Dose-schedule finding in phase I/II clinical trials using a Bayesian isotonic transformation
Dose-schedule finding in phase I/II clinical trials using a Bayesian isotonic transformation
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DOI：
10.1002/sim.3329
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发表时间：
2008-10-30
影响因子：
2
通讯作者：
Cook, John D.
中科院分区：
文献类型：
--
作者：
Li, Yisheng;Bekele, B. Nebiyou;Cook, John D.
剂量-方案寻找试验是一种新型的肿瘤试验，研究人员的目的是寻找一种剂量和治疗方案的组合，这种组合有很大的可能性有效，而毒性的可能性相对较小。我们证明，传统剂量发现试验和剂量计划发现试验之间的主要区别在于，在剂量发现试验中，毒性概率遵循简单的非递减顺序，而在剂量发现试验中，毒性概率可能遵循矩阵顺序。我们表明，剂量表查找方法的成功需要仔细的统计建模和合理的剂量表分配方案。提出了一种贝叶斯层次模型，该模型将毒性和有效性的无序概率联合建模，并对毒性概率的后验样本进行贝叶斯等渗变换，使变换后的后验样本服从矩阵阶约束。基于顺序约束毒性概率和无序有效性概率的联合后验分布，我们开发了一种剂量-方案寻找算法，该算法在一定的标准下顺序地将患者分配到最佳剂量-方案组合。我们通过在白血病临床试验中的应用来说明我们的方法，并将其与两种替代方法进行比较。版权所有(C) 2008约翰威利父子有限公司
A dose-schedule-finding trial is a new type of oncology trial in which investigators aim to find a combination of dose and treatment schedule that has a large probability of efficacy yet a relatively small probability of toxicity. We demonstrate that a major difference between traditional dose-finding and dose-schedule-finding trials is that while the toxicity probabilities follow a simple nondecreasing order in dose-finding trials, those of dose-schedule-finding trials may adhere to a matrix order. We show that the success of a dose-schedule-finding method requires careful statistical modeling and a sensible dose-schedule allocation scheme. We propose a Bayesian hierarchical model that jointly models the unordered probabilities of toxicity and efficacy and apply a Bayesian isotonic transformation to the posterior samples of the toxicity probabilities, so that the transformed posterior samples adhere to the matrix-order constraints. On the basis of the joint posterior distribution of the order-constrained toxicity probabilities and the unordered efficacy probabilities, we develop a dose-schedule-finding algorithm that sequentially allocates patients to the best dose-schedule combination under certain criteria. We illustrate our methodology through its application to a clinical trial in leukemia and compare it with two alternative approaches. Copyright (C) 2008 John Wiley & Sons, Ltd.