Fragile X Clinic and Reseach Cooperative Consortium Agreement: component C

 描述（由申请人提供）：脆性X综合征（FXS）是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。基础和转化FXS研究的巨大进展已经确定了许多神经元靶点，并允许针对潜在疾病的新疗法的早期临床试验。这些药物中的许多药物在开放标签和早期试验中显示出获益信号，但由于多种复杂问题，包括受试者的给药年龄、治疗时间、安慰剂效应和药物效应的主要结局脱靶，在较大的2b期和3期试验中满足主要行为结局一直具有挑战性。一个重要的问题是生物标志物和有效的认知和其他不依赖于父母报告的客观结果测量的可用性差。此外，需要多年的长期治疗，在此期间不可能进行安慰剂对照，以显示疾病轨迹的变化。为了了解疾病轨迹是否已经改变，关键是要对FXS患者的大型队列进行详细的纵向表型分析，包括认知、适应、语言、运动、行为、社会和生活质量，以确定疾病的自然史，以便在长期干预研究中进行比较。FORWARD纵向数据库跟踪健康，行为和社会问题，包括FXS患者的大型队列中的行为和社会功能的3个标准化指标，但缺乏良好的一致性认知和适应性数据。鉴于已经存在的基础设施，FORWARD项目是目前唯一可行的收集必要的详细纵向表型的地方。因此，通过这一应用程序，重点是增强测量和参与，我们计划与其他组件C FXS诊所合作，以增加队列规模，我们将每年收集一组全面的核心结局指标，至少持续3年，以开始定义FXS表型所有方面的纵向轨迹（目标1）。此外，仅在我们的研究中心，我们将纵向收集两个新的结果指标的试点数据，解决两个领域的需要（目标2）：客观的直接测量CNS功能（听觉事件相关电位），和敏感的直接测量沟通功能的非常年轻和非语言的个人与FXS（沟通复杂性量表）。最后，我们将实施计划，以改善我们从FXS成年人以及根据伊利诺伊州人口百分比（目标3）的种族和民族群体中收集的数据。本项目中收集的数据的分析计划将由FXS结果研究专家和CDC合作伙伴进行审查和修改。本应用程序中数据收集的分析结果将分发给所有利益相关者，包括FXCRC、NFXF、FXS社区支持网络团体、FXS家庭、其他研究人员和CDC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.