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INTRODUCTION
Duchenne muscular dystrophy (DMD) is one of the most commonly inherited genetic muscular disorders. While no curative treatments are currently available, the use of corticosteroids and assisted ventilation delays disease progression, prolongs function, and improves the overall quality of life in patients diagnosed with DMD [1]. With advances in basic and clinical DMD research, novel treatments and interventions are being developed and evaluated, with improvement in functional status serving as the benchmark of effectiveness [2,3]. Yet, clinical scales currently available to assess the functional capacity of patients with DMD present several limitations, which restrict their use as reliable outcome measures in evaluating the effectiveness of clinical interventions and predicting the prognosis.
Principal limitations of current functional scales include non-specificity; time required to complete the assessment and poor clinical applicability and relevance; low cultural sensitivity; and poor alignment with interventions currently used for the clinical management of patients with DMD. The Vignos Functional Scale highlights the poor alignment between assessment and current intervention trends, based on an assessment of the effect of knee-ankle-foot orthosis (KAFO) on function; KAFOs are no longer commonly used due to their discomfort and the weak scientific evidence supporting their effectiveness in prolonging functional walking [4,5]. From a perspective of cultural sensitivity, preference for floor-sitting in Asian cultures would further, artificially, reduce the use of KAFOs [6]. Additionally, the widespread use of powered wheelchairs to promote participation is not factored in currently available functional scales [7].
Our study addresses these specific limitations of current functional scales with the development of a simplified functional scale and classification system to evaluate functional abilities in patients with DMD. Our purpose, here, is to describe the methods of development of our Comprehensive Functional Scale for DMD (CFSD) and Ambulatory Functional Classification System for DMD (AFCSD), and to report the results of preliminary testing of inter-rater reliability and concurrent validity.
MATERIALS AND METHODS
All the study procedures were approved by the Institutional Review Board of Seoul National University Hospital (No. 1110-096-382 and 1104-032-357). Informed consent, or assent as appropriate for participants’ age, was obtained for the assessment of reliability and validity.
The CFSD was developed using the modified Delphi method [8]. The process consisted of three stages: item generation (stage 1); primary item reduction and scale development (stage 2); and scale evaluation (stage 3). The expert panel was composed of a single pediatric neurologist and six physiatrists. Reliability and validity testing was directed by two statisticians. Authors gathered opinions, provided feedback, and reported conclusions to the expert panel, by e-mail or mail as appropriate, throughout the developmental process and reliability and validity testing.
The AFCSD was based on the Gross Motor Function Classification System [9], the Communication Function Classification System [10], and the Manual Ability Classification System [11]. The AFCSD comprises 5 levels, defined as follows: level 1, walking at normal speed and with normal postural alignment ; level 2, walking independently without an assistive device or brace, with evidence of abnormal gait patterns, such as tip-toeing or waddling, and with impaired postural alignment, such as excessive trunk lordosis; level 3, walking across only short distances, using a hand-held mobility device, such as a walker or crutch; level 4, inability to walk and use of a powered wheelchair; and level 5, need for transportation in a manual wheelchair. These 5 classification levels are presented in Fig. 1.
Stage 1: Item generation
The MEDLINE database was searched from January 1965 to June 2009 using the following combinations of terms: (Duchenne muscular dystrophy OR muscular dystrophy) AND (functional evaluation OR functional scale OR activities of daily living). The search identified 305 articles, describing the following key functional scales: the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [12]; the Barthel Index [13]; the Modified Barthel Index [14]; the Muscular Dystrophy-Specific Functional Rating Scale [15]; the Modified Hammersmith Functional Motor Scale [16]; the Motor Performance Test [17]; the Pediatric Evaluation of Disability Inventory [18]; the Vignos Scale; the Brooke Scale [19]; the Wee Functional Independence Measure [20]; the Gross Motor Function Measure; the Physical Self-Maintenance Scale [21] and the measure of activities of daily living (ADL) and instrumental ADL [21]. A preliminary pool of items was generated following a series of expert panel meetings. Refinement of the preliminary item selection was conducted via a two-step process. In the first step, a closed questionnaire was sent to the members of the expert panel to obtain individual information pertaining to the importance of each item and sub-item (e.g., sitting item and related sub-items for each posture and activity, as described in Supplementary Table S1). The perceived importance of items and sub-items was measured on a Likert scale, ranging from 1 to 5, with the following descriptions provided: very unimportant, unimportant, not important or unimportant, important, and very important. In the second step, the results of the closed-questionnaire were tabulated and summarized as a total score and a mean (SD) score for each item and sub-item, and provided to the expert panel.
Each panel member was asked to review the results and to re-score items and sub-items as they deemed applicable.
Stage 2: Primary item reduction and scale development
Following the second round of scoring, ranked items were shared with the expert panel and classified into functional domains. A modified Delphi approach, in conjunction with subsequent meetings of the expert panel, was used to select relevant items and sub-items from the pool of items identified at the end of stage 1.
Stage 3: Preliminary evaluation of the inter-rater reliability and validity of the CFSD and AFCSD
The inter-rater reliability of the CFSD and the AFCSD was evaluated in 48 boys diagnosed with DMD, with a mean age of 5.29±3.51 years. All the items and sub-items were tested by two clinical experts on the same day, a pediatric physiatrist and a pediatric physical therapist. Items derived from established objective measurements, such as the Cobb angle of scoliosis or intelligence quotients, were not included in the evaluation of reliability.
Inter-rater reliability of the CFSD and AFCSD, as well as of the Vignos and the Brooke Scales, was evaluated using the intraclass correlation coefficient (ICC), with ICC values >0.7 suggesting acceptable level of reliability. Bland-Altman plots and limits of agreement (mean±1.96 SD) were also calculated.
The concurrent validity of the CFSD and AFCSD was evaluated against established functional scales, namely the Vignos and the Brooke Scales. Spearman correlation coefficients were calculated between the total scores of the AFCSD and both the Vignos and the Brooke scales, to provide a global measure of validity. Specific validity of the CFSD was evaluated by comparing total scores on the CFSD to scores for each grade of function on the Vignos and the Brooke scales, and for the 5 levels of the AFCSD. The level of concordance between the grades of the Vignos and Brooke scales and the levels of the AFCSD was assessed using the Kruskal-Wallis test, with the Wilcoxon rank sum test used for post-hoc analyses of differences detected between the scales, with corrections for multiple comparisons according to the false detection rate (FDR) method.
All the statistical analyses were performed using the R3.1.0 GUI, with the level of significance set at p<0.05.
RESULTS
The new functional scale for Duchenne muscular dystrophy
A preliminary pool of 174 items, described in Supplementary Table S1, was identified from the structured review of the literature and the series of the expert panel meetings. These items were classified into the following 9 functional domains: mobility, ADL, muscle power, joint contracture, pulmonary function, cardiac function, scoliosis, pain, and cognitive and social function. Highly scored items in each of the 9 domains of function were extracted. In circumstances involving two or more items within a domain sharing similar component activities (e.g., transferring from the bed to a wheelchair and from the wheelchair to a toilet seat), only one item was selected. In addition, when items with a broader meaning yielded scores similar to items measuring specific attributes (e.g., the activity of eating in comparison to individual items of feeding, swallowing, and drinking, which contribute to this activity), the item with the broader meaning was included. The importance of peak cough flow, pulmonary function tests, electrocardiograms, and echocardiograms was acknowledged, and these items were excluded as they are known to be independently associated with the functional prognosis of patients with DMD.
Following the methods for item reduction, 21 items and 78 sub-items were retained across the following 7 domains: mobility (8 items), ADL (6 items), contractures (2 items), pulmonary function (2 items), cardiac function (1 item), scoliosis (1 item), and cognition (1 item) (Table 1). A variable grading system was developed to produce a range of qualitatively different levels of functional performance. For example, the item ‘using drugs for heart disease’ was graded on a 2-point scale, 0 and 3 representing negative and affirmative responses, respectively. The total score on the CFSD ranged from a minimum score of 0 to a maximum score of 63, with higher scores representing higher function, and hence, less severe diseaserelated impairment. The full items and scoring systems are described in Table 1.
Reliability and validity
Reliability
The ICCs between two examiners are reported in Table 2. Two out of the 48 subjects were excluded from the analysis due to missing discrete item scores. Interrater ICC values were below the cutoff of 0.7, set a priori, for the following four CFSD items: indoor activities (ICC=0.680), personal computer utilization (ICC=0.638), ventilator assist (ICC=0.662), and presence of dyspnea (ICC=0.453). Evaluation of the limits of agreement of the total AFCSD score between the two examiners indicated disagreement for a discrete outlier within one level (Fig. 2). With this exception, the overall limits of agreements ranged between -6.21 and 3.11 (Fig. 3A). These limits of agreement narrowed to a range of -5.54 to 3.19 when the items scoring ICC values <0.7 were removed from the calculation (Fig. 3B).
Validity
The Spearman correlation coefficient between the total score on the CFSD and on the Vignos scale was 0.833 (p<0.001), and 0.714 (p<0.001) between the total score of the CFSD and the Brooke Scale. The following significant correlations were calculated between the total CFSD score and the Vignos and Brooke scales or AFCSD: -0.818, -0.645, and -0.686 for the Vignos Scale, the Brooke Scale, and the AFCSD, respectively (p<0.001 for all pairs).
The mean (SD) scores for the CFSD score and each grade of the Vignos and Brooke scales, and the levels of the AFCSD are presented in Table 3. As shown in Fig. 4A, the total scores varied significantly between the following functional grades of the Vignos scale: 1 and 2; 1 and 4; 1 and 9; 2 and 9; 3 and 9; and 4 and 9. For the Brooke scale, the total scores were distinct for functional grades 2 and 3 (Fig. 4B). For the AFCSD, the total scores varied significantly between the functional levels 1 and 5 and 2 and 5 (Fig. 5).
DISCUSSION
In this study, we describe the development and preliminary testing of inter-rater reliability and concurrent validity of a new functional scale and functional classification system for children diagnosed with DMD, the CFSD and AFCSD, respectively. These two new clinical assessments consist of items deemed essential to the function of patients with DMD based on the results of our longitudinal study [22]. By incorporating items from all three domains of the International Classification of Functioning, Disability, and Health (ICF), including body functions and structures, activities, and participation, our novel clinical tools provide a comprehensive functional assessment of patients with DMD. Furthermore, we have improved the relevance of our assessment compared with currently available clinical tools, by including items reflective of technology utilization, such as personal computers and powered-wheelchairs. Therefore, we propose that our functional scale and classification system provide meaningful outcomes in evaluating the effectiveness of novel treatments and interventions in an effort to improve the outcomes of patients with DMD, as well as to more reliably predict clinical prognosis. The CFSD and AFCSD, therefore, represent valuable tools to include in the large number of clinical trials investigating patients with DMD.
A new functional scale for Duchenne muscular dystrophy
Novel items of the CFSD evaluating indoor activities, personal computer utilization, ventilator assistance, and presence of dyspnea scored ICC values <0.7. A review of these items indicates that the low reliability of the scores may reflect the vagueness of terms used, such as ‘active’ and ‘simple’ social interactions, which may be interpreted differently by different examiners. Language subtleties may influence the reliability scores. As an example, while mechanical ventilators and mechanical insufflators and exsufflators have adistinct meaning in English, a common wording is used in Korean (‘hoheup-bojogi’ vs. ‘kichimbojogi’). The low reliability scores for items on dyspnea may specifically reflect the existing vagueness surrounding the description of respiratory symptoms in children with DMD. For example, dyspnea associated with ventilation insufficiency rather than oxygenation insufficiency tends to be poorly differentiated until symptoms become severe and require intervention.
The total CFSD scores correlated strongly with the total scores on the Vignos and the Brooke scales. These high correlation coefficient scores might be useful to differentiate mild functional impairments, as the scores varied significantly from those for grades 1 and 2 on the Vignos scale (Fig. 4A). This sensitivity of the CFSD and AFCSD in differentiating grades of function in children in the early (mild) phases of DMD progression might be important in measuring changes after medical interventions and rehabilitation in the early stages of DMD. However, we must also consider the benefit of less granular classification grades; as an example, grade 2 on the Brooke scale includes a broad range of total scores (Fig. 4B), which might reflect diverse compensatory strategies that children with DMD adopt to accomplish functional goals during the early stages of the disease.
Ambulatory functional classification system for Duchenne muscular dystrophy
The high Spearman correlation coefficients between the AFCSD and the Vignos and the Brooke scales indicate concurrent validity of the AFCSD. However, as 34 of the 46 participants in this study (73.9%) were classified under level 1 or 2 on the AFCSD, with only a few children classified under levels 3 and 4, the total CFSD scores varied significantly only between levels 1 and 5 and levels 2 and 5. As the scores were not normally distributed, the mean (SD) values of total scores within each classification level could not be calculated.
Limitations
The study group manifested a skewed distribution of disease severity, with the majority of children in the mild phase of the disease: 28/46 (60.9%) and 33/46 (71.7%) classified under grades 1 and 2 of the Vignos and Brooke scales, respectively, whereas 34/46 (73.9%) were classified under levels 1 and 2 of the AFCSD. Validation of the CFSD and AFCSD for children at more progressive stages of disease severity requires large-scale clinical trials, with a normal distribution of participants across all stages of DMD disease severity.
Each stage of the AFCSD represents the functional levels of children with DMD. However, it does not contain age-specific or developmental stage-specific information. Further validation and modification of each stage requires testing in a larger population of children with DMD.
The intra-rater reliability of each item of the CFSD was not tested in this study as the participants and their legal guardians refused to undergo prolonged evaluation. Intra-rater reliability of each item should be further investigated in a subsequent study. The validity of the CFSD also needs to be tested further using comprehensive evaluation tools such as the Gross Motor Functional Measure, Modified Barthel Index, Pediatric Evaluation of Disability Inventory, and Functional Independence Measure for Children (WeeFIM).
Relatively new functional scales, such as North Star Ambulatory Assessment [23] or motor function measurement scale were not included in the item generation because they were not widely used at the time this study was conducted.
Conclusions
We have developed a new scale, and associated classification system, to assess function in patients diagnosed with DMD. Preliminary evaluation of the psychometric properties of the functional scale and classification system indicate sufficient reliability and concurrent validity to include the CFSD and AFCSD in large-scale clinical trials.
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