Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom.
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
PLoS One. 2018 Dec 13;13(12):e0208876. doi: 10.1371/journal.pone.0208876. eCollection 2018.
A stepped wedge cluster randomised trial (SWCRT) is a multicentred study which allows an intervention to be rolled out at sites in a random order. Once the intervention is initiated at a site, all participants within that site remain exposed to the intervention for the remainder of the study. The time since the start of the study ("calendar time") may affect outcome measures through underlying time trends or periodicity. The time since the intervention was introduced to a site ("exposure time") may also affect outcomes cumulatively for successful interventions, possibly in addition to a step change when the intervention began.
Motivated by a SWCRT of self-monitoring for bipolar disorder, we conducted a simulation study to compare model formulations to analyse data from a SWCRT under 36 different scenarios in which time was related to the outcome (improvement in mood score). The aim was to find a model specification that would produce reliable estimates of intervention effects under different scenarios. Nine different formulations of a linear mixed effects model were fitted to these datasets. These models varied in the specification of calendar and exposure times.
Modelling the effects of the intervention was best accomplished by including terms for both calendar time and exposure time. Treating time as categorical (a separate parameter for each measurement time-step) achieved the best coverage probabilities and low bias, but at a cost of wider confidence intervals compared to simpler models for those scenarios which were sufficiently modelled by fewer parameters. Treating time as continuous and including a quadratic time term performed similarly well, with slightly larger variations in coverage probability, but narrower confidence intervals and in some cases lower bias. The impact of misspecifying the covariance structure was comparatively small.
We recommend that unless there is a priori information to indicate the form of the relationship between time and outcomes, data from SWCRTs should be analysed with a linear mixed effects model that includes separate categorical terms for calendar time and exposure time. Prespecified sensitivity analyses should consider the different formulations of these time effects in the model, to assess their impact on estimates of intervention effects.
阶梯式楔形群组随机对照试验（SWCRT）是一种多中心研究，可以随机顺序在各个站点推出干预措施。一旦在某个站点启动干预措施，该站点内的所有参与者在研究的剩余时间内都将继续接受干预。自研究开始以来的时间（“日历时间”）可能会通过潜在的时间趋势或周期性影响结果测量值。干预措施引入站点以来的时间（“暴露时间”）也可能会对成功干预措施的结果产生累积影响，可能除了干预开始时的阶跃变化之外还有影响。
受针对双相情感障碍的自我监测的 SWCRT 的启发，我们进行了一项模拟研究，以比较 36 种不同情况下分析 SWCRT 数据的模型公式，这些情况下时间与结果（情绪评分改善）有关。目的是找到一种模型规格，以便在不同情况下可靠地估计干预效果。对这些数据集拟合了九种不同的线性混合效应模型公式。这些模型在日历时间和暴露时间的规范方面有所不同。
通过包含日历时间和暴露时间的术语来建模干预效果最佳。将时间视为分类（每个测量时间步的单独参数）可以获得最佳的覆盖率概率和低偏差，但与那些通过较少参数充分建模的简单模型相比，置信区间较宽。将时间视为连续并包含二次时间项的效果也很好，覆盖率概率略有变化，但置信区间较窄，在某些情况下偏差较低。协方差结构指定不当的影响相对较小。
除非有先验信息表明时间与结果之间的关系形式，否则应使用包含日历时间和暴露时间的单独分类术语的线性混合效应模型来分析 SWCRT 数据。预设的敏感性分析应考虑模型中这些时间效果的不同公式，以评估它们对干预效果估计的影响。
