Introduction:

In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity.

Methods:

We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches.

Results:

Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose.

Conclusion:

Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

中文翻译：

---

用于不确定性评估结果的贝叶斯剂量发现设计

介绍：

在某些 I 期试验环境中，评估特定患者是否符合剂量限制性毒性标准存在不确定性。

方法：

我们提出了一种设计，该设计适用于对某些患者进行不确定评估的剂量限制性毒性结果。我们的方法可用于许多可用的 I 期试验设计，但由于其流行，我们专注于持续重新评估方法。我们假设对于某些患者，不是通常的二元剂量限制毒性结果，而是观察医生评估的特定患者特有的剂量限制毒性概率。基于完全观察到的和部分观察到的患者结果，数据增强用于估计每个剂量水平的剂量限制性毒性的后验概率。

结果：

在利用部分观察结果的设计中，我们提出的设计在选择正确最大耐受剂量的概率和以最大耐受剂量治疗的患者数量方面具有最佳的整体性能。

结论：

在剂量限制性毒性评估中加入不确定性可以提高持续重新评估方法设计的性能。