Identifying Patterns of ALS Progression from Sparse Longitudinal Data

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that is complex in its onset, pattern of spread, and disease progression. The heterogeneity of ALS makes it extremely challenging to determine if a disease modifying therapy is effectively slowing progression. While accurately modeling ALS progression is critical to developing therapeutics, current computational methods fail to capture the complexity of disease progression. We aimed to robustly characterize disease progression patterns in ALS. We obtained data from four clinical cohorts that cover more than 3,500 patients and include both observational and clinical trial studies. To determine whether there were common patterns of disease progression, we developed an approach based on a Mixture of Gaussian Processes (MoGP) to model longitudinal clinical data. Our approach automatically identifies clusters of patients who show similar disease progression patterns, modeling their average trajectory and the spread of the distribution in each cluster. Importantly, the method does not require any prior knowledge of the expected number of clusters. The MoGP approach revealed that ALS progression, as measured using the ALS functional rating scale (ALSFRS-R) or forced vital capacity, is often non-linear with periods of stable disease preceded or followed by rapid decline. Patterns of progression in ALSFRS-R were robust to sparse data. When at least one year of longitudinal data were available, MoGP predictions were significantly more accurate than linear models, which are commonly used in clinical trials. Progression patterns were consistent across different cohorts despite differences in the frequency of data collection and the lengths of follow-up periods. We further showed that clusters identified from one large, publicly available study population could be used to stratify unseen participants in other studies. We also showed that these progression trajectories correspond with survival outcomes. This work highlights the importance of modeling nonlinear disease progression for developing more advanced clinical trial endpoint analysis models. In ALS, sporadic, rapid decline (functional cliffs) and sigmoidal patterns in disease progression in untreated patients may obscure detection of therapeutic efficacy if linear models are used. We provide a pre-trained computational model of observed clinical patterns that can be used by others to analyze new ALS patient cohorts. We expect that the MoGP approach can also be applied to additional ALS outcome measures and to other progressive diseases. Our results provide a critical advance in characterizing the complex disease progression patterns of ALS.

Longitudinal comparison of the self‐entry Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised (ALSFRS‐RSE) and Rasch‐Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) as outcome measures in people with amyotrophic lateral sclerosis

“…9,10 At the same time, scores can improve with symptomatic therapy despite disease progression. 9,11 Though the ALSFRS-R is not a true PRO, efforts to reword and use the ALSFRS-R as a self-entry scale (ALSFRS-RSE) show strong agreement between the ALSFRS-R and ALSFRS-RSE. 7,12 Work is underway to develop digital quantitative outcome measures for use in ALS clinical trials.…”

“…Pooled clinical trial data of 3132 people with ALS (PALS) showed that 25% of trial participants do not experience progression on ALSFRS‐R over 6 mo 9,10 . At the same time, scores can improve with symptomatic therapy despite disease progression 9,11 . Though the ALSFRS‐R is not a true PRO, efforts to reword and use the ALSFRS‐R as a self‐entry scale (ALSFRS‐RSE) show strong agreement between the ALSFRS‐R and ALSFRS‐RSE 7,12 …”

Order from chaos: Using CSF proteomics to predict ALS progression

“…Amyotrophic lateral sclerosis (ALS) carries a uniformly poor prognosis with a median survival of 2–5 years after onset 1 . However, individual patient disease trajectories vary widely 2 . Variability in the rate of ALS progression remains poorly understood, poses a major hurdle for clinical trial design and interpretation, and limits clinicians' ability to counsel patients.…”

“…Variability in the rate of ALS progression remains poorly understood, poses a major hurdle for clinical trial design and interpretation, and limits clinicians' ability to counsel patients. Moreover, clinical progression, as commonly assessed by the Revised ALS Functional Rating Scale (ALSFRS‐R), does not occur in a linear manner as once assumed 2,3 . There is an unmet need for biomarkers of ALS disease activity and progression, which Vu and colleagues seek to address in the current issue 4…”

“…1 However, individual patient disease trajectories vary widely. 2 Variability in the rate of ALS progression remains poorly understood, poses a major hurdle for clinical trial design and interpretation, and limits clinicians' ability to counsel patients. Moreover, clinical progression, as commonly assessed by the Revised ALS Functional Rating Scale (ALSFRS-R), does not occur in a linear manner as once assumed.…”