Kittelson John M, Sharples Katrina, Emerson Scott S
Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, 80262, USA.
Stat Med. 2005 Aug 30;24(16):2457-75. doi: 10.1002/sim.2127.
Longitudinal endpoints are used in clinical trials, and the analysis of the results is often conducted using within-individual summary statistics. When these trials are monitored, interim analyses that include subjects with incomplete follow-up can give incorrect decisions due to bias by non-linearity in the true time trajectory of the treatment effect. Linear mixed-effects models can be used to remove this bias, but there is a lack of software to support both the design and implementation of monitoring plans in this setting. This paper considers a clinical trial in which the measurement time schedule is fixed (at least for pre-trial design), and the scientific question is parameterized by a contrast across these measurement times. This setting assures generalizable inference in the presence of non-linear time trajectories. The distribution of the treatment effect estimate at the interim analyses using the longitudinal outcome measurements is given, and software to calculate the amount of information at each interim analysis is provided. The interim information specifies the analysis timing thereby allowing standard group sequential design software packages to be used for trials with longitudinal outcomes. The practical issues with implementation of these designs are described; in particular, methods are presented for consistent estimation of treatment effects at the interim analyses when outcomes are not measured according to the pre-trial schedule. Splus/R functions implementing this inference using appropriate linear mixed-effects models are provided. These designs are illustrated using a clinical trial of statin treatment for the symptoms of peripheral arterial disease.
纵向终点在临床试验中被使用，并且结果分析通常使用个体内汇总统计量来进行。当监测这些试验时，包含随访不完全的受试者的中期分析可能会由于治疗效果真实时间轨迹中的非线性偏差而给出错误的决策。线性混合效应模型可用于消除这种偏差，但缺乏支持在此设置下监测计划的设计和实施的软件。本文考虑了一项临床试验，其中测量时间安排是固定的（至少对于试验前设计而言），并且科学问题通过这些测量时间的对比来参数化。这种设置确保了在存在非线性时间轨迹的情况下进行可推广的推断。给出了使用纵向结局测量在中期分析时治疗效果估计值的分布，并提供了计算每次中期分析信息量的软件。中期信息指定了分析时间，从而允许将标准的组序贯设计软件包用于具有纵向结局的试验。描述了实施这些设计的实际问题；特别是，当结局未按照试验前计划测量时，提出了在中期分析时一致估计治疗效果的方法。提供了使用适当的线性混合效应模型实现此推断的Splus/R函数。使用他汀类药物治疗外周动脉疾病症状的临床试验对这些设计进行了说明。
