Original Paper Eur Neurol 2014;71:196–202 DOI: 10.1159/000356116
Received: August 2, 2013 Accepted: September 29, 2013 Published online: January 21, 2014
Validity of Minimal Clinically Important Difference Values for the Multiple Sclerosis Walking Scale-12? Robert W. Motl Yvonne C. Learmonth Lara A. Pilutti Deirdre Dlugonski Rachel Klaren Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, Ill., USA
Key Words Walking · Multiple sclerosis · Clinical meaningfulness · Disability
MCID values of 4- or 6-point changes in MSWS-12 scores. Conclusions: We did not confirm that MCID values of 4 and 6 points for the MSWS-12 correspond with changes in performance, gait, and free-living assessments of walking in MS. © 2014 S. Karger AG, Basel
Abstract Background and Objective: Minimal clinically important difference (MCID) values of 4 and 6 points have been proposed for interpreting meaningful change in Multiple Sclerosis Walking Scale-12 (MSWS-12) scores. This study examined the validity of those MCID values based on capturing corresponding changes in other walking outcomes in persons with multiple sclerosis (MS). Methods: On 2 occasions separated by 6 months, 82 persons with MS completed the MSWS-12, timed 25-ft walk (T25FW), 6-min walk (6MW), and gait analysis, and then wore an accelerometer over a 7-day period. We generated change scores for the MSWS-12 and formed groups of stable, worsened, and improved perceived walking based on both 4- and 6-point changes. The groups were compared for corresponding changes in other walking measures over time using mixed-model ANOVAs. Results: The mixed-model ANOVAs did not identify statistically significant group-by-time interactions on the T25FW (p = 0.98 and p = 0.67), the 6MW (p = 0.89 and p = 0.72), gait (p = 0.54 and p = 0.21), or accelerometry (p = 0.40 and p = 0.68) for
© 2014 S. Karger AG, Basel 0014–3022/14/0714–0196$39.50/0 E-Mail [email protected] www.karger.com/ene
There has been increasing emphasis placed on including patient-reported outcomes (PROs) in clinical research involving persons with multiple sclerosis (MS) [1]. By definition [2], PROs are ‘any report of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else’. Such PROs provide information on the clinical relevance of changes in objective outcomes [3]. This indicates that changes in scores on PROs should correspond with changes in objective outcomes. The Multiple Sclerosis Walking Scale-12 (MSWS-12) [4], in particular, has become a popular PRO for measuring perceived walking impairment in clinical research of MS. The popularity of the MSWS-12 is based on its strong psychometric properties (i.e. data quality, scaling assumptions, acceptability, and reliability) and evidence for the validity of inferences from its scores [4, 5]. Further, there are minimal clinically important difference (MCID) Robert W. Motl, PhD University of Illinois at Urbana-Champaign Department of Kinesiology and Community Health, 233 Freer Hall 906 South Goodwin Ave., Urbana, IL 61801 (USA) E-Mail robmotl @ illinois.edu
values for interpreting meaningful changes in MSWS-12 scores [6]. The MCID values of 4- and 6-point changes in MSWS-12 scores were developed based on consensus recommendations of the IMMPACT group [7] and secondary analyses of data from 2 phase-III clinical trials of fampridine and 5 additional studies [6]. The provision of MCID values for the MSWS-12 affords an exciting opportunity to establish the clinical relevance of therapeutic interventions for improving walking in MS. To date, we are not aware of a single published study that has independently examined whether the MCID values from the MSWS-12 capture corresponding changes in objective measures of walking. The present study examined the validity of MCID values for the MSWS-12 based on capturing convergent changes in timed 25-ft walk (T25FW) and 6-min walk (6MW) performance, gait, and free-living accelerometry over a 6-month period of time in the absence of an intervention. We further included the Multiple Sclerosis Impact Scale-29 (MSIS-29) [8] to demonstrate that MCID values for the MSWS-12 do not capture corresponding changes in physical and mental health status.
Methods Participants The data were secondary outcomes from a 6-month observational period before the administration of an ongoing behavioral intervention for changing physical activity in MS. Participants were contacted via a flyer that was distributed among patients in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry or participants in our laboratory database. There were 511 potential participants who initially expressed interest in the research. The project coordinator successfully contacted 230 of those who expressed interest and undertook screening for inclusion. The inclusion criteria involved: (a) diagnosis of MS, (b) relapse-free status for the past 30 days, (c) ability to walk with or without an assistive device, (d) age between 18 and 64 years, (e) willingness and ability to travel to the research site and complete the walking assessments, and (f) physician’s approval for participation in the study. There were 106 persons who did not meet one or more of the inclusion criteria, 39 who did not provide physician’s approval for participation, and 3 who cancelled the scheduled appointment before the first testing session. The final sample included 82 persons with MS who completed the assessments on 2 occasions that were separated by 6 months.
and then multiplying the result by 100. The transformation scales MSWS-12 scores between 0 and 100 [4]; higher scores indicate greater perceived walking impairment. 6MW. The 6MW was administered as a measure of endurance walking performance [9]. Participants were instructed to walk as fast and as far as possible in a single corridor with 180-degree turns for 6 min. One researcher followed approximately 3 ft behind the participant with a measuring wheel (Stanley MW50, New Briton, Conn., USA) and recorded the total distance traveled (ft); longer distances reflect better walking endurance. T25FW. The T25FW was performed along a clearly marked 25-ft-long path on a carpeted surface that was clear of obstructions and foot traffic. We provided standardized instructions and emphasized walking as fast and as safely as possible [10]. One researcher followed alongside the participant for safety and another recorded the time in seconds using a stopwatch. The T25FW was performed twice and the average of the 2 trials was included for the analysis; shorter times reflect a faster walking speed. Gait. Participants completed 2 walking trials at a self-selected, comfortable pace across a 4.6-meter GAITRite mat (CIR Systems, Havertown, Pa., USA). The GAITRite and its associated software automatically collect data on temporal-spatial parameters of gait and provided an overall metric of gait based on the functional ambulatory profile (FAP) score. The FAP score is an integration of selected temporal and spatial parameters into a single, numerical representation of gait (i.e. the FAP score is based on the linear association of the step length/leg length ratio with step time when velocity is ‘normalized’ based on leg length). The FAP score ranges between 0 and 100 [11]; higher scores reflecting less gait impairment. Accelerometry. We included ActiGraph accelerometers (model GT3X; ActiGraph) to measure the number of steps per day as an indication of free-living ambulatory physical activity in MS [12]. The ActiGraph accelerometers were worn on a belt over the hip and measured the acceleration of the body using a solid-state digital accelerometer that generates an electrical signal proportional to the force acting upon it during movement. The raw signal was recorded over a 1-min interval, stored in the accelerometer’s memory, and later downloaded using a personal computer. The raw accelerometer data were checked against participant-recorded wear times from a log sheet, and only valid days (≥10 h of wear time without periods of continuous zeros exceeding 60 min) were included for data processing. The raw signal was processed into steps per 1-min interval and then summed over the course of the day into steps per day. The outcome of steps per day was averaged over 3 or more available days of valid data [13]; higher scores reflect greater community-based ambulatory physical activity. MSIS-29. The MSIS-29 contains 29 items that provide a disease-specific measure of physical and mental health status over the past 4 weeks [8]. The physical subscale contains 20 items and the mental subscale contains 9 items. Scores from the physical and psychological subscales are transformed similarly to the MSWS-12 and range between 0 and 100; higher scores indicate worse physical and mental health status.
Measures MSWS-12. The MSWS-12 is a 12-item PRO of the impact of MS on walking [4]. The 12 items on the MSWS-12 are rated on a scale of 1 (not at all) to 5 (extremely). The total MSWS-12 score is computed by summing the individual item scores, subtracting the minimum possible score (12), dividing by the maximal score (48),
Procedure On arrival to the research laboratory, the study was explained to each participant, who then provided written informed consent if willing to volunteer. We collected demographic and clinical data (i.e. age, gender, education level, MS type, and years since
Validity of MCID Values for the MSWS-12?
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MS diagnosis) through a self-report questionnaire and administered the MSWS-12, the MSIS-29, and the Patient-Determined Disease Steps (PDDS) scale [14]; the PDDS characterized the disability status of the sample. We provided standardized instructions for administering the ambulatory measures (6MW, T25FW, and FAP) and there were breaks of 15 min between tests. We provided participants with an accelerometer in a pouch on an elastic belt that was worn during the waking hours of the day, except when in contact with water, over a 7-day period. The accelerometer was returned in a preaddressed and prestamped envelope through the US Postal Service. This same procedure was completed 6 months later and there was no intervention between the 2 assessments. Participants received USD 50 remuneration per assessment period.
Table 1. Descriptive statistics, ICCs, and paired-samples t tests for measures over a 6-month observational period
Data Analysis All data analyses were performed using SPSS. We initially generated descriptive statistics reported as means and standard deviations (SD) and, where indicated, medians and interquartile ranges (IQR). We then adopted paired-samples t tests for examining mean changes in MSWS-12, 6MW, T25FW, FAP, accelerometry, and MSIS-29 scores over time. This was followed by intraclass correlations (ICCs) to further examine the stability of scores over time. The main analysis required that we trichotomize subjects into groups classified as improved, stable, and worsened based on MCID values of both 4 and 6 points for interpreting changes in MSWS-12 scores. We next estimated the frequency and percent of persons classified as improved, stable, and worsened per MCID value. This was followed by a series of mixed-model ANOVAs with group as a between-subjects factor (3 levels: improved, stable, and worsened) and time as a within-subjects factor (2 levels: baseline and follow-up). The primary outcomes were 6MW, T25FW, FAP, and accelerometry scores, with MSIS-29 subscale scores serving as secondary outcomes. We focused on the group-by-time interactions and provided η2 estimates from the univariate F ratios to establish the magnitude of the interactions based on the explained variance in the outcomes (values of 0.01, 0.06, and 0.14 reflect small, moderate, and large effects, respectively) [15].
Values for baseline and follow-up are means (SD). t test = Pairedsamples t test for comparing changes over time; p value = p value from the paired-samples t test.
Results
Sample Characteristics Data were collected from 82 people with MS. The majority were female (n = 66 or 80%), with a mean age of 49.2 (9.0) years. The median PDDS score was 3.0 (IQR = 3) and the mean disease duration was 11.8 (8.2) years. The majority of participants had relapsing-remitting MS (n = 67 or 82%). There were 63 (77%) and 57 (70%) persons using a disease-modifying therapy at baseline and followup (Z = 1.13, p = 0.26) and 41 (50%) who were using a symptomatic agent at both baseline and follow-up (Z = 0.00, p = 1.00). There were 5 (6%) and 7 (9%) persons using fampridine at baseline and follow-up (Z = −1.44, p = 0.16) (the subsequent results were not altered when removing those taking fampridine; data not provided). 198
Eur Neurol 2014;71:196–202 DOI: 10.1159/000356116
Variable
Baseline
Follow-up
MSWS-12 40.3 (29.6) 41.1 (30.8) 6MW 1,404 (513) 1,473 (523) T25FW 7.6 (10.3) 7.5 (11.1) FAP 90.1 (11.6) 91.3 (12.1) Steps per day 4,368 (2,391) 4,546 (2,941) MSIS-29 Physical 31.3 (24.3) 31.6 (24.8) Mental 32.7 (24.5) 30.5 (22.5)
ICC
t test
p value
0.927 0.959 0.982 0.883 0.833
–0.639 –4.084 0.709 –1.116 –0.985
0.525 0.001 0.480 0.268 0.328
0.928 –0.237 0.813 0.804 1.372 0.174
Stability of the Measures The mean scores (SD) for the MSWS-12, T25FW, 6MW, FAP, accelerometry, and MSIS-29 for the 2 time points are provided in table 1. The ICCs exceeded 0.80 and indicated acceptable stability of the scores on these measures over time [16]. The paired-samples t tests indicated that only the 6MW mean scores changed significantly over time with an increase of 69 ft. Frequency of Meaningful Change in MSWS-12 Scores Data on the frequency and percent of cases classified as improved, stable, or worsened over the 6-month time period based on MCID values of both 4 and 6 are provided in table 2. Based on an MCID value of four, 29 persons or 35% of the sample had changes in MSWS-12 scores over the 6-month period that would indicate meaningful improvement, whereas 34 persons or 42% of the sample had changes that would indicate meaningful worsening of walking. Based on an MCID value of six, 24 persons or 29% of the sample had changes in MSWS-12 scores over the 6-month period that would indicate meaningful improvement, and 24 persons or 29% of the sample had changes that would indicate meaningful worsening of walking. Interestingly, only 4 persons or 5% of the sample had changes in T25FW scores over the 6-month period (i.e. 20% reduction in T25FW) that would indicate meaningful improvement, whereas only 1 person or 1% of the sample had a change (i.e. 20% increase in T25FW) that would indicate meaningful worsening of walking. There were significant group-by-time interactions on MSWS12 scores based on MCID values of 4 (F1, 81 = 82.35, p < 0.0001, η2 = 0.68) and 6 (F1, 81 = 110.54, p < 0.0001, η2 = Motl/Learmonth/Pilutti/Dlugonski/ Klaren
Table 2. Frequency and percent along with the mean change in MSWS-12 score for groups classified as stable,
worsened, or improved based on MCID values of 4- and 6-point changes in MSWS-12 MSWS-12 groups
MCID = 4
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frequency
percent
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19 34 29
23 42 35
0.2 (1.7) 11.0 (8.7) –10.5 (5.7)
34 24 24
42 29 29
0.5 (3.0) 13.9 (9.0) –11.8 (5.4)
ΔMSWS-12 = Mean (SD) change in MSWS-12 score over time.
0.74), and the mean (SD) changes in MSWS-12 scores per group are provided in table 1. The interactions explained 68 and 74% of the variance in MSWS-12 scores.
2.53, p = 0.09, η2 = 0.06) and 6 (F1, 81 = 2.40, p = 0.10, η2 = 0.06) for the MSWS-12; see the mean score (SE) per group over time in figure 2.
Meaningful Change in MSWS-12 Scores and Changes in Ambulatory Outcomes Over Time There were nonsignificant group-by-time interactions on 6MW distance based on MCID values of 4 (F1, 81 = 0.12, p = 0.89, η2 = 0.00) and 6 (F1, 81 = 0.34, p = 0.72, η2 = 0.01) for the MSWS-12. Similarly, there were nonsignificant group-by-time interactions on T25FW based on MCID values of 4 (F1, 81 = 0.02, p = 0.98, η2 = 0.00) and 6 (F1, 81 = 0.40, p = 0.67, η2 = 0.01) for MSWS-12. Further, there were nonsignificant group-by-time interactions on FAP scores based on MCID values of 4 (F1, 81 = 0.62, p = 0.54, η2 = 0.02) and 6 (F1, 81 = 1.58, p = 0.21, η2 = 0.04). Lastly, there were nonsignificant group-by-time interactions on steps per day from the accelerometer based on MCID values of 4 (F1, 81 = 0.92, p = 0.40, η2 = 0.03) and 6 (F1, 81 = 0.38, p = 0.68, η2 = 0.01) for the MSWS-12. The mean scores (standard error; SE) for 6MW, T25FW, FAP, and steps per day per group over time are provided in figure 1. The nonsignificant interactions only explained up to 4% of the variance in the ambulatory outcomes.
Exploratory Bivariate Correlations among Change Scores We performed an exploratory bivariate analysis of the correlation between change scores for the MSWS-12 and change scores for the T25FW, 6MW, FAP, accelerometry, and MSIS-29 subscales. This analysis was undertaken to determine whether the analyses based on MCID values were masking possible associations between changes in MSWS-12 scores and other ambulatory outcomes. The change score for MSWS-12 was not significantly associated with change scores for T25FW (r = 0.03, p = 0.78), 6MW (r = −0.07, p = 0.55), FAP (r = −0.11, p = 0.36), freeliving accelerometry (r = −0.11, p = 0.36), or the MSIS-29 mental subscale (r = 0.20, p = 0.07). The change score for the MSWS-12 was significantly associated with the change score for the MSIS-29 physical subscale (r = 0.56, p = 0.0001), and this association is displayed as a scatter plot along with lines of best fit and 95% CIs in figure 3.
Discussion
Meaningful Change in MSWS-12 Scores and Changes in Health Status There were statistically significant group-by-time interactions on MSIS-29 physical subscale scores based on MCID values of 4 (F1, 81 = 8.69, p < 0.0001, η2 = 0.18) and 6 (F1, 81 = 8.56, p < 0.0001, η2 = 0.18) for the MSWS-12. The mean scores (SE) for the MSIS-29 physical subscale per group over time are provided in figure 2 and indicate correspondent changes in MSIS-29 physical subscale scores with changes in MSWS-12 scores. There were nonsignificant group-by-time interactions on MSIS-29 mental subscale scores based on MCID values of 4 (F1, 81 =
We expected that the MCID values of 4- and 6-point changes in MSWS-12 scores would correspond with changes in walking as measured by the T25FW, 6MW, gait, and accelerometry but not with changes in physical and psychological health status. We were particularly interested in the results for the T25FW and 6MW as these are well-established measures of ambulation in MS [17, 18]. The results of the present study were not consistent with our expectations. Indeed, there was no correspondence between groups formed based on 4- or 6-point changes in MSWS-12 scores and changes in any of the
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Fig. 1. Changes in 6MW, T25FW, FAP, and steps per day across groups classified as worsened, stable, and improved based on MCID
values of 4- and 6-point changes in MSWS-12 scores over a 6-month period. Values are means (SE bars).
walking outcomes, but such groups did differ in physical health status on the MSIS-29. The exploratory correlation analyses further confirmed that changes in MSWS-12 scores were only associated with changes in MSIS-29 physical subscale scores. This raises some concern regarding the validity of MCID values for the MSWS-12 as well as the meaning of change in MSWS-12 scores over time. Such results seemingly suggest that change in 200
Eur Neurol 2014;71:196–202 DOI: 10.1159/000356116
MSWS-12 scores might better reflect change in physical health perceptions rather than walking in MS. The results of this prospective, observational study do not definitively disconfirm the validity of MCID values for the MSWS-12 or the interpretation of change in its scores over time. Indeed, one alternative interpretation is that the 6MW, T25FW, FAP, and steps per day from an accelerometer are poor measures of change in walkMotl/Learmonth/Pilutti/Dlugonski/ Klaren
50.000 45.000 40.000 35.000 30.000 25.000 20.000 15.000 10.000
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Fig. 2. Changes in MSIS-29 subscale scores across worsened, stable, and improved groups based on MCID values of 4- and 6-point
changes in MSWS-12 scores over a 6-month period. Values are means (SE).
ing status over time. We counter this possibility based on the weight of the evidence supporting the validity of the 4 objective outcomes [17, 18] combined with the observed relationship between changes in MSWS-12 and MSIS-29 physical subscale scores. Another possibility is
that the MSWS-12 and objective tests measure very different aspects of walking, but as all measures capture walking in some regard there should be associations based on the notion of construct validity. Accordingly, our results do raise some degree of concern and suggest that caution should be applied when interpreting the change in scores on the MSWS-12. There was minimal evidence of an association between change scores for the MSWS-12 and ambulatory outcomes in the current study and, as reported recently, in another sample of persons with MS [19]. If our results are replicated in subsequent studies, then researchers might reconsider the validity of this scale’s scores for capturing changes in walking from the patient’s perspective and perhaps develop new MCID values. This will be necessary given the importance of establishing the clinical relevance of interventions for improving walking as a component of disability in MS [3]. There are several limitations of the current study that should be considered when interpreting our results. We examined the validity of the MCID values for the MSWS12 and its change scores in a prospective, observational study. The actual MCID values were established using IMMPACT guidelines [7] in the context of reanalyzing data from clinical trials of fampridine and 5 other studies
Validity of MCID Values for the MSWS-12?
Eur Neurol 2014;71:196–202 DOI: 10.1159/000356116
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[6]. Perhaps the MCID values are meaningful in the context of an intervention but not longitudinal observational periods (i.e. naturally occurring changes in the absence of an intervention). Another limitation is that we included a self-reported measure of disability status rather than the Expanded Disability Status Scale [20] from a neurological examination repeated over time. This would have provided an additional clinical vantage point for interpreting the meaningfulness of changes in MSWS-12 scores. An additional possible limitation is that we examined changes over a 6-month period, and perhaps there might be correspondence between MSWS-12 and other ambulatory outcomes over shorter and/or longer periods of time. Lastly, the sample primarily included women with relapse-remitting MS who had moderate disability. This might limit broad conclusions regarding the results of this study among those with MS, and perhaps the MCID values for the MSWS-12 might still be valid in persons with severe disability.
Overall, we were surprised by the results of the present analysis that did not support the validity of MCID values from the MSWS-12 as reflecting an objective change in walking among persons with MS. We provide these data so that researchers might exert caution in interpreting changes in MSWS-12 scores until further evidence either confirms or disconfirms our observations.
Acknowledgement This project was funded by a pilot grant from the National Multiple Sclerosis Society (PP1695).
Disclosure Statement R.W.M. is a consultant and funded researcher for Biogen Idec and Acorda Therapeutics. The other authors have no conflicts of interest.
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Motl/Learmonth/Pilutti/Dlugonski/ Klaren
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Received: August 2, 2013 Accepted: September 29, 2013 Published online: January 21, 2014
Validity of Minimal Clinically Important Difference Values for the Multiple Sclerosis Walking Scale-12? Robert W. Motl Yvonne C. Learmonth Lara A. Pilutti Deirdre Dlugonski Rachel Klaren Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, Ill., USA
Key Words Walking · Multiple sclerosis · Clinical meaningfulness · Disability
MCID values of 4- or 6-point changes in MSWS-12 scores. Conclusions: We did not confirm that MCID values of 4 and 6 points for the MSWS-12 correspond with changes in performance, gait, and free-living assessments of walking in MS. © 2014 S. Karger AG, Basel
Abstract Background and Objective: Minimal clinically important difference (MCID) values of 4 and 6 points have been proposed for interpreting meaningful change in Multiple Sclerosis Walking Scale-12 (MSWS-12) scores. This study examined the validity of those MCID values based on capturing corresponding changes in other walking outcomes in persons with multiple sclerosis (MS). Methods: On 2 occasions separated by 6 months, 82 persons with MS completed the MSWS-12, timed 25-ft walk (T25FW), 6-min walk (6MW), and gait analysis, and then wore an accelerometer over a 7-day period. We generated change scores for the MSWS-12 and formed groups of stable, worsened, and improved perceived walking based on both 4- and 6-point changes. The groups were compared for corresponding changes in other walking measures over time using mixed-model ANOVAs. Results: The mixed-model ANOVAs did not identify statistically significant group-by-time interactions on the T25FW (p = 0.98 and p = 0.67), the 6MW (p = 0.89 and p = 0.72), gait (p = 0.54 and p = 0.21), or accelerometry (p = 0.40 and p = 0.68) for
© 2014 S. Karger AG, Basel 0014–3022/14/0714–0196$39.50/0 E-Mail [email protected] www.karger.com/ene
There has been increasing emphasis placed on including patient-reported outcomes (PROs) in clinical research involving persons with multiple sclerosis (MS) [1]. By definition [2], PROs are ‘any report of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else’. Such PROs provide information on the clinical relevance of changes in objective outcomes [3]. This indicates that changes in scores on PROs should correspond with changes in objective outcomes. The Multiple Sclerosis Walking Scale-12 (MSWS-12) [4], in particular, has become a popular PRO for measuring perceived walking impairment in clinical research of MS. The popularity of the MSWS-12 is based on its strong psychometric properties (i.e. data quality, scaling assumptions, acceptability, and reliability) and evidence for the validity of inferences from its scores [4, 5]. Further, there are minimal clinically important difference (MCID) Robert W. Motl, PhD University of Illinois at Urbana-Champaign Department of Kinesiology and Community Health, 233 Freer Hall 906 South Goodwin Ave., Urbana, IL 61801 (USA) E-Mail robmotl @ illinois.edu
values for interpreting meaningful changes in MSWS-12 scores [6]. The MCID values of 4- and 6-point changes in MSWS-12 scores were developed based on consensus recommendations of the IMMPACT group [7] and secondary analyses of data from 2 phase-III clinical trials of fampridine and 5 additional studies [6]. The provision of MCID values for the MSWS-12 affords an exciting opportunity to establish the clinical relevance of therapeutic interventions for improving walking in MS. To date, we are not aware of a single published study that has independently examined whether the MCID values from the MSWS-12 capture corresponding changes in objective measures of walking. The present study examined the validity of MCID values for the MSWS-12 based on capturing convergent changes in timed 25-ft walk (T25FW) and 6-min walk (6MW) performance, gait, and free-living accelerometry over a 6-month period of time in the absence of an intervention. We further included the Multiple Sclerosis Impact Scale-29 (MSIS-29) [8] to demonstrate that MCID values for the MSWS-12 do not capture corresponding changes in physical and mental health status.
Methods Participants The data were secondary outcomes from a 6-month observational period before the administration of an ongoing behavioral intervention for changing physical activity in MS. Participants were contacted via a flyer that was distributed among patients in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry or participants in our laboratory database. There were 511 potential participants who initially expressed interest in the research. The project coordinator successfully contacted 230 of those who expressed interest and undertook screening for inclusion. The inclusion criteria involved: (a) diagnosis of MS, (b) relapse-free status for the past 30 days, (c) ability to walk with or without an assistive device, (d) age between 18 and 64 years, (e) willingness and ability to travel to the research site and complete the walking assessments, and (f) physician’s approval for participation in the study. There were 106 persons who did not meet one or more of the inclusion criteria, 39 who did not provide physician’s approval for participation, and 3 who cancelled the scheduled appointment before the first testing session. The final sample included 82 persons with MS who completed the assessments on 2 occasions that were separated by 6 months.
and then multiplying the result by 100. The transformation scales MSWS-12 scores between 0 and 100 [4]; higher scores indicate greater perceived walking impairment. 6MW. The 6MW was administered as a measure of endurance walking performance [9]. Participants were instructed to walk as fast and as far as possible in a single corridor with 180-degree turns for 6 min. One researcher followed approximately 3 ft behind the participant with a measuring wheel (Stanley MW50, New Briton, Conn., USA) and recorded the total distance traveled (ft); longer distances reflect better walking endurance. T25FW. The T25FW was performed along a clearly marked 25-ft-long path on a carpeted surface that was clear of obstructions and foot traffic. We provided standardized instructions and emphasized walking as fast and as safely as possible [10]. One researcher followed alongside the participant for safety and another recorded the time in seconds using a stopwatch. The T25FW was performed twice and the average of the 2 trials was included for the analysis; shorter times reflect a faster walking speed. Gait. Participants completed 2 walking trials at a self-selected, comfortable pace across a 4.6-meter GAITRite mat (CIR Systems, Havertown, Pa., USA). The GAITRite and its associated software automatically collect data on temporal-spatial parameters of gait and provided an overall metric of gait based on the functional ambulatory profile (FAP) score. The FAP score is an integration of selected temporal and spatial parameters into a single, numerical representation of gait (i.e. the FAP score is based on the linear association of the step length/leg length ratio with step time when velocity is ‘normalized’ based on leg length). The FAP score ranges between 0 and 100 [11]; higher scores reflecting less gait impairment. Accelerometry. We included ActiGraph accelerometers (model GT3X; ActiGraph) to measure the number of steps per day as an indication of free-living ambulatory physical activity in MS [12]. The ActiGraph accelerometers were worn on a belt over the hip and measured the acceleration of the body using a solid-state digital accelerometer that generates an electrical signal proportional to the force acting upon it during movement. The raw signal was recorded over a 1-min interval, stored in the accelerometer’s memory, and later downloaded using a personal computer. The raw accelerometer data were checked against participant-recorded wear times from a log sheet, and only valid days (≥10 h of wear time without periods of continuous zeros exceeding 60 min) were included for data processing. The raw signal was processed into steps per 1-min interval and then summed over the course of the day into steps per day. The outcome of steps per day was averaged over 3 or more available days of valid data [13]; higher scores reflect greater community-based ambulatory physical activity. MSIS-29. The MSIS-29 contains 29 items that provide a disease-specific measure of physical and mental health status over the past 4 weeks [8]. The physical subscale contains 20 items and the mental subscale contains 9 items. Scores from the physical and psychological subscales are transformed similarly to the MSWS-12 and range between 0 and 100; higher scores indicate worse physical and mental health status.
Measures MSWS-12. The MSWS-12 is a 12-item PRO of the impact of MS on walking [4]. The 12 items on the MSWS-12 are rated on a scale of 1 (not at all) to 5 (extremely). The total MSWS-12 score is computed by summing the individual item scores, subtracting the minimum possible score (12), dividing by the maximal score (48),
Procedure On arrival to the research laboratory, the study was explained to each participant, who then provided written informed consent if willing to volunteer. We collected demographic and clinical data (i.e. age, gender, education level, MS type, and years since
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MS diagnosis) through a self-report questionnaire and administered the MSWS-12, the MSIS-29, and the Patient-Determined Disease Steps (PDDS) scale [14]; the PDDS characterized the disability status of the sample. We provided standardized instructions for administering the ambulatory measures (6MW, T25FW, and FAP) and there were breaks of 15 min between tests. We provided participants with an accelerometer in a pouch on an elastic belt that was worn during the waking hours of the day, except when in contact with water, over a 7-day period. The accelerometer was returned in a preaddressed and prestamped envelope through the US Postal Service. This same procedure was completed 6 months later and there was no intervention between the 2 assessments. Participants received USD 50 remuneration per assessment period.
Table 1. Descriptive statistics, ICCs, and paired-samples t tests for measures over a 6-month observational period
Data Analysis All data analyses were performed using SPSS. We initially generated descriptive statistics reported as means and standard deviations (SD) and, where indicated, medians and interquartile ranges (IQR). We then adopted paired-samples t tests for examining mean changes in MSWS-12, 6MW, T25FW, FAP, accelerometry, and MSIS-29 scores over time. This was followed by intraclass correlations (ICCs) to further examine the stability of scores over time. The main analysis required that we trichotomize subjects into groups classified as improved, stable, and worsened based on MCID values of both 4 and 6 points for interpreting changes in MSWS-12 scores. We next estimated the frequency and percent of persons classified as improved, stable, and worsened per MCID value. This was followed by a series of mixed-model ANOVAs with group as a between-subjects factor (3 levels: improved, stable, and worsened) and time as a within-subjects factor (2 levels: baseline and follow-up). The primary outcomes were 6MW, T25FW, FAP, and accelerometry scores, with MSIS-29 subscale scores serving as secondary outcomes. We focused on the group-by-time interactions and provided η2 estimates from the univariate F ratios to establish the magnitude of the interactions based on the explained variance in the outcomes (values of 0.01, 0.06, and 0.14 reflect small, moderate, and large effects, respectively) [15].
Values for baseline and follow-up are means (SD). t test = Pairedsamples t test for comparing changes over time; p value = p value from the paired-samples t test.
Results
Sample Characteristics Data were collected from 82 people with MS. The majority were female (n = 66 or 80%), with a mean age of 49.2 (9.0) years. The median PDDS score was 3.0 (IQR = 3) and the mean disease duration was 11.8 (8.2) years. The majority of participants had relapsing-remitting MS (n = 67 or 82%). There were 63 (77%) and 57 (70%) persons using a disease-modifying therapy at baseline and followup (Z = 1.13, p = 0.26) and 41 (50%) who were using a symptomatic agent at both baseline and follow-up (Z = 0.00, p = 1.00). There were 5 (6%) and 7 (9%) persons using fampridine at baseline and follow-up (Z = −1.44, p = 0.16) (the subsequent results were not altered when removing those taking fampridine; data not provided). 198
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Variable
Baseline
Follow-up
MSWS-12 40.3 (29.6) 41.1 (30.8) 6MW 1,404 (513) 1,473 (523) T25FW 7.6 (10.3) 7.5 (11.1) FAP 90.1 (11.6) 91.3 (12.1) Steps per day 4,368 (2,391) 4,546 (2,941) MSIS-29 Physical 31.3 (24.3) 31.6 (24.8) Mental 32.7 (24.5) 30.5 (22.5)
ICC
t test
p value
0.927 0.959 0.982 0.883 0.833
–0.639 –4.084 0.709 –1.116 –0.985
0.525 0.001 0.480 0.268 0.328
0.928 –0.237 0.813 0.804 1.372 0.174
Stability of the Measures The mean scores (SD) for the MSWS-12, T25FW, 6MW, FAP, accelerometry, and MSIS-29 for the 2 time points are provided in table 1. The ICCs exceeded 0.80 and indicated acceptable stability of the scores on these measures over time [16]. The paired-samples t tests indicated that only the 6MW mean scores changed significantly over time with an increase of 69 ft. Frequency of Meaningful Change in MSWS-12 Scores Data on the frequency and percent of cases classified as improved, stable, or worsened over the 6-month time period based on MCID values of both 4 and 6 are provided in table 2. Based on an MCID value of four, 29 persons or 35% of the sample had changes in MSWS-12 scores over the 6-month period that would indicate meaningful improvement, whereas 34 persons or 42% of the sample had changes that would indicate meaningful worsening of walking. Based on an MCID value of six, 24 persons or 29% of the sample had changes in MSWS-12 scores over the 6-month period that would indicate meaningful improvement, and 24 persons or 29% of the sample had changes that would indicate meaningful worsening of walking. Interestingly, only 4 persons or 5% of the sample had changes in T25FW scores over the 6-month period (i.e. 20% reduction in T25FW) that would indicate meaningful improvement, whereas only 1 person or 1% of the sample had a change (i.e. 20% increase in T25FW) that would indicate meaningful worsening of walking. There were significant group-by-time interactions on MSWS12 scores based on MCID values of 4 (F1, 81 = 82.35, p < 0.0001, η2 = 0.68) and 6 (F1, 81 = 110.54, p < 0.0001, η2 = Motl/Learmonth/Pilutti/Dlugonski/ Klaren
Table 2. Frequency and percent along with the mean change in MSWS-12 score for groups classified as stable,
worsened, or improved based on MCID values of 4- and 6-point changes in MSWS-12 MSWS-12 groups
MCID = 4
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frequency
percent
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frequency
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19 34 29
23 42 35
0.2 (1.7) 11.0 (8.7) –10.5 (5.7)
34 24 24
42 29 29
0.5 (3.0) 13.9 (9.0) –11.8 (5.4)
ΔMSWS-12 = Mean (SD) change in MSWS-12 score over time.
0.74), and the mean (SD) changes in MSWS-12 scores per group are provided in table 1. The interactions explained 68 and 74% of the variance in MSWS-12 scores.
2.53, p = 0.09, η2 = 0.06) and 6 (F1, 81 = 2.40, p = 0.10, η2 = 0.06) for the MSWS-12; see the mean score (SE) per group over time in figure 2.
Meaningful Change in MSWS-12 Scores and Changes in Ambulatory Outcomes Over Time There were nonsignificant group-by-time interactions on 6MW distance based on MCID values of 4 (F1, 81 = 0.12, p = 0.89, η2 = 0.00) and 6 (F1, 81 = 0.34, p = 0.72, η2 = 0.01) for the MSWS-12. Similarly, there were nonsignificant group-by-time interactions on T25FW based on MCID values of 4 (F1, 81 = 0.02, p = 0.98, η2 = 0.00) and 6 (F1, 81 = 0.40, p = 0.67, η2 = 0.01) for MSWS-12. Further, there were nonsignificant group-by-time interactions on FAP scores based on MCID values of 4 (F1, 81 = 0.62, p = 0.54, η2 = 0.02) and 6 (F1, 81 = 1.58, p = 0.21, η2 = 0.04). Lastly, there were nonsignificant group-by-time interactions on steps per day from the accelerometer based on MCID values of 4 (F1, 81 = 0.92, p = 0.40, η2 = 0.03) and 6 (F1, 81 = 0.38, p = 0.68, η2 = 0.01) for the MSWS-12. The mean scores (standard error; SE) for 6MW, T25FW, FAP, and steps per day per group over time are provided in figure 1. The nonsignificant interactions only explained up to 4% of the variance in the ambulatory outcomes.
Exploratory Bivariate Correlations among Change Scores We performed an exploratory bivariate analysis of the correlation between change scores for the MSWS-12 and change scores for the T25FW, 6MW, FAP, accelerometry, and MSIS-29 subscales. This analysis was undertaken to determine whether the analyses based on MCID values were masking possible associations between changes in MSWS-12 scores and other ambulatory outcomes. The change score for MSWS-12 was not significantly associated with change scores for T25FW (r = 0.03, p = 0.78), 6MW (r = −0.07, p = 0.55), FAP (r = −0.11, p = 0.36), freeliving accelerometry (r = −0.11, p = 0.36), or the MSIS-29 mental subscale (r = 0.20, p = 0.07). The change score for the MSWS-12 was significantly associated with the change score for the MSIS-29 physical subscale (r = 0.56, p = 0.0001), and this association is displayed as a scatter plot along with lines of best fit and 95% CIs in figure 3.
Discussion
Meaningful Change in MSWS-12 Scores and Changes in Health Status There were statistically significant group-by-time interactions on MSIS-29 physical subscale scores based on MCID values of 4 (F1, 81 = 8.69, p < 0.0001, η2 = 0.18) and 6 (F1, 81 = 8.56, p < 0.0001, η2 = 0.18) for the MSWS-12. The mean scores (SE) for the MSIS-29 physical subscale per group over time are provided in figure 2 and indicate correspondent changes in MSIS-29 physical subscale scores with changes in MSWS-12 scores. There were nonsignificant group-by-time interactions on MSIS-29 mental subscale scores based on MCID values of 4 (F1, 81 =
We expected that the MCID values of 4- and 6-point changes in MSWS-12 scores would correspond with changes in walking as measured by the T25FW, 6MW, gait, and accelerometry but not with changes in physical and psychological health status. We were particularly interested in the results for the T25FW and 6MW as these are well-established measures of ambulation in MS [17, 18]. The results of the present study were not consistent with our expectations. Indeed, there was no correspondence between groups formed based on 4- or 6-point changes in MSWS-12 scores and changes in any of the
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Fig. 1. Changes in 6MW, T25FW, FAP, and steps per day across groups classified as worsened, stable, and improved based on MCID
values of 4- and 6-point changes in MSWS-12 scores over a 6-month period. Values are means (SE bars).
walking outcomes, but such groups did differ in physical health status on the MSIS-29. The exploratory correlation analyses further confirmed that changes in MSWS-12 scores were only associated with changes in MSIS-29 physical subscale scores. This raises some concern regarding the validity of MCID values for the MSWS-12 as well as the meaning of change in MSWS-12 scores over time. Such results seemingly suggest that change in 200
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MSWS-12 scores might better reflect change in physical health perceptions rather than walking in MS. The results of this prospective, observational study do not definitively disconfirm the validity of MCID values for the MSWS-12 or the interpretation of change in its scores over time. Indeed, one alternative interpretation is that the 6MW, T25FW, FAP, and steps per day from an accelerometer are poor measures of change in walkMotl/Learmonth/Pilutti/Dlugonski/ Klaren
50.000 45.000 40.000 35.000 30.000 25.000 20.000 15.000 10.000
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Fig. 2. Changes in MSIS-29 subscale scores across worsened, stable, and improved groups based on MCID values of 4- and 6-point
changes in MSWS-12 scores over a 6-month period. Values are means (SE).
ing status over time. We counter this possibility based on the weight of the evidence supporting the validity of the 4 objective outcomes [17, 18] combined with the observed relationship between changes in MSWS-12 and MSIS-29 physical subscale scores. Another possibility is
that the MSWS-12 and objective tests measure very different aspects of walking, but as all measures capture walking in some regard there should be associations based on the notion of construct validity. Accordingly, our results do raise some degree of concern and suggest that caution should be applied when interpreting the change in scores on the MSWS-12. There was minimal evidence of an association between change scores for the MSWS-12 and ambulatory outcomes in the current study and, as reported recently, in another sample of persons with MS [19]. If our results are replicated in subsequent studies, then researchers might reconsider the validity of this scale’s scores for capturing changes in walking from the patient’s perspective and perhaps develop new MCID values. This will be necessary given the importance of establishing the clinical relevance of interventions for improving walking as a component of disability in MS [3]. There are several limitations of the current study that should be considered when interpreting our results. We examined the validity of the MCID values for the MSWS12 and its change scores in a prospective, observational study. The actual MCID values were established using IMMPACT guidelines [7] in the context of reanalyzing data from clinical trials of fampridine and 5 other studies
Validity of MCID Values for the MSWS-12?
Eur Neurol 2014;71:196–202 DOI: 10.1159/000356116
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[6]. Perhaps the MCID values are meaningful in the context of an intervention but not longitudinal observational periods (i.e. naturally occurring changes in the absence of an intervention). Another limitation is that we included a self-reported measure of disability status rather than the Expanded Disability Status Scale [20] from a neurological examination repeated over time. This would have provided an additional clinical vantage point for interpreting the meaningfulness of changes in MSWS-12 scores. An additional possible limitation is that we examined changes over a 6-month period, and perhaps there might be correspondence between MSWS-12 and other ambulatory outcomes over shorter and/or longer periods of time. Lastly, the sample primarily included women with relapse-remitting MS who had moderate disability. This might limit broad conclusions regarding the results of this study among those with MS, and perhaps the MCID values for the MSWS-12 might still be valid in persons with severe disability.
Overall, we were surprised by the results of the present analysis that did not support the validity of MCID values from the MSWS-12 as reflecting an objective change in walking among persons with MS. We provide these data so that researchers might exert caution in interpreting changes in MSWS-12 scores until further evidence either confirms or disconfirms our observations.
Acknowledgement This project was funded by a pilot grant from the National Multiple Sclerosis Society (PP1695).
Disclosure Statement R.W.M. is a consultant and funded researcher for Biogen Idec and Acorda Therapeutics. The other authors have no conflicts of interest.
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