Case Control Study Design

EPBI 490

Case-Control Design
Historical Perspective
Unique contribution of epidemiology to the repertoire of clinical research designs First case-control study performed in late 1950s
Doll and Hills study of lung cancer and smoking behavior among physicians

Jerome Cornfields classic description of Retrospective Studies New statistical tools were developed to analyze the study design - logistic regression

Select Study Design to Match the Research Goals

Objective Description of disease or spectrum Design Case series or report Cross-sectional study Determine operating characteristics Cross-sectional of a new diagnostic test Describe prognosis Cohort study Determine cause-effect Compare new interventions Summarize literature Cohort study Case-control study Randomized clinical trial Meta-analysis

Case-Control Designs
Family of epidemiologic study designs Traditional case-control design Case-control studies within cohorts
Nested case-control study design Case-cohort study design

Case-parent study design Case-only study design

Case-Control Study
A case-control study is a design in which individuals with an event or condition of interest, CASES, are identified and then compared with regard to one or more exposures to individuals without the event or condition of interest, CONTROLS.

Cohort Study Design

Exposed PAR S Study Group Unexposed Outcome PAR = S T = = Population at Risk Sampling design Elapsed time T No Outcome Outcome

Case-Control Study Design

Exposed
Cases Population at Risk Controls Unexposed Unexposed Exposed

Case-Control Study
How its done
Cases

Develop a case definition Identify new cases within a specified time period

Case-Control Study
Selection of Cases
Case definition must be pre-specified
Incident cases preferred over prevalent cases in most settings
If prevalent cases chosen, then risk factors identified for disease may be those related more to survival with disease than disease occurrence. Survivorship bias also true for incident cases, but minimized

Case-Control Study
Selection of Cases
Source of Cases
Hospital or clinic
Because risk factors may result from referral patterns to specific hospitals, multiple hospitals/clinics often chosen Referral of more ill patients to hospitals, especially tertiary care centers

Population-based or community
New cases reported to health departments, registries, hospital record departments, etc.

Cases cannot be selected based on known or unknown association with exposure of interest

Case-Control Study
How its done
Cases

Define and identify appropriate controls

Controls

Case Control Study

Selection of Controls
Fundamental questions:
Should control subjects be similar to cases in all respects except for having the disease of interest? Should control subjects be drawn from the same underlying population as the cases, i.e., share the same risk factors and exposures?

No simple answer to these questions

Controls who are identical to the cases in all respects except disease may underestimate risk factors Characterizing the underlying population is rarely possible

Case Control Study

Selection of Controls
The controls should be selected to represent the person-time distribution of exposure in the source population Probability of selection as a control is proportional to person-time in source population
Risk-set sampling Risk set is the unique set of individuals in the source population who are at risk for developing disease at the moment each case is diagnosed

Case Control Study

Selection of Controls
Source Population

Risk Set 1

Time

Risk Set 2

Case Control Study

Selection of Controls
Sources of controls
Hospital control group
Hospitalized patients, best if chosen from the same hospital as cases in order to control for unknown reference population Select from all patients admitted to the hospital Select from specific diagnosis

Community control group

Probability sample best, but not often practical Select from school rosters, insurance companies, etc. Neighbors of cases Random digit dialing Best friend

Case Control Study

Selection of Controls
Controls cannot be selected based on known or unknown association with exposure(s) or risk factors of interest
Multiple controls
Controls of the same type
May improve precision of the measure of association Precision rarely improved with more than 5 controls per case

Controls of Different Types

Hospital controls and community controls per case

Case-Control Study
How its done
Exposed
Cases For both cases and controls determine previous exposure Controls Unexposed Unexposed Exposed

Case-Control Study
Assessing Exposure
Exposure is determined in a retrospective manner, that is one must look back in time to assess exposure status before a person became a case. Exposure must be measured in a blinded manner
Data collectors must be unaware of whether subject is a case or control Data collectors should be unaware of the study hypothesis

Case-Control Study
Assessing Exposure
Cases and controls must be assessed for exposure in the same way

Case-Control Study
How its done
Exposed Cases Population at Risk Controls Unexposed Ensure that cases and controls arise from the same population at risk

Unexposed
Exposed

Case-Control Study
How its done
PAR 1 Exposed Cases Unexposed PAR 2 Exposed

Controls
Unexposed

Cases and controls may arise from different underlying populations with different exposure patterns.

Case Control Study

Selection of Controls
Result Study 1

Result Study 2 Brain Cancer Other Cancer Normal

Case-Control Study
Selection of Controls
Tuberculosis and cancer study, 1929
Autopsy-based study concluded that TB protected against cancer Controls without cancer at autopsy were selected Tuberculosis over-represented in controls as it was a common reason for hospitalization and death

Case-Control Study
Selection of Controls
Coffee and pancreatic cancer, MacMahon B et al. NEJM 1981
Coffee consumption was associated with pancreatic cancer
OR 2 3 Dose-response relationship

Controls were selected from other patients admitted to the hospital by the same physician as the case, often gastroenterologist This specialist would admit patients with other diseases (gastritis or esophagitis) for which he or the patient would reduce coffee intake Controls intake of coffee may be less than population - not representative of source population

Case-Control Study
How its done
Exposed - a Cases Population at Risk Controls Unexposed - d

Unexposed - c
Exposed - b

Case-Control Study
How its done
Case Exposed
Unexposed Control b d b+d a+b Odds Ratio = ad/bc OR is the odds of exposure given c + d disease divided by the odds of exposure given N no disease

a
c

a+c

Case Control Study

Interpretation
The power of the study design lies in the symmetry of the OR.
Remember that the odds of exposure among cases compared with controls is the same as the odds of disease among exposed and unexposed.

Hip fracture among women according to the number of months of estrogen replacement therapy, 1977 - 1979 Mo. Estrogen Replacement <6 6 Total Trauma Controls Non-trauma Controls

Cases
80 14 94 (85) (15) (100)

- - - - - N (%) - - - - -

60 (75) 579 (73) 20 (25) 213 (27) 80 (100) 792 (100)

Kreiger et al., 1982.

ORtc= 1.90 Ornc = 2.10

Case-Control Study
Interpretation
Case Control b d b+d a+b c+d N OR = a c b d

Exposed
Unexposed

a
c

a+c

Any procedure that distorts the ratio of exposure in either the cases or controls may lead to bias.

Case-Control Study
Bias
Case-control studies are subject to bias and confounding, both will distort the results of the study Bias is defined as the deviation of results, or inferences, from the truth, or processes leading to such deviation. There are about 75 different types of bias now identified in published case-control studies

Bias
Selection bias
Information bias Confounding

Selection Bias
A distortion in the relationship between exposure and outcome that results from selection of study participants The relation between exposure and outcome is different for those who participate and those who do not participate but would theoretically be eligible for the study. Examples
Self-selection bias Diagnostic bias

Information Bias
A distortion in measuring exposure or outcome data that results in different quality (i.e., accuracy or reliability) or frequency of information between comparison groups.
Differential misclassification Non-differential misclassification

No Misclassification
Breast Cancer No Breast Cancer Total X-ray Exposure 40 9,960 10,000 OR = 2.00 Classification of exposure comparable in cases and controls, perfect accuracy No X-ray Exposure 80 39,920 40,000

Non-differential Misclassification
Breast Cancer No Breast Cancer Total X-ray Exposure 60 19,940 20,000 OR = 1.50 Tendency to overestimate exposure, but comparable between cases and controls No X-ray Exposure 60 29,940 30,000

Differential Misclassification
Breast Cancer No Breast Cancer Total X-ray Exposure 40 19,940 19,980 OR = 0.75 Assessment of exposure different between cases and controls No X-ray Exposure 80 29,940 30,020

Case-Control Study
Bias
Berksons bias
The combination of exposure and disease lead to increased likelihood of being hospitalized Cases more likely to be exposed

Recall bias
Differential recall of exposure between cases and controls in a study Example
Mothers of children with congenital malformations may remember details about possible exposures during pregnancy that mothers without malformations forget.

Confounding
A situation in which a measure of the effect of an exposure on risk is distorted because of the association of exposure with other factor(s) that influence the outcome under study. Criteria for confounding
Factor is associated with exposure Factor is associated with disease in the absence of exposure Factor is not in the causal path between exposure and outcome

Case-Control Study
Matching
Matching is defined as the process of selecting controls so that they resemble the cases with regard to certain characteristics The goal of matching is to create similar distributions between cases and controls with regard to certain characteristics Matching can be used to
Adjust for potential confounding factors Increase precision of estimate

Case-Control Study
Matching
Types of matching
Individual level matching
For each case in the study, one or more controls are selected with identical (similar) characteristics as the case

Frequency, or group, matching

Select controls so that the proportion with a certain characteristic is identical to the proportion of cases with that characteristic

Case-Control Study
Problems with Matching
Difficult and expensive Cannot evaluate the effect of controlled variables May limit the ability to control for other variables Overmatching
Controls resemble cases in terms of known and unknown characteristics, some of which may be associated with the disease

Case-Control Study
Analytic Strategy
Assess relationship/association between
Exposure and independent variables Case/Control status and independent variables

Calculate crude, or unadjusted, OR for exposure - case association

Matched analysis required for matched studies

Case-Control Study
Matched Analysis
Control
Exposed Unexposed Exposed a c b OR = b/c d

Case
Unexposed

Case-control pairs that share the same exposure status do not contribute to the estimate of risk.

Case-Control Study
Analytic Strategy
Stratified analysis
Calculate stratum-specific ORs for exposure-case relationship Determine presence of confounding and interaction

Logistic Regression analysis

Regression technique used to adjust for confounding and interaction Special logistic model applied in matched studies

Case-Control Study Design

Strengths and Weaknesses
Strengths Rare disease Long latency between exposure and disease Explore multiple hypotheses Inexpensive Weaknesses Prone to bias Temporal relationships cannot be established Inefficient for rare exposures, unless exposure often lead to disease