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 Description of disease or spectrum Determine operating characteristics of a new diagnostic test Describe prognosis Determine cause-effect Compare new interventions Summarize literature Design Case series or report Cross-sectional study Cross-sectional Cohort study Cohort study Case-control study Randomized clinical trial Meta-analysis

Case-Control Studies
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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
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Historical Perspective Definition Types of Design

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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+c)

a

Cases
c

Unexposed

Exposed
b/(b+d)

b

Controls
d

Unexposed

Direction of inquiry

n

Types
Family of epidemiological study designs  Traditional case-control design  Case-control studies within cohorts
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Nested case-control study design Case-cohort study design

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Case-parent study design Case-only study design
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Matching
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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
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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 Select controls so that the proportion with a certain characteristic is identical to the proportion of cases with that characteristic

Frequency, or group, matching

Matchin g

Problems with Matching
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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.
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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 Ltryptophan.

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

n

Selection of Cases
Sources of Cases

Sources of Cases

Hospital or clinic
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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 New cases reported to health departments, registries, hospital record departments, etc.

Population-based or community

Cases cannot be selected based on known or unknown association with exposure of interest

n

Selection of Cases
Species of Cases
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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).

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Selection of Controls
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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

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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

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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

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

Collection of Data
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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 Controls Unexposed - d Exposed - b

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 Cases Controls Total
2

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

a c a+c

b d b+d
2

(ad − bc) n χ = (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 OR95%CI. = OR
(1±1.96/ χ 2 )

Data collection and analysis

Matched analysis
Control Exposed Case exposed a Case unexposed c Total a+c Control Unexposed b d b+d Total a+b c+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) χ = b+c OR = b c
2

2

OR95%CI. = OR

(1±1.96/ χ 2 )

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 Regression technique used to adjust for confounding and interaction Special logistic model applied in matched studies

Logistic regression analysis

Bias
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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

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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
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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.
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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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