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      The timed 25-foot walk in a large cohort of multiple sclerosis patients

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          Abstract

          Background:

          The timed 25-foot walk (T25FW) is a key clinical outcome measure in multiple sclerosis patient management and clinical research.

          Objectives:

          To evaluate T25FW performance and factors associated with its change in the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) Placebo Database ( n = 2465).

          Methods:

          We created confirmed disability progression (CDP) variables for T25FW and Expanded Disability Status Scale (EDSS) outcomes. We used intraclass correlation coefficients (ICCs) and Bland Altman plots to evaluate reliability. We evaluated T25FW changes and predictive validity using a mixed-effects model, survival analysis, and nested case–control analysis.

          Results:

          The mean baseline score for the T25FW in this study population was 9.2 seconds, median = 6.1 (standard deviation = 11.0, interquartile range (IQR) = 4.8, 9.0). The T25FW measure demonstrated excellent test–retest reliability (ICC = 0.98). Walk times increased with age, disability, disease type, and disease duration; relapses were not associated with an increase. Patients with T25FW progression had a faster time to EDSS-CDP compared to those without (hazards ratio (HR): 2.6; confidence interval (CI): 2.2, 3.1). Changes in the T25FW were more likely to precede changes in EDSS.

          Conclusion:

          This research confirms the association of the T25FW with disability and provides some evidence of predictive validity. Our findings support the continued use of the T25FW in clinical practice and clinical trials.

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          Most cited references22

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          Intraclass correlations: uses in assessing rater reliability.

          Reliability coefficients often take the form of intraclass correlation coefficients. In this article, guidelines are given for choosing among six different forms of the intraclass correlation for reliability studies in which n target are rated by k judges. Relevant to the choice of the coefficient are the appropriate statistical model for the reliability and the application to be made of the reliability results. Confidence intervals for each of the forms are reviewed.
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            Silent progression in disease activity–free relapsing multiple sclerosis

            Objective Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow‐up. Notably, “no evidence of disease activity” at 2 years did not predict long‐term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long‐term disability accumulation. Methods Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0–5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA‐DRB1*15:01 as covariates. Results Relapses were associated with a transient increase in disability over 1‐year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05). Interpretation Long‐term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing–remitting MS. Ann Neurol 2019;85:653–666
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              Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis

              The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with multiple sclerosis (MS). One of the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful in MS. This article addresses the history, application, and psychometric properties of one such MSOAC metric of ambulation or walking namely, the timed 25-foot walk (T25FW). The T25FW has strong reliability over both brief and long periods of time in MS across a large range of disability levels. The outcome of walking speed from the T25FW has obvious real-world relevance and has correlated strongly with other measures of walking and lower extremity function. The T25FW is responsive for capturing intervention effects in pharmacological and rehabilitation trials and has an established value for capturing clinically meaningful change in ambulation. Directions for future research involve validating clinically meaningful improvements on the T25FW as well as determining whether 20% change is clinically meaningful across the disability spectrum. Researchers might further consider synchronizing accelerometers and motion sensors with the T25FW for capturing walking speed in everyday life and the patient’s real environment.
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                Author and article information

                Contributors
                Journal
                Mult Scler
                Mult Scler
                MSJ
                spmsj
                Multiple Sclerosis (Houndmills, Basingstoke, England)
                SAGE Publications (Sage UK: London, England )
                1352-4585
                1477-0970
                8 June 2021
                February 2022
                : 28
                : 2
                : 289-299
                Affiliations
                [1-13524585211017013]Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
                [2-13524585211017013]School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA
                [3-13524585211017013]Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
                [4-13524585211017013]Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
                [5-13524585211017013]Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
                [6-13524585211017013]Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, USA
                [7-13524585211017013]Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
                [8-13524585211017013]Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
                Author notes
                [*]LM Nelson Department of Epidemiology and Population Health, Stanford University School of Medicine, HRP Redwood Building, Room T223, Stanford, CA 94305-5405, USA. lnelson@ 123456stanford.edu
                Author information
                https://orcid.org/0000-0003-3298-5580
                https://orcid.org/0000-0002-7886-9756
                https://orcid.org/0000-0003-4590-1083
                https://orcid.org/0000-0002-4934-2453
                https://orcid.org/0000-0002-5894-2290
                https://orcid.org/0000-0002-5974-3648
                Article
                10.1177_13524585211017013
                10.1177/13524585211017013
                8795230
                34100297
                fe45726d-ea2e-445a-b683-3f2dcaf45324
                © The Author(s), 2021

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 20 November 2020
                : 10 April 2021
                : 22 April 2021
                Categories
                Original Research Papers
                Custom metadata
                ts1

                Immunology
                multiple sclerosis,walking,disease progression,timed 25-foot walk),multiple sclerosis outcomes assessment consortium,expanded disability status scale,benchmarking,annual change,natural history,predictive validity,clinical trial

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