Development of a General Composite Scale (GENCOMS) for Progressive Neurodegenerative Diseases and Implications for the Assessment of Disease-Modifying Therapies.

IF 3.9 3区医学 Q1 CLINICAL NEUROLOGY

Neurology and Therapy Pub Date : 2024-12-01 Epub Date: 2024-09-17 DOI:10.1007/s40120-024-00661-2

Samuel P Dickson, Craig H Mallinckrodt, Basia Rogula, Lauren C Powell, Michele H Potashman, Vladimir Coric, Gilbert J L'Italien, Suzanne B Hendrix

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引用次数: 0

Abstract

Introduction: The reliable assessment of treatment outcomes for disease-modifying therapies (DMT) in neurodegenerative disease is challenging. The objective of this paper is to describe a generalized framework for developing composite scales that can be applied in diverse, degenerative conditions, termed "GENCOMS." Composite scales optimize the sensitivity for detecting clinically meaningful effects that slow disease progression.

Methods: The GENCOMS method relies on robust natural history data and/or placebo arm data from DMT trials. Validated scales that are core to the disease process have been identified, and item level data obtained to standardize the response outcomes from 0 (best possible score) to 1 (worst possible score). A partial least squares regression analysis was conducted with temporal change as the dependent variable and change scores in standardized items as the explanatory variables. The derived model coefficients constitute a weighted sum of items that most effectively measure disease progression.

Results: The resultant composite scale was optimized to detect disease progression and can be examined in a range of slow or fast progressing populations. The scale can be used in studies with comparable patient populations as an endpoint optimized to measure disease progression and therefore ideally suited to assess treatment effects in DMTs.

Conclusion: The methodology presented here provides a generalizable framework for developing composite scales in the assessment of neurodegenerative disease progression and evaluation of DMT effects. By objectively selecting and weighting items from previously validated measures based solely on their sensitivity to disease progression, this methodology allows for the creation of a more responsive measurement of clinical decline. This heightened sensitivity to clinical decline can be utilized to detect modest yet meaningful treatment effects in the early stages of neurogenerative diseases, when it is optimal to begin a DMT.

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针对渐进性神经退行性疾病的通用综合量表（GENCOMS）的开发及其对疾病调整疗法评估的影响。

导言：对神经退行性疾病的疾病修饰疗法（DMT）的治疗效果进行可靠评估是一项挑战。本文旨在描述一个通用框架，用于开发可应用于各种退行性疾病的复合量表，称为 "GENCOMS"。复合量表可优化检测具有临床意义的效应的灵敏度，从而减缓疾病的进展：GENCOMS方法依赖于DMT试验中可靠的自然病史数据和/或安慰剂组数据。经过验证的量表是疾病进程的核心，已确定的量表和项目级数据可将反应结果从 0（最佳得分）标准化为 1（最差得分）。以时间变化为因变量，以标准化项目的变化分数为解释变量，进行了偏最小二乘法回归分析。得出的模型系数构成了最有效衡量疾病进展的项目加权总和：结果：由此产生的复合量表在检测疾病进展方面进行了优化，可在一系列进展缓慢或快速的人群中进行检测。该量表可用于具有可比患者群体的研究中，作为衡量疾病进展的优化终点，因此非常适合评估DMTs的治疗效果：本文介绍的方法为神经退行性疾病进展评估和DMT疗效评估提供了一个可推广的复合量表开发框架。该方法仅根据项目对疾病进展的敏感性，客观地从以前验证过的量表中选择项目并对其进行加权，从而创建出对临床衰退反应更灵敏的量表。在神经退行性疾病的早期阶段，也就是开始使用 DMT 的最佳时机，可以利用这种对临床衰退的高度敏感性来检测适度但有意义的治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurology and Therapy CLINICAL NEUROLOGY-

CiteScore

5.40

自引率

8.10%

发文量

103

审稿时长

6 weeks

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