EPB PHC 6000 EPIDEMIOLOGY FALL, 1997

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Unit 10 Case-Control, Case-Crossover, and
Cross-Sectional Studies
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• 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.

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Case-Control Studies
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Case Control Studies
PRIMARY STEPS

• 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.

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Case Control Studies

• Typically, compare the proportions of exposure by
  means of a ratio ODDS RATIO

OR
Odds for exposure among cases
Odds for exposure among controls
D D-
E a b
E- c d
(a / c) OR ------- (b / d)
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Defining 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.

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Prevalent vs. Incident (Newly Diagnosed) Cases
To the extent possible, avoid including prevalent
cases! WHY?
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Prevalent vs. Incident (Newly Diagnosed) Cases

• 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.

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Prevalent vs. Incident (Newly Diagnosed) Cases

• 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.

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Prevalent vs. Incident (Newly Diagnosed) Cases

• ---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).

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Selecting Cases

• 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.

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Selecting 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.

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Defining and Selecting Cases

• Ascertainment of Disease Status
• Case registries (i.e. cancer)
• Office records of physicians
• Hospital admission or discharge records
• Pathology department log books

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Selecting Controls

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

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Selecting Controls

• 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.

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Selecting Controls

• 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).

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Selecting Controls

• 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

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Selecting Controls

• Sources of Controls
• --- General population
• --- Random digit dialing
• --- Neighborhood
• --- Friends/relatives
• --- Hospital or clinic-based

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Selecting Controls

• 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.

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Selecting Controls

• 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.

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Selecting 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.

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Selecting Controls

• 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).

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Selecting Controls

• 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.

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Selecting Controls

• 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.

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Selecting Controls

• 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).

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Selecting Controls

• 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.

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Selecting Controls

• 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.

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Selecting Controls

• For each control group, how many controls per
  case?
• -- the optimal case-control ratio is 11
• -- when the number of cases is small, the sample
  size for the study can be increased by using
  more than one control
• e.g. 12 13 14

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Selecting Controls

• AXIOM
• The benefit of increased sample size is not as
  relevant past the 14 ratio (e.g increase in
  statistical power).

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Ascertaining 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.).

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Ascertaining Exposure

• How far back should exposure be assessed?
• ---Define a part of the persons 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.).

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Nested Case-Control Study
Definition Hybrid design in which a
case- control study is nested in a cohort study.
Exposure Status Ascertained
Cohort Study Population
Subjects Develop Disease
Do Not Develop Disease
CASES
CONTROLS
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Nested Case-Control Study
Advantages ---Exposure data are collected
before disease development eliminates recall
bias. ---Can be economical if complete
exposure ascertainment is limited to only cases
and controls nested in the total cohort. Often
used in occupational epidemiology where the
occupational cohort is the source population.
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Summary 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.
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Summary Case Control Studies
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.
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Summary Case Control Studies
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.
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Summary Case Control Studies
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.
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Review of Recommended ReadingPPA 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.
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Discussion 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 3431826-1832.
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Discussion Question 2
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 3431826-1832.
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Discussion Question 3
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 3431826-1832.
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Discussion Question 4
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 3431826-1832.
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Discussion Question 5
Interpret the results in table 4. Are the
findings similar among men and women?
Source NEJM 2000 3431826-1832.