A Cognitive Test Battery for Intellectual Disabilities

摘要 智力和发育障碍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有针对性的治疗记录正常化， 动物模型中的神经生物学和行为表型是先进的实验 IDD患者的评估，结果测量的局限性以及缺乏共识， 研究人员一直是翻译管道取得进展的主要障碍。事实上， 认为在一些所谓的“失败”中，实验性治疗的真正好处被忽视了 由于对关注疾病的结局指标变化缺乏敏感性，和/或 对掩盖这些潜在的真实的变化的大的安慰剂效应的易感性。过去5 多年来，我们已经取得了实质性的进展，验证了美国国立卫生研究院的 认知成套测验（NIHTB-CB），用作IDDs患者的一组结局指标， 已经产生了坚实的心理测量证据，证明它对高比例的个人有用， 心理年龄在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 对于更严重的受影响者或非常年轻的受影响者来说，不可行或缺乏可接受的心理测量特性 IDD患者-仍然是干预的关键目标的亚组-和组合 没有涵盖可以在开发早期测量的重要领域。第二，当交叉- 截面数据可从电池的规范性样本中获得，NIHTB-CB的纵向轨迹 缺乏缺碘症患者的测试成绩。第三，尽管有证据表明， 发展变化，目前没有数据证明NIHTB-CB对 治疗相关变化。对于当前项目，我们将a）优化NIHTB-CB，以降低 B）完成开发和验证 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 概念形成和算术，c）扩展对NIHTB发展变化的理解- 在患有IDD的儿童和青少年中使用扩展纵向观察的CB测试，以及d）检查 NIHTB-CB检测治疗相关认知变化的初步灵敏度， 随机、双盲、安慰剂对照的兴奋剂（哌甲酯缓释液）试验 IDD + ADHD儿童和青少年。预计这些成功的实现 知识差距将导致一个可扩展的和标准化的认知电池适合广泛的 在该领域的使用和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.