Abstract
Rationale: A model for stratifying progression of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) would identify disease mechanisms and phenotypes suitable for future investigations. This study sought to categorize progression of FVC after presentation to an outpatient ALS clinic.Objectives: To identify clinical phenotypes of ALS respiratory progression based on FVC trajectories over time.Methods: We derived a group-based trajectory model from a single-center cohort of 837 patients with ALS who presented between 2006 and 2015. We applied our model to the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7,461 patients with ALS. Baseline characteristics at first visit were used as predictors of trajectory group membership. The primary outcome was trajectory of FVC over time in months.Measurements and Main Results: We found three trajectories of FVC over time, termed "stable low," "rapid progressor," and "slow progressor." Compared with the slow progressors, the rapid progressors had shorter diagnosis delay, more bulbar-onset disease, and a lower ALS Functional Rating Scale-Revised (ALSFRS-R) total score at baseline. The stable low group had a shorter diagnosis delay, lower body mass index, more bulbar-onset disease, lower ALSFRS-R total score, and were more likely to have an ALSFRS-R orthopnea score lower than 4 compared with the slow progressors. We found that projected group membership predicted respiratory insufficiency in the PRO-ACT cohort (concordance statistic = 0.78, 95% CI, 0.76-0.79).Conclusions: We derived a group-based trajectory model for FVC progression in ALS, which validated against the outcome of respiratory insufficiency in an external cohort. Future studies may focus on patients predicted to be rapid progressors.