Case-control

studies
 This version is made for bilingual
teaching .Case-control study is an essential
research design of Epidemiology, which
involves identifying patients who have the
outcome of interest (cases) and control
patients who do not have that same outcome,
and looking back to see if they had the
exposure of interest. The exposure could be
some environmental factor, a behavioural
factor, or exposure to a drug or other
therapeutic intervention.
 Select Study Design to
Match the Research Goals
Objective Design
Description of disease or spectrum Case series or report
Cross-sectional study
Determine operating characteristics Cross-sectional
of a new diagnostic test
Describe prognosis Cohort study
Determine cause-effect Cohort study
Case-control study
Compare new interventions Randomized clinical trial
Summarize literature Meta-analysis
 Case-Control Studies
 Introduction
 Matching
 Investigate Example
 Design of Case-Control Studies
 Data collection and analysis
 Bias
 Strengths and Weaknesses
 Several important features
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 Introduction

 Historical Perspective
 Definition
 Types of Design

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n

Historical Perspective
 Unique contribution of epidemiology to the repertoire
of clinical research designs
 First case-control study performed in late 1950s
 Doll and Hill’s study of lung cancer and smoking behavior
among physicians
 Jerome Cornfield’s classic description of
“Retrospective Studies”
 New statistical tools were developed to analyze the
study design - logistic regression
n

Definition
A case-control study is a design in which
individuals with an event or condition of
interest, CASES, are identified and then
compared with regard to one or more exposures
to individuals without the event or condition of
interest, CONTROLS. Case-control
investigations typically are designed to assess
the association between occurrence of disease
and an exposure suspected of causing (or
preventing) that disease.
n

Exposed a
a/(a+c) Cases
Unexposed c

Exposed b

b/(b+d) Controls
Unexposed d

Direction of inquiry
n

Types
Family of epidemiological study designs
 Traditional case-control design

 Case-control studies within cohorts

 Nested case-control study design

 Case-cohort study design
 Case-parent study design
 Case-only study design
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 Matching

 Summarize
 Types
 Problems with Matching

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Matchin
g

Summarize
 Matching is defined as the process of selecting
controls so that they resemble the cases with
regard to certain characteristics
 The goal of matching is to create similar
distributions between cases and controls with
regard to certain characteristics
 Matching can be used to
 Adjust for potential confounding factors
 Increase precision of estimate
Matchin
g

Types
 Individual level matching
 For each case in the study, one or more controls
are selected with identical (similar)
characteristics as the case
 Frequency, or group, matching
 Select controls so that the proportion with a
certain characteristic is identical to the
proportion of cases with that characteristic
Matchin
g

Problems with Matching

 Difficult and expensive
 Cannot evaluate the effect of controlled
variables
 May limit the ability to control for other
variables
 Overmatching
 Controls resemble cases in terms of known and
unknown characteristics, some of which may be
associated with the disease
 Investigate Example

 the association between occurrence of

Eosinophilia-myalgia syndrome(EMS) and
Ingestion of L-tryptophan.
 Background
 conduct
 results
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Investigate
Example

Background
EMS was first recognized in October 1989, it
occurs predominantly in women and is relatively
rare. when astute physicians determined that
three people with unexplained myalgias and
eosinophilia had consumed L-tryptophan. Prompt
response by health departments quickly led to
case-control studies,the results of which
suggested that ingestion of L-tryptophan was the
cause of EMS.
Investigate
Example

Conduct
 The Centers for Disease Control and Prevention(CDC)
conducted a series of case-control studies in 1989 and
1990.
 One of the studies conducted in Minnesota, Researchers
selected 63 case subjects of EMS in the metropolitan
area of Minneapolis-St.Paul.
 Researchers randomly selected 5188 control subjects in
the same area.
 Researchers interviewed subjects and asked abort
potential risk factors and about their use of L-
tryptophan.
Investigate
Example

Results
 L-tryptophan was taken significantly more
frequently by cases than by controls— 61 of
63 case subjects (97%),but only 101 of
5188 control subjects (2%).
 L-Tryptophan-containing products were
taken off the market in November1989,In
1990,after the recall of L-tryptophan,the
number of reported cases fell to near zero.
 Design
 Selection of Cases
Develop a case definition then identify new cases
within a specified time period
 Selection of Controls
The sample of controls should have the same
prevalence of exposure as the source population of
unaffected persons.
 Determination of Exposure
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n

Selection of Cases

 Sources of cases
 Species of cases
 Something important
n Selection of Cases

Sources of Cases

 Sources of Cases
 Hospital or clinic

Because risk factors may result from referral patterns to
specific hospitals, multiple hospitals/clinics often chosen

Referral of more ill patients to hospitals, especially tertiary
care centers
 Population-based or community

New cases reported to health departments, registries,
hospital record departments, etc.

 Cases cannot be selected based on known or

unknown association with exposure of interest
n
Selection of Cases
Species of Cases

 Newly diagnosed or incident cases

 Previously existing or prevalent cases
 Incident cases preferred over prevalent cases in
most settings
 If prevalent cases chosen, then risk factors identified for
disease may be those related more to survival with
disease than disease occurrence.
 Survivorship bias also true for incident cases, but
minimized
n Selection of Cases

Something Important
 Specify the definition of a case
 The criteria should minimize the likelihood that
an affected person (true case) is missed (i.e,the
criteria must be sensitive).
 A nonaffected person is falsely classified as a
case (i.e, the criteria must be specific).
n

Selection of Controls

 Sources of controls
 Multiple controls
 Something important
n Selection of Controls

Sources of Controls (1)

 Hospital control group
 Hospitalized patients, best if chosen from the
same hospital as cases in order to control for
unknown reference population
 Select from all patients admitted to the

hospital
 Select from specific diagnosis
n Selection of Controls

Sources of Controls (2)

 Community control group

Probability sample best, but not often
practical
 Select from school rosters, insurance

companies, etc.

Neighbors of cases
 Random digit dialing

 Best friend
n Selection of Controls

Multiple Controls
 Controls of the same type

May improve precision of the measure of
association
 Precision rarely improved with more than 5

controls per case

 Controls of different types
 Hospital controls and community controls
per case
n Selection of Controls

Something Important

 Controls cannot be selected based on

known or unknown association with
exposure(s) or risk factors of interest
n

Determination of Exposure

 Exposure
 Something important
n
Determination of Exposure
Exposure

 Exposure is determined in a ‘retrospective’

manner, that is one must look back in time
to assess exposure status before a person
became a case.
 Each individual’s prior exposure to the risk
factor of interest
 Other exposures
n
Determination of Exposure
Something Important (1)

 Cases and controls must be assessed for

exposure in the same way
 Interviews should be standardized, monitored,
and conducted by trained interviewers.
n
Determination of Exposure
Something Important (2)

 Exposure must be measured in a blinded

manner
 Data collectors must be unaware of whether
subject is a case or control
 Data collectors should be unaware of the study
hypothesis
Data collection and analysis

 Collection of Data
 Analysis of Data
 OR
 Unmatched analysis
 Matched analysis
 Analytic Strategy
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Data collection and analysis

Collection of Data
 Interviews and questionnaires
 Information concerning risk factors may also
be obtained from medical,occupational,or
other records.
Data collection and analysis

Analysis of Data

Exposed - a
Cases
Unexposed - c
Population
at Risk
Exposed - b
Controls
Unexposed - d
Data collection and analysis

Odds Ratio
 The power of the study design lies in the
symmetry of the OR.
 OR is the odds of exposure given disease divided
by the odds of exposure given no disease.
 Remember that the odds of exposure among cases
compared with controls is the same as the odds of
disease among exposed and unexposed.
Data collection and analysis

Unmatched analysis

Exposed Unexposed Total

Cases a b a+b
Controls c d c+d
Total a+c b+d a+b+c+d

(ad − bc) n 2
χ =
2

(a + b)(c + d)(a + c)(b + d)

Data collection and analysis

Unmatched analysis

Odds of case exposure

OR =
Odds of control exposure
a
b ad
= =
c bc
d
(1±1.96/ χ 2 )
OR95%CI. = OR
Data collection and analysis

Matched analysis

Control Control Total

Exposed Unexposed
Case exposed a b a+b
Case unexposed c d c+d
Total a+c b+d a+b+c+d

Case-control pairs that share the same exposure

status do not contribute to the estimate of risk.
Data collection and analysis

Matched analysis

(b − c) 2
χ =
2

b+c
OR = b c
(1±1.96/ χ 2 )
OR95%CI. = OR
Data collection and analysis

Analytic Strategy

 Assess relationship/association between

 Exposure and independent variables
 Case/Control status and independent variables

 Calculate crude, or unadjusted, OR for

exposure - case association
 Matched analysis required for matched studies
Data collection and analysis

Analytic Strategy
 Stratified analysis
 Calculate stratum-specific ORs for exposure-case
relationship
 Determine presence of confounding and interaction
 Logistic regression analysis
 Regression technique used to adjust for confounding
and interaction
 Special logistic model applied in matched studies
 Bias
 Introduction
 Selection bias
 Information bias
 Confounding

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Bias

Introduction
 Case-control studies are subject to bias and
confounding, both will distort the results of the
study
 Bias is defined as the deviation of results, or
inferences, from the truth, or processes leading to
such deviation.
 There are about 75 different types of bias now
identified in published case-control studies
Bias

Selection Bias

 Features
 Types
Bias

Features (1)
 Selection bias reflects systematic errors that arise
from the way in which subjects are selected.
 If the prior exposure of the cases studied differs
from that of all cases arising from the source
population — or if prior exposure of controls
differs from that of persons in the source
population without the disease or interest —
selection bias may be present.
Bias

Features (2)
 Preferential diagnosis of exposed cases may
lead to selection bias.
 Low participation may lead to selection
bias.
 Errors in sampling controls from the source
population can also create selection bias.
Bias

Types

 Admission rate bias

 Prevalence-incidence bias
 Detection signal bias
 Time effect bias
Bias

Information Bias
 A distortion in measuring exposure or
outcome data that results in different quality
(i.e., accuracy or reliability) or frequency of
information between comparison groups.
 Recall bias
 Confoumding bias
Bias

Confounding Bias
 Confounding is a distortion of results that occurs when
the apparent effects of the exposure of interest are
attributable entirely or in part to the effects of an
extraneous variable.
 Criteria for confounding
 Factor is associated with exposure
 Factor is associated with disease in the absence of exposure
 Factor is not in the causal path between exposure and outcome
 Strengths and Weaknesses

Strengths
 Rare disease

 Long latency between exposure

and disease
 Explore multiple hypotheses

 Inexpensive

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 Strengths and Weaknesses

Weaknesses
 Prone to bias

 Temporal relationships cannot be

established
 Inefficient for rare exposures, unless

exposure often lead to disease

 Several important features
 The study provides an efficient means to study
rare diseases.Case-control studies tend to be more
feasible than other studies.
 Case-control studies allow researchers to
investigate several risk factors.
 A single case-control investigation does not
“prove” causality, but it can provide suggestive
evidence of a causal relationship that warrants
intervention by public health officials to reduce
exposure to the implicated risk factor.
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