Original ArticleThe exposure-crossover design is a new method for studying sustained changes in recurrent events
Introduction
Clinical epidemiology is sometimes chastised as the science of unfair comparisons [1], [2], [3]. As a consequence, observational studies usually endeavor to identify cases and controls that are reasonably similar so that inferences are not unduly slanted by hidden confounding [4], [5], [6]. One method for ensuring equivalence is randomization, although doing so typically requires substantial sample size and individual cooperation [7]. Alternative methods include regression modeling, propensity score stratification, individual pair matching, subgroup stratification, or other analytical methods for making separate patient groups appear similar [8], [9], [10]. None of these methods is ideal, and methodological work developing new designs remains a priority for future progress.
One major advance in clinical epidemiology was the development of the case-crossover design in 1991 [11]. The main strength of this repeated-exposure approach is to define each patient as their own control and explore the transient effects of a brief exposure on the onset of an acute outcome [12]. An early contribution from this design examined heart attack patients (n = 1,228) and identified that 54 patients had exercised in the hour before the onset, whereas only nine patients had exercised in the same hour 1 day before the onset, equivalent to a sixfold temporary increase in heart attack risk associated with exercise [13]. Scientists in subsequent years expanded on the case-crossover design with further theory, modeling, and practical applications [14], [15], [16], [17].
The purpose of this article is to introduce a new approach called the “exposure-crossover” design. Similar to other epidemiology methods, the intent of the design is to test for a potential link between exposure and outcome [18], [19]. The name is selected to convey a notion that each patient serves as their own control and undergoes observation during a time with an exposure and a time without an exposure. The name is also intended to be reminiscent of the case-crossover design, the epidemiologic approach that the exposure-crossover design most closely resembles. Some additional names that were considered but rejected include the exposed crossover design, sustained impact design, interventional analysis design, and individual-level interrupted time-series design.
Section snippets
Background
The exposure-crossover design was first inspired by the methods for examining large economic changes [20], [21]. For example, the 23% decrease on Monday October 19, 1987, in the US stock market is apparent when evaluated as a time-series graph (Fig. 1). Such time-series analytical studies are not limited to financial markets and have extended to several other nonmedical fields, for example, a study on the effect of contaminated milk leading to a sustained decrease in dairy product consumption
Case study 1
Consider the following pilot data based on a validation study. The purpose was to test the hypothesis that formal warnings about sexually transmitted infections might alter the subsequent risk of a motor vehicle crash of a patient. This simple hypothesis is implausible and serves to check for the lack of an association when no association would be anticipated. That is, patients who develop sexually transmitted infections might have additional risky behaviors related to lifestyle [41], [42].
Confounding
The inescapable limitation of the exposure-crossover design is that the intervention is not randomly assigned. Hence, a transient factor might cause the patient to both receive treatment and subsequently change. The intervention, therefore, might be a marker but not a mechanism for subsequent differences. Such within-person confounding can be controlled if sufficient data are available on relevant factors before and after the intervention, yet such details are rarely complete. Tracer analyses
Summary
The exposure-crossover design is essentially a before-and-after comparison. Just as an electron microscope shares similarities with an optical microscope, however, the new epidemiology design has distinct features (Table 1). The structure of the exposure-crossover design provides an opportunity for separating the observations before intervention into discrete baseline and induction intervals (each with their own insights). The statistical power further segments each interval into finer
Acknowledgments
The views expressed are those of the author and do not necessarily reflect the Ontario Ministry of Health or the Institute for Clinical Evaluative Sciences. The following individuals merit thanks for providing helpful comments: Peter Austin, Eric Ho, Andrew Lustig, John Staples, Therese Stukel, Deva Thiruchelvam, Robert Tibshirani, Jason Woodfine, Wu, and Christopher Yarnell.
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Conflicts of interest: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. The author has no financial or personal relationships or affiliations that could influence the decisions and work on this article. The author (D.A.R.) had full access to all the data in the study, takes responsibility for the integrity of the data, and is accountable for the accuracy of the analysis.
Funding: This project was supported by the Canada Research Chair in Medical Decision Sciences and the Canadian Institutes of Health Research.