Time‐to‐Event Analysis of Clinical Milestones in the ALS Natural History Consortium Dataset

INTRODUCTION/AIMS: Study of clinical milestones, particularly intermediate events like loss of ambulation, in large amyotrophic lateral sclerosis (ALS) cohorts is limited. Here, we leverage the ALS Natural History Consortium dataset to evaluate the time-to-event for several outcomes and prognostic factors that predict risk. METHODS: Longitudinal data from 1950 participants were used in time-to-event analyses based on time from diagnosis. Outcomes were gastrostomy, loss of ambulation, loss of useful speech, non-invasive ventilation (NIV) usage, and death equivalent (death or mechanical ventilation). Median times-to-event were calculated along with Kaplan-Meier curves. Cox proportional hazards models for each outcome estimated (through adjusted hazard ratios [HR]) the impact of several prognostic factors, including sex, region of onset, age at diagnosis, and the initial rate of change (delta-FRS) in ALS Functional Rating Scale-Revised (ALSFRS-R) scores. RESULTS: Estimated median times-to-event for clinical outcomes ranged from 1.44 to 6.21 years, with a median time to death equivalent of 2.12 years. A higher delta-FRS was the greatest risk factor for all outcomes (HRs between 2.01 and 3.05). Limb onset decreased risk of loss of speech, NIV use, gastrostomy, and death equivalent (HRs 0.41-0.78). Older age at diagnosis increased risk of gastrostomy, NIV use, and death equivalent (HRs 1.08-1.27). DISCUSSION: These findings further inform expectations of time to various outcomes, especially rarely investigated intermediate events, and their risk factors. The importance of progression rate supports other recent findings, highlighting delta-FRS as a key prognostic factor with potential utility in clinical trial designs.

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Journal
Muscle & Nerve
Published
2026-10-27
DOI
https://doi.org/10.1002/mus.70440
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
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article

Time‐to‐Event Analysis of Clinical Milestones in the ALS Natural History Consortium Dataset

Terry D Heiman-Patterson, Andrés Arguedas, Mark Joseph A. Fiecas, Tawfiq Al-Lahham et al.
Muscle & Nerve
Amyotrophic Lateral Sclerosis Research
article

Time‐to‐Event Analysis of Clinical Milestones in the ALS Natural History Consortium Dataset

Terry D Heiman-Patterson, Andrés Arguedas, Mark Joseph A. Fiecas, Tawfiq Al-Lahham, Kelly Graham Gwathmey, Nicholas T. Olney, Ximena Arcila-Londono, Erjia Cui, Ghazala R. Hayat, Annette Xenopoulos-Oddsson, Mehdi Ghasemi, David Walk, Alexander V. Sherman, Senda Ajroud‐Driss, Kelly A. Duffy, James P. Wymer, Christian Lunetta, Federica Cerri, David D. Schneck
article en

Abstract

INTRODUCTION/AIMS: Study of clinical milestones, particularly intermediate events like loss of ambulation, in large amyotrophic lateral sclerosis (ALS) cohorts is limited. Here, we leverage the ALS Natural History Consortium dataset to evaluate the time-to-event for several outcomes and prognostic factors that predict risk. METHODS: Longitudinal data from 1950 participants were used in time-to-event analyses based on time from diagnosis. Outcomes were gastrostomy, loss of ambulation, loss of useful speech, non-invasive ventilation (NIV) usage, and death equivalent (death or mechanical ventilation). Median times-to-event were calculated along with Kaplan-Meier curves. Cox proportional hazards models for each outcome estimated (through adjusted hazard ratios [HR]) the impact of several prognostic factors, including sex, region of onset, age at diagnosis, and the initial rate of change (delta-FRS) in ALS Functional Rating Scale-Revised (ALSFRS-R) scores. RESULTS: Estimated median times-to-event for clinical outcomes ranged from 1.44 to 6.21 years, with a median time to death equivalent of 2.12 years. A higher delta-FRS was the greatest risk factor for all outcomes (HRs between 2.01 and 3.05). Limb onset decreased risk of loss of speech, NIV use, gastrostomy, and death equivalent (HRs 0.41-0.78). Older age at diagnosis increased risk of gastrostomy, NIV use, and death equivalent (HRs 1.08-1.27). DISCUSSION: These findings further inform expectations of time to various outcomes, especially rarely investigated intermediate events, and their risk factors. The importance of progression rate supports other recent findings, highlighting delta-FRS as a key prognostic factor with potential utility in clinical trial designs.

Muscle & Nerve
Northwestern University (US), Lahey Hospital and Medical Center (US), University of Minnesota (US), Henry Ford Health System (US), University of Pittsburgh (US), Virginia Commonwealth University (US), University of Florida Health (US), Providence Portland Medical Center (US), Henry Ford Hospital (US), University of Florida (US), Massachusetts General Hospital (US), Istituti Clinici Scientifici Maugeri (IT), Lahey Medical Center (US), Centro Clinico Nemo (IT), Saint Louis University (US), Virginia Commonwealth University Medical Center (US), Temple University (US)
Openalex Percentile: Top 13%
Amyotrophic Lateral Sclerosis Research
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