Case-Control Studies : Case-Control Studies •••••
Marc Schenker M.D., M.P.H
Dept. of Public Health Sciences
UC Davis Case-Control Studies : Case-Control Studies After this session, you will be familiar with:
The basic design features of a case-control study
Rationale for applying case-control designs
Limitations of case-control studies
Example applications applying case-control designs OBJECTIVES I. Overview : I. Overview Design of Case-Control Studies
The investigator selects
cases with the disease,
controls without the disease
and obtains data regarding past exposure to possible etiologic factors in both groups. The investigator then compares the frequency of exposure of the two groups. Design of a Case-Control Study : Design of a Case-Control Study Not Exposed Exposed Not Exposed Disease No Disease “CASES” “CONTROLS” Exposed Figure 1 : Figure 1 FIRST: Select CASES CONTROLS
(With Disease) (Without Disease) THEN: Were exposed a b
Exposure Were not exposed c d
TOTALS a + c b + d Proportions a b
Exposed a + c b + d Figure 1 (continued) : Figure 1 (continued) a
Odds Ratio = =
Risk = a
a + b
c + d a b c d Case Control E+ E- I. Overview : I. Overview B. When to use a case-control approach 1. Rare disease: Case-control approaches are the most efficient for rare diseases, e.g idiopathic pulmonary fibrosis, most cancers. Cohort approaches would require large populations and prohibitive expense and follow-up time. Case-control designs may also be appropriate for more common diseases, such as COPD. B. When should a case-control approach be used : B. When should a case-control approach be used 2. Case ascertainment system in place: The conduct of a case-control study may be facilitated by the availability of a case-ascertainment system.
a) Population-based cancer registry
b) Hospital-based surveillance systems
c) Mandated disease reporting systems
3. When funding and time constraints are not compatible with a cohort study. II. Issues in Case-Control Studies : II. Issues in Case-Control Studies Issues in Ascertainment of Cases
1. Diagnostic criteria for case studies
e.g. lung cancer vs wheezing
b) Diagnostic bias
2. Sources (hospital, general population)
3. Incident or prevalent cases II. Issues in Case-Control Studies : II. Issues in Case-Control Studies B. Issues in Selection of Controls
1. General questions
(i) Should the controls be comparable to the cases in all respects other than having the disease?
(ii) Should the controls be representative of all non-diseased people in the population from which the cases are selected? Figure 2 : Figure 2 “Total” Population
Population Cases Controls B. Issues in Selection of Controls : B. Issues in Selection of Controls b) Practical Questions
(i) Is the approach selected for control selection feasible?
(ii) Can this approach be used given the funds available? 2. Sources of controls : 2. Sources of controls a) Population of defined area
b) Hospital patients
c) Probability sample of total population
(i) walk (door to door)
(ii) phone (random digit dialing)
(iii) letter carrier routes
e) Friends or associates of cases
f) Siblings, spouses or other relatives
g) Other C. Methodologic Issues : C. Methodologic Issues Handling potential confounding factors
a) In the process of selecting controls:
The process of selecting controls so that they are similar to the cases in regard to certain characteristics such as age, sex and race.
(i) Group matching (frequency matching, stratification)
(ii) Individual matching (matched pairs) C. Methodologic Issues : Handling potential confounding factors in matching:
(iii) Problems with matching:
- Matching on many variables may make it difficult or impossible to find an appropriate control.
- Cannot explore possible association of disease with any variable on which cases and controls have been matched. C. Methodologic Issues Slide 16: Handling potential confounding factors in matching:
b) In the process of selecting controls:
c) In the data analysis:
(ii) Adjustment C. Methodologic Issues C. Methodologic Issues : C. Methodologic Issues 2. Evaluating Information on Exposure
a) Problems of recall in case-control studies
(i) Limitations in human ability to recall
(ii) Recall bias (cases may remember their exposure with a higher or lower accuracy than controls do) 2. Evaluating Information on Exposure : 2. Evaluating Information on Exposure b) Avoiding other biases
(i) Selection bias
(ii) Information bias
(iii) Non-response bias
(iv) Analysis bias
c) Validity testing (reliability, sensitivity and specificity) 3. Using Multiple Controls in Case-Control Studies : 3. Using Multiple Controls in Case-Control Studies Multiple controls of a similar type (e.g. 2 controls per case)
Different types of controls (e.g. hospital and neighborhood controls) III. Nested Case-Control Studies : III. Nested Case-Control Studies Figure 3 Study Population TIME 1
TIME 2 Develop
Disease Do Not
Disease CASES CONTROLS
CASE-CONTROL STUDY Obtain interviews, bloods, urines, etc. A. Advantages of Nested Case-Control Studies : A. Advantages of Nested Case-Control Studies Possibility of recall bias is eliminated, since data on exposure are obtained before disease develops.
Exposure data are more likely to represent the pre-illness state since they are obtained years before clinical illness is diagnosed.
Costs are reduced compared to those of a prospective study, since laboratory tests need to be done only on specimens from subjects who are later chosen as cases or as controls. Specific Respiratory Disease Applications : Specific Respiratory Disease Applications Causes of disease
Incident asthma: Childhood or adulthood, use nested designs within exposed cohorts
COPD: Use to investigate factors other than cigarette smoking
Symptom syndromes: Tight-building syndrome and multiple chemical sensitivity as examples
Rare diseases, i.e. idiopathic pulmonary fibrosis Respiratory Disease Applications : Respiratory Disease Applications B. Course of disease
Use to assess factors leading to poor/good outcomes
Use for surveillance for complications of therapy
C. For disease surveillance The Association between Tuberculosis and Cancer : The Association between Tuberculosis and Cancer From the first 7500 autopsies at the Johns Hopkins Hospital, the following were identified and selected:
Cancer cases 816
Controls (no cancer) 816
Pearl, 1929 Summary of Data from Study ofTuberculosis and Cancer : Summary of Data from Study ofTuberculosis and Cancer Cancer “Controls”
n % n %
Autopsies 816 100 816 100
With Tbc. 54 6.6 133 16.3
Pearl, 1929 B. Childhood Asthma and Passive Smoking : B. Childhood Asthma and Passive Smoking How would you design a study to evaluate whether passive smoking is a risk factor for childhood asthma?
What are advantages and disadvantages of different study designs?
How would you evaluate exposure? B. Childhood Asthma and Passive Smoking Urinary cotinine as a biomarker of exposure* : B. Childhood Asthma and Passive Smoking Urinary cotinine as a biomarker of exposure* Design: Two case groups of asthmatics were compared with a control group for passive smoking exposure by comparing urinary cotinine levels.
Cases: 72 children aged 3-14 years who were seen at a pediatric ER and walk-in clinic with an acute asthma attack comprised one of the case groups. The other case group consisted of 35 children aged 3-14 years attending an asthma clinic with a history of episodic or chronic airflow obstruction requiring some form of bronchodilator therapy.
*Ehrlich R, Kattan M, Godbold J, et al
Am Rev Respir Dis 145:594-599, 1992 B. Childhood Asthma and Passive Smoking : B. Childhood Asthma and Passive Smoking 3. Controls: 121 children attending the ER for problems other than asthma.
4. Data: Questionnaires and urinary cotinine/creatinine levels were used to assess passive smoking exposure.
5. Results: Smoking by the maternal caregiver was most strongly associated with asthma in the child.
Odds ratio was 1.9 (95% C.I.: 1.04 - 3.35; p=.04). Table 4. Asthma Versus Control: Exposure Variables : Table 4. Asthma Versus Control: Exposure Variables Asthma Control
Factor (n - 107) (n = 121)
Any smoker at home, % 54 51
Daily cigarettes by all 8.7+/-12.8 6.1+/-10.3
smokers, mean +/- SD
Maternal caregiver smokes, % 44 28a
CCR > 30 ng/mg, % 38 25b
Mean CCR, ng/mgc 43.6+/-87.7 25.8+/-46.5d
aOdds ratio = 2.0(1.1, 3.4), p = 0.03
bOR = 1.9 (1.04, 3.35), p = 0.04
cAitchison transformation, see METHODS
dp = 0.06 B. Childhood asthma and passive smoking : B. Childhood asthma and passive smoking 6. The results could not show, however, that recent elevations in tobacco exposure triggered acute asthma attacks requiring visits to the ER.