Time-to-Event Analysis of Clinical Milestones in the ALS/MND Natural History Consortium Dataset

Document Type

Conference Proceeding

Publication Date

10-6-2025

Publication Title

Muscle Nerve

Abstract

Background: Understanding ALS disease progression, and factors influencing the risk of specific outcomes, can inform clinical decision making and optimize clinical trial design. However, study of disease course in real-world ALS cohorts is limited. Here, we leverage the ALS/MND Natural History Consortium (NHC) dataset to calculate the median time-to-event for several clinical outcomes and evaluate the impact of prognostic factors on predicted risk. Methods: Longitudinal data from 2744 participants in the NHC dataset were used in time-to-event analyses based on time since diagnosis. Overall survival was considered along with gastrostomy and four intermediate outcomes determined from ALSFRS-R scores: loss of ambulation, loss of useful speech, non-invasive ventilation (NIV) usage, and continuous NIV usage. The median time-to-event was calculated along with traditional Kaplan-Meier curves. Cox proportional hazards models were then fit for each outcome to determine the impact of several prognostic factors: biological sex, riluzole use, race, onset location, diagnostic delay, age at diagnosis, baseline ALSFRS-R subscores, and the initial rate of change (slope) in ALSFRS-R scores. Adjusted hazard ratios (HR) were estimated for each factor. Results: Median times for intermediate outcomes ranged from 0.863 years from diagnosis for NIV usage to 2.997 years for continuous NIV usage, with a median time to death of 1.995 years. A higher slope was the greatest risk factor for all outcomes (HRs between 2.44 and 5.12), and an older age at diagnosis increased risk of loss of ambulation, gastrostomy, NIV use, and death (HRs 1.18–1.44). Limb onset decreased risk for loss of speech, gastrostomy, and NIV use (HRs 0.54–0.76), but increased risk for loss of ambulation (HR=1.27). White (relative to non-white) participants had decreased risk for loss of ambulation (HR=0.69) and continuous NIV use (HR=0.71), while females had increased risk for loss of speech (HR=1.52) and gastrostomy (HR=1.22). Discussion: Our findings from a large, population-based natural history sample provide insights into the typical course of ALS disease progression. The results also demonstrate that certain factors can be expected to affect the risk of certain intermediate events, which may refine clinical decision making.

Volume

72

First Page

S97

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