{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T07:57:08Z","timestamp":1778399828992,"version":"3.51.4"},"reference-count":40,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000030","name":"Centers for Disease Control and Prevention","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000030","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease that typically results in death within 3\u20135\u2009years 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\u2014the United States' National ALS Registry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Incident ALS cases, defined as confirmed and likely, cases between 2012 and 2019 were obtained from the National ALS Registry. Age\u2010standardized 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Findings<\/jats:title><jats:p>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 (<jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090.99), for men (<jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090.99), and for women (<jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090.98). The incidence slope estimates were 4.8 (95% CI: 4.4\u20135.1) overall, 4.7 (95% CI: 4.4\u20135.1) for men, and 5.0 (95% CI: 4.5\u20135.5) for women.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>The linear relationships observed overall, for men, and for women are consistent with a multi\u2010step process. The slope estimates, on average, are approximately 5.0, which suggests that the development of ALS is a six\u2010step process. Further investigation of these steps can elucidate potential risk factors and treatments for ALS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70096","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T20:38:47Z","timestamp":1753216727000},"page":"1858-1864","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Amyotrophic Lateral Sclerosis as a Multistep Process in the United States: A Population\u2010Based Study"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3903-6460","authenticated-orcid":false,"given":"Jasmine","family":"Berry","sequence":"first","affiliation":[{"name":"Office of Innovation and Analytics Agency for Toxic Substances and Disease Registry\/Centers for Disease Control and Prevention  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5594-6931","authenticated-orcid":false,"given":"Jaime","family":"Raymond","sequence":"additional","affiliation":[{"name":"Office of Innovation and Analytics Agency for Toxic Substances and Disease Registry\/Centers for Disease Control and Prevention  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4719-4829","authenticated-orcid":false,"given":"Theodore","family":"Larson","sequence":"additional","affiliation":[{"name":"Office of Innovation and Analytics Agency for Toxic Substances and Disease Registry\/Centers for Disease Control and Prevention  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6214-6687","authenticated-orcid":false,"given":"D. Kevin","family":"Horton","sequence":"additional","affiliation":[{"name":"Office of Innovation and Analytics Agency for Toxic Substances and Disease Registry\/Centers for Disease Control and Prevention  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2246-3618","authenticated-orcid":false,"given":"Moon","family":"Han","sequence":"additional","affiliation":[{"name":"Office of Innovation and Analytics Agency for Toxic Substances and Disease Registry\/Centers for Disease Control and Prevention  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3515-6011","authenticated-orcid":false,"given":"Theresa","family":"Nair","sequence":"additional","affiliation":[{"name":"Office of Innovation and Analytics Agency for Toxic Substances and Disease Registry\/Centers for Disease Control and Prevention  Atlanta Georgia 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