论文标题
在具有多个时间表的II期试验中的剂量反应建模的收缩估计
Shrinkage estimation for dose-response modeling in phase II trials with multiple schedules
论文作者
论文摘要
最近,具有多个时间表(管理频率)的II期试验变得越来越流行,例如开发特应性皮炎的治疗方法。如果通过参数模型描述剂量和响应的关系,则一种简单的方法是从不同的时间表中进行池剂量。但是,这种方法忽略了时间表之间剂量反应曲线的潜在异质性。一种更合理的方法是部分池,即共享剂量响应曲线的某些参数,而其他参数则可以变化。我们不使用计划特定的固定效应,而是提出一个具有随机效应的贝叶斯分层模型,以模拟有关某些参数的划分间异质性。然后可以使用收缩估计来估算计划特定的剂量反应关系。考虑到EMAX模型,与完整的合并相比,提出的方法在平均绝对误差和剂量反应曲线的覆盖范围方面表现出了理想的性能。此外,它通过产生较低的平均绝对误差和较短的可靠间隔,优于计划特定的固定效应,超过了部分合并。使用模拟和特应性皮炎的II期试验示例来说明这些方法。开发了一个公开可用的R软件包,\ Texttt {modstan},以自动化所提出的方法的实现(\ href {https://github.com/gunhanb/modstan} {https://github.com/gunhanb/modstan})。
Recently, phase II trials with multiple schedules (frequency of administrations) have become more popular, for instance in the development of treatments for atopic dermatitis. If the relationship of the dose and response is described by a parametric model, a simplistic approach is to pool doses from different schedules. However, this approach ignores the potential heterogeneity in dose-response curves between schedules. A more reasonable approach is the partial pooling, i.e. certain parameters of the dose-response curves are shared, while others are allowed to vary. Rather than using schedule-specific fixed-effects, we propose a Bayesian hierarchical model with random-effects to model the between-schedule heterogeneity with regard to certain parameters. Schedule-specific dose-response relationships can then be estimated using shrinkage estimation. Considering Emax models, the proposed method displayed desirable performance in terms of the mean absolute error and the coverage probabilities for the dose-response curve compared to the complete pooling. Furthermore, it outperformed the partial pooling with schedule-specific fixed-effects by producing lower mean absolute error and shorter credible intervals. The methods are illustrated using simulations and a phase II trial example in atopic dermatitis. A publicly available R package, \texttt{ModStan}, is developed to automate the implementation of the proposed method (\href{https://github.com/gunhanb/ModStan}{https://github.com/gunhanb/ModStan}).