Development of an Ecological Momentary Assessment Outcome Measure for Down Syndrome Clinical Trials

摘要 有越来越多的翻译研究努力，以了解功能障碍的大脑机制， 神经发育障碍，包括唐氏综合征（DS）和其他引起智力和 发育性残疾（IDD）。正在开发的靶向治疗方法，通常得到动物研究的支持， 有可能正常化，或至少大大减轻，神经生物学，认知和行为 与DS相关的问题。然而，一些对照临床试验集中在DS和其他IDDs（如 脆性X综合征）在过去的十年中已经完成了有限的成功。虽然 药物实际上可能无效或不足以提供临床获益，试验的其他解释 失败包括研究的成年人或青少年的大脑可塑性有限， 模糊活性药物的真正益处，以及对变化不够敏感的结局指标 发生在日常生活中。优化生态上有效、可靠和敏感的结果措施， 条件将有助于评价和确定有效和有临床意义的干预措施。 执行功能障碍（艾德），跨越计划和目标导向行为的过程和行为， 认知灵活性、工作记忆、抑制控制和几种形式的注意力，已经得到强调 由NIH DS工作组和其他研究人员作为试验的关键领域。艾德是 DS的认知表型，是适应功能限制的预测，并可能与 在这一人群中晚期痴呆症的风险。该项目的主要目的是完善和发展初步的 基于智能手机的电子生态瞬时评估（eEMA）的可行性、可靠性和有效性 工具（iBehavior），用于护理人员和教师对日常生活中与艾德相关的行为（家庭和 教室环境）的儿童和青少年与DS和IDD。该项目的第二个目标是 在已经计划和资助的（R 01 HD 076189）双盲安慰剂背景下使用该工具- 哌甲酯缓释剂在儿童和青少年DS和其他疾病中的对照交叉试验 IDD与ADHD的共病。这一目标将决定iBehavior对治疗的敏感性， 与其他评定量表和认知测试相比，对安慰剂效应的易感性。的实证验证 适合在未来DS试验中用作结局指标的eEMA应用程序将在技术上提供 用于家庭和教室环境的新方法，有可能检测治疗相关的 日常生活的变化，实验室检查或回顾性检查可能无法充分捕捉的变化 护理人员问卷调查和访谈。

Abstract There is a growing translational research effort to understand the brain mechanisms of dysfunction in neurodevelopmental disorders including Down syndrome (DS) and other conditions that cause intellectual and developmental disability (IDD). Targeted treatments under development, often supported by animal studies, have the potential to normalize, or at least substantially mitigate, the neurobiological, cognitive, and behavioral problems associated with DS. However, several controlled clinical trials focused on DS and other IDDs (such as fragile X syndrome) in the past decade have been completed with limited success. Although the medications may actually be ineffective or inadequately provide clinical benefit, other explanations for trial failures include limited brain plasticity in the adults or adolescents studied, robust placebo effects that may obscure true benefits of active drug, and outcome measures that are inadequately sensitive to changes occurring in daily life. Optimization of ecologically valid, reliable and sensitive outcome measures for these conditions will facilitate the evaluation and identification of effective and clinically meaningful interventions. Executive dysfunction (ED), spanning processes and behaviors of planning and goal-directed behavior, cognitive flexibility, working memory, inhibitory control, and several forms of attention, has been emphasized by NIH DS working groups and other investigators as a key domain to target in trials. ED is a key component of the cognitive phenotype of DS, is predictive of limitations in adaptive functioning, and may be associated with risk for later dementia in this population. The primary aim of this project is to refine and develop the preliminary feasibility, reliability and validity of a smartphone-based electronic Ecological Momentary Assessment (eEMA) tool (iBehavior) for caregiver and teacher ratings of behaviors associated with ED in the daily lives (home and classroom environments) of children and adolescents with DS and IDD. The second aim of the project is to utilize the tool in the context of an already planned and funded (R01HD076189) double-blind placebo- controlled crossover trial of extended release methylphenidate in children and adolescents with DS and other forms of IDD with comorbid ADHD. This aim will determine iBehavior’s sensitivity to treatment and relative susceptibility to placebo effects compared to other rating scales and cognitive tests. The empirical validation of an eEMA app appropriate for use as an outcome measure in future DS trials will provide a technologically novel method for use in the home and classroom setting that has the potential to detect treatment-related changes in daily life, changes that may not be adequately captured by laboratory tests or retrospective caregiver questionnaires and interviews.