cohort sampling

Disease No disease Total

a c
Rexp = and Run exp =
a+b c+d Exposed a b a+b

given that controls are selected from Not exposed c d c+d

base population, then the proportion Total a+c b+d a+b+c+d

of exposure vs. non exposure among controls

represents proportion of exposure vs. non - exposure
in the population, that is
b a+b d c+d
= or =
d c+d b a+b
therefore
a
a c+d a d
RR = a + b = * = * = OR
c c a+b c b
c+d
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 Summary of controls in a case control
study
a d a*d
In case control study, the only statistic is * , or
c b c*b
d PYOun exp
Therefore, if control selection is such that =
b PYOe xp
then OR is an unbiased estimate of IRR
d total unexposed
and if conrol selection is such that =
b total exposed
then OR is an unbiased estimate of RR
No
Disease Time Total
disease

Exposed a b PYOexp a+b

Not
c d PYOexp c+d
exposed

Total a+c b+d PYOtotal a+b+c+d

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 And if...(old-fashioned)

controls
are
selected
from those
who are no
longer
cases at
the end of
the study

Here we are overestimating the risk ratio because, at end of study, the proportion of exposure among
those who are controls is less than population (assuming a positive exposure-disease association)
When disease is “rare”, this is not much of an issue since there are very few cases so the proportion
of exposure among controls approximates population anyway
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 Sampling fractions

Target population

Exposed Unexposed

a b c d
Cases Non-cases Cases Non-cases

F1 F2 F3 F4

Cases Controls

Exposed Unexposed Exposed Unexposed

Sample 44
 Case control study as sampling from a
cohort study

a * d (exposed cases * unexposed non - cases)

Cohort OR =
c* b (unexposed cases* exposed non - cases)

a * F1 * d * F4 ad *( F1 * F4 )
Case control OR = =
c * F3 * b * F2 cb *( F3 * F2 )
F1 * F4
Case control OR = Cohort OR *
F3 * F2 Disease
No
Total
disease

F1 * F4
Case control OR = Cohort OR if =1
F3 * F2
Exposed a b a+b

Not
c d c+d
exposed

Total a+c b+d a+b+c+d

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The “underlying cohort”, 2x2 table

Brain cancer PYO

Smoking 140 55,360

No smoking 40 35,060

Total 180 90,420

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 And...

140
IR of brain cancer among smokers =
55,360
40
IR of brain cancer among non − smokers =
35, 060
140
Odds ratio of brain cancer = 55,360 = 2.2
40
35, 060
Therefore, the incidence rate ratio of brain cancer is 2.2 times higher
among smokers vs. non - smokers
Therefore, when controls are sampled from person time of observation of
population, IRR = OR
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 A note about number of controls

We do not need to sample as many controls as there are

cases
Selecting 4 controls for every case (i.e., 4:1 control: case
selection) improves statistical power, i.e., the ability of a
study to detect associations
There is little statistical advantage to selecting more than 4
controls for every case

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Special topic: Exchangeability of odds ratio
a
a
odds of being a case among exp osed = a + b = Disease No disease Total
a b
1−
a+b Exposed a b a+b
c
Not Exposed c d c+d
c
odds of being a case among un exp osed = c + d =
c d
1- Total a+c b+d a+b+c+d
c+d
a
a* d
relative odds of being a case, comparing exp to un exp = b =
c b* c
d
a
a
odds of being exposed among cases = a + c =
a c
1−
a+c
b
b
odds of being exposed among controls = b + d =
b d
1−
b+d
a
a* d
relative odds of being exp osed , comparing cases to controls = c =
b b* c 49
d
Comparing cohort and case control studies
Cohort
Complete source population experience
tallied
Can calculate incidence, risk, and
relative incidence
Convenient for many diseases
Prospective or retrospective
Case control
We sample from source population and
its experience
Can calculate OR, which, under proper
sampling conditions, mimics either RR
or IRR
Convenient for many exposures
Prospective or retrospective
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