Hypothesis Testing: The Design and Conduct of Case Control Studies

1
Hypothesis Testing The Design and Conduct of
Case Control Studies

• PH 2610
• October 14, 2002
• Lowell E. Sever

2
Assumptions

• Disease does NOT occur randomly
• Human disease has identifiable causal and
  preventive factors

3
Overview of Epidemiology

• Frequency, Distribution, Other Factors
• Hypotheses
• Determinants

4
Development of a Conceptual Hypothesis

• Theory/ Conceptual
• Knowledge Hypothesis
• Formulate
• Refine
• Human Studies
• Animal Studies
• Logic
• Hunch

5
Development of a Study Hypothesis

• Conceptual Study Hypothesis
• Hypothesis Who
• What
• Where
• When
• Natural History of Disease
• Population
• Exposure

6
Hypothesis Development

• Objective the overall goal or purpose of the
  study generally broad in scope
• Study question what the study plans to address
  regarding distribution or determinants of
  disease also referred to as the research
  question the specific aim(s) of the study

7
Research Questions/Hypotheses

• Exposure (E) Disease (D) ??
• Is there an association between E D?
• Is the association real, i.e. causal?

8
Hypothesis Development

• Formulation of a hypothesis
• derived from descriptive studies (i.e.,
  studies that describe patterns of disease
  occurrence in terms of frequency and
  distribution)
• tested in analytic studies
• observational case-control or cohort
• intervention clinical trial or field trial

9
Hypothesis Development

• Hypothesis a study question that is specific to
  risk or cause of disease
• null hypothesis (H0) no relationship between
  exposure and disease
• alternative hypothesis (HA) assertion that
  there is an association

10
Hypothesis Testing

• A working hypothesis (research question) is
  tested in two stages
• 1) carrying out a well-designed study to assess
  the risk factor(s) of interest along with
  potential factors (confounders) that may also be
  associated with development of disease

11
Hypothesis Testing

• 2) conducting a statistical test (e.g.,
  chi-square, t-test) to quantify significance of
  difference
• requires making an explicit statement about the
  difference or relationship between the two groups
  regarding exposure

12
Epidemiologic Study Designs
13
Analytical Epidemiology

• Definition and ascertainment of cases and
  non-cases
• Definition and identification of exposure (risk
  factors)
• Determination of associations between risk
  factors and outcome

14
Chief Characteristic of a Case-control Study

• ..it begins with people with the disease (cases)
  and compares them to people without the disease
  (controls).
• Source Gordis, page 142.

15
Conducting the Study

• Define study population
• Define CASES CONTROLS
• Inclusion criteria
• Exclusion criteria
• Assess exposure status

16
Distinguishing Characteristics

• Individuals with a particular disease or
  condition (cases) are selected for comparison
  with individuals in whom the disease or condition
  is absent (controls).
• Looks for an association by comparing history of
  exposure between a group of diseased individuals
  (cases) and a group of non-diseased individuals
  (controls).

17
Design of Case Control Study
Time
Direction of inquiry
Cases (diseased)
Exposed
Population
Not exposed
Exposed
Controls (disease free)
Not exposed
18
Distinguishing Characteristics

• Tests a hypothesis about an association between
  disease and exposure
• Looks retrospectively to past exposure (or
  current exposure as a surrogate for past
  exposure)
• Explores data to identify exposures for further
  studies

19
Case-Control Studies

• The first step in a case-control or retrospective
  study is to detect a number of people with the
  disease under study the cases.
• We then select a number of people similar to the
  cases who are free of the disease the controls.
• The cases and controls are then investigated to
  see if there are differences in the distributions
  of risk factors of interest between them.

20
Study Population

TOTAL POPULATION
Reference Population
CASES
CONTROLS
-Source Gordis, pg. 145
21
Variables

• Exposure (independent variables)
• Data obtained through interviews or records of
  past exposures
• Data on more than one exposure can be gathered
  during a case control study

22
Variables

• Disease (dependent variable)
• The disease spectrum should be known.
• The CASE definition should take into account the
  stage of disease and be established before data
  collection.
• Data are obtained from medical records,
  interviews, physical examination, laboratory
  examinations or testing.

23
Study Population

• Selection of cases
• Case definition is very important
• All cases have an equal probability for
  selection reduce selection bias
• Selection of controls
• Identical to cases in every respect except
  disease of interest

24
Selection of Controls

• from the same population that gave rise to the
  cases
• independently of exposure status
• during the same time period this person would
  have also been eligible to become a case
• -Source Rothman Greenland, pg. 97

25
Matching

• Matching is done so that the control has
  identical (or, at least, very similar)values of
  the confounding variable.
• Common matching variable are age and sex.

26
Matching Controls to CasesAdvantages

• There is direct control of potential confounders.
• It ensures that adjustment is possible.
• Under certain conditions, matching improves the
  efficiency of he investigation.

27
Matching Controls to CasesDisadvantages

• Data collection is more complex.
• Data analysis must take account of the matching.
• The effect (on disease) of the matching variable
  cannot be estimated.
• Adjustment cannot be removed

28
Matching Controls to CasesDisadvantages

• There may be overmatching. This is where the
  matching has been done incorrectly or
  unnecessarily. That is, the matching variable
  has some relationship with the risk factor or
  disease, but it is either not a true confounder
  or is so highly correlated with other matching
  variables as to be superfluous.

29
Analytical Epidemiology

• Definition and ascertainment of cases and
  non-cases
• Definition and identification of exposure (risk
  factors)
• Determination of associations between risk
  factors and outcome

30
Conducting the study

• Determining exposure status for CASES and
  CONTROLS
• Be aware of limitations in recall
• Both CASES and CONTROLS may not recall accurately
  their past exposures
• CASES may have a vested interest in recalling
  more accurately (results in Recall bias)

31
Research Questions

• Among the CASES, is an attribute more (or less)
  prevalent than among the CONTROLS?
• Is the mean level of factor Y greater among CASES
  than among CONTROLS?

32
Research Questions

• What characteristics are more common among those
  with disease (CASES) than among those without
  disease (CONTROLS)?
• Are CASES more likely to have been exposed to X
  than CONTROLS?

33
Retrospective vs. Prospective
Retrospective (Case-control)
Disease
Present (Cases)
Absent (Controls)
Risk Factor
Present (Exposed)
b
a
Prospective (Cohort)
Absent (Not Exposed)
d
c
34
Data Analysis

• Present data on reliability and validity of
  measurements
• Compare CASES and CONTROLS on factors that may be
  related to disease and/or exposure status
• Produce the appropriate measure of association
• THE ODDS RATIO

35
Case Control Study
DISEASE (OUTCOME)
EXPOSURE
36
The Odds Ratio
Disease
Y
N
a
b
ab
How much risk is too much risk?
Y
Exposure
cd
d
c
N
ac
N
bd
Odds of exposure if case a / (ac) / c /
(ac) a/c Odds of exposure if control b /
(bd) / d /(bd) b/d
37
THE ODDS RATIO (O.R.)

• Definition
• The ratio of two odds
• In a case control study, it is the ratio of odds
  of exposure among the CASES to the odds of
  exposure among the CONTROLS.
• (Source Last,J. Dictionary of Epidemiology.)

38
Measure of Association in a Case-Control Study
Odds Ratio

• Odds of exposed vs non-exposed among cases and
  controls

39
Interpretation of OR

• Cases have OR times the odds of exposure than
  Controls
• Cases are OR times more (or less) likely to be
  exposed to X than Controls

40
Case-control Odds Ratio
OR (70/30) / (300/700) 5.4
OR (30/70) / (700/300) .18
41
Data from a Study of Oral Clefts and Agricultural
Chemical Exposure in Iowa
Odds Ratio 18 x 266 2.85
48 x 35
42
Neural Tube Defects and Water Disinfection
Byproducts
43
Case-Control StudiesAdvantages

• Case-control studies are quicker and cheaper than
  prospective cohort studies because there is no
  waiting time involved.
• Many risk factors can be studied simultaneously.
• Case-control studies are particularly well suited
  to investigations of risk factors for rare
  diseases.

44
Case-Control StudiesAdvantages

• Case-control studies usually require much smaller
  sample sizes than do equivalent cohort studies.
• Case-control studies are generally able to
  evaluate confounding and interaction rather more
  precisely for the same overall sample size than
  are cohort studies.

45
Case-Control StudiesDisadvantages

• Case-control studies often do not involve a time
  sequence, and so are limited in their ability to
  demonstrate causality.
• Being identified as a case might reflect survival
  rather than morbidity.
• Case-control studies can investigate only one
  disease outcome.

46
Case-Control StudiesDisadvantages

• Case-control studies cannot provide valid
  estimates of risk, and can only provide
  approximate estimates of relative risk.
• Case-control studies potentially suffer from
  exposure recall bias.

47
The Case-Control Study

• Retrospective study design
• identifies cases
• selects controls
• determines history of exposure
• Measure of association
• odds ratio

48
Hypothesis Testing

• Ho null hypothesis or no real relation between
  exposure and disease
• Ha alternative hypothesis that asserts exposure
  affects disease

49
Case-control Study

• Groups defined by outcome
• Search for exposure is retrospective
• Quick and inexpensive
• Good for rare outcomes

50
Case-control Study

• Susceptible to bias (selection and information)
• May be confounded by unknown exposures
• Appropriate control group often difficult to find

51
Case-control Study

• Should be the first approach to the testing of a
  hypothesis
• Useful for exploratory study of a variety of
  variables (fishing expedition) - looking for clues

52
Case-control Study

• May be definitive in describing relationship
  between exposure and outcome if disease if very
  rare and exposure is quite harmful
• Adenocarcinoma of the vagina and DES
• given how rare adenocarcinoma of the vagina is -
  numbers
• Smoking and lung cancer
• given the latency in lung cancer development -
  time

53
Problems / Limitations

• Choice of appropriate controls
• Potential bias recall, response, selection,
  ascertainment, interviewer
• Information on exposure obtained after disease
  (temporality?)
• Cannot estimate disease frequency