Deconstructing progression of amyotrophic lateral sclerosis in stages: a Markov modeling approach

Abstract

Objectives: Propose an empirical amyotrophic lateral sclerosis (ALS) staging approach called Fine’til 9 (FT9) based on how many of the patient’s ALS functional rating scale (ALSFRS-R) subscores are 9 or less (of normal 12). Gain insights into progression of ALS by applying Markov models to ALS stages by multiple systems (King’s, Milan–Torino system (MITOS) and FT9).

Methods: Patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) dataset were staged using ALSFRS-R responses. Risks of progression through stages and death were estimated, as were effects of prognostic variables on these risks.

Results: A total of 29,947 time points in 3199 patients from the PRO-ACT dataset were assigned stages. Although the three systems were moderately correlated, MITOS stages were heavily skewed toward advanced disease, whereas King’s and FT9 stages were more balanced. Non-sequential progression was observed with King’s system. Markov models adequately described transitions from stage to stage in the first year of observation, but underestimated risks beyond that point. Regardless of staging method, initial rate of ALSFRS-R decline had a powerful effect on rate of progression through sequential stages, whereas age predominantly influenced stage-specific mortality.

Conclusion: King’s and FT9 are more sensitive to observed progression of disease in clinical trials than MITOS. FT9 can partition the course similar to King’s, and may have advantages of sequential progression and easy applicability to retrospective data. Markov transition intensity estimates may be of value for counseling, health economic studies, and research design. In particular, this framework permits estimation of multidimensional effects of variables (including treatment) on outcome.

Keywords:

• Amyotrophic lateral sclerosis
• staging
• Markov multistate model
• prognosis
• survival

Acknowledgments

We would like to thank the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Consortium for volunteering data that we have used in this study. As such, the following organizations and individuals within the PRO-ACT Consortium contributed to the design and implementation of the PRO-ACT Database and/or provided data, but did not participate in the analysis of the data or the writing of this report: Neurological Clinical Research Institute, MGH, Northeast ALS Consortium, Novartis, Prize4Life Israel, Regeneron Pharmaceuticals, Inc., Sanofi and Teva Pharmaceutical Industries, Ltd. We are especially grateful to Dr. Noa Davis and Dr. Alexander Sherman for clarifications relating to PRO-ACT data. We would also like to thank the Neurological Institute Center for Outcomes, Research and Evaluation (NI-CORE), and Quantitative Health Sciences (QHS) at Cleveland Clinic for supporting this effort.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

This study was not supported by any external or internal grant. NJT receives research support from Novartis Pharmaceuticals Corporation for unrelated work. EPP is holder of the Barry Winovich (Bright Side of the Road Foundation) Chair in ALS Research, receives support from Samuel J. and Connie M. Frankino Charitable Foundation. Receives clinical trial and research funding from NIH/CDC, ALS Association, Iron Horse Diagnostics, and serves as consultant to Avanir Pharmaceuticals, Inc., Otsuka America, Inc., MT Pharma America, Inc., and Cytokinetics, Inc.

Additional information

Funding

This study was not supported by any external or internal grant. NJT receives research support from Novartis Pharmaceuticals Corporation for unrelated work. EPP is holder of the Barry Winovich (Bright Side of the Road Foundation) Chair in ALS Research, receives support from Samuel J. and Connie M. Frankino Charitable Foundation. Receives clinical trial and research funding from NIH/CDC, ALS Association, Iron Horse Diagnostics, and serves as consultant to Avanir Pharmaceuticals, Inc., Otsuka America, Inc., MT Pharma America, Inc., and Cytokinetics, Inc.