Improving the statistical design and analysis of randomized controlled trials of delirium prevention and treatment for critically ill older adults

项目摘要/摘要 在重症监护病房(ICU)接受护理的危重老年人中，精神错乱非常常见(&gt；70%) 并与类似于阿尔茨海默病的长期认知损害密切相关 痴呆(ADRD)。随着人们对这一主要问题的日益认识，有越来越多的 随机对照试验(RCT)评估对精神错乱的预防和治疗干预 病情危重的老年人。正在努力提高这类试验的科学严谨性；具体地说， NIH/NIA NIDUS协作(R24AG054259)和加拿大CIHR资助的旨在协调使用的项目 结果测量工具的使用，以提高精神错乱随机对照试验的可比性和一致性。 然而，尽管作出了这些努力，关于精神错乱终点定义和适当统计的指导意见 目前还缺乏评价神志不清RCT治疗效果的方法。定义和评估精神错乱 对于ICU中的老年人来说，终点尤其具有挑战性，因为在随访期间，精神错乱的状态可能会有所不同 期限(例如28天)和测量可因患者出院或死亡而终止，称为 统计文献中的“竞争事件”。出院和死亡都与 精神错乱，但可能是相反的方向，并可能受到干预的影响，进一步复杂化 对精神错乱终点的评估。因此，我们的总体目标是改进设计和统计 老年危重患者预防性和治疗性妄想的随机对照试验分析。要做到这一点 目的，我们将对妄想终点的定义和统计分析方法进行系统的回顾， 然后严格评估它们的统计性能(例如，假阳性率(I类错误)和 统计能力)，使用基于来自6个不同的RCT样本和2个大型 临床队列(目标1)。联合模型，包括复发性精神错乱和单纯性精神错乱的生存模型 竞争事件，最近已在两个著名的药物干预RCT中应用 ICU中的精神错乱(目标2)。在这项提案中，将开发这些联合模型的新扩展 通过纳入复发事件存活期更好地模拟危重老年人精神错乱的关键特征 用于精神错乱的模型，以及允许两个生存模型，每个竞争项目一个。此后，当前 并将关节模型的新扩展与端点定义和统计分析进行比较 方法在前面的系统回顾中确定，使用模拟研究(目标3)。基于这些 研究结果，我们将提出建议，以设计和统计分析的精神错乱，占 出院和死亡的可能性可能受到研究干预的影响。我们将传播这些信息 新的联合模式，除了我们的调查结果和建议，通过出版物，开放源码 统计软件、独立的统计应用程序、既定的ICU研究方法 传播基础设施，以及老龄化、精神错乱和统计专业协会。

Project Summary/Abstract Among critically ill older adults receiving care in an intensive care unit (ICU), delirium is very common (>70%) and strongly associated with long-term cognitive impairment similar to Alzheimer's Disease and Related Dementias (ADRD). With growing recognition of this major problem, there is an increasing number of randomized controlled trials (RCTs) evaluating preventative and therapeutic interventions for delirium among critically ill older adults. Efforts are underway to improve the scientific rigor of such trials; specifically, a NIH/NIA NIDUS collaborative (R24AG054259) and a Canadian CIHR-funded project that aim to harmonize use of outcome measurement instruments to improve comparability and consistency across delirium RCTs. However, despite these efforts, guidance regarding delirium endpoint definition and appropriate statistical methods for evaluating treatment effects in delirium RCTs is lacking. Defining and evaluating a delirium endpoint is especially challenging for older adults in the ICU as delirium status can vary during the follow-up period (e.g. 28 days) and measurement may be terminated by patient discharge or death, referred to as “competing events” in the statistical literature. Both discharge and death are correlated with the risk of delirium, but likely in opposite directions, and may be affected by the intervention, further complicating evaluation of delirium endpoints. Thus, our overall objective is to improve the design and statistical analysis of preventative and therapeutic delirium RCTs in critically ill older adults. To achieve this objective, we will conduct a systematic review of delirium endpoint definitions and statistical analysis methods, followed by a rigorous evaluation of their statistical performance (e.g., false positive rate (Type I error) and statistical power), using simulation studies based on real data from 6 diverse RCT exemplars and 2 large clinical cohorts (Aim 1). Joint models, that include survival models for both recurring delirium and a single competing event, have recently been applied in two prominent RCTs of pharmacological interventions for delirium in the ICU (Aim 2). In this proposal, novel extensions of these joint models will be developed that better mimic key features of delirium among critically ill older adults by including a recurrent event survival model for delirium, as well as allowing two survival models, one for each competing event. Thereafter, current and novel extensions of the joint models will be compared to the endpoint definitions and statistical analysis methods identified in the preceding systematic review, using simulation studies (Aim 3). Based on these findings, we will make recommendations for the design and statistical analysis of delirium RCTs, accounting for the possibility that discharge and death may be affected by the study intervention. We will disseminate these novel joint models, in addition to our findings and recommendations, through publications, open source statistical software, a stand-alone statistical application, an established ICU research methodology dissemination infrastructure, and aging, delirium, and statistical professional societies.