用于偏序持续重评估方法的贝叶斯模型平均
Bayesian Model Averaging for Partial Ordering Continual Reassessment Methods
AI总结：
针对联合用药剂量探索中POCRM的毒性估计不一致问题，提出BMA-POCRM，利用贝叶斯模型平均同时处理多种可能排序，提升试验安全性与剂量推荐准确性。
摘要：
I期临床试验对于将新疗法从化学开发推进到广泛应用至关重要。I期试验中传统的剂量探索方法，如“3+3”方法和持续重评估方法（CRM），为跨剂量水平递增提供了有原则的途径。然而，这些方法无法纳入联合药物试验中存在的剂量—毒性排序方面的不确定性。在这种情形下，剂量水平会随多种药物同时变化，从而产生多种可能的剂量—毒性排序。偏序CRM（POCRM）通过允许多种剂量—毒性排序而扩展到这些情形。本文表明，POCRM容易受到“估计不一致性”的影响，即毒性估计会以不合逻辑的方式发生偏移，从而威胁患者安全并削弱临床医生对剂量探索模型的信任。为此，提出了贝叶斯模型平均POCRM（BMA-POCRM）。BMA-POCRM采用贝叶斯模型平均同时考虑所有可能的排序，从而降低估计不一致的发生频率。通过POCRM估计不一致的一个具体实例以及模拟研究，证明了BMA-POCRM在药物联合情形下的有效性。结果表明，与POCRM模型相比，应用BMA-POCRM的试验在安全性、准确性方面有所提升，并且估计不一致的发生减少。
英文摘要：
Phase I clinical trials are essential to bringing novel therapies from chemical development to widespread use. Traditional approaches to dose-finding in Phase I trials, such as the '3+3' method and the Continual Reassessment Method (CRM), provide a principled approach for escalating across dose levels. However, these methods lack the ability to incorporate uncertainty regarding the dose-toxicity ordering as found in combination drug trials. Under this setting, dose-levels vary across multiple drugs simultaneously, leading to multiple possible dose-toxicity orderings. The Partial Ordering CRM (POCRM) extends to these settings by allowing for multiple dose-toxicity orderings. In this work, it is shown that the POCRM is vulnerable to 'estimation incoherency' whereby toxicity estimates shift in an illogical way, threatening patient safety and undermining clinician trust in dose-finding models. To this end, the Bayesian model averaged POCRM (BMA-POCRM) is proposed. BMA-POCRM uses Bayesian model averaging to take into account all possible orderings simultaneously, reducing the frequency of estimation incoherencies. The effectiveness of BMA-POCRM in drug combination settings is demonstrated through a specific instance of estimate incoherency of POCRM and simulation studies. The results highlight the improved safety, accuracy and reduced occurrence of estimate incoherency in trials applying the BMA-POCRM relative to the POCRM model.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
