case control, case crossover,

Unit 10:Case-Control, Case-Crossover,

and Cross-Sectional Studies

Unit 10 Learning Objectives:• Understand design features of case-control,

case-crossover, and cross-sectional studies.• Understand strengths and limitations of case-

control, case-crossover, and cross-sectional studies.

• Recognize potential biases from case-control, case-crossover, and cross-sectional studies.

• Recognize the impact of using prevalent versus incident cases in case-control studies.

• Recognize the difficulty in selecting an appropriate control group in case-control studies.

• Understand the nested case-control study design.• Recognize the difference between fixed and time-

dependent variables, including confounding variables.

Case-ControlCase-ControlStudiesStudies

Case-ControlCase-ControlStudiesStudies

Case Control StudiesCase Control Studies

Define and select the cases.

Assemble an appropriate comparison group (controls).

Determine and compare the proportion of cases who have experienced the exposure of

interest -- with the proportion of controls who experienced the exposure.

PRIMARY STEPS:

Case Control StudiesCase Control Studies Typically, compare the proportions of

exposure by means of a ratio: ODDS RATIO

OR =OR = Odds for exposure among casesOdds for exposure among cases

Odds for exposure among controlsOdds for exposure among controls

D+ D-

E+ a b

E- c d

(a / c)OR = -------

(b / d)

Defining CasesDefining Cases

Ensure cases are as homogenous as possible. Establish strict diagnostic criteria (e.g. certain histologic characteristics).

Sub-definitions of cases such as definite, probable or possible may be needed.

Analysis can be conducted for each sub-group.

Prevalent vs. Incident Prevalent vs. Incident (Newly Diagnosed) Cases(Newly Diagnosed) Cases

To the extent possible, avoid including prevalent cases!

WHY?


Why?Why? Determinants of disease duration may

be related to the exposure such that the magnitude of the exposure (e.g. low vs. high) may be inaccurate.

Prevalent cases with long disease duration may not accurately recall antecedent events.


Why?Why? With prevalent cases, it is more difficult

to ensure that reported events preceded disease development rather than being a consequence of the disease process.


---However, case-control studies of congenital malformations are inevitably based on prevalent cases.

---Prevalent cases are commonly used in studies of chronic conditions with ill-defined onset times (e.g. multiple sclerosis).

Sources of Cases:

–Hospitals, medical care facilities, etc.

– General population - locate and obtain data from all or a random sample of individuals from a defined population.

Selecting CasesSelecting Cases

Selecting CasesSelecting Cases

Note: DO NOT compromise validity in the goal of generalization.

Select cases from a defined population in whom complete and reliable information can be obtained, and where the exposure/disease relationship is presumed to be present.

Ascertainment of Disease Status:

– Case registries (i.e. cancer)– Office records of physicians– Hospital admission or discharge

records– Pathology department log books

Defining and Selecting CasesDefining and Selecting Cases

Selecting ControlsSelecting Controls

Axiom: Selection of an appropriate comparison group is the most difficult and critical issue in the design of case-control studies.


Controls are subjects free of the disease (or outcome of interest).

– Controls are seldom subjected to medical exam to rule out the disease of interest.

– Usually, they are assumed disease free if they have not been diagnosed.


1. The prevalence of exposure among controls should reflect the prevalence of exposure in the source population.

2. Controls should come from the same source population as cases (e.g. would have been cases if diagnosed with the disease).


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 #1, #2, or #3 are not met = Selection Bias

Sources of Controls:

--- General population

--- Random digit dialing

--- Neighborhood

--- Friends/relatives

--- Hospital or clinic-based


General Population Controls:

--- Population defined by geographic boundaries (or specific characteristics).

--- Cases may include all cases, or a random sample of all cases.

--- Controls should be a random sample of non-diseased individuals eligible to be cases.


General Population Controls:--- If entire population is sampled for cases

and controls, can calculate incidence rates of disease in exposed and non-exposed.

--- Selection of controls may be costly, time consuming, and exposure recall may not be as accurate as “sick” controls.

--- Subjects in general population may be less motivated to participate than hospital-based controls.


Random Digit Dialing Controls:

--- May approximate random sampling from the source population.

--- Controls are often matched to cases on area code and prefix (i.e. SES matching).

--- Probability of contacting each eligible subject may differ due to time of day, number in household, answering machines, etc.


Neighborhood Controls:--- May approximate random sampling

from the source population.--- Controls are often matched to cases

from the same neighborhood.--- If cases are from a particular hospital,

neighborhood controls may include people who would not have been treated at the same hospital had they developed the disease (e.g. VA hospital).


Friend/Relative Controls:--- Tend to be more cooperative than

general population controls.

--- Often similar to cases on factors such as SES, lifestyle, and ethnic background.

--- However, being named as a friend by the case may be related to exposure status of the potential control.


Friend/Relative Controls:--- The list of potential friend/relative

controls is often derived from the case; this dependence may add a potential source of bias.

--- Hence, friend/relative controls may be too similar to cases regarding the exposure of interest.


Hospital/Clinic-Based Controls:--- Source population refers to people

who “feed” the hospital or clinic.

--- Usually easier and less expensive than general population controls.

--- May be more aware of exposures and likely to cooperate than general population controls (healthier).


Hospital/Clinic-based Controls:--- Controls are ill; distribution of the

exposure may not reflect the distribution of exposure in the source population for cases.

--- Controls should be limited to diagnoses for which there is no prior indication of a relation with exposure.

--- Subjects may have changed their exposure status as a result of being sick.


General Remarks:--- Often, there is no perfect control group;

several groups can be selected, if feasible.

--- If study results are consistent across control groups, may indicate a valid result, but also possibly similar net bias.

--- If different effects are observed, may provide useful information as to nature of the association or potential biases.


For each control group, how many controls per case?

-- 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 than one control

e.g. 1:2 1:3 1:4



AXIOM:

The benefit of increased sample size is not as relevant past the 1:4 ratio (e.g increase in statistical power).

Ascertaining ExposureAscertaining Exposure Sources of exposure data (cases and

controls):

---Study subjects (self-report). Particularly vulnerable to recall bias as cases may recall their exposure history more thoroughly than controls.

---Records (preferably completed before the occurrence of outcome events).

---Interviews with surrogates (spouses, siblings, etc.).

Ascertaining ExposureAscertaining Exposure

How far back should exposure be assessed?

---Define a part of the person’s exposure history considered relevant to the etiology of disease (e.g. the “empirical induction” period).

---Code the exposure data in an etiologically-relevant manner (e.g. magnitude of exposure, years of exposure, ever exposed, etc.).

Nested Case-Control StudyNested Case-Control StudyDefinition: Hybrid design in which a case-control study is nested in a cohort study.

Cohort Study Population Exposure StatusAscertained

SubjectsDevelopDisease

Do NotDevelopDisease

CASES CONTROLS

Nested Case-Control StudyNested Case-Control Study

Advantages:

---Exposure data are collected before diseasedevelopment; eliminates recall bias.---Can be economical if complete exposureascertainment is limited to only cases andcontrols nested in the total cohort.

Often used in occupational epidemiology where the occupational cohort is the source population.

Summary – Case Control StudiesSummary – Case Control Studies

---Selection of an appropriate comparison group is the most challenging and important aspect of the study design.

---In population-based studies, incidence can be calculated when entire population is sampled.

---Hospital-based studies are often easiest and cheapest to conduct, but may be prone to biased exposure ascertainment.


Advantages:

---Relatively quick and inexpensive.

---Well suited to evaluation of diseases with long induction periods.

---Optimal for evaluation of rare diseases.

---Can examine multiple etiologic factors for a single disease.


Disadvantages:

---Inefficient for evaluation of rare exposures unless the disease is common among the exposed.

---If not population based, cannot compute incidence among the exposed and non-

exposed.


Disadvantages (cont.):

---May be difficult to establish the temporal relationship between exposure and disease.

---Prone to bias compared to other analytic designs, in particular, selection and recall bias.

Review of Recommended ReadingReview of Recommended ReadingPPA and Risk of Hemorrhagic StrokePPA and Risk of Hemorrhagic Stroke

Review of Recommended ReadingReview of Recommended ReadingPPA and Risk of Hemorrhagic StrokePPA and Risk of Hemorrhagic Stroke

--- Case control study investigating exposure to products containing phenylpropanolamine (PPA) and risk of hemorrhagic stroke in persons 18-49 years of age.

--- 702 cases and 1,376 matched control subjects (random-digit dialing) from 43 hospitals in 4 states (1994 to 1999)

--- Multiple definitions of exposure to PPA, including any use, first use, specific type of product (i.e. appetite suppressant).

--- Primary focal time to assess prior exposure history was day/time that symptoms led subject to seek medical attention.

--- Trained interviewers used structured instrument to document prior exposure history.

---Analyses conducted separately for men and women.

Discussion Question 1Discussion Question 1

The investigators excluded stroke victims who

died or did not have the ability to communicate

because they felt that proxy data (i.e. spouse) on

exposure status would be unreliable.

How might this exclusion of potential case

subjects bias (if at all) the study results?

Source: NEJM 2000; 343:1826-1832.


The primary time in which exposure to PPA

was assessed occurred immediately preceding

the time in which medical attention was sought.

What type of bias (if any) could this strategy

have introduced?

Source: NEJM 2000; 343:1826-1832.


On average, cases were required to recall PPA

exposure status over a more remote period

than control subjects. Do you think this

strategy offset the potential greater motivation

for cases to recall exposures to over-the-

counter medications than control subjects?

Source: NEJM 2000; 343:1826-1832.


Not stated in the article, the participation

rate for eligible subjects was 75% for cases

compared to 36% for controls.

How might this differential rate of participation

bias (if at all) the study results?

Source: NEJM 2000; 343:1826-1832.


Interpret the results in table 4.

Are the findings similar among men

and women?

Source: NEJM 2000; 343:1826-1832.

case control, case crossover,

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