有限边界约化与主动计数耦合多臂疗效-毒性监测中强族系误差的精确验证

中文摘要 AI 辅助

随机剂量优化试验可使用二元疗效和毒性结局筛选多个候选剂量。若某剂量的疗效不足或毒性过高，则该剂量不可接受，因此每个剂量特定的零假设是一个联合区域，且强族系误差控制必须在不可接受剂量与有前景剂量的任意混合情形下成立。我们研究多阶段监测规则的精确验证，其中各臂决策可通过每次期中分析时剩余主动臂的数量而耦合。对于非耦合规则，我们推导出精确的乘积表示，并证明完全零假设边界配置是最不利的。在主动计数耦合下，该因子分解不再成立，因为有前景的剂量可保持主动状态并改变零假设剂量未来的边界。假设各臂独立抽样、每剂量分析计划预先指定、分析时机不受观察到的疗效或毒性结局驱动、各臂监测统计量特定，以及阶段单调性，我们在臂内疗效-毒性联合分布无参数限制的情况下建立了精确的有限边界刻画。每个剂量只需在疗效零边界、毒性零边界或最大有利备选处进行评估。确定性有限状态递归随后可在无蒙特卡洛误差的情况下验证固定决策表。数值研究确认了预先指定的强族系误差控制，并表明主动计数耦合可将最不利配置从完全零假设转移，同时改善多个有前景剂量的联合保留。一项已发表的随机剂量范围试验被用作临床示例，说明该框架如何前瞻性实施。该框架将监测规则构建与严格的误差验证分离。

英文摘要

Randomized dose-optimization trials may screen several candidate doses using binary efficacy and toxicity outcomes. A dose is inadmissible if efficacy is insufficient or toxicity is excessive, so each dose-specific null hypothesis is a union region and strong familywise error control must hold across arbitrary mixtures of inadmissible and promising doses. We study exact verification of multistage monitoring rules in which armwise decisions may be coupled through the number of active arms remaining at each interim analysis. For uncoupled rules, we derive an exact product representation and show that a complete-null boundary configuration is least favourable. Under active-count coupling, this factorization no longer holds because a promising dose can remain active and alter future boundaries for null doses. Assuming independent sampling across arms, prespecified per-dose analysis schedules, analysis timing not driven by the observed efficacy or toxicity outcomes, arm-specific monitoring statistics, and stagewise monotonicity, we establish an exact finite-boundary characterization without parametric restrictions on the within-arm joint efficacy-toxicity distribution. Each dose need only be evaluated at an efficacy-null boundary, a toxicity-null boundary, or a maximally favourable alternative. A deterministic finite-state recursion then verifies a fixed decision table without Monte Carlo error. Numerical studies confirmed the prespecified strong familywise error control and showed that active-count coupling can shift the least-favourable configuration away from the complete null while improving joint retention of multiple promising doses. A published randomized dose-ranging trial was used as a clinical illustration of how the framework could be prospectively implemented. The framework separates monitoring-rule construction from rigorous error verification.

发表机构

• Chuo University（中央大学）
• Kyowa Kirin Co., Ltd.（兴和株式会社）
• The University of Osaka（大阪大学）
• Astellas Pharma Global Development Inc.（安斯泰来全球开发公司）

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