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

项目总结 本研究的最终目标是提高临床实践水平，加快 通过开发一种评估球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)。根据患者的报告，延髓功能障碍是最令人衰弱的 肌萎缩侧索硬化症的后果，因为它导致无法传达自己的愿望和正常进食，以及 因为它增加了严重医疗并发症的风险，如吸入性肺炎和窒息。 绝大多数被诊断为肌萎缩侧索硬化症的人都经历过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，而且在 肌萎缩侧索硬化症、延髓功能障碍迄今尚未受到足够的研究重视。延髓功能障碍也是 通常不会在临床试验中进行评估，除非患者报告症状。出于这些原因，有 肌萎缩侧索硬化症专家一致认为需要一个客观的临床医生管理的延髓 功能障碍评估工具。 这个项目的总体目标是设计一个有效和可靠的球状马达严重程度评估工具- ALS延髓功能障碍指数(ALS-IBD)。在前期工作中，我们已经取得了专家的共识 关于要包含在工具中的域，然后对文献进行了详尽的采样，确定了 在已确定的领域中评估球运动功能障碍的大量候选项目。我们的 工具开发计划遵循当前的成果衡量标准开发的最佳实践，这些最佳实践具有 确定了以下具体目标：(1)通过调查语音队列进一步提炼候选项目- 语言病理学专家；(2)评估评分员之间和每个项目的重测信度，并减少项目 基于预先设定的信度标准；(3)评价各信度项目的结构效度 在我们之前的工作中建立的工具测量以及ALS-IBD作为一个整体相对于 当前基于症状的标准；以及最后(4)评估ALS-IBD对随时间变化的反应性 以及它在对患者有意义的变化背景下的可解释性。 为了实现这些目标，我们将招募100名被诊断为肌萎缩侧索硬化症的患者，展示一系列的球部 损伤严重程度。为了确定ALS-IBD的内容和表面效度，我们将调查30名专家演讲- 语言病理学家关于语言的内容、可行性、措辞的清晰度和应对方案 候选项目。为了评估评分员间和评分员内的可靠性，我们将多次实施ALS-IBD 在参与者的子集中。为了建立结构效度，单个条目的分数将与 高度敏感的工具性措施，用于标识相对于 它们代表着。工具措施将从运动学分析中提取，并将 语音运动.音节和相关语音任务的声学分析.空气动力学测量 声音和咳嗽；吞咽的视频透视分析。作为结果创建的优化项目集 项目的信度和效度评估将包括ALS-IBD。该工具的最终版本将是 必须重新计算其信度，并评估其相对于症状的结构效度- 基于措施(例如，ALS-功能评定量表-修订)。ALS-IBD还将接受评估，以确定其 使用基线会议和第二次会议之间的分数变化的响应性和可解释性 会议记录在六个月内。 这一努力将产生一种简短、科学有效、廉价、易于使用、由临床医生管理的 评估工具，可用于跟踪ALS诊所的球部疾病进展并作为结果 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.