The development and validation of a novel tool for the assessment of bulbar dysfunction in ALS

项目摘要 本研究的最终目的是提高临床实践水平，加快 通过开发评估延髓功能障碍进展的临床工具进行治疗试验 肌萎缩侧索硬化症（ALS）。根据患者报告，延髓功能障碍是最令人衰弱的 ALS的后果，因为它导致无法传达一个人的愿望和正常饮食， 因为它增加了严重的医疗并发症的风险，如吸入性肺炎和窒息。 绝大多数被诊断患有ALS的人经历肌肉运动功能的丧失 负责说话和吞咽。尽管它对生活质量有重大影响， ALS，延髓功能障碍迄今尚未得到足够的研究关注。延髓功能障碍也是 通常不在临床试验中评估，除了患者的症状报告。由于这些原因， ALS专家强烈同意需要客观的临床医生管理的延髓 功能障碍评估工具。 本项目的总体目标是设计一个有效和可靠的延髓运动严重程度评估工具- 延髓功能障碍的ALS指数（ALS-IBD）。在我们的前期工作中， 关于要包括在工具中的领域，然后详尽地抽样文献， 大量的候选项目，用于评估延髓运动功能障碍跨所确定的领域。我们 工具开发计划遵循当前成果衡量开发的最佳实践， 确定了以下具体目标：（1）通过调查一组语音，进一步细化候选项- 语言病理学专家;（2）评估各项目的评分员间信度和重测信度，并减少项目 （3）评价各信度项目相对于 工具措施建立在我们以前的工作和有效性的ALS-IBD作为一个整体相对于 最后（4）估计ALS-IBD随时间变化的响应性 以及它在对患者有意义的变化的背景下的可解释性。 为了实现这些目标，我们将招募100名被诊断患有ALS的人，他们表现出一系列的延髓病变。 损伤严重程度。为了建立ALS-IBD的内容效度和表面效度，我们将调查30名专家演讲- 语言病理学家关于内容，可行性，措辞的清晰度，和响应选项， 候选项。为了评估评估者间和评估者内的可靠性，我们将多次使用ALS-IBD 参与者的一个子集。为了建立结构效度，将单个项目得分与 高度敏感的工具性措施，以确定最有效的结构， 他们代表。仪器测量将从运动学分析中提取， 语言运动.音节和连接语言任务的声学分析.空气动力学测量 声音和咳嗽;以及吞咽的视频透视分析。因此创建的优化项集 的项目的信度和效度评价将包括ALS-IBD。该工具的最终版本将是 重新计算其可靠性并评估其相对于症状的结构效度- 基于测量（例如，ALS功能评定量表-修订版）。ALS-IBD还将评估其 反应性和可解释性，使用基线会话和第二次会话之间的分数变化 六个月内记录的会话。 这一努力将产生一个简短的，科学有效的，廉价的，易于使用的，临床医生管理 评估工具，可用于在ALS诊所跟踪延髓疾病进展，并作为一种结果 在临床试验中进行测量。

PROJECT SUMMARY The ultimate goal of this research is to improve clinical practice standards and expedite the pace of therapeutic trials through the development of a clinical tool for assessing the progression of bulbar dysfunction in amyotrophic lateral sclerosis (ALS). As per patient reports, bulbar dysfunction is the most debilitating consequence of ALS, because it leads to the inability to communicate one’s wishes and to eat normally, and because it increases the risk of serious medical complications such as aspiration pneumonia and choking. The great majority of persons diagnosed with ALS experience the loss of motor function in the muscles responsible for speaking and swallowing. Despite its significant impact on quality of life and widespread in ALS, bulbar dysfunction has not received sufficient research attention to date. Bulbar dysfunction is also typically not assessed in clinical trials, beyond a patient report of symptoms. For these reasons, there is strong agreement among the ALS experts on the need for an objective clinician-administered bulbar dysfunction assessment tool. The overall goal of this project is to design a valid and reliable bulbar motor severity assessment tool - the ALS Index of Bulbar Dysfunction (ALS-IBD). In our preliminary work, we have obtained expert consensus regarding the domains to be included in the tool and then exhaustively sampled the literature identifying a large number of candidate items for assessing bulbar motor dysfunction across the identified domains. Our tool development plan adheres to the current best practices for outcome measure development, which have determined the following specific aims: (1) further refine the candidate items by surveying a cohort of speech- language pathology experts; (2) evaluate inter-rater and test-retest reliability of each item and reduce items based on the pre-set reliability criterion; (3) evaluate construct validity of each reliable item relative to the instrumental measures established in our prior work and the validity of the ALS-IBD as a whole relative to the current symptom-based standards; and finally (4) estimate the ALS-IBD’s responsiveness to change over time and its interpretability in the context of changes that are meaningful to the patients. To achieve these aims, we will recruit 100 people diagnosed with ALS, presenting with a range of bulbar impairment severity. To establish content and face validity of ALS-IBD, we will survey 30 expert speech- language pathologists regarding the content, feasibility, clarity of wording, and response options of the candidate items. To estimate inter-rater and intra-rater reliability, we will administer the ALS-IBD multiple times in a subset of participants. To establish construct validity, the individual item scores will be correlated with the highly sensitive instrumental measures to identify items that are most valid with respect to the constructs that they represent. The instrumental measures will be extracted from the kinematic analyses of oromotor and speech movements; acoustic analyses of syllables and connected speech tasks; aerodynamic measures of voice and cough; and the videofluoroscopic analysis of swallowing. The optimized item set created as a result of the item reliability and validity evaluations will comprise the ALS-IBD. The final version of the tool will be subjected to recalculation of its reliability and the assessment of its construct validity relative to the symptom- based measures (e.g. ALS-Functional Rating Scale – Revised). The ALS-IBD will also be assessed for its responsiveness and interpretability using the change in scores between the baseline session and a second session recorded in six months. This effort will yield a brief, scientifically valid, inexpensive, easy-to-use, clinician-administered assessment tool that can be used to track bulbar disease progression in ALS clinics and as an outcome measure in clinical trials.