Case control Study

Advanced Epidemiology for MPH students

By: Fantahun Ayenew (MPH, MPHM, Ass. Prof. of Epidemiology)

Department of Epidemiology and Biostatistics
University of Gondar

By Fantahun Ayenew for Epid-Biostat and

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 Question#1
Discuss in group on study designs; one group should
discuss on one study design (definition, type, measure
of association, limitation and strength)

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 Study design

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 Definition

• Persons with a condition ("cases") are identified,

suitable comparison subjects ("controls") are
identified, and the two groups are compared with
respect to prior exposure
‘Look backward for the exposure’

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 Def…cont.

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Def…cont…

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 Def…cont.
• Case control study is also called as case comparison
study, case compeer study, case history study, case
referent study and retrospective study

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 Steps in conducting case control study

Step 1: Define cases

• A case definition is usually based on a combination of
- signs and symptoms,
- physical and pathological examinations, and results
of diagnostic tests.
• It is best to use all available evidence to define with as
much accuracy as possible the true cases of disease.

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 Step 1: Define cases cont…

• If nonspecific criteria are used, most but not all

people with the disease will be captured, but many
people who do not have the disease will be included
erroneously.

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 Step 2: Select cases

• Places - can be health institution or community.

Consider both accuracy and efficiency in selecting a
particular source
• Incident or prevalent cases: incident cases are
preferred to study the cause of disease
• Sometimes rely on prevalent cases (for example,
when studying the causes of insidious diseases
whose exact onset is difficult to pinpoint)

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 Step 2: Select cases cont…

• But, must be interpreted cautiously because it is

impossible to determine if the exposure is related to
the inception of the disease, its duration, or a
combination of the two

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 Step 2: Select cases cont…
Complete or partial cases: There is a common
misconception that a case-control study must include
all cases of disease occurring within a defined
population.
• This erroneous thinking arises from a desire to make
the study results as generalizable as possible.
• However, validity is the primary goal of an
epidemiologic study, and validity should never be
sacrificed for generalizability.

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 Step 2: Select cases cont…

• Thus, it is appropriate to conduct a study using cases

identified at only one hospital, even when there are
many hospitals in the same geographic area.
• However, regardless of whether ascertainment is
complete, one must be able to define the case
group’s source population so that comparable
controls from the same population can be selected.

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 Step 2: Select cases cont…

• The cases identified in a single clinic or treated by a

single medical practitioner are possible case series
for case-control studies.
• The corresponding source population for the cases
treated in a clinic is all people who would attend that
clinic and be recorded with the diagnosis of interest
if they had the disease in question.

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 Step 3: Select control
• Selection of controls should consider following;
1) Controls should represent the population at risk of
becoming cases
2) The prevalence of exposure among controls should
reflect the prevalence of exposure in the source
population.
3) The time during which a subject is eligible to be a
control should be the time in which the individual is
also eligible to be a case.
If the above three points are not fulfilled the study will
be liable for selection bias.
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Sources of Controls

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Sources of controls…

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 Methods of selecting controls

Survivor sampling (exclusive controls); control selected

from non-case or survivors at the end of the case
diagnosis and accrual period
• estimates the incidence (i.e., risk)
• For a rare disease, odds ratio estimates the
cumulative incidence rate

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 Methods of selecting controls…

Case-base or case-cohort sampling: controls selected

from the population at risk at the beginning of the case
diagnosis and accrual period (inclusive controls).
• odds ratio estimates the risk ratio with no rare
disease assumption.

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 Methods of selecting controls

Risk set sampling: when controls are selected from the

population at risk as cases are diagnosed
• such controls are usually matched in time to the
cases
• the odds ratio computation estimates the relative
rate on the assumption that the it does not change
during the follow up period.
• Thus, it is reasonable for the control group to include
future cases of disease because it is merely an
efficient way to obtain the denominator data for the
risks and rates. By Fantahun Ayenew for Epid-Biostat and 20
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Methods of selecting controls

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 Number of control groups and case-control
ratio

• A single control group is optimal in most of the

times.
• But, increased when the selected group has a
specific deficiency that could be overcome by inclusion
of another control group.
• In this case for example, the researcher may take one
control group from hospital and the second control
group from the general population.

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 Number of control groups and case-control
ratio cont…

Case - control ratio:

• The optimal case-control ratio is 1:1.
• When the number of cases is small, the sample size
for the study can be increased by using more
controls (e.g. 1:2, 1:3,and 1:4).
• As the number of controls per case increases, the
power of the study also increases.
• But, beyond 1:4, there is only a small increase in
statistical power, which cannot justify the
expenditure of additional resources

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 Step Four: exposure ascertainment

• Obtain sufficiently detailed information on the

nature, sources, frequency, and duration of these
exposures
• Use similar Procedures for cases and controls to
obtain information .
• For example,
- Place and circumstances of interview
- Blind interviewers or record reviewers, if possible.
- Data collectors should be unaware of the specific
hypotheses being tested to reduce observation bias.
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 Step Four: exposure ascertainment…

• Collect information in such a way that it allows you

to identify the most appropriate time window for the
evaluation of the possible harmful effects of an
exposure
• Avoid collecting information over too wide period,
such as “ever use” in order to avoid the inclusion of
some period in time that cannot be causally related
to the disease
• A critical period is a time when the subject is
susceptible to the action of an exposure

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Sources of exposure data (cases and controls)

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 Step Five: Analysis and Interpretation of result

The measure of association in case control study is

Odds Ratio (OR)

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 Step Five: Analysis and Interpretation of result

An odds is defined as the probability or chance that an

event will occur divided by the probability that it will
not occur.
Odds = The chances of something happening
The chances of it not happening

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 Step Five: Analysis and Interpretation of
result cont…
• Odds of exposure in disease = a/ (a+c) = a/c
c/(a+c)
• Odds of exposure in non-disease = b/(b+d) = b/d
d/(b+d)
• Relative odds/ odds ratio
= (a/c)/(b/d) = ad/bc

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 Variants of a case-control study

Nested case-control studies

• conducted within cohorts of exposed and unexposed
people
• In the ordinary case-control studies there is
undefined source populations.
• Where as in the nested case-control studies, there
are well defined source populations

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Nested case-control studies

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 Advantages of nested case-control study

• The investigator is able to test new hypotheses

• Baseline data collected before outcome
• Saves money and time
• Has the advantage of both case-control and
retrospective cohort

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 Case-cohort studies

• A variant of case control study in which the

controls are drawn from the same cohort as the
cases but are identified before the cases develop.
• Some of them may later become cases.
• It is a case-control study in which the source
population is a cohort and every person in this
cohort has an equal chance of being included in
the study as a control, regardless of:

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 Cumulative (“Epidemic”) case-control studies

• In some research settings, case control studies may

address a risk that ends before subject selection begins.
• For example, a case-control study of an epidemic of
diarrheal illness after a social gathering may begin after all
potential cases have occurred (because the maximum
induction time has elapsed)
• In such a situation, an investigator might select controls
from that portion of the population that remains after
eliminating the accumulated cases; i.e. one selects controls
from among non-cases (those who remain non-cases at the
end of the epidemic followup.

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 Case-crossover study

• In the case-crossover study, cases serve as their

own controls, and the exposure frequency during
the hazard period is compared to that from a control
period.
• Because cases serve as their own controls, this
design has several advantages including the
elimination of confounding by characteristics such
as gender and race and the elimination of a type
of bias that results from selecting unrepresentative
controls.
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 Sample size for a case-control study

• To calculate sample size for a case-control study, we

need to decide on values for,
- OR
- type I error
- proportion of exposure among controls and
- power required to detect the difference
• For manual calculation of the sample size in case
control study, we use two population proportion
formula.
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 sample size calculation using Epi Info

Use the hypothetical information below to calculate the

sample size using StatCalc from Epi Info.
• prevalence of exposure in controls = 9%
• Effect size (OR) =2.0
• Ratio of cases to controls= 1:2
• significance level = 0.05
• level of statistical power = 80%
After having these figures in the Epi Info statcalc the
sample size calculated become 242 cases and 484
controls. By Fantahun Ayenew for Epid-Biostat and
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 Bias in case control study

Selection bias: It may be present if the control group

does not come from the same population as the cases.
• Control Selection Bias: Using identical selection
criteria will ensure that cases and controls come
from the same source population.
• Self-Selection Bias: refusal or agreement by
participants that is related to both the exposure and
disease.

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 Way of minimizing selection bias in a case-
control study:

• Pick controls whose eligibility for inclusion in the

study is the same as cases
• pick controls who have the same opportunity for
exposure as cases
• pick controls who have same access to being
diagnosed for the illness or disease as cases

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 Information bias

The common types are recall, interviewer and

misclassification biases
• Recall bias: arise when individuals with a disease
(cases) remember past exposures more completely
(or less completely) than controls.
minimize recall bias by;
- selecting a diseased control group.
- designing a structured questionnaire

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 Information bias…

Interviewer bias: can occur when interviewers are

aware of the disease status of a subject and question
cases and controls differently about their exposures.
Misclassification: also called measurement error, is
probably the most common form of bias in
epidemiologic research.

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 Advantage of case control study

• Most efficient design for rare diseases

• Efficient for diseases with long induction and latent
periods
• Ethical - cannot affect onset of disease
• evaluate multiple exposures in relation to a disease,
so good for diseases about which little is known.
• Time and cost effective because
• Desirable when the population under study is
dynamic because it is difficult to keep trace of a
population that is constantly changing.
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 Disadvantage of case control study

• Uncertainty of exposure-disease time relationship

• Inability to provide a direct estimate of risk
• Not efficient for studying rare exposures
• Subject to biases (recall and selection bias)

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 Applications of the case-control design

used to;
• Determine the cause of a disease or outcome of
interest
• Measuring the effect of procedures or interventions
• Investigation of disease outbreaks

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Many Thanks !

By Fantahun Ayenew for Epid-Biostat and

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