Rasch analysis of clinical outcome measures in spinal muscular atrophy

Introduction: Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). Methods: Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. Results: Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. Conclusions: The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges. Muscle Nerve 49 :422–430, 2014     

Rasch analysis of the Pediatric Evaluation of Disability Inventory–computer adaptive test (PEDI‐CAT) item bank for children and young adults with spinal muscular atrophy

Introduction: In this study we evaluated the suitability of a caregiver‐reported functional measure, the Pediatric Evaluation of Disability Inventory–Computer Adaptive Test (PEDI‐CAT), for children and young adults with spinal muscular atrophy (SMA). Methods: PEDI‐CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. Results: Unidimensional content for each domain was confirmed. The PEDI‐CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. Conclusions: The PEDI‐CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54 : 1097–1107, 2016     

International clinimetric evaluation of the MG‐QOL15, resulting in slight revision and subsequent validation of the MG‐QOL15r

Introduction: The MG‐QOL15 is a validated, health‐related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties. Methods: We first performed Rasch analysis on >1,300 15‐item Myasthenia Gravis Quality of Life scale (MG‐QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG‐QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on >1,300 MG‐QOL15r scales. Results: The MGQOL15r performed slightly better than the MG‐QOL15. The 3‐response option MG‐QOL15r demonstrated better clinimetric properties than the 4‐ or 5‐option scales. Relative distributions of item and person location estimates showed good coverage of disease severity. Conclusions: The MG‐QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG‐QOL15. Muscle Nerve 54 : 1015–1022, 2016     

Establishing conversion of the 16-item Informant Questionnaire on Cognitive Decline in the Elderly scores into interval-level data across multiple samples using Rasch methodology

Background

The 16-item Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE-16) is a well-validated and widely-used measure of cognitive changes (CCs) among older adults. This study aimed to use Rasch methodology to establish psychometric properties of the IQCODE-16 and validate the existing ordinal-to-interval transformation algorithms across multiple large samples.

Methods

A Partial Credit Rasch model was employed to examine psychometric properties of the IQCODE-16 using data (n = 918) from two longitudinal studies of participants aged 57–99 years: the Older Australian Twins Study (n = 450) and the Canberra Longitudinal Study (n = 468), and reusing the Sydney Memory and Ageing Study (MAS) sample (n = 400).

Results

Initial analyses indicated good reliability for the IQCODE-16 (Person Separation Index range: 0.82–0.90). However, local dependency was identified between items, with several items showing misfit to the model. Replicating the existing Rasch solution could not reproduce the best Rasch model fit for all samples. Combining locally dependent items into three testlets resolved all misfit and local dependency issues and resulted in the best Rasch model fit for all samples with evidence of unidimensionality, strong reliability, and invariance across person factors. Accordingly, new ordinal-to-interval transformation algorithms were produced to convert the IQCODE-16 ordinal scores into interval data to improve the accuracy of its scores.

Conclusions

The findings of this study support the reliability and validity of the IQCODE-16 in measuring CCs among older adults. New ordinal-to-interval conversion tables generated using samples from multiple independent datasets are more generalizable and can be used to enhance the precision of the IQCODE-16 without changing its original format. An easy-to-use converter has been made available for clinical and research use.     

Fatigue and daytime sleepiness scale in myotonic dystrophy type 1

Introduction: Fatigue and excessive daytime sleepiness are frequent complaints in myotonic dystrophy type 1 (DM1) that often overlap. We aimed to construct a combined fatigue and daytime sleepiness rating scale for DM1 using the Rasch measurement model. Methods: Questionnaires, including the Epworth Sleepiness Scale, Fatigue Severity Scale, and Daytime Sleepiness Scale, were completed by 354 patients. Data were subjected to Rasch analyses and tested for required measurement issues such as appropriate response categories, absence of item bias, local independence, and unidimensionality. Results: The initial 22 items did not meet Rasch model expectations. After rescoring and removing misfitting items, the final 12‐item scale showed good model fit and unidimensionality. High internal consistency (person separation index = 0.80) and validity were demonstrated. Conclusions: The Rasch‐built Fatigue and Daytime Sleepiness Scale, developed specifically for DM1 patients, provides interval measures on a single continuum. Its use is suggested for future clinical trials and therapeutic follow‐up. Muscle Nerve, 2013     

Psychometric evaluation of the myasthenia gravis composite using Rasch analysis

Introduction: The MG Composite (MGC) is a validated outcome measure of the clinical manifestations of myasthenia gravis. Methods: We performed Rasch analyses of the MGC to investigate additional properties, including its unidimensionality and the appropriateness of the weights assigned to the response categories for the MGC items. Results: The fit statistics indicated that the 10 items belong together and can be summated for a total score. There was an overall absence of item order distortion between response categories. The Rasch model's expected category response values were compatible with item weights previously assigned. Conclusions: Our analysis suggests that: (1) the score can be summated to estimate an overall disease severity score; (2) the response options of the 10 items are not significantly distorted; and (3) the assigned weights of the response options are appropriate. Muscle Nerve 45: 820–825, 2012     

Clinical trial of L‐Carnitine and valproic acid in spinal muscular atrophy type I

Introduction: The aim of this study was to determine the safety and therapeutic potential of L ‐carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). Methods: Our investigation was an open‐label phase 2 multicenter trial of L ‐carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. Results: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. Discussion: This trial provides evidence that, in infants with SMA type I, L ‐carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end‐points within 6 months of enrollment underscores the urgent need for pre‐symptomatic treatment in SMA type I. Muscle Nerve 57 : 193–199, 2018     

A new look at the construct validity of the K6 using Rasch analysis

The Kessler six‐item psychological distress (K6) scale is widely used to screen for mental disorders; however, information is lacking on the rating scale performance or dimensionality structure of the scale. This study used a population based sample (n = 7596) to evaluate the construct validity of the K6 scale using Rasch partial credit analysis. The analysis showed that almost all of the five‐point rating scales in the K6 items were used appropriately to differentiate psychological distress of the study participants. The analysis provided evidence of unidimensionality of the scale, although items 1 (so sad) and 3 (restless or fidgety) might offer a potential second off‐dimensional component. All items appeared to fit the Rasch model's expectation as demonstrated by the acceptable item fit statistics. The study participants demonstrated valid response patterns when answering K6 items, except for some who were younger or had higher psychological distress. This study using Rasch analysis confirms the construct validity of the K6 scale and suggests that the K6 is a useful and valid instrument for assessing psychological distress in the mid‐aged general population. Further research can facilitate better understanding about the unidimensionality of the scale. Copyright © 2014 John Wiley & Sons, Ltd.     

Severe brain involvement in 5q spinal muscular atrophy type 0

Spinal muscular atrophy (SMA) type 0 is the most severe form of SMA, associated with the SMN1 gene and manifesting at birth. Most patients die in the first weeks of life. In this work, we present 3 patients with SMA type 0 who survived >1 year and presented diffuse and progressive brain abnormalities on magnetic resonance imaging, which are not usually seen in patients with SMA. Thus, severe brain involvement may likely be the full end manifestation of an already extreme SMA phenotype caused by substantial reduction of the SMN protein in the brain. ANN NEUROL 2019;86:458–462     

Short apraxia screening test

Background: Limb apraxia comprises many different and common disorders, which are largely unrecognized essentially because there is no easy-to-use screening test sensitive enough to identify all types of limb praxis deficits. Method: We evaluated 70 right-handed patients with limb apraxia due to a single focal lesion of the left hemisphere and 40 normal controls, using a new apraxia screening test. The test covered 12 items including: intransitive gestures, transitive gestures elicited under verbal, visual, and tactile modalities, imitation of meaningful and meaningless postures and movements, and a multiple object test. Results: Interrater reliability was maximum for a cutoff of >2 positive items identifying apraxia on the short battery (Cohen’s kappa .918, p < .0001), and somewhat less for >3 items (Cohen’s kappa .768, p < .0001). Although both results were statistically significant, >2 was higher, indicating greater apraxia diagnosis agreement between raters at this cutoff value. Conclusions: The screening test proved to have high specificity and sensitivity to diagnose every type of upper limb praxis deficit, thus showing advantages over previously published tests.     

Ictal SPECT in supplementary motor area seizures

Abstract

Objectives: We used ictal single photon emission computed tomography (SPECT) to clarify the propagation pathways of epileptic discharges in patients with supplementary motor area (SMA) seizure.

Methods: In four patients (four males, age range, 18–27 years) with SMA seizures, SPECT studies by radioisotope 99mTc-ECD were performed as a preoperative evaluation. Two of the patients remained seizure-free after complete resection of the focal cortical dysplasia on magnetic resonance (MR) images including epileptic foci. In the other two patients, MR images were normal, but subdural electrode monitoring allowed for verifying the ictal onset in the left SMA. After partial resection of the SMA including epileptic foci, these patients experienced a significant (>90%) reduction of seizure frequency. Regional cerebral blood flow (rCBF) measurements obtained under ictal and interictal conditions were compared on a voxel-by-voxel basis by means of the SPM99 paired t-test option (uncorrected p<0.001).

Results: Significant increases in rCBF under ictal conditions were identified in the bilateral anterior cingulate cortex (ACC), the globus pallidus ipsilateral to epileptic foci and the contralateral cerebellar hemisphere. The right ACC included a cluster with a submaximum in the right primary sensorimotor area.

Discussion: In patients with SMA seizures, the hyperperfusion areas of ictal SPECT did not localize within the SMA but spread to the adjacent cortex such as the ACC and sensorimotor cortex ipsilateral to epileptic foci. Additionally, the epileptic discharges propagated to the remote areas such as the globus pallidus and cerebellum. We caution that ictal SPECT localization in patients with SMA seizures is not always concordant to epileptic focus but reveals already spread seizure activities.     

High incidence of a survival motor neuron gene/ c BCD541 gene ratio of 2 in Japanese parents of spinal muscular atrophy patients: a characteristic background of spinal muscular atrophy in Japan?

Most spinal muscular atrophy (SMA) patients lack the survival motor neuron gene (SMN). However, the patients retain at least one copy of the ^c BCD541 gene (BCD), which is highly homologous with SMN. Here, we determined the SMN/BCD copy number ratios (the S/B ratios) of 12 parents of Japanese SMA patients with a homozygous SMN deletion, using competitive oligonucleotide priming polymerase chain reaction. We identified an S/B ratio of 2 in 25% of the parents examined, whereas less than 2% of parents of SMA patients in Western populations have an S/B ratio of 2. The high incidence of an S/B ratio of 2 in Japanese parents of SMA patients may reflect the characteristic genetic background of SMA in Japan. Received: 5 November 1997 ƒReceived in revised form: 29 May 1998 ƒAccepted: 31 May 1998     

Refinement of the SWN-20 based on the Rasch rating model

ObjectivesThe aim of the present study was to refine the 20-item Subjective Well-Being under Neuroleptic Treatment Scale (SWN-20) using the Rasch rating model to validate measurements of subjective well-being in patients with schizophrenia undergoing antipsychotic treatment.MethodsIn total, 854 (403 males, 451 females) inpatients (n = 213) and outpatients (n = 641) with schizophrenia participated in this study, which was designed as an open-label investigation of paliperidone extended release. The participants completed the Korean version of the SWN-20 themselves. Refinement of the Korean version of the SWN-20 was accomplished using the Rasch rating model.ResultsInfit and outfit statistics for all 20 items satisfied the criterion for construct validity. Second, all items except items 2 and 20 had suitable point–measure correlations, reflecting content validity. Third, item characteristic curves indicated that roughly 18 items were evenly distributed along the person ability continuum. Finally, option analysis of the category characteristics showed that categories 3 and 4 in the SWN-20 response format were unnecessary.ConclusionsWe offer several recommendations for improving the SWN-20: (a) items 2 and 20 should be omitted to ensure construct validity; (b) easier items would be added related to the person ability estimates in the process of validating a short form of the SWN scale based on item response theory; and (c) the number of response categories should be reduced for schizophrenic patients.     

Age and baseline values predict 12 and 24-month functional changes in type 2 SMA

The aim of this retrospective study was to establish the range of functional changes at 12 and 24-month in 267 type 2 Spinal Muscular Atrophy (SMA) patients with multiple assessments. We included 652 Hammersmith Functional Motor Scale Expanded (HFMSE) assessments at 12 month- and 305 at 24 month- intervals. The cohort was subdivided by functional level, Survival of Motor Neuron copy number and age. Stable scores (± 2 points) were found in 68% at 12 months and in 55% at 24 months. A decrease ≥2 points was found in 21% at 12 months and in 35% at 24 months. An increase ≥2 points was found in 11% at 12 months and 9.5% at 24 months. The risk of losing ≥2 points increased with age and HFMSE score at baseline both at 12 and 24-month. For each additional HFMSE point at baseline, the relative risk of a >2 point decline at 12 months increases by 5% before age 5 years (p = 0.023), by 8% between 5 and 13 (p<0.001) and by 26% after 13 years (p = 0.003). The combination of age and HFMSE scores at baseline increased the ability to predict progression in type 2 SMA.     

Motor milestone assessment of infants with spinal muscular atrophy using the hammersmith infant neurological Exam—Part 2: Experience from a nusinersen clinical study

Introduction: In this study we examined the feasibility of assessing motor milestone performance of infants with spinal muscular atrophy (SMA) using the Hammersmith Infant Neurological Exam—Part 2 (HINE‐2) in a phase 2 study of nusinersen. Methods: Nineteen SMA infants were assessed using the HINE‐2 at baseline (≤7 months of age), and periodically up to 39 months of age. We evaluated whether the HINE‐2 was feasible, reliable, and sensitive to change. Results: Motor milestone assessments in SMA infants were feasible using the HINE‐2. Baseline test–retest reliability was excellent (R = 0.987; P < 0.0001). SMA infants were extremely low functioning at baseline and the HINE‐2 was able to detect changes over time in 16 of 19 infants within all 8 domains. HINE‐2 improvements were correlated with changes in other neuromuscular outcome measures. Conclusion: Results support the use of the HINE‐2 motor milestone assessment in clinical trials of SMA infants. Muscle Nerve 57 : 143–146, 2017     

A novel points system to predict the prognosis of ulnar neuropathy at the elbow

Introduction: In this study we aimed to identify prognostic factors of ulnar neuropathy at the elbow (UNE) and developed a scoring system to establish the prognosis. Methods: We collected baseline clinical, electrophysiologic, and ultrasonographic data from 2 cohorts. The outcomes for all patients were determined on follow‐up. Prognostic factors were determined using single and multiple variable analyses. A points system was developed to determine the risk for an unfavorable outcome. Results: Of the 220 patients with UNE 178 (81%) could be re‐evaluated. Four variables were retained in the prediction model for a points system. An unfavorable outcome was associated with right‐sided UNE, more severe weakness of the abductor digiti minimi (ADM), and more pronounced ulnar nerve thickening. A compound muscle action potential amplitude reduction across the elbow of ≥16% (particularly if ≥ 50%) was associated with a more favorable outcome. Conclusion: Outcome in UNE may be predicted by scoring 4 parameters. Muscle Nerve 55: 698–705, 2017     

Development of a disease-specific disability instrument for Pompe disease

Purpose : The purpose of this study was to modify the Paediatric Evaluation of Disability Inventory (PEDI) to create a Pompe disease-specific disability instrument for use in clinical trials and natural history studies. Methods : PEDI item content was revised to include self-care and mobility items appropriate for children and youth with Pompe disease. Data were collected on 30 individuals with Pompe disease (mean age 7.7 &#45 5.6 years; range 0.4-22.1 years) by parent proxy through telephone interviews. New items were merged with original PEDI items using Rasch rating scale methods. Results : The Pompe-PEDI extended the content range and scoring precision of the original PEDI. Construct validity was demonstrated and test-re-test reliability was excellent. Conclusions : The Pompe-PEDI is a reliable and valid instrument to assess and monitor the functional changes of children and youth with Pompe disease.     

A natural history study of late onset spinal muscular atrophy types 3b and 4

Background   Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene plays a disease modifying role. SMA is classified into four different subtypes based on age of onset and clinical course (SMA types 1–4). The natural history of early onset SMA types 1–3a has been studied extensively. Late onset SMA is rare and disease course has not been studied in detail. Objective   To perform a prospective study on the clinical course and the correlation with SMN2 copy numbers of late onset SMA. Methods   Patients fulfilling the diagnostic criteria for late onset SMA (types 3b and 4) were included in the study. At inclusion and follow-up, muscle strength, respiratory function, functional status and quality of life were assessed. SMN2 copy number was determined in all patients. Results   Twelve patients were identified and included. Six patients were siblings from one family, two patients were brothers from a second family and four patients were sporadic cases. All patients carried four copies of the SMN2 gene. Median age of disease onset was 22.2 years (10–37). Age of disease onset in patients from family one was lower as compared to the other patients. None of the outcome measures changed after a follow-up of 2.5 years. Five patients reported an increase in fatigue and muscle weakness. None of the patients showed symptoms of respiratory insufficiency. Conclusions   This study indicates that late onset SMA is not characterized by disease progression and that alternative or surrogate disease markers are required for the design of future trials. This study confirms the finding that SMN2 copy number is a SMA disease course modifier.     

An IRT validation of the Affective Self Rating Scale

Background: The Affective Self Rating Scale (AS-18) is intended for the use in bipolar outpatients. It includes subscales for the rating of depressive and manic-type symptoms. It has previously been validated using methods from Classical Test Theory. Aims: The aim of this study was to evaluate the psychometric properties of the AS-18 when used at an outpatient clinic for patients with bipolar disorder at routine visits, and to analyze the potential for improvement of the scale. Methods: 231 patients with mainly bipolar I disorder doing ratings on routine visits at an affective disorder outpatient clinic were included. Ratings were analyzed using the Mokken non-parametric and the Rasch parametric model statistical methods. Results: In the Mokken analysis, both subscales of the AS-18 showed a strong ability to rank respondents according to their total score and all items contributed adequately to the measurement. In the Rasch model, there were no indications of disturbing influence from secondary dimensions in the subscales. The depression subscale had the capacity reliably to separate the sample in at most three levels and the mania subscale in two levels. The limited capacity to separate respondents can mainly be explained by a lack of items reflecting lower levels of depressive and manic symptoms. Conclusions: AS-18 has good basic psychometric properties for use of rating of symptoms in bipolar I patients at routine visits, but there is also room for improvement. Item Response Theory (IRT) methods are suitable tools for evaluation and construction of rating scales.     

Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is characterized by degeneration of the anterior horn cells of the spinal cord, which leads to the axial and limb weakness associated with muscle atrophy. SMA is classified into three groups based on the clinical severity: type I (severe), type II (intermediate) and type III (mild). All three clinical subtypes of SMA are caused by mutations of the SMN1 gene. More than 95 % of SMA patients show homozygous deletion of SMN1. It is thought that SMN2, which is a highly homologous gene of SMN1, compensates for the SMN1 deletion to some degree. To clarify the relationship between SMN2 and the disease severity of SMA, we performed fluorescence-based quantitative polymerase chain reaction assay of the copy number of SMN2 in 27 patients (11 type I and 16 type II–III) homozygous for SMN1 deletion. The SMN2 copy number in type II–III patients was 3.1 ± 0.3 (mean ± SD), which is significantly higher than that observed in type I patients, 2.2 ± 0.6 (P < 0.01). However, three of the 11 type I patients carried 3 SMN2 copies. A type I patient with 3 SMN2 copies was studied further. RT-PCR analysis of the patient showed a trace of full-length SMN2 mRNA species, but a large amount of the truncated SMN2 mRNA species lacking exon 7. In conclusion, SMN2 alleles are not functionally equivalent among SMA patients, although in general the SMN2 copy number is correlated with the severity of SMA. Genetic background influencing splicing mechanisms of the SMN2 gene may be more critical in some SMA patients. Received: 11 December 2001, Received in revised form: 14 March 2002, Accepted: 19 March 2002