Abstract
BackgroundThe case-crossover design is suited to medication safety studies but is vulnerable to exposure misclassification. Using the example of tricyclic antidepressants and the risk of hip fracture, we present a data visualisation tool for observing exposure misclassification in case-crossover studies.MethodsA case-crossover study was conducted using Australian Government Department of Veterans’ Affairs claims data. Beneficiaries aged over 65 years who were hospitalised for hip fracture between 2009 and 2012 were included. The case window was defined as 1–50 days pre fracture. Control window one and control window two were defined as 101–150 and 151–200 days pre fracture, respectively. Patients were stratified by whether exposure status changed when control window two was specified instead of control window one. To visualise potential misclassification, each subject’s tricyclic antidepressant dispensings were plotted over the 200 days pre fracture.ResultsThe study population comprised 8828 patients with a median age of 88 years. Of these subjects, 348 contributed data to the analyses with either control window. The data visualisation suggested that 14% of subjects were potentially misclassified with control window one while 45% were misclassified with control window two. The odds ratio for the association between tricyclic antidepressants and hip fracture was 1.18 (95% confidence interval = 0.91–1.52) using control window one, whereas risk was significantly increased (odds ratio = 1.43, 95% confidence interval = 1.11–1.83) using control window two.ConclusionsExposure misclassification was less likely to be present with control window one than with an earlier control window, control window two. When specifying different control windows in a case-crossover study, data visualisation can help to assess the extent to which exposure misclassification may contribute to variable results.
Highlights
The case-crossover design is suited to medication safety studies but is vulnerable to exposure misclassification
The present study aimed to develop and demonstrate a novel data visualisation method for conducting an a posteriori assessment of the extent of exposure misclassification in the case-crossover design, using the previously-published example of risk of hip fracture associated with tricyclic antidepressant (TCA) [7]
In our prior case-crossover study [7], variation in the choice of control window led to differing results for the association between TCAs and hip fracture
Summary
The case-crossover design is suited to medication safety studies but is vulnerable to exposure misclassification. The casecrossover design compares each individual’s exposure status immediately before an outcome (the case window) with their own exposure status at an earlier stage or stages in recent history (the control window) This means that each case serves as his or her own control. The risk estimates obtained from a case-crossover analysis depend on the choice of case and control windows This is reflected in the underlying assumption of biologically plausible exposure windows with no carryover effects from the control window to the case window [5]. The ratio of the number of persons exposed in the case window only to the number of persons exposed in the control window only gives the odds ratio (OR) for the case-crossover analysis This OR estimates the relative risk of the outcome in exposed versus unexposed time [6]. As the OR depends on the numbers of discordant cases and the choice of exposure windows, there is a need to develop methods for assessing exposure classification
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