The case-time-control design.
Assessing the known or intended effects of a drug using non-experimental epidemiologic designs is often infeasible because of the absence of accurate data on a major confounder, the severity of the disease treated by this drug. To circumvent this problem of confounding by indication, I propose the case-time-control design, which does not require a measure of this confounder. Instead, the design uses subjects from a conventional case-control design as their own controls and thus requires that exposure be measurable at two or more points in time. I present a logistic model to estimate relative risks under this design and illustrate the method with data from a case-control study of 129 cases of fatal or near-fatal asthma and 655 controls. The exposure of interest was quantity of use of inhaled beta-agonists, drugs prescribed for the treatment of asthma. I found that the "best" estimate of relative risk for high vs low beta-agonist use using the conventional case-control approach is 3.1 [95% confidence interval (CI) = 1.8-5.4], which inherently includes the confounding effect of unmeasured severity. The corresponding estimate of drug effect using the proposed case-time-control approach is 1.2 (95% CI = 0.5-3.0), which excludes the confounding effect of unmeasured severity. This example indicates that the class of beta-agonists may not play the leading role attributed to it in the risk of fatal or near-fatal asthma, as had been previously suspected, except perhaps at excessive doses, as indicated by the dose-response analyses.
Suissa
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Department of Epidemiology and Biostatistics, McGill University, Quebec, Canada.
D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000401:mortality; D001699:Biometry; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D015986:Confounding Factors, Epidemiologic; D004812:Epidemiologic Methods; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D012107:Research Design; D012307:Risk Factors; D012525:Saskatchewan / Q000453:epidemiology; D013997:Time Factors
D000318:Adrenergic beta-Agonists