PROMIS-guided development and validation of a dimensional observer-report measure of positive and negative features of ASD

项目总结 自闭症谱系障碍(Asd)个体的显著异质性是面临的一个重要问题。 自闭症社区。异质性使得识别核心生物干扰变得困难。它还阻碍了 开发和验证有针对性的和一贯有效的治疗方法。特别是，缺乏 核心症状学的精确、心理测量学稳健、变化敏感的结果衡量标准代表着 临床试验和检测显性症状潜在机制的关键障碍。这个项目 建议为ASD开发和验证一项创新的新观察员报告措施，试图捕获 核心症状在积极和消极维度上的异质性，类似于 成功地量化了异质性并促进了关键的生物学和治疗发现 精神分裂症。使用由NIH患者报告的结果测量提出的最先进的程序 信息系统(PROIS®)计划，该项目将开发、校准和验证一个新工具-- ASD阳性和阴性清单(PNI)-用于评估ASD核心症状，具有前所未有的 症状描述和辨别的精确度，以及概念上的新维度。首先，我们的 初步项目库将根据主要利益攸关方来自照顾者和国家专家的意见进行完善。下一首, 1,000名患有自闭症的3-11岁儿童和400名典型的发展中和非自闭症临床对照儿童的照顾者 将完成PNI。将使用经典项目分析和因子分析相结合的方法来确定 表现最佳的项目，然后将使用项目反应理论(IRT)进行校准，并与 遗留措施，展示PNI项目和规模功能的优越性。基准评价员间和6周 重测可靠性、24周变化敏感度和即将进行的临床试验的敏感度 将进行评估，将测试收敛和发散效度，并将开发一种简短的形式。 初步数据显示了分析个人行为的效用，目前包含在更大的 分类，分为积极和消极两个维度，以及PROMIS®方法和IRT的成功 为ASD开发敏感工具。我们预计，这项创新的、科学严谨的研究将导致 经过校准和验证的ASD评估工具，具有经验支持的因素结构和条目， 在对症状的描述性捕捉方面都是精确的，并且对潜在维度中的变化敏感， 在儿童内部和儿童之间。我们还预计PNI将表现出极好的可靠性和变化敏感度， 为ASD临床试验提供了一种有希望的结果衡量标准。从长远来看，我们预计这项研究将 有显著的临床益处，包括：1)提供了评估实验疗法的新工具，2) 提供了一个新的框架，在其中测试大脑机制和基因对特定功能的贡献 表现，以及3)有助于在社区临床中更微妙地应用靶向治疗 通过提供一种快速、创新、准确和灵敏的方法来量化ASD中的异质性进行实践。

PROJECT SUMMARY Marked heterogeneity among individuals with autism spectrum disorder (ASD) is a significant problem facing the autism community. Heterogeneity makes it difficult to identify core biological disruptions. It also hampers the development and validation of targeted and consistently effective therapeutics. In particular, the lack of precise, psychometrically robust, change sensitive outcome measures for core symptomatology represents a key barrier for clinical trials and for detecting mechanisms underlying manifest symptoms. This project proposes to develop and validate an innovative new observer report measure for ASD that attempts to capture heterogeneity in core symptoms along positive and negative dimensions, akin to those that have been successful in quantifying heterogeneity and facilitating key biological and therapeutic discoveries in schizophrenia. Using state-of-the-art procedures put forth by the NIH Patient-Reported Outcome Measurement Information System (PROMIS®) initiative, this project will develop, calibrate, and validate a new tool - the Positive and Negative Inventory for ASD (PNI) - for assessing core ASD symptoms with unprecedented precision of symptom description and discrimination, along conceptually novel dimensions. First, our preliminary item pool will be refined with key stakeholder input from caregivers and national experts. Next, caregivers of 1,000 3-11 year old children with ASD and 400 typically developing and non-ASD clinical controls will complete the PNI. A combination of classical item analysis and factor analysis will be used to identify the best-performing items, which will then be calibrated using Item Response Theory (IRT) and co-calibrated with legacy measures to demonstrate superiority of PNI item and scale function. Baseline inter-rater and 6-week test-retest reliability, 24-week change sensitivity, and sensitivity in the context of an upcoming clinical trial all will be assessed, both convergent and divergent validity will be tested, and a short form will be developed. Preliminary data demonstrate both the utility of parsing individual behaviors, currently subsumed within larger categories, into positive and negative dimensions and the success of PROMIS® methods and IRT for developing sensitive tools for ASD. We anticipate that this innovative, scientifically rigorous study will result in a calibrated and validated assessment tool for ASD with an empirically-supported factor structure and items that are both precise in their descriptive capturing of symptoms and sensitive to variability in the latent dimensions, within and across children. We also expect that the PNI will show excellent reliability and change sensitivity, offering a promising outcome measure for use in ASD clinical trials. Long term, we expect this research to have significant clinical benefits, including: 1) offering a new tool for assessing experimental therapeutics, 2) providing a new framework within which to test brain mechanisms and genetic contributions to specific feature manifestations, and 3) contributing to more nuanced application of targeted treatment in community clinical practice by offering a rapid, innovative, precise, and sensitive way to quantify heterogeneity in ASD.