Case-Control Study Design.pptx

CASE-CONTROL STUDY
Professor Dr. AB Rajar, MBBS, Dip-Diab, MPH, Ph.D. CPHE
Director of Research and Innovative Center
[IBN-E-SINA UNIVERSITY
AB Rajar /drabrajar@gmail.com 1

Learning objectives
I. Theme and Historical Perspective
II. Definition.
III. Classification.
IV. Analytical Study Design
V. Case-Control Study.
VI. Biases of Case-Control Study
VII. Advantages & Disadvantages.
VIII. MCQs

Theme
Imagine you are a clinician practicing private or public
sector.
You have seen a few patients with a certain type of
cancer.
Almost all of them have been exposed to a particular
chemical
You hypothesize that their exposure is related to
their risk of developing this type of cancer.
How will you go about confirming or refuting your
hypothesis?

Example from History
• Thalidomide Tragedy:
• Thalidomide was first marketed as a safe, non-barbiturate
hypnotic in Britain in 1958.
• In 1961 at a Gynecological congress it was discussed that a large
number of babies with congenital abnormalities were being born
(phocomelia) which was associated with thalidomide.
• Confirmed that thalidomide was Teratogenic.
No % who took thalidomide
Cases (with congenital defects) 46 41(89.13)
Controls 300 0

• OCP and Thromboembolic Disease:
• By Aug 1965, BRITISH COMMITTEE ON SAFETY DRUGS received 249 reports
of adverse reactions and 16 deaths in women taking OCPs.
• Thus there was a need to conduct an epidemiological study.
• A case-control study was conducted by Vassey and Doll in 1968.
• Controls were matched for age, marital status, and parity.
• Relative Risk of the users to the non-users was 6.3:1
• Confirmation was established.
No % who used OCP
Cases (venous thrombosis and pulmonary
embolism)
84 50 (59.52)
Controls 168 14 (8.33)

• Again in the 1940s, Sir Norman Gregg, an Australian
ophthalmologist, observed a number of infants and young
children in his ophthalmology practice who presented with an
unusual form of cataract.
• Gregg noted that these children had been in utero during the
time of the rubella (German measles) outbreak. He suggested
that there was an association between prenatal rubella
exposure and the development of unusual cataracts.
• Keep in mind that was a time there was no knowledge that a
virus could be teratogenic.
• Thus, he proposed his hypothesis solely on the bases of
observational data, the equivalent of data from ambulatory or
bedside practice today.

• In the early 1939s, Alton Ochsner, a surgeon of New
Orleans, observed that virtually all of the patients on whom
he was operating for lung cancer gave a history of cigarette
smoking.
• He hypothesized that cigarette smoking was linked to
lung cancer.
• Although this relationship is accepted and well-recognized
today, it was relatively new and controversial at the time
that Ochsner made his observation.
• Based only on his observations in cases of lung cancer, was this
conclusion valid?

DEFINITION
• "The study of the distribution and determinants of
health-related states or events in specified
populations, and the application of this study to the
prevention and control of health problems ".

CLASSIFICATION

TYPES OF EPIDEMIOLOGICAL STUDIES

ANALYTICAL STUDIES
• In analytical studies, the subject of interest is the individual
within the population.
• The object is not to formulate but to test the hypothesis.
• To evaluate an association between exposure and disease.
• Analytical studies focuses on the magnitude of the
association between the exposure and the health problem
under the study.

CASE-CONTROL STUDY
• The observational epidemiologist study of persons with
the disease (or other outcome variables) of interest and
a suitable control (comparison/reference) group of
persons without the disease.
(Descriptive of Epidemiology: 4th ed:John M Last.2001)

CASE-CONTROL STUDY [Retrospective Studies]
• A case-control study is an observational study in which
subjects are sampled based on the presence or absence of
disease and then their prior exposure status is determined.
• A case-control study involves two populations – cases and
controls and has three distinct features:
I. Both exposure and outcome occurred before the start of the
study.
II. The study proceeds backward from effect to cause.
III.It uses a control or comparison group to support or refute
an inference.

CASE-CONTROL STUDY
• The investigator selects
Cases with the disease
• And Appropriate
Controls without the disease
• And obtains
Data regarding past exposure to possible etiologic
factors in both groups.
• The investigator then compares the frequency of exposure of the
two groups

Dogma of case-control study

DESIGN OF CASE-CONTROL STUDY
CASES
Disease
Exposed
No
Exposed
CONTROLS
No
Disease
Exposed
No
Exposed
Hall Mark of case-control study: Begins with people with the disease (cases) and
compares them to people without the disease (controls) and searches for
exposure.

FRAMEWORK OF CASE-CONTROL STUDY
FIRST SELECT
Cases
(With disease)
Controls
(Without disease)
THEN Were exposed a b
Measure
Exposure
Were not exposed c d
TOTALS a+c b+d
Proportions
Exposed
𝑎
𝑎 + 𝑐
𝑏
𝑏 + 𝑑

STEPS OF CASE-CONTROL STUDY.
Selection of
cases
Selection of
control
Matching
Measurement
of Exposure
Analysis and
Interpretation

SELECTION OF
CASES

SELECTION OF CASES
• CASE: A person in the population or study group
identified as having a particular disease, health
disorder, or condition under investigation.
(Descriptive of Epidemiology: 4th ed:John M Last.2001)
• CONTROL: Person or persons in a comparison group
that differs, in disease experience (or other health-
related outcome) in not having the outcome being
studied. (Descriptive of Epidemiology: 4th ed:John M Last.2001)

SELECTION OF CASES
• Definition of the case: it involves two specifications-
• 1. Diagnostic Criteria:
• Enunciate clear-out diagnostic criteria for the disease of
interest.
• Must be specified before the study was undertaken.
• Once established, it should not be altered or changed till the
study is over.
• 2. Eligibility Criteria:
• It is always advisable to take the incident cases (new cases)
since the prevalent cases (old cases in advanced stage) might
have changed their exposure status due to medical advice etc.

SELECTION OF CASES
• 3-Hospitals:
• Convenient
• Can be chosen from one hospital or a network of hospitals.
• Admitted during a specified period of time
• Entire case series or random sample is selected
• 4-General Population:
• All cases of the study disease occurring within the same
geographical area during a specified period of time.
• Through a survey, disease registry or hospital network
• Entire case series or random sample should be fairly
representative of all cases in the community.

Selection of
cases
Selection of
control
Matching
Measurement
of Exposure
Analysis and
Interpretation

SELECTION OF
CONTROLS

SELECTION OF CONTROLS
• Sources of controls
1. Hospitals:
• control may be patient of another disease
• Chance of selection bias (one condition may influence another)
• Smoking & lung cancer Control are patients of MI
2. Relatives
3. Neighborhood
• Person living in the same locality
• Person working in the same factory
• Student of the same school, college, or University
4. General population: in a population-based study, random sample,
cases represent the community

• Control must be free from disease
• Similar to cases as much as possible except for the presence
of disease or some other factor influencing the disease
• COMPARABLE:
• Should the controls be similar to the cases in all respects
other than having the disease?
• REPRESENTATIVE:
• Should the controls be representative of all non-diseased
people in the population from which the cases are selected?

• Compatibility vs Representativeness
• The control group should be representative of the general
population in terms of the probability of exposure to the risk
factor.
• AND they should also have had the same opportunity to be
exposed as the cases have.
• Not that both cases and controls are equally exposed but only
that they have had the same opportunity for exposure.

SELECTION OF CONTROLS SOURCES
Source Advantage Disadvantage
Hospital Based
Easily identified
Available for interview
More willing to co-operate
Tend to give complete and
accurate information (↓Recall
bias)
Not typical of general
population
Possess more risk factors for
disease.
Some diseases may share risk
factors with the disease under
study. (whom to exclude)
Population-Based
(Registry cases)
Most representative of the
general population.
Generally healthy
Time, money, and energy.
Opportunity of exposure may
not be same as that of cases.
Neighborhood
controls/Telephone exchange
random dialing.
Controls and cases similar
residence.
Easier than sampling the
population
Non co-operation.
Security issues
Not representative of general
population
Best friend control/Sibling
control
Accessible, Cooperative, Similar
to cases in most aspects.
Over-matching

• Large study: Cases: Control:: 1:1
• Small study: Cases: Control:: 1:2, 1:3, 1:4.
• Use of multiple controls.
• Multiple control of different types:
• Control-1 hospital, 1 neighborhood e.g. Children with a brain
tumor, control- children with other cancer, normal children, risk
factor-h/o radiation exposure.

Example of multiple controls.

Selection of
cases
Selection of
control
Matching
Measurement
of Exposure
Analysis and
Interpretation

Matching

Matching
• The process by which we select controls in such a way
that they are similar to cases with regard to certain
pertinent selected variables.
• Like age, sex, occupation, social status, etc are all
known to influence the outcome of the disease and if
not adequately matched for comparability can distort or
confound the results.
• Gordis Epidemiology; 6th Ed

Matching
• Matching Types: Matching may be of two types
I. Group matching
II. Individual matching
• Group matching/Frequency matching: Consists of selecting the
controls in such a manner that the proportion of controls with a certain
characteristic is identical to the proportion of cases with the same
characteristic.
• If 25% of the cases are married, the controls will be selected so
that 25% of that group is also married.
• Individual matching/matched pairs: In this approach, for each
case selected for the study, a control is selected who is similar to the
case in terms of the specific variable or variables of concern.
-50 year old man with a disease compared with a 50-year-old man without a disease
-Pair of patients & control of the same age , sex, duration and severity of illness etc

Matching
A way to account for possible effects of confounding

Age wise comparison

Matching Problems
 Individual Matching on too many variables – is time consuming,
costly and may be lead to too less control.
 Cannot explore possible association of disease with any variable
on which cases and controls have been matched. Therefore only
factors which are known to be associated with the disease are
studied.
• Suppose we know that breast caner rates are higher among single women
than in married women; then matching cases for marital status would
spuriously NOT detect any relation regarding this factor.

Selection of
cases
Selection of
control
Matching
Measurement
of Exposure
Analysis and
Interpretation

Measurement
of exposure

• Information about the exposure should be obtained in
precisely the same manner for both cases and controls.
• This may be obtained by:
I. Interview
II. Questionnaire
III.Past records of cases
• Hospital records
• Employment records.
Measurement of exposure

• On analysis of the case-control study we find out
• Exposure Rates: The frequency of exposure to
suspected risk factors in cases and controls.
• Estimation of Risk: Relative Risk or Risk Ratio
• Odds Ratio: Strength of association between risk and
outcome.

• Exposure Rate:
• A case-control study provides a direct estimation of the exposure
rates (frequency of exposure) to the suspected factor in disease
and non-disease groups.
• Cases=
𝑎
(𝑎+𝑐)
=33/35=94.2%
• Controls=
𝑏
(𝑏+𝑑)
=55/82=67.0%
Cases
(Lung cancer)
Controls
(without lung cancer)
Smokers 33 (a) 55 (b)
Non-Smokers 2 (c) 27 (d)
Total 35 (a+c) 82 (b+d)
Outcome of case-control study

• Relative Risk or Risk Ratio (RR):
• RR=
𝐼𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑎𝑚𝑜𝑛𝑔 𝑒𝑥𝑝𝑜𝑠𝑒𝑑
𝐼𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑎𝑚𝑜𝑛𝑔 𝑛𝑜𝑛−𝑒𝑥𝑝𝑜𝑠𝑒𝑑
• RR=
𝑎
(𝑎+𝑏)
÷
𝑐
(𝑐+𝑑)
• A typical case Control study does not provide incidence rates
from which RR can be calculated directly.
• There is no appropriate population or denominator at risk.
• In general RR can be exactly calculated from a cohort study.

• Odds Ratio:
• Odds: Odds of an event are defined as the ratio of the number
of ways an event occurs to the number of ways an event cannot
occur.
• If the probability of event X occurring is P, then the odds of it occurring is
=P/P-1.
• Odds ratio: Ratio of the odds that the cases were exposed to
the odds that the controls were exposed.

• Odds ratio:
• Odds ratio=
𝑂𝑑𝑑𝑠 𝑡ℎ𝑎𝑡 𝑐𝑎𝑠𝑒𝑠 𝑤𝑒𝑟𝑒 𝑒𝑥𝑝𝑜𝑠𝑒𝑑
𝑂𝑑𝑑𝑠 𝑡ℎ𝑎𝑡 𝑐𝑜𝑛𝑡𝑟𝑜𝑙 𝑤𝑎𝑠 𝑒𝑥𝑝𝑜𝑠𝑒𝑑
• Odds ratio=
(
𝑎
𝑏
)
(
𝑐
𝑑
)
=
𝑎𝑑
𝑏𝑐
Cases
(Diseased)
Controls
(Not Diseased)
Exposed a b
Not exposed c d

• Odds ratio (=cross product ratio) can also be viewed
as the ratio of:
• the product of two cells that support the hypothesis of an
association (cells a & d-diseased people who were exposed
and non-exposed people who were not exposed)
• to the product of the two cells which negates the hypothesis
of an association (cells b & c-non diseased people who were
exposed and diseased people who were not exposed).

• Odds Ratio:
• Odds ratio=
𝑂𝑑𝑑𝑠 𝑡ℎ𝑎𝑡 𝑐𝑎𝑠𝑒𝑠 𝑤𝑒𝑟𝑒 𝑒𝑥𝑝𝑜𝑠𝑒𝑑
𝑂𝑑𝑑𝑠 𝑡ℎ𝑎𝑡 𝑐𝑜𝑛𝑡𝑟𝑜𝑙 𝑤𝑎𝑠 𝑒𝑥𝑝𝑜𝑠𝑒𝑑
• Odds ratio=
(
𝑎
𝑏
)
(
𝑐
𝑑
)
=
𝑎𝑑
𝑏𝑐
Cases
(Lung cancer)
Controls
(without lung cancer)
Smokers 33 (a) 55 (b)
Non-Smokers 2 (c) 27 (d)
Total 35 (a+c) 82 (b+d)

Selection of
cases
Selection of
control
Matching
Measurement
of Exposure
Analysis and
Interpretation

Analysis

• Odds ratio=
𝑎𝑑
𝑏𝑐
=
33×27
55×2
=
891
110
=8.1
INTERPRETATION:
• The odds of smoking more than5 cigarettes per day was 8.1 time
more in the lung cancer patient than without lung cancer.
OR
• Smoking (<5/day) was found be associated 8.1 times more in
patients with lung cancer than those without lung cancer.
Analysis & Interpretation

Interpretation of odds ratio
• OR=1: Exposure is not related to the disease.
• OR>1: Exposure is a related disease
• OR<1:Exposure is protective against disease.

Bias in Case-Control Study
• Definition:
• Any systemic error in the design, conduct, or analysis
of a study that results in mistaken estimates of the
effect of the exposure on disease.
• Types of bias in case control studies:
1. Selection bias
2. Information
3. Confounding bias

• SELECTION BIAS:
• Sources-
1. Selective loss to follow-up.
2. Incomplete ascertainment of cases (Detection or
Diagnostic bias).
3. Inappropriate control group
4. Differential motivation to participate

• Selection Bias:
• Selective Survival: only surviving subject available to
be studied; those surviving from those dying in
potentially important ways.

• INFORMATION BIAS:
• Occurs due to-
• Imperfect definition of study variables
OR
• Flawed data collection procedures.
• Leads to- Misclassification of disease and exposure
• Types of information bias-
• Recall bias
• Interviewer bias

• Recall Bias: [usually in case control studies].
• Cases who are aware of their disease status may be
more likely to recall exposure than controls.
• E.g, congenital malformation with prenatal infections
• Results in misclassification.

• Interviewer bias:
• When the interviewer is not blinded (knows) the case
status of subjects there is potential for interviewer bias.

• Confounding:
• When a measure of the effect of an exposure on risk is
distorted because of the association of exposure

Advantages
• Only realistic study design for uncovering etiology in rare
diseases.
• Efficient for the study of chronic diseases.
• Require comparatively few subjects.
• Commonly used in outbreaks investigation.
• Tend to require a smaller sample size than other designs.
• Relatively inexpensive

Limitation/ Disadvantages
• Risk of disease cannot be estimated directly
• Not efficient for the study od rare exposure
• More susceptible to selection bias than alternative designs
• Information on exposure may not be less accurate than that
available alternative designs

MCQs
• Q-Which one of the following studies has the highest risk of bias?
A- Case report/series
B- Cross-sectional study
C- Case-control study
D- Cohort study
E- RCT

MCQs
• Q-What is the main reason why it is important to use precise,
specific criteria for what constitutes a "case," i.e. in defining the
outcome? (Select the best answer.)
A. To avoid misclassification with respect to the outcome.
B. To limit the number of subjects in the study.
C. To avoid selection bias.
D. To avoid interviewer bias

MCQs
• Q-Which of the following are legitimate source of cases for a case-
control study? (Select all that apply).
A. Disease registries, e.g. cancer registries.
B. Hospitals.
C. Members of the general population responding to an
advertisement seeking subject with a particular condition.
D. Patients at an outpatient clinic

MCQs
• Q-Which of the following are advantages to case-control studies?
(Select all that apply).
A. They tend to be less expensive and more efficient than
prospective cohort studies.
B. They are feasible for rare diseases.
C. They allow you to study multiple outcomes of a single risk factor.
D. They are good for diseases that have a long latency period (i.e., a
long time between exposure and manifestation of disease.)

MCQs
• Q-Suppose a study looking at the association between smoking
and bladder cancer found an odds ratio = 2.4. What would be
the best way to interpret this? (Select one answer.)
A. Smokers are 140% times as likely to develop bladder cancer
compared to non-smokers.
B. People with bladder cancer are about 40% more likely to e
smokers compared to people who don't have bladder cancer.
C. Smokers have a 2.4 % more risk of bladder cancer compared to
nonsmokers.
D. Smokers have 2.4 times the risk of developing bladder
cancer compared to non-smokers

MCQs
• Q-All of the following are true of odds ratio except:
A. It is an estimate of the relative risk
B. It is the only measure of risk that can be obtained directly form a
case-control study
C. It tends to be biased towards 1 (neither risk or protection at high
rates of disease
D. It is the ratio of incidence in exposed divided by incidence in
nonexposed
E. It can be calculated without data on rates (as in a case-control
study

Thank You

Case-Control Study Design.pptx

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