Modern psychometrics applied in rheumatology - a systematic review

Background Although item response theory (IRT) appears to be increasingly used within health care research in general, a comprehensive overview of the frequency and characteristics of IRT analyses within the rheumatic field is lacking. An overview of the use and application of IRT in rheumatology to date may give insight into future research directions and highlight new possibilities for the improvement of outcome assessment in rheumatic conditions. Therefore, this study systematically reviewed the application of IRT to patient-reported and clinical outcome measures in rheumatology. Methods Literature searches in PubMed, Scopus and Web of Science resulted in 99 original English-language articles which used some form of IRT-based analysis of patient-reported or clinical outcome data in patients with a rheumatic condition. Both general study information and IRT-specific information were assessed. Results Most studies used Rasch modeling for developing or evaluating new or existing patient-reported outcomes in rheumatoid arthritis or osteoarthritis patients. Outcomes of principle interest were physical functioning and quality of life. Since the last decade, IRT has also been applied to clinical measures more frequently. IRT was mostly used for evaluating model fit, unidimensionality and differential item functioning, the distribution of items and persons along the underlying scale, and reliability. Less frequently used IRT applications were the evaluation of local independence, the threshold ordering of items, and the measurement precision along the scale. Conclusion IRT applications have markedly increased within rheumatology over the past decades. To date, IRT has primarily been applied to patient-reported outcomes, however, applications to clinical measures are gaining interest. Useful IRT applications not yet widely used within rheumatology include the cross-calibration of instrument scores and the development of computerized adaptive tests which may reduce the measurement burden for both the patient and the clinician. Also, the measurement precision of outcome measures along the scale was only evaluated occasionally. Performed IRT analyses should be adequately explained, justified, and reported. A global consensus about uniform guidelines should be reached concerning the minimum number of assumptions which should be met and best ways of testing these assumptions, in order to stimulate the quality appraisal of performed IRT analyses

Targeting and activation of Rac1 are mediated by the exchange factor β-Pix

Rho guanosine triphosphatases (GTPases) are critical regulators of cytoskeletal dynamics and control complex functions such as cell adhesion, spreading, migration, and cell division. It is generally accepted that localized GTPase activation is required for the proper initiation of downstream signaling events, although the molecular mechanisms that control targeting of Rho GTPases are unknown. In this study, we show that the Rho GTPase Rac1, via a proline stretch in its COOH terminus, binds directly to the SH3 domain of the Cdc42/Rac activator β-Pix (p21-activated kinase [Pak]–interacting exchange factor). The interaction with β-Pix is nucleotide independent and is necessary and sufficient for Rac1 recruitment to membrane ruffles and to focal adhesions. In addition, the Rac1–β-Pix interaction is required for Rac1 activation by β-Pix as well as for Rac1-mediated spreading. Finally, using cells deficient for the β-Pix–binding kinase Pak1, we show that Pak1 regulates the Rac1–β-Pix interaction and controls cell spreading and adhesion-induced Rac1 activation. These data provide a model for the intracellular targeting and localized activation of Rac1 through its exchange factor β-Pix

How age and sex affect the erythrocyte sedimentation rate and C-reactive protein in early rheumatoid arthritis

BACKGROUND: The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are two commonly used measures of inflammation in rheumatoid arthritis (RA). As current RA treatment guidelines strongly emphasize early and aggressive treatment aiming at fast remission, optimal measurement of inflammation becomes increasingly important. Dependencies with age, sex, and body mass index have been shown for both inflammatory markers, yet it remains unclear which inflammatory marker is affected least by these effects in patients with early RA. METHODS: Baseline data from 589 patients from the DREAM registry were used for analyses. Associations between the inflammatory markers and age, sex, and BMI were evaluated first using univariate linear regression analyses. Next, it was tested whether these associations were independent of a patient's current disease activity as well as of each other using multiple linear regression analyses with backward elimination. The strengths of the associations were compared using standardized beta (beta) coefficients. The multivariate analyses were repeated after 1 year. RESULTS: At baseline, both the ESR and CRP were univariately associated with age, sex, and BMI, although the association with BMI disappeared in multivariate analyses. ESR and CRP levels significantly increased with age (beta-ESR = 0.017, p < 0.001 and beta-CRP = 0.009, p = 0.006), independent of the number of tender and swollen joints, general health, and sex. For each decade of aging, ESR and CRP levels became 1.19 and 1.09 times higher, respectively. Furthermore, women demonstrated average ESR levels that were 1.22 times higher than that of men (beta = 0.198, p = 0.007), whereas men had 1.20 times higher CRP levels (beta = -0.182, p = 0.048). Effects were strongest on the ESR. BMI became significantly associated with both inflammatory markers after 1 year, showing higher levels with increasing weight. Age continued to be significantly associated, whereas sex remained only associated with the ESR level. CONCLUSIONS: Age and sex are independently associated with the levels of both acute phase reactants in early RA, emphasizing the need to take these external factors into account when interpreting disease activity measures. BMI appears to become more relevant at later stages of the disease

Performance of the Dutch SF-36 version 2 as a measure of health-related quality of life in patients with rheumatoid arthritis

BACKGROUND: The aim of this study was to examine the measurement properties of the Dutch SF-36 version 2 (SF-36v2) health survey in patients with rheumatoid arthritis (RA). METHODS: Scaling assumptions, internal reliability, and internal construct validity were examined using available data from 1884 RA patients included in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. External construct validity and responsiveness to change were examined using baseline and 6-month follow-up data from a subset of 387 early RA patients participating in the DREAM remission induction cohort. RESULTS: The individual items of the SF-36v2 adequately met scaling assumptions, although four items correlated too highly with items from different scales. Internal consistency was high for all eight scales and the physical and mental health components underlying the scales were replicated, supporting the use of the standard scoring algorithms. The SF-36v2 scales demonstrated minimal floor effects and ceiling effects were noteworthy only for the role-physical, social functioning, and role-emotional scales. Correlations with other core measures were as expected and the SF-36v2 showed excellent known-groups validity in distinguishing between patients with low or moderate-high disease activity. All scales related to physical health showed moderate to large responsiveness to change in patients that achieved low disease activity at six months. CONCLUSION: The SF-36v2 appears to be a psychometrically sound tool for the assessment of health-related quality of life of Dutch patients with RA

Identifying Responders and Exploring Mechanisms of Action of the Endobronchial Coil Treatment for Emphysema

Background: So far, 3 randomized controlled trials have shown that the endobronchial treatment using coils is safe and effective. However, the more exact underlying mechanism of the treatment and best predictors of response are unknown. Objectives: The aim of the study was to gain more knowledge about the underlying physiological mechanism of the lung volume reduction coil treatment and to identify potential predictors of response to this treatment. Methods: This was a prospective nonrandomized single-center study which included patients who were bilaterally treated with coils. Patients underwent an extensive number of physical tests at baseline and 3 months after treatment. Results: Twenty-four patients (29% male, mean age 62 years, forced expiratory volume in 1 s [FEV1] 26% pred, residual volume (RV) 231% pred) were included. Three months after treatment, significant improvements were found in spirometry, static hyperinflation, air trapping, airway resistance, treated lobe RV and treated lobes air trapping measured on CT scan, exercise capacity, and quality of life. The change in RV and airway resistance was significantly associated with a change in FEV1, forced vital capacity, air trapping, maximal expiratory pressure, dynamic compliance, and dynamic hyperinflation. Predictors of treatment response at baseline were a higher RV, larger air trapping, higher emphysema score in the treated lobes, and a lower physical activity level. Conclusions: Our results confirm that emphysema patients benefit from endobronchial coil treatment. The primary mechanism of action is decreasing static hyperinflation with improvement of airway resistance which consequently changes dynamic lung mechanics. However, the right patient population needs to be selected for the treatment to be beneficial which should include patients with severe lung hyperinflation, severe air trapping, and significant emphysema in target lobes

A Rac1 inhibitory peptide suppresses antibody production and paw swelling in the murine collagen-induced arthritis model of rheumatoid arthritis

Introduction: The Rho family GTPase Rac1 regulates cytoskeletal rearrangements crucial for the recruitment, extravasation and activation of leukocytes at sites of inflammation. Rac1 signaling also promotes the activation and survival of lymphocytes and osteoclasts. Therefore, we assessed the ability of a cell-permeable Rac1 carboxy-terminal inhibitory peptide to modulate disease in mice with collagen-induced arthritis (CIA). Methods: CIA was induced in DBA/1 mice, and in either early or chronic disease, mice were treated three times per week by intraperitoneal injection with control peptide or Rac1 inhibitory peptide. Effects on disease progression were assessed by measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. Serum levels of anti-collagen type II antibodies were measured by enzyme-linked immunosorbent assay. T-cell phenotypes and activation were assessed by fluorescence-activated cell sorting analysis. Results were analyzed using Mann-Whitney U and unpaired Student t tests. Results: Treatment of mice with Rac1 inhibitory peptide resulted in a decrease in paw swelling in early disease and to a lesser extent in more chronic arthritis. Of interest, while joint destruction was unaffected by Rac1 inhibitory peptide, anti-collagen type II antibody production was significantly diminished in treated mice, in both early and chronic arthritis. Ex vivo, Rac1 inhibitory peptide suppressed T-cell receptor/CD28-dependent production of tumor necrosis factor a, interferon. and interleukin-17 by T cells from collagen-primed mice, and reduced induction of ICOS and CD154, T-cell costimulatory proteins important for B-cell help. Conclusions: The data suggest that targeting of Rac1 with the Rac1 carboxy-terminal inhibitory peptide may suppress T-cell activation and autoantibody production in autoimmune disease. Whether this could translate into clinically meaningful improvement remains to be show

The effects of hip muscle strengthening on knee load, pain, and function in people with knee osteoarthritis: a protocol for a randomised, single-blind controlled trial

BACKGROUND: Lower limb strengthening exercises are an important component of the treatment for knee osteoarthritis (OA). Strengthening the hip abductor and adductor muscles may influence joint loading and/or OA-related symptoms, but no study has evaluated these hypotheses directly. The aim of this randomised, single-blind controlled trial is to determine whether hip abductor and adductor muscle strengthening can reduce knee load and improve pain and physical function in people with medial compartment knee OA. METHODS/DESIGN: 88 participants with painful, radiographically confirmed medial compartment knee OA and varus alignment will be recruited from the community and randomly allocated to a hip strengthening or control group using concealed allocation stratified by disease severity. The hip strengthening group will perform 6 exercises to strengthen the hip abductor and adductor muscles at home 5 times per week for 12 weeks. They will consult with a physiotherapist on 7 occasions to be taught the exercises and progress exercise resistance. The control group will be requested to continue with their usual care. Blinded follow up assessment will be conducted at 12 weeks after randomisation. The primary outcome measure is the change in the peak external knee adduction moment measured during walking. Questionnaires will assess changes in pain and physical function as well as overall perceived rating of change. An intention-to-treat analysis will be performed using linear regression modelling and adjusting for baseline outcome values and other demographic characteristics. DISCUSSION: Results from this trial will contribute to the evidence regarding the effect of hip strengthening on knee loads and symptoms in people with medial compartment knee OA. If shown to reduce the knee adduction moment, hip strengthening has the potential to slow disease progression. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTR12607000001493

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD

Personal non-commercial use only

ABSTRACT. Objective. To compare the psychometric functioning of multidimensional disease-specific, multiitem generic, and single-item measures of fatigue in patients with rheumatoid arthritis (RA). Methods. Confirmatory factor analysis (CFA) and longitudinal item response theory (IRT) modeling were used to evaluate the measurement structure and local reliability of the Bristol RA Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ), the Medical Outcomes Study Short Form-36 (SF-36) vitality scale, and the BRAF Numerical Rating Scales (BRAF-NRS) in a sample of 588 patients with RA. Results. A 1-factor CFA model yielded a similar fit to a 5-factor model with subscale-specific dimensions, and the items from the different instruments adequately fit the IRT model, suggesting essential unidimensionality in measurement. The SF-36 vitality scale outperformed the BRAF-MDQ at lower levels of fatigue, but was less precise at moderate to higher levels of fatigue. At these levels of fatigue, the living, cognition, and emotion subscales of the BRAF-MDQ provide additional precision. The BRAF-NRS showed a limited measurement range with its highest precision centered on average levels of fatigue. Conclusion. The different instruments appear to access a common underlying domain of fatigue severity, but differ considerably in their measurement precision along the continuum. The SF-36 vitality scale can be used to measure fatigue severity in samples with relatively mild fatigue. For samples expected to have higher levels of fatigue, the multidimensional BRAF-MDQ appears to be a better choice. The BRAF-NRS are not recommended if precise assessment is required, for instance in longitudina