A Cognitive Test Battery for Intellectual Disabilities

摘要 智力和发育障碍(IDDS)的基础科学和临床前研究 超过了人类临床治疗反应测量工具的开发和验证 审判。虽然越来越多的靶向治疗被记录为正常化 动物模型的神经生物学和行为表型可用于实验 对患有IDDS的人类的评估、结果测量的局限性和缺乏共识 调查人员一直是翻译管道取得进展的主要障碍。事实上，它一直是 认为试验性治疗的真正好处在一些所谓的“失败”中被忽略了 试验“由于对利益紊乱的结果衡量标准的变化缺乏敏感性，和/或 容易受到大的安慰剂效应的影响，掩盖了这些潜在的真实变化。在过去5年中 多年来，我们在验证国家卫生研究院工具箱方面取得了实质性进展 认知成套测验(NIHTB-CB)，用于IDDS和IDDS患者的一套结果测量 已经产生了确凿的心理测量学证据，证明它对高比例的有 精神年龄在5岁或以上。尽管取得了这些重要进展，但我们的工作也突出了 关键的知识差距和潜在的解决方案。首先，一些已建立的NIHTB-CB测试是 对于受影响更严重的或非常年轻的人来说，不可行或缺乏可接受的心理测量学特性 患有IDD的人-仍然是干预的关键目标的亚群-而电池确实做到了 没有涵盖可以在开发早期进行测量的重要领域。第二，在交叉的同时- 截面数据来自电池的标准样品，NIHTB-CB的纵向轨迹 IDD患者的考试成绩不得而知。第三，尽管有证据表明对 发育变化，目前还没有数据表明NIHTB-CB对 与治疗相关的变化。对于当前项目，我们将a)优化NIHTB-CB以降低 患有中度和重度缺碘的有功能的个人，b)完全发展和确认 新的NIHTB-CB测试，以填补目前尚未评估的认知结构的关键空白，包括 概念形成和数字能力，c)扩展对NIHTB的发展变化的理解-- 在患有IDD的儿童和青年中使用扩展的纵向观察进行CB测试，以及d)检查 NIHTB-CB对检测治疗相关认知改变的初步敏感性 安慰剂对照兴奋剂(哌醋甲酯缓释液)随机双盲试验 在患有IDD和ADHD的儿童和青少年中。预计这些目标的成功实现 知识空白将导致可扩展和标准化的认知电池，适合广泛应用 在现场使用和FDA注册的考虑。

Abstract The basic science and preclinical studies of intellectual and developmental disabilities (IDDs) have outpaced the development and validation of tools to measure treatment response in human clinical trials. While an ever-increasing number of targeted treatments documented to normalize neurobiological and behavioral phenotypes in animal models are advanced for experimental evaluation in humans with IDDs, limitations of outcome measures and lack of consensus among investigators have been major barriers to progress in the translational pipeline. In fact, it has been argued that true benefits of experimental treatments have been missed in some so-called “failed trials” due to lack of sensitivity to change in the outcome measures for the disorder of interest, and/or susceptibility to large placebo effects that obscure these potentially real changes. For the past 5 years we have made substantial progress validating the National Institutes of Health Toolbox Cognitive Battery (NIHTB-CB) for use as a set of outcome measures for individuals with IDDs and have generated solid psychometric evidence of its utility for a high proportion of individuals with mental ages at or above 5 years. Despite these important advances, our work has also highlighted critical knowledge gaps, and potential solutions. First, some of the established NIHTB-CB tests were not feasible or lacked acceptable psychometric properties for more severely affected or very young individuals with IDD – subgroups that remain critical targets for intervention – and the battery does not cover important domains which can be measured very early in development. Second, while cross- sectional data is available from the battery’s normative sample, longitudinal trajectories of NIHTB-CB test scores among people with IDD are not available. And third, despite evidence of sensitivity to developmental changes, there are currently no data to demonstrate that the NIHTB-CB is sensitive to treatment-related change. For the current project we will a) optimize the NIHTB-CB for lower functioning individuals with moderate and severe IDD, b) complete development and validation of new NIHTB-CB tests to fill critical gaps in cognitive constructs not currently assessed, including Concept Formation and Numeracy, c) extend understanding of developmental changes in the NIHTB- CB tests using expanded longitudinal observations in children and youth with IDD, and d) examine the preliminary sensitivity of the NIHTB-CB to detect treatment-related cognitive changes utilizing a randomized, double-blind placebo-controlled stimulant (methylphenidate extended release liquid) trial in children and adolescents with IDD + ADHD. It is anticipated that successful fulfillment of these knowledge gaps will result in a scalable and standardized cognitive battery suitable for widespread use in the field and consideration for FDA registration.