Isotonic designs for phase I trials in partially ordered groups.
Isotonic designs for phase I trials in partially ordered groups.
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DOI：
10.1177/1740774517722760
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发表时间：
2017-10
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影响因子：
--
通讯作者：
Conaway M
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文献类型：
--
作者：
Conaway M
可以进行剂量探索试验，以便在分配剂量之前首先将患者分层为多个风险组。风险组通常是完全有序的，因为对于固定剂量，毒性的概率在各组之间单调增加。在某些试验中，这些组只是部分有序的。例如，试验中的几组中的一组可能已知对于给定剂量具有最小的毒性风险，但其余组中的风险排序可能未知。本文的目的是介绍一种在完全或部分有序的患者组中设计细胞毒性药物剂量探索试验的方法。本文提出了一种方法，结合先前提出的数学模型，增强了使用顺序限制推理的结果，剂量发现。由此产生的方法是计算方便，并允许剂量发现完全或部分有序组的试验。进行了广泛的模拟，以评估该方法的性能，使用随机生成的剂量-毒性曲线，其中，在每组内，毒性的风险是剂量的递增函数。我们的模拟结果表明，混合方法，其中顺序限制估计适用于参数的一个简约的数学模型，给出的结果是类似于以前提出的方法完全有序组。我们的方法推广到广泛的偏序之间的群体。在统计学文献中尚未广泛研究偏序组中的剂量发现问题。所提出的方法是计算上可行的，并提供了一个潜在的解决方案，在完全或部分有序组的剂量探索研究的设计。
Dose finding trials can be conducted such that patients are first stratified into multiple risk groups before doses are allocated. The risk groups are often completely ordered in that, for a fixed dose, the probability of toxicity is monotonically increasing across groups. In some trials, the groups are only partially ordered. For example, one of several groups in a trial may be known to have the least risk of toxicity for a given dose, but the ordering of the risk among the remaining groups may not be known. The aim of the paper is to introduce a method for designing dose-finding trials of cytotoxic agents in completely or partially ordered groups of patients. The paper presents a method for dose-finding that combines previously proposed mathematical models, augmented with results using order restricted inference. The resulting method is computationally convenient and allows for dose finding in trials with completely or partially ordered groups. Extensive simulations are done to evaluate the performance of the method, using randomly generated dose-toxicity curves where, within each group, the risk of toxicity is an increasing function of dose. Our simulations show that the hybrid method, in which order restricted estimation is applied to parameters of a parsimonious mathematical model, gives results that are similar to previously proposed methods for completely ordered groups. Our method generalizes to a wide range of partial orders among the groups. The problem of dose-finding in partially ordered groups has not been extensively studied in the statistical literature. The proposed method is computationally feasible, and provides a potential solution to the design of dose finding studies in completely or partially ordered groups.
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影响因子：
2
作者：
Conaway, Mark R.;Wages, Nolan A.
通讯作者：
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影响因子：
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0.9
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