Berry Jasmine, Raymond Jaime, Larson Theodore, Horton D Kevin, Han Moon, Nair Theresa, Al-Chalabi Ammar, Mehta Paul
Office of Innovation and Analytics, Agency for Toxic Substances and Disease Registry/Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
Ann Clin Transl Neurol. 2025 Sep;12(9):1858-1864. doi: 10.1002/acn3.70096. Epub 2025 Jul 22.
Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease that typically results in death within 3-5 years from symptom onset. However, little is known about the environmental exposures, clinical aspects, or social determinants of health factors that may be associated with the disease. Multistep modeling has been previously applied to cancer research, demonstrating a linear relationship between logs of incidence and age. This method may help to understand the mechanisms involved in the development of ALS in the United States (e.g., environmental exposures, genetic mutations). We aim to assess whether ALS is a multistep process among patients enrolled in the largest ALS registry in the world-the United States' National ALS Registry.
Incident ALS cases, defined as confirmed and likely, cases between 2012 and 2019 were obtained from the National ALS Registry. Age-standardized incidence was calculated for all cases and by sex. The log incidence of ALS was regressed against the log of age (years) at case determination, on average, for each year and by sex.
Between 2012 and 2019, there was a mean of 5253 incident ALS cases (confirmed or likely) per year. We identified a linear relationship between the log of the average incidence and log age overall (r = 0.99), for men (r = 0.99), and for women (r = 0.98). The incidence slope estimates were 4.8 (95% CI: 4.4-5.1) overall, 4.7 (95% CI: 4.4-5.1) for men, and 5.0 (95% CI: 4.5-5.5) for women.
The linear relationships observed overall, for men, and for women are consistent with a multi-step process. The slope estimates, on average, are approximately 5.0, which suggests that the development of ALS is a six-step process. Further investigation of these steps can elucidate potential risk factors and treatments for ALS.
肌萎缩侧索硬化症（ALS）是一种致命的进行性神经退行性疾病，通常在症状出现后3至5年内导致死亡。然而，对于可能与该疾病相关的环境暴露、临床特征或健康因素的社会决定因素知之甚少。多步骤建模先前已应用于癌症研究，显示出发病率对数与年龄之间存在线性关系。这种方法可能有助于了解美国ALS发病机制（例如，环境暴露、基因突变）。我们旨在评估ALS在世界上最大的ALS登记处——美国国家ALS登记处登记的患者中是否为多步骤过程。
从国家ALS登记处获取2012年至2019年期间确诊和疑似的ALS发病病例。计算所有病例以及按性别划分的年龄标准化发病率。将ALS的发病率对数与确诊时年龄（岁）的对数进行回归分析，每年和按性别分别进行。
2012年至2019年期间，每年平均有5253例ALS发病病例（确诊或疑似）。我们确定了总体平均发病率对数与年龄对数之间存在线性关系（r = 0.99），男性（r = 0.99）和女性（r = 0.98）亦是如此。总体发病率斜率估计值为4.8（95%置信区间：4.4 - 5.1），男性为4.7（95%置信区间：4.4 - 5.1），女性为5.0（95%置信区间：4.5 - 5.5）。
总体、男性和女性中观察到的线性关系与多步骤过程一致。平均斜率估计值约为5.0，这表明ALS的发展是一个六步骤过程。对这些步骤的进一步研究可以阐明ALS的潜在风险因素和治疗方法。
