Related Experiment Video
Updated: Sep 2, 2026
A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
Data-Driven SuStaIn Model of Disability Progression in Amyotrophic Lateral Sclerosis
Giammarco Milella1, Veria Vacchiano2, Vittorio Velucci1
1Neurology and Stroke Unit "F.M. Puca", University Hospital AOU Consorziale Policlinico, Bari, Italy.
Objective:
To determine whether ordinal Subtype and Stage Inference (SuStaIn) applied to routine ALSFRS-R item scores can identify reproducible disability progression patterns in amyotrophic lateral sclerosis (ALS) and provide clinically meaningful staging.
Methods:
We analysed baseline ALSFRS-R item responses from 866 PRO-ACT participants. Ordinal SuStaIn inferred subtype-specific sequences of functional deterioration and assigned each participant to a subtype and a SuStaIn-derived functional stage. Longitudinal stability was assessed across 3625 consecutive follow-up visit pairs from 697 participants. Structural reproducibility was evaluated in an independent cohort of 301 consecutive ALS patients. Associations of baseline subtype and stage with survival and subsequent ALSFRS-R decline were examined using Cox and piecewise-linear models.
Results:
A three-subtype solution identified fine motor-, gross motor- and bulbar-predominant patterns of early disability. Within each subtype, SuStaIn reconstructed ordered multidomain sequences of functional deterioration and assigned each participant a SuStaIn-derived stage. Subtype assignment was stable across 90.4% of consecutive visit pairs, and stage was non-decreasing in 98.8%. Subtype-specific event ordering was reproduced in the validation cohort. Higher baseline stage was associated with increased mortality risk in the fine motor- and gross motor-predominant subtypes, but not clearly in the bulbar-predominant subtype. Baseline stage showed subtype-dependent, non-linear associations with subsequent functional decline, with acceleration up to mid-stage breakpoints in the fine motor- and gross motor-predominant subtypes and less evident stage-dependent acceleration in the bulbar-predominant subtype.
Interpretation:
Routine ALSFRS-R item-level data can define clinically interpretable ALS progression subtypes and latent SuStaIn-derived functional stages. Joint subtype-stage modelling may refine prognostic stratification and support prognosis-informed trial enrichment.
