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

项目摘要 孤独症谱系障碍（ASD）个体之间的显著异质性是一个重要的问题， 自闭症社区。杂合性使得识别核心生物破坏变得困难。它也阻碍了 开发和验证有针对性和持续有效的治疗方法。特别是缺乏 精确的、心理测量学上稳健的、变化敏感的核心精神病学结局指标代表了 临床试验和检测明显症状的潜在机制的关键障碍。这个项目 建议为ASD开发并验证一种创新的新观察员报告措施， 核心症状的异质性沿着积极和消极的维度，类似于那些已经被 成功量化异质性，促进关键的生物学和治疗发现， 精神分裂症使用NIH患者报告结局测量提出的最先进程序 信息系统（PROMIS®）倡议，该项目将开发，校准和验证一个新的工具- ASD阳性和阴性量表（PNI）-用于评估ASD的核心症状， 症状描述和辨别的精确性，沿着概念上新颖的维度。一是我们 初步项目库将根据护理人员和国家专家的关键利益攸关方投入加以完善。接下来， 1，000名3 - 11岁ASD儿童和400名典型发展和非ASD临床对照儿童的照顾者 将完成PNI。将采用经典项目分析和因子分析相结合的方法来确定 最佳表现的项目，然后将使用项目反应理论（IRT）进行校准，并与 遗留措施，以显示PNI项目和规模功能的优越性。基线评估者间和6周 重测信度、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，收敛和发散效度将被测试，并将开发一个简短的形式。 初步数据表明，分析个人行为的效用，目前包含在更大的 分类，分为积极和消极的方面和成功的PROMIS®方法和IRT， 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一个 经过校准和验证的ASD评估工具，其具有一个经过验证的因素结构和项目， 在描述性地捕捉症状方面是精确的，并且对潜在维度的可变性敏感， 在孩子们之间和之间。我们还期望PNI将表现出出色的可靠性和变化敏感性， 为ASD临床试验提供了一个有希望的结果测量。从长远来看，我们希望这项研究能够 具有显著的临床益处，包括：1）提供了一种评估实验治疗的新工具，2） 提供了一个新的框架，在其中测试大脑机制和遗传贡献的特定功能 表现，3）有助于在社区临床中更细致入微地应用靶向治疗 通过提供一种快速、创新、精确和灵敏的方法来量化ASD的异质性。

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.