Summary
For sequential analysis hypothesis testing, various alpha spending functions have been proposed. Given a prespecified overall alpha level and power, we derive the optimal alpha spending function that minimizes the expected time to signal for continuous as well as group sequential analysis. If there is also a restriction on the maximum sample size or on the expected sample size, we do the same. Alternatively, for fixed overall alpha, power and expected time to signal, we derive the optimal alpha spending function that minimizes the expected sample size. The method constructs alpha spending functions that are uniformly better than any other method, such as the classical Wald, Pocock or O’Brien–Fleming methods. The results are based on exact calculations using linear programming. All numerical examples were run by using the R Sequential package.
Sequential analysis is now commonly used for post-market drug and vaccine safety surveillance, and a Poisson stochastic process is typically used for rare adverse events. The conditional maximized sequential probability ratio test, CMaxSPRT, is a powerful tool when there is uncertainty in the estimated expected counts under the null hypothesis. This paper derives exact critical values for CMaxSPRT, as well as statistical power and expected time to signal. This is done for both continuous and group sequential analysis, and for different rejection boundaries. It is also shown how to adjust for covariates in the sequential design. A table of critical values is provided for selected parameters and rejection boundaries, while new functions in the R Sequential package can be used for other calculations. In addition, the method is illustrated for monitoring adverse events after pediarix vaccination data.
Statistical sequential hypothesis testing is meant to analyze cumulative data accruing in time. The methods can be divided in two types, group and continuous sequential approaches, and a question that arises is if one approach suppresses the other in some sense. For Poisson stochastic processes, we prove that continuous sequential analysis is uniformly better than group sequential under a comprehensive class of statistical performance measures. Hence, optimal solutions are in the class of continuous designs. This paper also offers a pioneer study that compares classical Type I error spending functions in terms of expected number of events to signal. This was done for a number of tuning parameters scenarios. The results indicate that a log-exp shape for the Type I error spending function is the best choice in most of the evaluated scenarios.
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