In determining dose limiting toxicities in Phase I studies, it is necessary to attribute adverse events (AE) to being drug related or not. Such determination is subjective and may introduce bias. In this paper, we develop methods for removing or at least diminishing the impact of this bias on the estimation of the maximum tolerated dose (MTD). The approach we suggest takes into account the subjectivity in the attribution of AE by using model-based dose escalation designs. The results show that gains can be achieved in terms of accuracy by recovering information lost to biases. These biases are a result of ignoring the errors in toxicity attribution.

中文翻译：

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第一阶段设计考虑到不良事件的归因不确定性。

在确定I期研究的剂量限制性毒性时，有必要将不良事件（AE）归因于与药物无关。这样的确定是主观的，可能会引起偏差。在本文中，我们开发了消除或至少减小此偏差对最大耐受剂量（MTD）估算的影响的方法。我们建议的方法通过使用基于模型的剂量递增设计来考虑AE归因的主观性。结果表明，通过恢复丢失到偏差中的信息可以在准确性方面获得收益。这些偏见是忽略毒性归因错误的结果。