Exact Confidence Bounds Following Adaptive Group Sequential Tests
Exact Confidence Bounds Following Adaptive Group Sequential Tests
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DOI：
10.1111/j.1541-0420.2008.01101.x
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发表时间：
2009-06-01
期刊：
影响因子：
1.9
通讯作者：
Posch, Martin
中科院分区：
文献类型：
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作者：
Brannath, Werner;Mehta, Cyrus R.;Posch, Martin
我们提供了一种方法，用于在两组序贯临床试验结束时获得主要效应大小参数的可信区间、点估计和p值，在该试验中，适应性改变已在过程中实施。该方法基于将Muller和Schafer(2001，Biometrics 57,886-891)的自适应假设检验程序应用于从Tsiatis、Rosner和Mehta(1984，Biometrics 40,797-803)的阶段性调整的置信度区间导出的双重测试的序列。在非自适应设置中，已知该置信度区间提供准确的覆盖。在自适应设置中，如果自适应发生在倒数第二阶段，则保证准确的复盖范围。然而，总的来说，从理论上讲，所有可以声称的是，覆盖范围肯定是保守的。然而，广泛的模拟实验，在条件误差函数的经验描述的支持下，令人信服地证明，对于所有实际目的，覆盖是准确的，点估计是中值无偏的。以前还没有程序可用于在自适应组顺序设置中产生具有这些期望属性的置信度区间和点估计。通过对帕金森氏病深部脑刺激临床试验的应用，说明了这种方法。
We provide a method for obtaining confidence intervals, point estimates, and p-values for the primary effect size parameter at the end of a two-arm group sequential clinical trial in which adaptive changes have been implemented along the way. The method is based on applying the adaptive hypothesis testing procedure of Muller and SchAfer (2001, Biometrics 57, 886-891) to a sequence of dual tests derived from the stage-wise adjusted confidence interval of Tsiatis, Rosner, and Mehta(1984, Biometrics 40, 797-803). In the nonadaptive setting this confidence interval is known to provide exact coverage. In the adaptive setting exact coverage is guaranteed provided the adaptation takes place at the penultimate stage. In general, however, all that can be claimed theoretically is that the coverage is guaranteed to be conservative. Nevertheless, extensive simulation experiments, supported by an empirical characterization of the conditional error function, demonstrate convincingly that for all practical purposes the coverage is exact and the point estimate is median unbiased. No procedure has previously been available for producing confidence intervals and point estimates with these desirable properties in an adaptive group sequential setting. The methodology is illustrated by an application to a clinical trial of deep brain stimulation for Parkinson's disease.