Improving the measurement properties of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): deriving a valid measurement total for the calculation of change.

BACKGROUND: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score is a widely used measure of functional status in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS), but recent evidence has raised doubts about its validity. The objective was to examine the measurement properties of the ALSFRS-R, aiming to produce valid measurement from all 12 scale items. METHOD: Longitudinal ALSFRS-R data were collected between 2013-2020 from 1120 people with ALS recruited from 35 centers, together with other scales in the Trajectories of Outcomes in Neurological Conditions-ALS (TONiC-ALS) study. The ALSFRS-R was analyzed by confirmatory factor analysis (CFA), Rasch Analysis (RA) and Mokken scaling. RESULTS: No definite factor structure of the ALSFRS-R was confirmed by CFA. RA revealed the raw score total to be invalid even at the ordinal level because of multidimensionality; valid interval level subscale measures could be found for the Bulbar, Fine-Motor and Gross-Motor domains but the Respiratory domain was only valid at an ordinal level. All four domains resolved into a single valid, interval level measure by using a bifactor RA. The smallest detectable difference was 10.4% of the range of the interval scale. CONCLUSION: A total ALSFRS-R ordinal raw score can lead to inferential bias in clinical trial results due to its non-linear nature. On the interval level transformation, more than 5 points difference is required before a statistically significant detectable difference can be observed. Transformation to interval level data should be mandatory in clinical trials.

Dyspnea (breathlessness) in amyotrophic lateral sclerosis/motor neuron disease: prevalence, progression, severity, and correlates.

Objective: Dyspnea, or breathlessness, is an important symptom in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We examined the measurement properties of the Dyspnea-12. Methods: Rasch analysis enabled conversion of raw Dyspnea-12 scores to interval level metric equivalents. Converted data were used to perform trajectory modeling; those following different trajectories were compared for demographic, clinical, symptom, and functioning characteristics. Logistic regression examined differences between distinct trajectories. Results: In 1022 people, at baseline, mean metric Dyspnea-12 was 7.6 (SD 9.3). 49.8% had dyspnea, severe in 12.6%. Trajectory analysis over 28 months revealed three breathlessness trajectories: group 1 reported none at baseline/follow-up (42.7%); group 2 significantly increased over time (9.4%); group 3 had a much higher level at baseline which rose over follow-up (47.9%). Group 3 had worse outcomes on all symptoms, functioning and quality of life; compared to group 1, their odds of: respiratory onset sixfold greater; King's stage ≥3 2.9 greater; increased odds of being bothered by choking, head drop, fasciculations, and muscle cramps; fatigue and anxiety also elevated (p < .01). Conclusion: Dyspnea is a cardinal symptom in ALS/MND and can be quickly measured using the Dyspnea-12. Raw scores can easily be converted to interval level measurement, for valid change scores and trajectory modeling. Dyspnea trajectories reveal different patterns, showing that clinical services must provide monitoring which is customized to individual patient need. Almost half of this large population had worsening dyspnea, confirming the importance of respiratory monitoring and interventions being integrated into routine ALS care.

Multiple Sclerosis vision questionnaire (MSVQ-7): Reliability, validity, precision and discrimination.

BACKGROUND: Visual dysfunction is common in people with Multiple Sclerosis (pwMS), associated with a variety of visual symptoms. Capturing the patient experience of these complex patterns of visual pathology is challenging. A valid and reliable patient reported measure, capable of detecting clinically significant change, would have considerable research and clinical benefits. We examined the properties of the MS Vision Questionnaire (MSVQ-7) in a large MS population. METHODS: Data were collected from participants in the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study: MS subtype and Expanded Disability Status Scale (EDSS) band from the clinical team, as well as serial packs including the MSVQ-7 and questionnaires on depression, anxiety and stigma. A calibration sample of 1000 pwMS contributing several years of follow-up were split into training and validation samples for a Confirmatory Factor Analysis and Rasch analysis. The Minimal Detectable Change (MDC) was computed as well as the Minimal Clinically Important Change (MIC), by an anchor-based method, for different MS subtypes. RESULTS: The MSVQ-7 is unidimensional and can be fit to the Rasch model with a solution discarding 3% of variance. Providing all 7 items are answered, the total can be converted to an interval-level metric for calculation of change scores and other parametric analyses. The % of missing values did not exceed 1.7%. Among 5478 pwMS, 80% reported visual problems. MSVQ-7 scores were categorised as mild for 36.1%, moderate for 33.6% and severe for 10.3%, and varied by MS subtype. In the follow-up sample of 2227 pwMS, 42.5% changed MSVQ-7 category between baseline and first follow-up (mean 22.6 months). The MIC exceeded the MDC so clinically significant change exceeds measurement error. While MDC was identical for relapsing and progressive MS, MIC varied by MS subtype, with smaller MIC in relapsing MS. Over one-quarter of the follow-up sample reported a clinically significant change in MSVQ-7: 12.2% improved and 13.5% deteriorated. For pwMS recruited within 2 years of diagnosis, 17.3% reported significant change on follow-up, all improving. MSVQ-7 scores showed strong associations with anxiety, depression and stigma (effect sizes>0.8). Duration, EDSS band and MS subtype all had effect sizes 0.2-0.49. A multinomial logistic regression exploring vision disturbance and depression, adjusted for age, gender, MS subtype, duration and disability, showed vision is the strongest significant predictor of depression. Each unit increase in interval MSVQ-7 increases risk by 10% of 'possible' and by 17% of 'probable' depression. CONCLUSIONS: The MSVQ-7 is a brief self-report measure of visual problems for pwMS. It can easily be converted to interval-level measurement for change scores or power calculations and has good precision and discrimination. Visual problems were reported by 80% of pwMS and changed over time, evidencing the need for regular monitoring. MIC varied by MS subtype, indicating that perception of impact changes over the disease course. Visual dysfunction significantly affects depression risk and perceived stigma, highlighting the importance of routine assessment of visual problems in comprehensive care. The MSVQ-7 has strong psychometric properties for adoption as a measure for vision in clinical and research settings.

Correlates and trajectories of relapses in relapsing-remitting multiple sclerosis.

BACKGROUND AND AIMS: In people with relapsing-remitting multiple sclerosis (pwRRMS), data from studies on non-pharmacological factors which may influence relapse risk, other than age, are inconsistent. There is a reduced risk of relapses with increasing age, but little is known about other trajectories in real-world MS care. METHODS: We studied longitudinal questionnaire data from 3885 pwRRMS, covering smoking, comorbidities, disease-modifying therapy (DMT), and patient-reported outcome measures, as well as relapses during the past year. We undertook Rasch analysis, group-based trajectory modelling, and multilevel negative binomial regression. RESULTS: The regression cohort of 6285 data sets from pwRRMS over time showed that being a current smoker was associated with 43.9% greater relapse risk; having 3 or more comorbidities increased risk and increasing age reduced risk. Those diagnosed within the last 2 years showed two distinct trajectories, both reducing in relapse frequency but 25.8% started with a higher rate and took 4 years to reduce to the rate of the second group. In the cohort with at least three data points completed, there were three groups: 73.7% followed a low stable relapse rate, 21.6% started from a higher rate and decreased, and 4.7% had an increasing then decreasing pattern. These different trajectory groups showed significant differences in fatigue, neuropathic pain, disability, health status, quality of life, self-efficacy, and DMT use. CONCLUSIONS: These results provide additional evidence for supporting pwRRMS to stop smoking and underline the importance of timely DMT decisions and treatment initiation soon after diagnosis with RRMS.

Psychometric testing of the Rheumatoid Arthritis Work Instability Scale in employed people with fibromyalgia.

OBJECTIVE: The aim of the study was to establish whether the Rheumatoid Arthritis Work Instability Scale (RA-WIS), in its current form, is applicable for use with employed people with fibromyalgia (FM) to identify the risk of work disability and need for work rehabilitation. METHODS: Content validity was first investigated using cognitive debriefing interviews. Participants completed a postal questionnaire. Construct validity was assessed using Rasch analysis. Concurrent validity included testing between the RA-WIS and work (e.g., Workplace Activity Limitations Scale) and health (FM Impact Questionnaire-Revised (FIQ-R) scales. Two weeks later, participants were mailed a second questionnaire to measure test-retest reliability. RESULTS: Interviews were conducted with 13 participants with FM. All RA-WIS items were considered very or extremely relevant by almost all participants, with only one suggesting other items (anxiety and brain fog). Questionnaire responses were analysed from 156 employed participants: 94% women; 45.71 (SD 10.05) years of age; with time since FM diagnosis 2.99 (4.17) years (symptom duration 8.36 (SD 7.16) years). The RA-WIS mostly satisfied Rasch model requirements and a Rasch transformation scale was created. Concurrent validity was generally good (rs = 0.55-0.66) with work scales and the FIQ-R. Internal consistency (Person Separation Index values) was consistent with group use in FM, not individual level use. Test-retest reliability was excellent, with intraclass coefficient (2, 1) = 0.90. DISCUSSION: The RA-WIS is valid and reliable for group use in employed people with FM. However, further work is needed to develop a WIS for individual use in FM.

Measuring disability in multiple sclerosis: the WHODAS 2.0.

INTRODUCTION: Reliable measurement of disability in multiple sclerosis (MS) using a comprehensive, patient self-reported scale, such as the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, would be of clinical and research benefit. METHODS: In the Trajectories of Outcome in Neurological Conditions-MS study, WHODAS 2.0 (WHODAS-36 items for working, WHODAS-32 items if not working, WHODAS-12 items short-form) was examined using Rasch analysis in 5809 people with MS. RESULTS: The 36- and 32-item parallel forms, and the cognitive and physical domains, showed reliability consistent with individual or group use. The 12-item short-form is valid for group use only. Interval level measurement for parametric statistics can be derived from all three scales which showed medium to strong effect sizes for discrimination across characteristics such as age, subtype, and disease duration. Smallest detectable difference for each scale was < 6 on the standardised metric of 0-100 so < 6% of the total range. There was no substantial differential item functioning (DIF) by age, gender, education, working full/part-time, or disease duration; the finding of no DIF for time or sample supports the use of WHODAS 2.0 for longitudinal studies, with the 36- and 32-item versions and the physical and cognitive domains valid for individual patient follow-up. CONCLUSIONS: Disability in MS can be comprehensively measured at interval level by the WHODAS 2.0, and validly monitored over time. Routine use of this self-reported measure in clinical and research practice would give valuable information on the trajectories of disability of individuals and groups.

Psychometric testing of the British-English Perceived Workplace Support Scale, Work Accommodations, Benefits, Policies and Practices Scale, and Work Transitions Index in four rheumatic and musculoskeletal conditions.

OBJECTIVE: The aims were to validate linguistically British-English versions of the Perceived Workplace Support Scale (PWSS), Work Accommodations, Benefits, Policies and Practices Scale (WABPPS), and Work Transitions Index (WTI) in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), osteoarthritis (OA) and fibromyalgia (FM). METHODS: The three scales were adapted into British-English and reviewed by an expert panel prior to cognitive debriefing interviews. Participants completed postal questionnaires. Construct validity for the PWSS was assessed using Rasch analysis. Concurrent validity included testing between the three scales and work, job strain and work-life balance scales. Two weeks later, participants were mailed a second questionnaire to measure test-retest reliability. RESULTS: The questionnaire was completed by 831 employed participants: 68% women, 53.50 (SD 8.9) years of age, with condition duration 7.70 (SD 8.00) years. The PWSS satisfied Rasch model requirements. Concurrent validity was mostly as hypothesised, that is, weak to moderate negative correlations for the PWSS (rs  = 0.07 to -0.61), and weak to moderate positive correlations for the WABPPS and WTI (rs  = 0.20-0.52). Some correlations were stronger, mostly in axSpA. Internal consistency (Cronbach's alpha) for all three scales was consistent with group use in all conditions. Test-retest reliability was generally excellent, with intraclass coefficients (2,1) of 0.80-0.93 for the three scales in the four conditions. DISCUSSION: Reliable, valid versions of the British-English PWSS, WABPPS, and WTI are now available for use in research, organisational level studies and vocational rehabilitation.

Application of the Rasch measurement model in rehabilitation research and practice: early developments, current practice, and future challenges.

The application of the Rasch measurement model in rehabilitation is now well established. Both its dichotomous and polytomous forms provide for transforming ordinal scales into interval-level measures, consistent with the requirements of fundamental measurement. The growth of applying the model in rehabilitation spans 30 years, during which both the protocol has steadily developed and several software packages have emerged that provide for analysis, together with the "R" language that has an increasing set of codes for applying the model. This article reviews that development and highlights current practice requirements, including those for providing the relevant information for the methods, and what is expected of the analysis. In addition, this provides a worked example and looks at the remaining issues and current developments of its application.

Psychometric testing of the British-English Long-Term Conditions Job Strain Scale, Long-Term Conditions Work Spillover Scale and Work-Health-Personal Life Perceptions Scale in four rheumatic and musculoskeletal conditions.

OBJECTIVE: The aims were to validate linguistically British-English versions of the Long-Term Conditions Job Strain Scale (LTCJSS), Long-Term Conditions Work Spillover Scale (LTCWSS) and Work-Health-Personal Life Perceptions Scale (WHPLPS) in rheumatoid arthritis, axial spondyloarthritis, osteoarthritis and fibromyalgia (FM). METHODS: The three scales were forward translated and reviewed by an expert panel prior to cognitive debriefing interviews. Participants completed a postal questionnaire. Construct validity was assessed using Rasch analysis. Concurrent validity included testing between the three scales and work (e.g., Workplace Activity Limitations Scale [WALS]) and condition-specific health scales. Two weeks later, participants were mailed a second questionnaire to measure test-retest reliability. RESULTS: The questionnaire was completed by 831 employed participants: 68% women, 53.5 (SD 8.9) years of age, with condition duration 7.7 (SD 8.0) years. The LTCJSS, LTCWSS and WHPLPS Parts 1 and 2 satisfied Rasch model requirements, but Part 3 did not. A Rasch transformation scale and Reference Metric equating scales with the WALS were created. Concurrent validity was generally good (rs = 0.41-0.85) for the three scales, except the WHPLPS Part 3. Internal consistency (Person Separation Index values) was consistent with group use in all conditions, and individual use except for the LTCWSS and WHPLSP Parts 1 and 2 in FM. Test-retest reliability was excellent, with intraclass coefficients (2,1) of 0.80-0.96 for the three scales in the four conditions. DISCUSSION: Reliable, valid versions of the British-English LTCJSS, LTCWSS and WHPLPS Parts 1 and 2 are now available for use in the UK.

Validation of the Pediatric Quality of Life Inventory 3.0 Cerebral Palsy Module (Parent Form) for use in Türkiye.

Objectives: This study was planned to test the reliability and validity of the Turkish version of the Pediatric Quality of Life Inventory (PedsQL) 3.0 cerebral palsy (CP) module (parent form) in children with CP. Patients and methods: In the validation study conducted between June 2007 and June 2009, 511 children (299 normal children, 212 children with CP) were assessed by the seven scales of PedsQL [daily activities (DA), school activities (SA), movement and balance (MB), pain and hurt (PH), fatigue (F), eating activities (EA), and speech and communication (SC)]. Reliability was tested by internal consistency and person separation index (PSI); internal construct validity by Rasch analysis and external construct validity by correlation with the Gross Motor Function Classification System (GMFCS) and Functional Independence Measure for Children (WeeFIM). Results: Only 13 children with CP completed the inventory by themselves and thus were excluded. Consequently, 199 children with CP (113 males, 86 females; mean age: 7.3±4.2 years; range, 2 to 18 years) and 299 normal children (169 males, 130 females; mean age: 9.4±4.0 years; range, 2 to 17 years) were included in the final analysis. Reliabilities of the seven scales of the PedsQL 3.0 CP module were adequate, with Cronbach's alphas between 0.66 and 0.96 and the PSI between 0.672 and 0.943 for the CP group. In Rasch analysis, for each scale, items showing disordered thresholds were rescored; then testlets were created to overcome local dependency. Internal construct validity of the unidimensional seven scales was good with the mean item fit of -0.107±1.149, 0.119±0.818, 0.232±1.069, -0.442±0.672, 0.221±0.554, -0.091±0.606, and -0.333±1.476 for DA, SA, MB, PH, F, EA, and SC, respectively. There was no differential item functioning. External construct validity of the instrument was confirmed by expected moderate to high correlations with WeeFIM and GMFCS (Spearman's r=0.35-0.89). Conclusion: Turkish version of the PedsQL 3.0 CP module is reliable, valid, and available for use in clinical setting to evaluate health-related quality of life of children with CP.

Psychometric testing of the British English Workplace Activity Limitations Scale in four rheumatic and musculoskeletal conditions.

Objectives: The aims were to validate a British English version of the Workplace Activity Limitations Scale (WALS) linguistically, then test this psychometrically in RA, axial spondyloarthritis (axSpA), OA and FM. Methods: The WALS was forward translated, reviewed by an expert panel, and cognitive debriefing interviews were conducted. Participants completed a postal questionnaire booklet. Construct (structural) validity was examined by fit to the Rasch measurement model. Concurrent validity included testing between the WALS and the Work Limitations Questionnaire-25 (WLQ-25). Two weeks later, participants were mailed a second questionnaire booklet for test-retest reliability. Results: Minor wording changes were made to the WALS, then 831 employed participants completed questionnaires: 267 men and 564 women; 53.5 (s.d. 8.9) years of age; with condition duration 7.7 (s.d. 8.0) years. The WALS satisfied Rasch model requirements, and a WALS Rasch transformation table was created. Concurrent validity was strong with the WLQ-25 (RA r s = 0.78; axSpA r s = 0.83; OA r s = 0.63; FM r s = 0.64). Internal consistency was consistent with group use (α = 0.80-0.87). Test-retest reliability was excellent, with intraclass correlation coefficient (2,1) at ≥0.90. Conclusion: A reliable, valid British English version of the WALS is now available for use in the UK.

Measuring disability in amyotrophic lateral sclerosis/motor neuron disease: the WHODAS 2.0-36, WHODAS 2.0-32, and WHODAS 2.0-12.

Aim: To investigate whether the World Health Organization Disability Assessment Schedule 2.0 (WHODAS) can provide interval level measurement of disability in Amyotrophic Lateral Sclerosis (ALS), allowing parametric analyses. Methods: Data on the WHODAS 12, 32, and 36-item versions, from 1120 patients studied at one or more time points, were fit to the Rasch model and comparisons made against ALSFRS-R, King's staging, and mortality. Trajectory modeling was undertaken for a newly diagnosed (≤6 months) cohort of 454 individuals. Results: Total scores for WHODAS 32 and 36-item versions can be converted to interval level measurement suitable for individual clinical use, and the 12-item WHODAS total for group use. The 36-item version is shown to be equivalent to the 32-item version. Expected correlations were seen with King's staging, ALSFRS-R, and EQ-5D-5L. Trajectory analysis of disability (WHODAS 2.0) showed three clearly demarcated groups with differences in King's staging, depressive symptomatology and mortality, but not age. Conclusions: The WHODAS 2.0 is a brief patient reported outcome measure which can be used to measure disability in ALS. Provided the patient answers all 36 (32 if not working) items, the conversion table produces an interval level estimate for parametric analyses. The different trajectories demonstrated from diagnosis support the concept of a prodromal period, and suggest the WHODAS 2.0 could be used for surveillance of at risk populations, such as those with genetic predisposition.

Mild allergic airways responses to an environmental mixture increase cardiovascular risk in rats.

Recent epidemiological findings link asthma to adverse cardiovascular responses. Yet, the precise cardiovascular impacts of asthma have been challenging to disentangle from the potential cardiovascular effects caused by asthma medication. The purpose of this study was to determine the impacts of allergic airways disease alone on cardiovascular function in an experimental model. Female Wistar rats were intranasally sensitized and then challenged once per week for 5 weeks with saline vehicle or a mixture of environmental allergens (ragweed, house dust mite, and Aspergillus fumigatus). Ventilatory and cardiovascular function, measured using double-chamber plethysmography and implantable blood pressure (BP) telemetry and cardiovascular ultrasound, respectively, were assessed before sensitization and after single and final allergen challenge. Responses to a single 0.5 ppm ozone exposure and to the cardiac arrhythmogenic agent aconitine were also assessed after final challenge. A single allergen challenge in sensitized rats increased tidal volume and specific airways resistance in response to provocation with methacholine and increased bronchoalveolar lavage fluid (BALF) eosinophils, neutrophils, lymphocytes, cytokines interleukin (IL)-4, IL-5, IL-10, IL-1ß, tumor necrosis factor-α, and keratinocyte chemoattract-growth-related oncogene characteristic of allergic airways responses. Lung responses after final allergen challenge in sensitized rats were diminished, although ozone exposure increased BALF IL-6, IL-13, IL-1 ß, and interferon-γ and modified ventilatory responses only in the allergen group. Final allergen challenge also increased systolic and mean arterial BP, stroke volume, cardiac output, end-diastolic volume, sensitivity to aconitine-induced cardiac arrhythmia, and cardiac gene expression with lesser effects after a single challenge. These findings demonstrate that allergic airways responses may increase cardiovascular risk in part by altering BP and myocardial function and by causing cardiac electrical instability.

Measuring coping in multiple sclerosis: The Coping Index-MS.

BACKGROUND: Coping in multiple sclerosis (MS) refers to cognitive and behavioural efforts to manage stresses imposed by the illness. Existing generic and disease-specific coping scales do not meet modern guidelines for scale development and cannot produce interval-level metrics to allow for change scores. OBJECTIVE: The main aim of this study was to develop a brief patient-reported outcome measure for coping in MS, capable of interval-level measurement. METHODS: Qualitative work in 43 people with MS leads to a draft scale which was administered to 5747 participants, with longitudinal collection in 2290. A calibration sample of 1000 subjects split into development and validation sets was used to generate three scales consistent with Rasch model expectations. RESULTS: The total Coping Index-MS (CI-MS-T), CI-MS-Internal (CI-MS-I) and CI-MS-External (CI-MS-E) cover total, internal and externally focused coping. All three scales are capable of interval-level measurement. Trajectory analysis of 9000 questionnaires showed two trajectories in CI-MS-T: Group 1 showed a low level of coping with slight decline over 40 months, while Group 2 had a better and stable level of coping due to improving CI-MS-I which compensated for the deteriorating CI-MS-E over time. CI-MS-T < 30 identified group membership at baseline. CONCLUSION: The CI-MS-T, CI-MS-I and CI-MS-E, comprising 20 items, provide interval-level measurement and are free-for-use in not-for-profit settings.

The four self-efficacy trajectories among people with multiple sclerosis: Clinical associations and implications.

BACKGROUND: Longitudinal studies among people with Multiple Sclerosis (pwMS) have shown that self-efficacy is linked to physical, cognitive and psychological functioning. OBJECTIVES: To determine the distribution of self-efficacy in a large sample of pwMS, examining whether there are distinct groups which show different self-efficacy trajectories over time, and the health status characteristics of any groups identified. METHODS: Participants completed serial questionnaire packs, including Unidimensional Self-efficacy-MS (USE-MS) scale, for the Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study over an average 46-month period. The resulting longitudinal data were analysed by a group-based trajectory model. RESULTS: 5887 pwMS were studied: mean age 50.2 years (SD 12.0); 73.6% female; Relapsing Remitting MS (61.8%), Secondary Progressive (22.9%), Primary Progressive (11.1%), Rapidly Evolving Relapsing Remitting MS (4.2%). Four distinct self-efficacy trajectories emerged, with declining, slightly declining, stable or improving self-efficacy, each showing different patterns of health status indicators such as EQ-5D-5L, disability and depression. USE-MS ≤ 18 at baseline detected all participants in the two declining groups. CONCLUSION: Future trials on interventions for self-efficacy should assume a priori that those with low levels of self-efficacy (USE-MS ≤ 18 at baseline) are likely to be on a declining trajectory and may need different interventions from those with stable self-efficacy.

Fatigue and anxiety mediate the effect of dyspnea on quality of life in amyotrophic lateral sclerosis.

Introduction: Dyspnea (or breathlessness) due to progressive neuromuscular respiratory failure is common in amyotrophic lateral sclerosis (ALS). It is associated with anxiety, depression and reduced quality of life (QoL). For effective treatment, it is essential to understand the relationships between dyspnea, anxiety, depression and QoL.Methods: The UK Trajectories of Outcomes in Neurological Conditions-ALS study (TONiC-ALS) collected self-report measures from patients with ALS. Ordinal scales were transformed to interval-scaled estimates by the Rasch Measurement model. They were subsequently included in a series of path models where the focal relationships were dyspnea to QoL and dyspnea to depression.Results: Path analyses using 1022 participants showed that 60.5% of the variance of QoL was explained by fatigue, anxiety, dyspnea and disability. For depression, 54.1% of the variance was explained by a model of these factors. Dyspnea played an important but mostly indirect role in influencing QoL and depressive symptoms. Disability was dominated by all other factors in the model.Discussion: Dyspnea in ALS influences quality of life and depression largely through indirect effects, principally acting via anxiety and fatigue. Recognition of this is essential for clinicians to understand where to intervene for greatest benefit. Researchers must be aware that studies of the effect of dyspnea on QoL and depression require path models, measuring both direct and indirect effects, as the impact of dyspnea is likely to be significantly miscalculated if only direct effects are assessed.

Scale Banking for Patient-Reported Outcome Measures That Measure Functioning in Rheumatoid Arthritis: A Daily Activities Metric.

OBJECTIVE: Functioning is an important outcome for the management of rheumatoid arthritis (RA). Heterogeneity of respective patient-reported outcome measures (PROMs) challenges direct comparisons between their results. This study aimed to standardize reporting of such PROMs measuring functioning in RA to facilitate comparability. METHODS: Common-item nonequivalent group design with the Health Assessment Questionnaire (HAQ) as a common scale across data sets from various countries (including the UK, Turkey, and Germany) to establish a common metric was used. Other PROMs included are the physical function items of the Multidimensional HAQ (MDHAQ), the Disabilities of the Arm, Shoulder, and Hand questionnaire, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the World Health Organization Disability Assessment Schedule II (WHODAS II), the Medical Outcomes Study Short Form 36 (SF-36) health survey, and 4 short forms (20, 10, 6, and 4 physical function items) from the Patient-Reported Outcomes Measurement Information System. As the HAQ includes mobility, self-care, and domestic life items, this study focuses on these 3 domains. PROMs were described using standard error of measurement (SEM) and smallest detectable difference (SDD). A Rasch measurement model was used to create the common metric. RESULTS: The range of the SEM was 0.2 (MDHAQ) to 7.4 (SF-36 health survey physical functioning domain). The SDD revealed a range from 9.7% (WOMAC rating scale) to 33.5% (WHODAS physical functioning domain). PROMs co-calibration revealed fit to the Rasch measurement model. A transformation table was developed to allow exchange between PROM scores. CONCLUSION: Scores between the daily activity PROMs commonly used in RA can now be compared. Factors such as SEM and SDD help to determine the choice of a PROM in clinical practice and research.

Genomic comparisons between hepatocarcinogenic and non-hepatocarcinogenic organophosphate insecticides in the mouse liver.

Short-term biomarkers of toxicity have an increasingly important role in the screening and prioritization of new chemicals. In this study, we examined early indicators of liver toxicity for three reference organophosphate (OP) chemicals, which are among the most widely used insecticides in the world. The OP methidathion was previously shown to increase the incidence of liver toxicity, including hepatocellular tumors, in male mice. To provide insights into the adverse outcome pathway (AOP) that underlies these tumors, effects of methidathion in the male mouse liver were examined after 7 and 28 day exposures and compared to those of two other OPs that either do not increase (fenthion) or possibly suppress liver cancer (parathion) in mice. None of the chemicals caused increases in liver weight/body weight or histopathological changes in the liver. Parathion decreased liver cell proliferation after 7 and 28 days while the other chemicals had no effects. There was no evidence for hepatotoxicity in any of the treatment groups. Full-genome microarray analysis of the livers from the 7 and 28 day treatments demonstrated that methidathion and fenthion regulated a large number of overlapping genes, while parathion regulated a unique set of genes. Examination of cytochrome P450 enzyme activities and use of predictive gene expression biomarkers found no consistent evidence for activation of AhR, CAR, PXR, or PPARα. Parathion suppressed the male-specific gene expression pattern through STAT5b, similar to genetic and dietary conditions that decrease liver tumor incidence in mice. Overall, these findings indicate that methidathion causes liver cancer by a mechanism that does not involve common mechanisms of liver cancer induction.

Use and detailed metric properties of patient-reported outcome measures for rheumatoid arthritis: a systematic review covering two decades.

INTRODUCTION: The importance of patient-reported outcome measures (PROMs) for rheumatoid arthritis (RA) clinical studies has been recognised for many years. The current study aims to describe the RA PROMs used over the past 20 years, and their performance metrics, to underpin appropriate tool selection. METHODS: The study included a systematic search for PROMs that have been in use over the period 2000-2019, with detailed documentation of their psychometric properties, and a user-friendly presentation of the extensive evidence base. RESULTS: 125 PROMs were identified with psychometric evidence available. The domains of pain, fatigue, emotional functions, mobility, physical functioning and work dominated, with self-efficacy and coping as personal factors. Domains such as stiffness and sleep were poorly served. The most frequently used PROMs included the Health Assessment Questionnaire Disability Index (HAQ), the Short Form 36 (SF-36), the EuroQoL and the Modified HAQ which, between them, appeared in more than 3500 papers. Strong psychometric evidence was found for the HAQ, and the SF-36 Physical Functioning and Vitality (fatigue) domains. Otherwise, all domains except stiffness, sleep, education and health utility, had at least one PROM with moderate level of psychometric evidence. CONCLUSION: There is a broad range of PROMs for measuring RA outcomes, but the quality of psychometric evidence varies widely. This work identifies gaps in key RA domains according to the biopsychosocial model.

Quality of life in multiple sclerosis is dominated by fatigue, disability and self-efficacy.

BACKGROUND AND OBJECTIVE: Quality of life in multiple sclerosis (MS) reflects complex relationships between symptoms (fatigue, spasticity pain, and bladder or vision dysfunction), disability, health perceptions, and self-efficacy. METHODS: In this cross-sectional study, a self-report questionnaire pack of patient reported outcome measures was collected from 5695 people with MS (pwMS) alongside clinical data from their neurologists. Each patient reported outcome measure was converted to interval-scaled estimates following fit to the Rasch model. The patient reported outcome measures, as well as perceived health, age, disease subtype and gender, were then subject to path analysis to analyse their relationships with quality of life (QoL), guided by the Wilson and Clearly conceptual framework. RESULTS: The final model explains 81.2% of the variance of QoL. Fatigue is clearly dominant, suggesting a means to intervene and improve QoL. The next most influential factors were disability and self-efficacy, which have similar effect levels. The model can be replicated for pwMS on disease modifying therapy and is largely invariant for gender and disease subtype. Age had an insignificant effect. CONCLUSIONS: In order to promote better QoL, MS care should include management of fatigue, interventions to ameliorate disability, and support to enhance self-efficacy. The range of skills needed for these treatments will require input from medical, nursing, therapy and psychology staff, so these findings provide evidence substantiating the need for pwMS to be provided with care by comprehensive multidisciplinary teams.