Neurological Impairment as Confounder or Moderater of Association Between Symptoms and Physical Activity in Multiple Sclerosis

Transcription

1 Neurological Impairment as Confounder or Moderater of Association Between and Activity in Multiple Sclerosis Robert W. Motl, PhD; Erin M. Snook, MS; Randall T. Schapiro, MD The article examines neurological impairment as a possible confounding and moderating influence of the association between symptoms and physical- behavior in individuals with multiple sclerosis (MS). The study sample included 292 individuals with a definite diagnosis of MS. Participants completed self-report measures of the frequency and intensity of symptoms, wore an accelerometer for 7 days, and completed self-report measures of physical and neurological impairment. Data analyses indicated that symptoms had a statistically significant moderate, negative relationship with physical (γ =.48); the relationship between symptoms and physical was statistically significant but attenuated when controlling for neurological impairment (β =.20); and the relationship between symptoms and physical was statistically significant and similar in magnitude for those with symptom-based (γ =.22) versus gait/ambulation-based (γ =.35) neurological impairment. These findings support the importance of considering neurological impairment as a confounding influence of the association between symptoms and physical in people with MS. Int J MS Care. 2008;10: Agrowing body of evidence supports the importance of health-promoting behaviors such as physical among people with multiple sclerosis (MS). can be described as body movement produced by the contraction of skeletal muscles that increases energy expenditure above resting levels, which would include leisuretime physical, exercise, sport, occupational work, and household chores. 1 has been associated with improvement in fitness parameters, walking mobility, and quality of life in people with MS. 2-5 Nevertheless, individuals with MS are largely sedentary, 6,7 prompting the examination of variables that are correlates of physical. The study of correlates is based on the assumption that such variables might serve as targets of a well-designed intervention for increasing physical among people with MS. From the Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL (RWM, EMS); and Department of Neurology, University of Minnesota, Minneapolis, MN (RTS), USA. are perceived indicators of change in normal functioning, sensation, or appearance 8 and have been identified as a correlate of physical in people with MS For example, one study reported that worsening of overall symptoms across a 3- to 5-year period was independently and negatively associated with self-reported levels of physical. 10 Other studies indicated that a higher number, frequency, or intensity of overall symptoms was directly and indirectly associated with lower levels of physical and with indirect-pathway involved mediator variables such as difficulty walking 11 or self-efficacy for physical. 9,12 Neurological impairment defined by Expanded Disability Status Scale (EDSS) 13 or Patient-Determined Disease Step (PDDS) 14,15 scores may play a role in the relationship between symptoms and physical by acting as either a confounder or a moderator variable. Confounders change the relationship between two variables because the confounder is jointly related to both variables and may falsely obscure or accentuate 99

2 Motl et al. the relationship. 16 Accordingly, the relationship between symptoms and physical might be the result of a joint influence of neurological impairment. Moderators influence the strength or direction of the relationship between two variables. 17 Therefore, the relationship between symptoms and physical might be stronger among people who have neurological impairment that is based primarily on symptoms (eg, EDSS <4.0 or PDDS <3.0) and weaker among those who have neurological impairment that is based primarily on gait/ambulation (eg, EDSS 4.0 or PDDS 3.0). 15 The current study extended previous research by considering neurological impairment as a confounder and moderator of the association between symptoms and physical in individuals with MS. We initially replicated previous research and tested the hypothesis that symptoms would exhibit a moderate and inverse relationship with physical. We then examined neurological impairment as a confounder and tested the hypothesis that the association between symptoms and physical would be attenuated when controlling for neurological impairment. Finally, we examined neurological impairment as a possible moderator and tested the hypothesis that the association between symptoms and physical would be stronger in people with symptom-based neurological impairment than in those with gait/ambulation-based neurological impairment. Methods Participants The convenience sample of individuals with MS was recruited from three Midwestern chapters of the National MS Society. Recruitment was conducted through mailed research announcements, advertisements placed in MS Connection quarterly publications, and messages. Individuals interested in participation underwent a brief screening for inclusion criteria by a member of the research team. The inclusion criteria involved having a definite diagnosis of MS, being relapse free in the past 30 days, and being ambulatory with minimal assistance (ie, able to walk with or without a cane). The sample consisted of 292 individuals with MS, and the descriptive features of the sample have been reported elsewhere. 18 Measures. were measured with the MS- Related Symptom Scale () 19 and the Symptom Inventory 20 ; the results facilitated the formation of an overall symptom latent variable for our data analysis. The has 26 items that are rated on a scale of 0 (never) to 5 (always). The items represent the frequency of symptoms experienced in the previous 4 weeks and yield five subscales: motor, brain stem, sensory, mental/emotional, and elimination symptoms. The items further yield an overall or composite symptom score. The overall scores on the can range between 0 and 130 and are interpreted such that higher scores represent more frequent overall symptoms. Evidence exists for the reliability and validity of the composite scores on the. 19 The internal-consistency reliability of the in the this study was The Symptom Inventory is comprised of 99 items that are rated on a scale of 0 (not at all) to 4 (a great deal). The items represent the severity of symptoms experienced in the past month and reflect six subscales (correlated with localization of brain lesions): visual, left hemisphere, right hemisphere, brain stem and cerebellum, spinal cord, and nonlocalized symptoms. The Symptom Inventory is scored by computing the mean item score for each subscale and summing the subscale mean scores for a total symptom severity score. Overall scores on the Symptom Inventory can range between 0 and 24, and higher scores indicate more intense overall symptoms. This scale has good evidence for its internal consistency and test-retest reliability and preliminary evidence for the construct, discriminant, and incremental validity of the overall score from the Symptom Inventory as a measure of symptom severity in MS. 20 The internal consistency reliability of the Symptom Inventory in this study was was measured by the Godin Leisure-Time Exercise Questionnaire () 21 and the ActiGraph single-axis accelero - meter (model 7164 version, Manufacturing Technology, Fort Walton Beach, FL). The use of both self-report and objective measures has been recognized as ideal by experts and enabled the modeling of physical as a latent variable in our data analyses. 22 is a self-administered two-part measure of usual physical ; we only included the first part in this study, consistent with previous research. 23,24 The first part has three items that measure the frequency of strenuous 100

3 (eg, jogging, vigorous swimming), moderate (eg, fast walking, easy swimming), and mild (eg, easy walking, yoga) exercise for >15 minutes during a person s free time in a typical week. The weekly frequencies of strenuous, moderate, and mild activities are multiplied by 9, 5, and 3 metabolic equivalents, respectively, and summed to form a measure of total leisure. This study used the previous week as a time frame for the, and participants completed the after wearing an accelerometer for the 7-day period. The ActiGraph accelerometer has a vertical-axis piezoelectric bender element that generates an electrical signal proportional to the force acting on it. The positive and negative acceleration signal is digitized by an analog-to-digital converter numerically integrated over an epoch interval, the integrated value of movement counts is stored in RAM, and the integrator is reset. The accelerometer is programmed for start time and epoch interval, and the movement counts are retrieved for analysis via a personal computer interface and software provided with the ActiGraph. The downloaded data from the accelerometers are then entered into Microsoft Excel for processing. Within this study, the counts for each day across a 7-day period were summed and then averaged across the 7 days, resulting in accelerometer data expressed in total movement counts per day across a 7-day period (ie, usual physical ). We have used the and accelerometers and the same procedures in our previous research on validity of physical- measures in people with MS. 23,24 Neurological impairment. Neurological impairment was measured with the PDDS scale. 14 PDDS is a self-report questionnaire that contains a single item for measuring self-reported neurological impairment with an eight-level ordinal scale. Scores between 0 and 2 represent symptom-based neurological impairment, whereas scores between 3 and 6 represent gait/mobility-based neurological impairment and approximate EDSS scores between 4 (gait disability without need for assistive device) and 6.5 (gait disability with need for assistive device). 15 Indeed, PDDS is a surrogate measure of the EDSS, and scores from the PDDS are linearly and strongly related to physician-administered EDSS scores (r = 0.93). 14 Procedure After initial telephone contact and voluntary participation, an informed-consent document and a form letter for verifying the participant s diagnosis of MS were sent to all participants through the US Postal Service. The researchers called to make sure the participants received the documents, understood the directions, and signed the informed-consent document. Once the signed informed consent was returned, two batteries of questionnaires and an accelerometer were mailed to all participants. The researchers called to make sure the participants received the package and understood the directions. Participants completed the first battery of questionnaires, which included the Symptom Inventory and, and then wore the accelerometer for 7 days. After the 7-day period, participants completed the second battery of questionnaires, which included the and PDDS. Participants then mailed the study materials back. All participants received $20 on return of the study materials. Data Analysis The data were analyzed via covariance modeling and Full-Information Maximum Likelihood estimation in Mplus This estimator was selected because accelerometer data were missing (4%), and the estimator is an optimal method for treatment of missing data in covariance modeling in that it has yielded accurate fit indices with simulated missing data. 26 The first model that we tested included a direct association between symptoms and physical. were modeled as a latent variable by using and Symptom Inventory overall scores as indicators (Figure 1). Physi Figure 1. Model tested with covariance modeling to understand association between symptom and physical latent variables in individuals with multiple sclerosis. Notes: N = 292. All coefficients are standardized estimates., MS-Related Symptom Scale;, Symptom Inventory;, Godin Leisure-Time Exercise Questionnaire;, accelerometer counts. 101 and Activity

4 Motl et al cal was modeled as a latent variable by using scores and accelerometer counts as indicators. This model gave an indication of the strength of association between symptoms and physical in the current study. The second model that we tested included a direct association between symptoms and physical, controlling for the confounding influence of neurological impairment (Figure 2). The third model included a direct association between symptoms and physical within dichotomous groups of individuals who had symptom- or gait/ambulation-based neurological impairment based on previously described guidelines for PDDS scores (Figure 3). 15 As noted above, individuals with PDDS scores 2 were placed in the symptom-based neurological impairment group (n = 145), whereas those with PDDS scores 3 were placed in the gait/ambulation-based neurological impairment group (n = 146). 15 One individual had a missing PDDS score and was not placed in either group. The moderator analysis was undertaken by testing the equivalence of the overall model structure, factor loadings, and then path coefficients, which is an accepted approach for testing moderation. 16 The latter test of equivalent path coefficients directly compares the magnitude of the correlation between symptoms and physical between groups differing in neurological impairment (ie, moderation). Model fit was assessed with the χ 2 test, standardized root-mean-squared residual (SRMR), and comparativefit index (CFI). The χ 2 test provides a simultaneous test PDDS D Figure 2. Model tested with covariance modeling for understanding neurological impairment as confounder of association between symptom and physical in individuals with multiple sclerosis. Notes: N = 292. All coefficients are standardized estimates., MS-Related Symptom Scale;, Symptom Inventory;, Godin Leisure-Time Exercise Questionnaire;, accelerometer counts; PDDS, Patient-Determined Disease Steps. Table 1. Descriptive statistics for measures in individuals with multiple sclerosis Mean Standard Measure score deviation Range MS-Related Symptom Scale Symptom Inventory Godin Leisure-Time Exercise Questionnaire erometer counts 220, ,059 32, ,722 Patient-Determined Disease Steps Note: N = that all residuals in the specified versus obtained variance/covariance matrices are zero. 27 SRMR is the average of the standardized residuals between the specified and obtained variance/covariance matrices. 27 CFI tests the proportionate improvement in fit by comparing the target model with the independence model (ie, model with no correlations among observed variables). We based a good model data fit on a nonsignificant χ 2 value 27 and combinatory rules of SRMR 0.08 and CFI The nested models were compared based on χ 2 difference tests, with a nonsignificant change in model fit supporting the invariance of the model parameters. 27 Results Descriptive statistics for the variables are given in Table 1 and the correlations among the variables in Table 2. The correlations were all statistically significant (P <.05). The first model that we tested had a direct path between symptoms and physical, and it represented an excellent fit for the data (χ 2 = 0.06, df = 1, P =.80, SRMR = 0.00, CFI = 1.00). The factor loadings and path coefficient are shown in Figure 1. The path coefficient between symptoms and physical was statistically significant (γ =.48) and indicated that individuals who had more frequent and intense symptoms were less physically active.

5 Table 2. Correlations among variables for individuals with multiple sclerosis Measure MS-Related Symptom Scale 2. Symptom Inventory Godin Leisure-Time Exercise Questionnaire erometer counts Patient-Determined Disease Steps Note: N = 292. All correlations are statistically significant (P <.05). The second model included neurological impairment as a confounder of the association between symptoms and physical. This model represented an excellent fit for the data (χ 2 = 3.94, df = 3, P =.27, SRMR = 0.02, CFI = 1.00). The statistically significant path coefficients are shown in Figure 2. Neurological impairment had significant relationships with both symptoms (γ =.64) and physical (γ =.35). The relationship between symptoms and physical was significant but reduced in magnitude (β =.20), suggesting that neurological impairment is a possible confounder of the association between symptoms and physical. The third model included neurological impairment as a moderator of the association between symptoms and physical. The analysis was conducted by testing the equivalence of the overall model structure, factor loadings, and path coefficients between peop l e with symptom-based (PDDS 2; n = 145) and gait/ ambulation-based (PDDS 3; n = 146) neurological impairment. All three analyses provided an excellent fit for the overall model structure (χ 2 = 0.03, df = 2, P =.93, SRMR = 0.00, CFI = 1.00), factor loadings (χ 2 = 1.31, df = 4, P =.86, SRMR = 0.00, CFI = 1.00), and path coefficients (χ 2 = 1.51, df = 5, P =.91, SRMR = 0.00, CFI = ). The χ 2 difference tests did not identify statistically significant changes in fit between nested models: overall model structure versus factor loadings (χ 2 = diff 1.28, df = 2, P =.53) and factor loadings versus path coefficients (χ 2 = 0.20, df = 1, P =.65). Indeed, the diff relationship between symptom and physical was statistically significant and similar in magnitude in participants with symptom-based (γ =.22) and gait/ambulation-based (γ =.35) neurological impairment, suggesting that neurological impairment might not moderate the association between symptoms and physical. Discussion MS is associated with a high prevalence of physical in, 6,7 and symptoms have been identified as a correlate of physical in this population The current study extended previous research by examining neurological impairment as both a confounder and a moderator of the association between symptoms and physical in individuals with MS. The initial analysis indicated that symptoms were negatively and moderately associated with physical. Subsequent analyses demonstrated that neurological impair- Symptom-based neurological impairment (PDDS 2; n = 145) Gait/ambulation-based neurological impairment (PDDS 3; n = 146) Figure 3. Model tested with covariance modeling for understanding neurological impairment as moderator of association between symptom and physical in individuals with multiple sclerosis. Notes: N = 291. All coefficients are standardized estimates., MS-Related Symptom Scale;, Symptom Inventory;, Godin Leisure-Time Exercise Questionnaire;, accelerometer counts; PDDS, Patient-Determined Disease Steps. 103 and Activity.55.52

6 Motl et al. ment weakened the magnitude of the relationship between symptoms and physical, but the magnitude of the relationship did not differ significantly between groups of individuals with MS who had symptom- and gait/ambulation-based neurological impairment. These findings indicate that neurological impairment is a confounder rather than a moderator of the association between symptoms and physical in people with MS. Therefore, symptoms are a possible target for increasing the physical- behavior of these individuals regardless of the source of neurological impairment, although the association appears weaker than previously reported after controlling for neurological impairment. A growing body of research has identified symptoms as a correlate of physical in MS Those studies have reported a moderate inverse association whereby the number, frequency, intensity, and worsening of symptoms are associated with reduced physical. Only one of the studies accounted for the possible confounding influence of neurological impairment, and controlling for neurological impairment based on EDSS scores did not weaken the relationship between the dichotomous worsening of symptoms and selfreported physical in the small sample (N = 51) of individuals with MS. 10 By comparison, the current study included a much larger sample (N = 292) and indicated that controlling for neurological impairment based on PDDS scores attenuated the association between symptoms and physical. Four obvious differences between the two studies could explain the discrepant findings, including the measure of neurological impairment, sample size, measurement of symptoms and physical, and data analyses. PDDS is a surrogate of the EDSS, 15 and EDDS and PDDS are strongly correlated (r = 0.93). 14 Therefore, the measurement of neurological impairment would seemingly not represent a strong explanation for the discrepancy in findings between studies. Rather, the current study included a larger sample, better measurement of symptoms and physical, and more sophisticated data analyses, and these differences more strongly characterized the association between symptoms and physical, controlling for neurological impairment. To that end, our results provided preliminary evidence that neurological impairment is a confounding variable in the association between symptoms and physical in people with MS. Therefore, symptoms are a correlate of physical behavior in individuals with MS; however, the association appears weaker than previously reported after controlling for neurological impairment. This study further extended previous research by examining neurological impairment as a moderator of the association between symptoms and physical. To that end, the analysis indicated that the association between symptoms and physical was similar in magnitude between groups that had symptom- and gait/ambulation-based neurological impairment. This finding might have implications for the promotion and maintenance of a physically active lifestyle in people with MS. Indeed, individuals with MS are often physically inactive and sedentary, 6,7 and emerging evidence indicates that symptoms might be a determinant of in in this population. Management of symptoms is one possible strategy for the promotion and maintenance of physical among people with MS regardless of the latent cause of neurological impairment (ie, symptom vs gait/ambulation). Accordingly, one direction for future research should incorporate pharmacological and nonpharmacological approaches for symptom management into a program for promoting physical- behavior in people with MS, regardless of the latent cause of neurological impairment. The focus on symptoms as a method of increasing physical might be as salient for clinicians and rehabilitation specialists. This study has some limitations. For example, we focused on neurological impairment as a dichotomous moderator of the association between symptoms and physical. We recognize that statistical approaches exist for examining moderators as a continuous variable, but these approaches have significant weaknesses, primarily involving poor statistical power and precision. 16 Also, we focused on global rather than specific symptoms (eg, incontinence or confusion), but previous research has not supported the notion that specific symptoms including incontinence, pain, fatigue, and depression are stronger correlates of physical than general symptoms in people with MS. 11,12 The most obvious area for future clinical research is to examine the effects of symptom-management pro- 104

7 and Activity grams individually and as part of a physical- intervention on increasing levels of physical- behavior among people with MS. Perhaps an additional benefit of these programs would be an increase in physical among this population, but such an effect has not yet been clinically evaluated. Another research direction would be a longitudinal examination of the association between changes in symptoms as a predictor of changes in physical across time in MS. In conclusion, the results of this study are a basis on which to consider the role of neurological impairment as a confounder, but not a moderator, within the growing body of knowledge that symptoms play a role in physical among people with MS. The role of symptoms in the physical- behavior of these individuals is an area ripe with research potential for promoting and maintaining physical. An active lifestyle is an important health-promoting behavior for people with MS. 2-5 References 1. Bouchard C, Shephard RJ., fitness and health: the model and key concepts. In: Bouchard C, Shephard RJ, Stephens T, eds. Activity, Fitness, and Health: International Proceedings and Consensus Statement. Champaign, IL: Human Kinetics; 1994: Brown TR, Kraft GH. Exercise and rehabilitation for individuals with multiple sclerosis. Phys Med Rehabil Clin N Am. 2005;16: Motl RW, Gosney JL. Effect of exercise training on quality of life in multiple sclerosis: a meta-analysis. Mult Scler. 2008;14: Rietberg MB, Brooks D, Uitdehaag BMJ, et al. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rev. 2004;3: CD Snook EM, Motl RW. Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis. Neurorehabil Neural Repair. In press. 6. Motl RW. and its measurement and determinants in multiple sclerosis. Minerva Med. 2008;99: Motl RW, McAuley E, Snook EM. and multiple sclerosis: a meta-analysis. Mult Scler. 2005;11: Lenz ER, Pugh LC, Milligan RA, et al. The middle-range theory of unpleasant symptoms: an update. Adv Nurs Sci. 1997;19: Motl RW, Arnett PA, Smith MM, et al. Worsening of symptoms is associated with lower physical levels in individuals with multiple sclerosis. Mult Scler. 2008;14: Motl RW, Snook EM, McAuley E, et al., self-efficacy, and physical among individuals with multiple sclerosis. Res Nurs Health. 2006;29: Motl RW, Snook EM, Schapiro RT. and physical behavior in individuals with multiple sclerosis. Res Nurs Health. 2008;31: Snook EM, Motl RW. behaviors in individuals with multiple sclerosis: roles of overall and specific symptoms, and selfefficacy. J Pain Symptom Manage. 2008;36: Kurtzke JF. Historical and clinical perspectives of the Expanded Disability Status Scale. Neuroepidemiology. 2008;31: Hadjimichael O, Kerns RB, Rizzo MA, et al. Persistent pain and uncomfortable sensations in persons with multiple sclerosis. Pain. 2007;127: Marrie RA, Cutter G, Tyry T, et al. Does multiple sclerosis-associated disability differ between races? Neurology. 2006;66: MacKinnon DP. Introduction to Statistical Mediation Analysis. New York: Lawrence Erlbaum Associates; Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986;5: Motl RW, McAuley E, Snook EM, et al. and quality of life in multiple sclerosis: intermediary roles of disability, fatigue, mood, pain, self-efficacy, and social support. Psychol Health Med. In press. 19. Gulick EE. Model confirmation of the MS-Related Symptom Checklist. Nurs Res. 1989;38: Schwartz CE, Vollmer T, Lee H. Reliability and validity of two selfreport measures of impairment and disability for MS. Neurology. 1999;52: Godin G, Shephard RJ. A simple method to assess exercise behavior in the community. Can J Appl Sport Sci. 1985;10: Dishman RK, Washburn RA, Schoeller DA. Measurement of physical. Quest. 2001;53: Gosney JL, Scott JA, Snook EM, et al. and multiple sclerosis: validity of self-report and objective measures. Fam Commun Health. 2007;30: Motl RW, McAuley E, Snook EM, et al. Validity of physical measures in ambulatory individuals with multiple sclerosis. Disabil Rehabil. 2006;28: Muthén LK, Muthén BO. Mplus User s Guide. Los Angeles, CA: Muthén & Muthén; Enders CK, Bandalos DL. The relative performance of full information maximum likelihood estimation for missing data in structural equation models. Struct Equat Model. 2001;8: Bollen KA. Structural Equations With Latent Variables. New York: Wiley; Hu L, Bentler PM. Cutoff criteria for fit indices in covariance structure analysis: conventional criteria versus new alternatives. Struct Equat Model. 1999;6:1 55. Acknowledgments: This study was funded by the National Institute of Neurological Diseases and Stroke (NS054050). The authors have no conflicts of interest to disclose. 105