Abstract
Prescription sequence symmetry analysis (PSSA), a case-only design introduced in 1996, has been increasingly used to identify unintentional drug effects, and has potential applications as a hypothesis-testing and a hypothesis-generating method, due to its easy application and effective control of time-invariant confounders. The aim of this study is to systematically compare effect estimates from the PSSA to effect estimates from conventional observational parallel group study designs, to assess the validity and constraints of the PSSA study design. We reviewed the MEDLINE, EMBASE, and Web of Science databases until February 2016 to identify studies that compared PSSA to a parallel group design. Data from the eligible articles was extracted and analyzed, including making a Bland-Altman plot and calculating the number of discrepancies between the designs. 63 comparisons (from two studies) were included in the review. There was a significant correlation (p < 0.001) between the effect estimates of the PSSA and the parallel group designs, but the bias indicated by the Bland-Altman plot (0.20) and the percentage of discrepancies (70–80%) showed that this correlation was not accompanied by a considerable similarity of the effect estimates. Overall, the effect estimates of the parallel group designs were higher than those of the PSSA, not necessarily further away from 1, and the parallel group designs also generated more significant signals. However, these results should be approached with caution, as the effect estimates were only retrieved from two separate studies. This review indicates that, even though PSSA has a lot of potential, the effect estimates generated by the PSSA are usually lower than the effect estimates generated by parallel group designs, and PSSA mostly has a lower power than the conventional study designs, but this is based on limited comparisons, and more comparisons are needed to make a proper conclusion.
Highlights
Conventional observational parallel group studies, such as the cohort study and the case-control study, are still predominantly used to determine causal effects of risk factors and to assess drug safety [1]
This review indicates that, even though prescription sequence symmetry analysis (PSSA) has a lot of potential, the effect estimates generated by the PSSA are usually lower than the effect estimates generated by parallel group designs, and PSSA mostly has a lower power than the conventional study designs, but this is based on limited comparisons, and more comparisons are needed to make a proper conclusion
Even though the method was rarely used after its introduction in 1996, there is a clear increasing trend in the number of PSSA studies during the last three to four years
Summary
Conventional observational parallel group studies, such as the cohort study and the case-control study, are still predominantly used to determine causal effects of risk factors and to assess drug safety [1]. Case-only designs, such as the case-crossover study design and the self-controlled caseseries are alternatives to parallel group designs, and they aim to decrease the possibility of introducing bias [3,4]. In 1996, Hallas introduced another case-only study design: the prescription sequence symmetry analysis (PSSA) [6]. Since PSSA can be sensitive to temporal prescribing trends, the null-effect sequence ratio is calculated. This is the expected SR in absence of a causal relationship between the index- and marker drug. Variations on the PSSA, such as (event) sequence symmetry analysis ((E)SSA), are described in literature, and these variations look at index- and marker events instead of drugs, such as surgeries or behavioral interventions [11]
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