论文标题
持续时间随机试验设计:估计目标,分析方法和操作特征
The DURATIONS randomised trial design: estimation targets, analysis methods and operating characteristics
论文作者
论文摘要
背景。在包括结核病和抗生素在内的几个治疗区域,设计以减少治疗持续时间的试验很重要。我们最近提出了一种新的随机试验设计,以克服标准两臂非劣效试验的某些局限性。该持续时间设计涉及将患者随机多持续臂,并为所谓的持续响应曲线进行建模。本文研究了从估计曲线中绘制推断的不同统计方法的工作特性(1型和2型错误)。方法。我们的第一个估计目标是在特定风险差距内最短的持续时间(最大)持续时间。我们比较了估计此数量的不同方法,包括使用模型置信带,三角洲方法和引导程序。然后,我们探索结果对估计目标的普遍性,该目标侧重于绝对事件率,风险比和曲线的梯度。结果。我们通过模拟显示,在大多数情况下和大多数估计目标中,使用引导程序来估计目标持续时间周围的变异性可在持续时间内良好的结果设计 - 适当的数量类似于Power和Type-1误差。不建议使用模型置信带,而在某些情况下,增量方法会导致膨胀1型误差,尤其是当最佳持续时间非常接近随机持续时间之一时。结论。使用Bootstrap在持续时间设计中估计最佳持续时间在各种场景中具有良好的操作特征,并且可以通过希望设计持续时间试验以减少治疗持续时间的研究人员充满信心地使用。通过这种自举方法可以估计几个不同目标的不确定性。
Background. Designing trials to reduce treatment duration is important in several therapeutic areas, including TB and antibiotics. We recently proposed a new randomised trial design to overcome some of the limitations of standard two-arm non-inferiority trials. This DURATIONS design involves randomising patients to a number of duration arms, and modelling the so-called duration-response curve. This article investigates the operating characteristics (type-1 and type-2 errors) of different statistical methods of drawing inference from the estimated curve. Methods. Our first estimation target is the shortest duration non-inferior to the control (maximum) duration within a specific risk difference margin. We compare different methods of estimating this quantity, including using model confidence bands, the delta method and bootstrap. We then explore the generalisability of results to estimation targets which focus on absolute event rates, risk ratio and gradient of the curve. Results. We show through simulations that, in most scenarios and for most of the estimation targets, using the bootstrap to estimate variability around the target duration leads to good results for DURATIONS design-appropriate quantities analogous to power and type-1 error. Using model confidence bands is not recommended, while the delta method leads to inflated type-1 error in some scenarios, particularly when the optimal duration is very close to one of the randomised durations. Conclusions. Using the bootstrap to estimate the optimal duration in a DURATIONS design has good operating characteristics in a wide range of scenarios, and can be used with confidence by researchers wishing to design a DURATIONS trial to reduce treatment duration. Uncertainty around several different targets can be estimated with this bootstrap approach.