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

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.

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.

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).

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.