论文标题

两臂试验的最佳最佳设计以及侧面信息

Robust Optimal Design of Two-Armed Trials with Side Information

论文作者

Zhang, Qiong, Khademi, Amin, Song, Yongjia

论文摘要

已经有大量证据可以强调医学中个性化的重要性。实际上,普遍认为个性化医学是医学的未来。个性化医学的核心是设计临床试验的能力,以研究患者协变量对治疗效果的作用。在这项工作中,我们研究了两臂临床试验的最佳设计,以最大程度地提高统计模型的准确性,其中纳入了患者协变量与治疗效果之间的相互作用以实现精确药物。这样的建模扩展为产生的优化问题带来了显着的复杂性,因为它们包括对设计的优化和协变量同时进行的。我们采用强大的优化方法,并将治疗与患者协变量之间相互作用效应的最大(超过人群)差异最小化。这导致了最小的双层混合整数非线性编程问题,这一点尤其具有挑战性。为了应对这一挑战,我们通过近似提出两种解决方案方法的目标函数来引入一个替代模型。第一种方法提供了基于重新制定和分解技术的精确解决方案。在第二种方法中,我们为内部优化问题提供了下限,并在下限上解决了外部优化问题。我们使用合成和现实世界数据集测试我们提出的算法,并将其与标准(重)随机方法进行比较。我们的数值分析表明,下边界方法在各种环境中提供了高质量的解决方案。

Significant evidence has become available that emphasizes the importance of personalization in medicine. In fact, it has become a common belief that personalized medicine is the future of medicine. The core of personalized medicine is the ability to design clinical trials that investigate the role of patient covariates on treatment effects. In this work, we study the optimal design of two-armed clinical trials to maximize accuracy of statistical models where the interaction between patient covariates and treatment effect are incorporated to enable precision medication. Such a modeling extension leads to significant complexities for the produced optimization problems because they include optimization over design and covariates concurrently. We take a robust optimization approach and minimize (over design) the maximum (over population) variance of interaction effect between treatment and patient covariates. This results in a min-max bi-level mixed integer nonlinear programming problem, which is notably challenging to solve. To address this challenge, we introduce a surrogate model by approximating the objective function for which we propose two solution approaches. The first approach provides an exact solution based on reformulation and decomposition techniques. In the second approach, we provide a lower bound for the inner optimization problem and solve the outer optimization problem over the lower bound. We test our proposed algorithms with synthetic and real-world data sets and compare it with standard (re-)randomization methods. Our numerical analysis suggests that the lower bounding approach provides high-quality solutions across a variety of settings.

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