Case-Control Studies

Objectives
1. Describe the case-control study design and the rationale for its use 2. Define source population 3. Discuss elements of case and control selection 4. List potential sources of cases and controls 5. Describe types of case-control studies 6. Discuss primary design concerns in case-control studies 7. List the strengths and weaknesses of casecontrol studies

Case-Control Study
An alternative to the cohort study for assessing exposure-disease relationships Subjects chosen based on disease status and assessed for previous exposure Exposure data may be measured at the time of the study or gathered from existing data Analysis by the odds ratio (as an estimate of the relative risk) Particularly susceptible to certain types of bias which dictates design characteristics But optimized speed and efficiency.

Basic Analytical Approach in a Casecontrol Study

 Primary design issues:

selection of cases and controls collection of accurate exposure data control of extraneous factors

Rationale for Case-Control Study

Used to answer the same research question as in cohort studies:
Is the rate/risk of disease among the exposed different than that among the non-exposed? If yes, in what direction and by how much?

Used as an efficient version of a cohort study Used to estimate the IDR/CIR with the OR

Efficiency of a case-control study - example:

Cohort study calculate rate of disease in the exposed:

population E 10,000 E 100,000 Total 110,000

IDR = 10.02

cases 50 50 100

P-Y at risk 9,975 999,75 109,950

Efficiency of a case-control study - example:

Cohort Design: Diseased (cases) E 50 = A E 50 = B Case-control design: Cases 50 x 1.0 = 50 50 x 1.0 = 50 OR = 10.0 ~ IDR Controls 9975 x .005 ~ 50 99975 x .005 = ~ 500 HOW DOES THIS WORK and does it always work?

PT 9975 = C 99975 = D

Recall.
OR ~ IDR/CIR when either,
The disease is rare in the population (prevalence 0.05) Controls are selected to represent the same source population that gives rise to the cases, not just the non-cases

For valid case-control studies

Cases must be representative of all cases in the source population the same ones who would be considered cases if a cohort study was done.
Controls selected so that their exposure distribution reflects the exposure distribution among the person time in the source population,
i.e. the same source cohort (population) as the cases.

Both cases and controls must be selected independent of exposure status

Source Population
The Source Population is:
The source of subjects for a particular study Defined by the participant selection methods of your study.

Selection of Cases
Clearly define the source population

Establish strict diagnostic criteria for case definition, independent of exposure (cases really cases)
Either incident or prevalent cases, but incident are ideal Can be selected cross-sectionally (at a point in time) or longitudinally longitudinally is a better choice Can use all cases within the population or a sample of the population

Selection of Controls
Without a well defined source population, it is difficult or impossible to select unbiased controls.

Selection of Controls, Cont.

Is critical and can be difficult Controls must come from the same source population that gives rise to the cases Controls must have the same exposure distribution as in the source of the cases Chosen independent of exposure status, i.e. the same sampling rate for exposed and unexposed controls If sample size is large enough, problems due to sampling error are avoided

Goal is to choose cases and controls so that their proportion with the risk factor (E) in the study does not vary much more than sampling error from the source population. Example: Cohort study:
Cases 50 = A 50 = B Population 10000 100,000 Person-Time 9975 = C 99975 = D

E E

IDR = 50 / 9975 = 10.02 50 / 99975

Sampling fraction for cases = 100% Sampling fraction for controls = .5%

E E

Cases 50 = A 50 = B

PT 9975 = C 99975 = D Controls 9975 x .005 ~ 50 99975 x .005 = ~ 500

Cases E 50 x 1.0 = 50 E 50 x 1.0 = 50 OR = 10.0 ~ IDR

Sampling Strategies to Select Controls

When selecting the controls we want to minimize selection bias and maximize the potential for the OR ~~ the RR If a disease is rare, all sampling strategies will give the same result (OR ~ IDR/CIR) If disease is common, different sampling strategies will give different results Types of Sampling strategies:
1. 2. Traditional (cumulative) sampling Density Sampling

Types of Case-control Studies

Case-based case-control study (traditional):
cases and controls are selected at a given point in time from a hypothetical cohort (i.e. at the end of followup).

Case-control study within a cohort (hybrid, ambidirectional):

Case cohort study: controls are selected from the baseline cohort. Nested case-control study: controls selected at time when each case occurs (incidence density sampling).

1. Case-Based (Traditional): Cumulative Sampling

Typically, cases identified as diagnosed during study period from a stated source population
Controls (non-cases) identified from the same source population from among the non-cases at the end of the study period (cumulative sampling). Exposure to the risk factor of interest is measured/gathered OR is calculated as an estimate of the IDR/CIR

Case- Based Case-Control Study: (cumulative sampling)

1. Case-Based (Traditional): Cumulative Sampling

Selecting controls from those disease-free at the end of the observation period during which cases are identified.
Primarily used only when the disease is rare, otherwise OR doesnt estimate the IDR/CIR Selecting controls with this method, they do not represent the source population from which cases come, represent only non-cases (although they do still come from the same source population).

1. Case-Based (Traditional) Sampling: Issues

Selection bias may occur when cases and non-cases are not selected from the same source population, or populations with similar relevant characteristics.
Selection bias may occur if loss to follow that happens before the study groups are selected affect their comparability.

Bias in a case-based case-control study with a cross-sectional ascertainment: only cases with long survival are included.

Selection bias in a case-based casecontrol study

A cross-sectional ascertainment identifies primarily prevalent cases, that is, those with the longest survival. Cases and controls who die before they can be included in the study may have a different exposure experience compared with the rest of the source population. It is preferable to ascertain cases concurrently, i.e. to identify and obtain exposure information from cases as soon as possible after diagnosis. Same rules apply to controls.

Types of Case-control Studies

Case-based case-control study (traditional):
cases and controls are selected at a given point in time from a hypothetical cohort of a population at risk of developing disease

Case-control study within a cohort :

Preferable alternative to case-based case-control studies Also known as hybrid or ambidirectional designs because they combine some of the features and advantages of both cohort and case-control designs

Case-control Studies within a Cohort

Controls may be selected from the baseline cohort, i.e. case-cohort design. Controls may be selected from individuals at risk at time each case occurs, i.e. nested case-control design. Likelihood of selection bias diminished with either approach compared to case-based study design.

2. Case-control studies within a

defined cohort: Case Cohort
C-C study conducted within the framework of existing, defined cohort, which becomes the source population Cases are selected from the cohort (all or a sample) as they develop

Controls are selected by random sample of the total cohort at baseline

Controls have potential to become a case OR ~ CIR, no rarity assumption needed Selection bias is reduced due to control selection within the source population

Case-Cohort Study Case-control study in which the controls are selected from the baseline cohort

2. Case-Cohort Example
X = occurrence of outcome of case control study
12 11 10 9 8 7 6 5 4 3 2 1
X

X
X

X X X

Time
Potential controls: A random sample of the total cohort at baseline.

Case-Cohort Example
Cardiac Autonomic Function and Incident Coronary Heart Disease: A Population-base Case-Cohort Study (AJE
1997;145:696-706)

Cohort: Atherosclerosis Risk in Communities Study (4 centers) Baseline cohort = 15,800 men and women 45-64 years old Case-cohort sample:
Cases = 137 incident cases of CHD Controls = stratified random sample of 2,253 examinees free of CHD at baseline

2. Studies within a defined cohort: Nested Case-Control

Within framework of existing, defined cohort, the source population Controls are a random sample of the cohort (non-cases) at the time the case occurs Called incidence density sampling or risk set sampling Matching on duration of follow-up

Controls have the potential to become a case

OR ~ IDR, no rarity assumption needed

Hybrid Design: Nested Case-Control study the controls are selected at each time when a case occurs (incidence density sampling).

Incidence Density Sampling

When a case occurs, a control (non-case) is selected (controls selected longitudinally) Matches control to case based on time Controls have the potential to later become a case Ensures that controls represent the source population from which cases come

Rare disease assumption not needed, OR ~ IDR/CIR for both common and rare diseases using this strategy

3. Nested Case-Control Example

X = occurrence of outcome of case control study
12 11 10 9 8 7 6 5 4 3 2 1 X X
X

X X X

Time Potential controls: individuals at risk of developing CaseControl outcome at time ti, when a case occurs. Example: For case #1 (subject 3), all other subjects are potential controls, even though some of them later become cases

Nested Case-Control Study

Example: Levels of Maternal Serum AFP in Pregnant Women and

Subsequent Breast Cancer Risk (AJE 1998;148:719-727)

Univ. of Ca. Berkeley Child Health & Development Studies (CHDS)
1959-1994 Cohort of 12,552 pregnant women

Follow-up conducted by using license records from the department of motor vehicles, and review of death certificates

Nested design
Cases women in the CHDS cohort who developed breast cancer, identified through the California Cancer Registry Controls were members of the cohort who had not been diagnosed at that point in time with breast cancer Exposure assessment: Frozen sera accrued between 1959-1966 Data analysis: logistic regression

Advantages of Case-Control Studies within a Cohort

The estimated exposure odds ratio is a statistically unbiased estimate of the relative risk since cases are included in the sampling frame for the selection of controls. Efficient when need additional information (particularly detailed exposure information) that are not available for the entire cohort.

Measure of Association for a CaseControl study: Odds Ratio

OR dis = OR exp There is a built-in bias away from the null OR can approximate the RR in specific situations

Rationale for Case-Control Study

Used to answer the same research question as in cohort studies:
Is the rate/risk of disease among the exposed different than that among the non-exposed? If yes, in what direction and by how much?

Used as an efficient version of a cohort study Used to estimate the IDR/CIR with the OR

OR ~ RR
Only used when you want to estimate RR Rare = disease < 0.10 Most diseases are rare If controls are selected to represent the source population In a case cohort study OR ~ CIR In a nested case-control study OR ~ IDR

Primary design concerns with the case-control design

Selection Bias
can occur when cases and controls are not selected from the same source population

When selective survival occurs

Information Bias
can occur when there is bias in the measurement of exposure resulting in misclassification since exposure is ascertained after disease has occurred.

Strengths of Case-Control Design

Less expensive and time consuming than cohort design Good for studying the etiology of rare diseases Good for studying diseases with long latency periods Possible to study many different exposures with respect to outcome of interest

Weaknesses of Case-Control Design

Causal inference less clear (temporal ambiguity) Often cannot estimate the frequency of disease in a population Insufficient for studying rare exposures Particularly susceptible to both selection and information biases