Fragile X Clinic and Reseach Cooperative Consortium Agreement: component C

 描述(申请人提供)：脆性X综合征(FXS)是导致智力残疾和自闭症谱系障碍的最常见遗传原因，估计频率约为1：4000-5000，影响全球所有种族和民族。基础和翻译FXS研究的巨大进步已经确定了许多神经元靶点，并使针对潜在疾病的新治疗方法的早期临床试验成为可能。其中许多药物已经在开放标签和早期阶段试验中显示出有益的信号，但在更大的2b期和3期试验中，由于包括受试者的服药年龄、治疗时间、安慰剂效果以及药物效果的主要结果偏离目标等多个复杂问题，满足主要行为结果一直具有挑战性。一个重要的问题是生物标记物的可用性很差，以及经过良好验证的认知和其他不依赖于父母报告的客观结果衡量标准。此外，为了显示疾病轨迹的变化，有必要进行多年非常长期的治疗，在这段时间内，安慰剂控制是不可能的。为了知道疾病轨迹是否发生了变化，在一大群FXS患者中进行详细的纵向表型分析，包括认知、适应性、语言、运动、行为、社交和生活质量，以确定疾病的自然历史，以便在未来的长期干预研究中进行比较，这是至关重要的。前向纵向数据库跟踪健康、行为和社会问题，包括对大量FXS患者的行为和社会功能的3项标准化衡量标准，但缺乏良好的一致性认知和适应数据。鉴于基础设施已经存在，FORWARD项目是目前唯一可能收集必要的详细纵向表型的地方。因此，通过这项专注于增强测量和参与的应用，我们计划与其他C组FXS诊所合作，扩大队列规模，在这一队列中，我们将在至少3年内每年收集一组全面的结果测量核心指标，以开始定义FXS表型所有方面的纵向轨迹(目标1)。此外，仅在我们的网站上，我们将为两个新的结果测量纵向收集试点数据，这两个新结果测量针对该领域的两个需求领域(目标2)：客观的中枢功能直接测量(听觉事件相关电位)，以及使用FXS(通信复杂性量表)对非常年轻和非语言的个人的交流功能的敏感直接测量。最后，我们将实施计划，根据伊利诺伊州的人口百分比(目标3)，改进从患有FXS的成年人以及从种族和民族群体收集的数据。本项目中收集的数据的分析计划将由FXS成果研究专家和疾控中心合作伙伴审查和修改。本申请中数据收集的分析结果将分发给所有利益攸关方，包括FXCRC、NFXF、FXS社区支持网络小组、FXS家庭、其他研究人员和疾控中心项目合作伙伴。

 DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder with an estimated frequency of about 1:4000-5000, affecting all racial and ethnic groups worldwide. Enormous progress in basic and translational FXS research has identified many neuronal targets and allowed early clinical trials of new treatments targeted to the underlying disease. A number of these agents have shown signal for benefit in open-label and early phase trials, but it has been challenging to meet primary behavioral outcomes in larger phase 2b and 3 trials, due to multiple complex issues including dosing age of subjects, length of treatment, placebo effects, and primary outcome off target for drug effect. A significant problem has been poor availability of biomarkers and well-validated cognitive and other objective outcome measures that do not rely on parent report. Further, very long-term treatment over years, a time frame over which placebo controls are not possible, will be necessary to show changes in the trajectory of disease. In order to know whether the disease trajectory has been changed, it will be CRITICAL to have detailed longitudinal phenotyping including cognitive, adaptive, language, motor, behavioral, social, and quality of life on a large cohort of individuals with FXS, in order to define the naturl history of the disease for future comparison in long-term intervention studies. The FORWARD longitudinal database tracks health, behavior and social issues including 3 standardized measures of behavior and social function in a large cohort of individuals with FXS but lacks good consistent cognitive and adaptive data. Given the infrastructure already present, the FORWARD project is the only currently plausible place to collect the necessary detailed longitudinal phenotyping. Thus, through this application, focused on both enhanced measurement and participation, we plan to collaborate with the other Component C FXS clinics to enhance the cohort size in which we will collect a comprehensive core battery of outcome measures yearly for a minimum of 3 years to begin to define the longitudinal trajectory of all aspects of the FXS phenotype (Aim 1). Additionally at our site alone we will collect pilot data longitudinally for two new outcome measures that address two areas of need in the field (Aim 2): objective direct measures of CNS function (auditory event-related potentials), and sensitive direct measures of communication function in very young and non-verbal individuals with FXS (Communication Complexity Scale). Finally, we will implement plans to improve our collection of this data from adults with FXS and from racial and ethnic groups according to the population percentages from the state of Illinois (Aim 3). Analysis plans for the data collected in this projet will be reviewed and modified by experts in FXS outcomes research and CDC partners. Results of analyses resulting from the data collection in this application will be disseminated to all stakeholders including the FXCRC, NFXF, FXS Community Support Network groups, FXS families, other researchers and CDC project partners.