In studies of infectious disease prevention, the level of protective efficacy of medicinal products such as vaccines and prophylactic drugs tends to vary over time. Many products require administration of multiple doses at scheduled times, as opposed to one‐off or continual intervention. Accurate information on the trajectory of the level of protective efficacy over time facilitates informed clinical recommendations and implementation strategies, for example, with respect to the timing of administration of the doses. Based on concepts from pharmacokinetic and pharmacodynamic modeling, we propose a non‐linear function for modeling the trajectory after each dose. The cumulative effect of multiple doses of the products is captured by an additive series of the function. The model has the advantages of parsimony and interpretability, while remaining flexible in capturing features of the trajectories. We incorporate this series into the Andersen‐Gill model for analysis of recurrent event time data and compare it with alternative parametric and non‐parametric functions. We use data on clinical malaria disease episodes from a trial of four doses of an anti‐malarial drug combination for chemoprevention to illustrate, and evaluate the performance of the methods using simulation. The proposed method out‐performed the alternatives in the analysis of real data in terms of Akaike and Bayesian Information Criterion. It also accurately captured the features of the protective efficacy trajectory such as the area under curve in simulations. The proposed method has strong potential to enhance the evaluation of disease prevention measures and improve their implementation strategies.

中文翻译：

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使用重复事件时间估计传染病预防试验中保护功效的轨迹

在传染病预防的研究中，疫苗和预防药物等药品的保护功效水平往往会随着时间的推移而变化。许多产品需要在预定时间施用多次剂量，而不是一次性或持续干预。关于保护功效水平随时间变化的轨迹的准确信息有助于提供明智的临床建议和实施策略，例如关于给药时间的建议。基于药代动力学和药效学建模的概念，我们提出了一个非线性函数来对每次剂量后的轨迹进行建模。产品多剂量的累积效应由函数的累加系列捕获。该模型具有简约性和可解释性的优点，同时在捕获轨迹特征方面保持灵活。我们将这个系列纳入 Andersen-Gill 模型中，以分析经常性事件时间数据，并将其与替代参数和非参数函数进行比较。我们使用四种剂量的抗疟疾药物组合进行化学预防试验中的临床疟疾疾病发作数据来说明，并使用模拟评估这些方法的性能。在赤池和贝叶斯信息准则方面，所提出的方法在实际数据分析中优于其他方法。它还准确地捕捉了防护功效轨迹的特征，例如模拟中的曲线下面积。该方法在加强疾病预防措施的评估和改进其实施策略方面具有强大的潜力。