Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility
Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility
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DOI：
10.1002/sim.3506
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发表时间：
2009-02-28
影响因子：
2
通讯作者：
Koopmeiners, Joseph
中科院分区：
文献类型：
--
作者：
Pepe, Margaret Sullivan;Feng, Ziding;Koopmeiners, Joseph
疾病筛查生物标记物的开发包括几个阶段。在第二阶段，将其敏感度和特异度与最低可接受性能的既定阈值进行比较。由于我们预计大多数候选标记不会被证明是有用的，而且样本和资金的可获得性有限，如果积累的数据表明标记不充分，那么提前终止研究是合适的。然而，对于完成第二阶段的标记物，我们寻求对敏感性和特异性的估计，以继续进行后续第三阶段研究的设计。我们建议提前终止标准和估计程序，以调整由提前终止选项造成的偏差。我们方法的一个重要方面是专注于估计的性质，条件是达到充分的学习登记。我们提出了条件UMVUE，并将其与其他估计进行了比较，包括朴素估计、研究广泛的无条件UMVUE以及均值和中位数怀特黑德调整估计。有条件的UMVUE似乎是一个非常好的选择。版权所有(C)2008 John Wiley&Sons，Ltd.
Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a Study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional-UMVUE and contrast it with other estimates, including naive estimators, the well-studied unconditional-UMVUE and the mean and median Whitehead-adjusted estimators. The conditional-UMVUE appears to be a very good choice. Copyright (C) 2008 John Wiley & Sons, Ltd.