Optimal Significance Levels and Sample Sizes for Signal Detection Methods Based on Non-constant Hazards.

Background and objectives: Statistical methods for signal detection of adverse drug reactions (ADRs) in electronic health records (EHRs) need information about optimal significance levels and sample sizes to achieve sufficient power. Sauzet and Cornelius proposed tests for signal detection based on the hazard functions of Weibull type distributions (WSP tests) which use the time-to-event information available in EHRs. Optimal significance levels and sample sizes for the application of the WPS tests are derived.

Method: A simulation study was performed with a range of scenarios for sample size, rate of event due (ADRs), and not due to the drug and random time to ADR occurrence. Based on the area under the curve of the receiver operating characteristic graph, we obtain optimal significance levels of the different WSP tests for the implementation in a hypothesis free signal detection setting and approximate sample sizes required to reach a power of 80% or 90%.

Results: The dWSP-pPWSP (combination of double WSP and power WSP) test with a significance level of 0.004 was recommended. Sample sizes needed for a power of 80% were found to start at 60 events for an ADR rate equal to the background rate of 0.1. The number of events required for a background rate of 0.05 and an ADR rate equal to a 20% increase of the background rate was 900.

Conclusion: Based on this study, it is recommended to use the dWSP-pWSP test combination for signal detection with a significance level of 0.004 when the same test is applied to all adverse events not depending on rates.