Psychometric properties of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy: a Rasch analysis

<p><b>Purpose:</b> To explore the psychometric properties of the full 22-item English (UK and US) version of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy.</p> <p><b>Materials and methods:</b> Caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States, recruited through the TREAT-NMD network, completed the Zarit Caregiver Burden Interview online. The psychometric properties of the Zarit Caregiver Burden Interview were examined using Rasch analysis.</p> <p><b>Results:</b> A total of 475 caregivers completed the Zarit Caregiver Burden Interview. Model misfit was identified for 9 of 22 items (mean item fit residual 0.061, SD: 2.736) and 13 of 22 items displayed disordered thresholds. The overall item-trait interaction chi-square value was 499 (198 degrees of freedom, <i>p</i> < 0.001). The mean person fit residual was estimated at −0.213 (SD: 1.235). The Person Separation Index and Cronbach’s α were estimated at 0.902 and 0.914, respectively. Item dependency was low and we found no significant differential item functioning by country or sex.</p> <p><b>Conclusion:</b> Our Rasch analysis shows that the Zarit Caregiver Burden Interview fails to fully operationalize a quantitative conceptualization of caregiver burden among caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States. Further research is needed to understand the psychometric properties of the Zarit Caregiver Burden Interview in other populations and settings.Implications for Rehabilitation</p><p>Duchenne muscular dystrophy is a terminal disease characterized by progressive muscle degeneration resulting in substantial disability and a significant burden on family caregivers.</p><p>The Zarit Caregiver Burden Interview is one of the most widely applied measures of caregiver burden.</p><p>Our Rasch analysis suggests that the Zarit Caregiver Burden Interview is not fit for purpose to measure burden in UK and US caregivers to patients with Duchenne muscular dystrophy.</p><p>Clinicians and decision-makers should interpret Zarit Caregiver Burden Interview data from these populations with caution.</p><p></p> <p>Duchenne muscular dystrophy is a terminal disease characterized by progressive muscle degeneration resulting in substantial disability and a significant burden on family caregivers.</p> <p>The Zarit Caregiver Burden Interview is one of the most widely applied measures of caregiver burden.</p> <p>Our Rasch analysis suggests that the Zarit Caregiver Burden Interview is not fit for purpose to measure burden in UK and US caregivers to patients with Duchenne muscular dystrophy.</p> <p>Clinicians and decision-makers should interpret Zarit Caregiver Burden Interview data from these populations with caution.</p

Effect of metoprolol treatment on left ventricular function.

<p>(A) Left ventricular volume to body weight (BW) ratios; (B) Ejection fraction; (C) Cardiac output (CO) to body weight ratio. Reductions in left ventricular end-diastolic and (LV EDV) and left ventricular stroke volume index (LV SV) in untreated <i>mdx</i> mice were no longer evident after metoprolol treatment. In untreated <i>Sgcd-/-</i> mice there was normal left ventricular function, and after treatment with metropolol there were increases in end-diastolic, end-systolic (LV ESV) and stroke volume indexes relative to untreated <i>mdx</i> mice. (*different from C57 Bl10 control, ^$different from <i>Sgcd-/-</i> control, ?different from <i>mdx</i> control; number of symbols denotes level of significance e.g. *p<0.05, **p<0.01, ***p<0.001); (– sign indicates without metoprolol and + indicates with).</p

Deterioration in right ventricular function with metoprolol in mdx mice.

<p>Right ventricular ejection fraction (RV EF, panel A), and right ventricular volume data (with abbreviations as for LV in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057260#pone-0057260-g002" target="_blank">figure 2</a>, panel B). (*Different from C57 Bl10 control, ^$different from <i>Sgcd-/-</i> control, ^#different from metoprolol-treated C57 Bl10, number of symbols denotes level of significance e.g. *p<0.05, **p<0.01, ***p<0.001); (BW = body weight, – sign indicates without metoprolol and + indicates with).</p

<i>Mdx</i> mice have RV dilatation.

<p>Representative 2 chamber short axis cine slices at the level of the papillary muscles (basal to apical slices from left to right) at end diastole in <i>mdx</i> and C57 Bl10 mice. The right ventricle is highlighted in blue in the first slices.</p

Body and heart weights of metoprolol treated mice.

<p>Mean<u>+</u>SEM. * different from C57 B10 control, $ different from <i>Sgcd</i>-/- control. Number of symbols denotes level of significance e.g. *p<0.05, **p<0.01, ***p<0.001</p

Metoprolol does not significantly alter increased manganese uptake in <i>Sgcd</i>-/- and <i>mdx</i> mice.

<p>There is a significant strain effect (p<0.05, ANOVA) on (B) early (5-15 mins) and (D) steady state (10-25 mins) manganese uptake enhancement ratio, such that Sgcd-/- (A) and <i>mdx</i> (C) mice have a significantly higher manganese uptake than C57 Bl10 mice. Beta-Blocker treatment has no significant effect on manganese uptake. MEMRI data is expressed as an enhancement ratio over baseline levels. (*p<0.05 vs C57 Bl10, – sign indicates without metoprolol and + indicates with).</p

NeurOmics: -omics research for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases – an EU funded FP7 project

<p>Neuromics is an EU-funded translational research project which has the primary aim of greatly improving understanding of neuromuscular and neurodegenerative diseases. The research will study around 1100 exomes from undiagnosed patients in its aim to discover novel disease-causing and disease-modifying genes and to identify potential new therapeutic targets. Partners have also undertaken deep-phenotyping of patients using human phenotype ontology (HPO) terms. Agreements are in place to allow the secure sharing of this standardised clinical information along with WES and other –omics data both within Neuromics and with the wider rare-disease field. This will encourage collaborative partnerships and speed progress towards therapeutic and diagnostic breakthrough and improvements in care for patients. The project focusses on 10 rare, genetic neuromuscular and neurodegenerative disease groups: frontotemporal lobe degeneration; Huntington’s disease; ataxia; hereditary spastic paraplegia; spinal muscular atrophy; hereditary motor neuropathy; congenital myasthenic syndrome; muscular dystrophy and muscular channelopathy. The project brings together the leading research groups in Europe, five highly innovative SMEs and overseas experts to work together using the most sophisticated -omics technologies employing genomics, transcriptomics, proteomics and metabolomics.</p> <p>The consortium is coordinated by Olaf Riess at Tübingen University, Brunhilde Wirth at Cologne University and Gert-Jan van Ommen at Leiden University. Neuromics is working closely with RD-Connect, the rare-disease platform, in order to develop a global infrastructure for the wide sharing of research outputs of Neuromics, and other rare disease projects.</p> <p>At the end of its first year of activity, this poster describes the aims and methods used in the Neuromics project and reports on progress made so far. It highlights how Neuromics will contribute significantly to the ambitious goals of the International Rare Diseases Research Consortium (IRDiRC): deciphering the genetic causes of all rare diseases and the development of 200 new therapies by 2020.</p

The TREAT-NMD Care and Trial Site Registry: A powerful tool for clinical research on neurodegenerative and neuromuscular diseases

<p>Established in 2007 in the scope of the TREAT-NMD project (EU-funded Network of Excellence, FP6) to identify possible trial sites for rare neuromuscular diseases, the Care and Trial Site Registry (CTSR) collects information on personnel and the experience of the study team, facilities and equipment, as well as patient numbers per disease and age group.</p> <p>Within the CARE-NMD project (2010-2013, funded by DG Sanco) the CTSR was extended with Duchenne-specific care questions and used to evaluate current clinical practice in different European countries.</p> <p>In September 2013, the CTSR expanded to cover the field of rare neurodegenerative diseases as a branch of NeurOmics (FP7, 2012-2017) and now encompasses 32 rare diseases.</p> <p>The CTSR is an online self-registration database hosted by the University Medical Center Freiburg, Germany. This allows swift self-registration and update of information by any web browser and regardless of geographic location. Once registered, data is entered into online forms organised by topic categories such as Patient Cohort, Diagnostic Tools, Personnel and Experience, Equipment, Care Settings and Research and Education. The quality of the data is ensured by regularly contacting the sites and asking them to update their records, usually when an official enquiry has been submitted to the CTSR.</p> <p>As of September 2013 the CTSR contained 280 centres in 44 countries with an overall count of 41,500 reported patients.</p> <p>Fourteen official requests for site identification, often in combination with TREAT-NMD patient registry information, were received between 2009 and 2013: Ten were trial feasibiltiy enquiries from major industrial firms and four enquiries from academia..</p> <p>As an ideal complement to patient registries, the CTSR provides a powerful infrastructure for feasibility and trial site selection by pharmaceutical industry and investigators, as well as improving clinical networking in rare diseases.</p

Dystromirs as Serum Biomarkers for Monitoring the Disease Severity in Duchenne Muscular Dystrophy

<div><p>Duchenne muscular Dystrophy (DMD) is an inherited disease caused by mutations in the dystrophin gene that disrupt the open reading frame, while in frame mutations result in Becker muscular dystrophy (BMD). Ullrich congenital muscular dystrophy (UCMD) is due to mutations affecting collagen VI genes. Specific muscle miRNAs (dystromirs) are potential non-invasive biomarkers for monitoring the outcome of therapeutic interventions and disease progression. We quantified miR-1, miR-133a,b, miR-206 and miR-31 in serum from patients with DMD, BMD, UCMD and healthy controls. MiR-1, miR-133a,b and miR-206 were upregulated in DMD, but unchanged in UCMD compared to controls. Milder DMD patients had higher levels of dystromirs than more severely affected patients. Patients with low forced vital capacity (FVC) values, indicating respiratory muscle weakness, had low levels of serum miR-1 and miR-133b. There was no significant difference in the level of the dystromirs in BMD compared to controls.</p><p>We also assessed the effect of dystrophin restoration on the expression of the five dystromirs in serum of DMD patients treated systemically for 12 weeks with antisense oligomer eteplirsen that induces skipping of exon 51 in the dystrophin gene. The dystromirs were also analysed in muscle biopsies of DMD patients included in a single dose intramuscular eteplirsen clinical trial. Our analysis detected a trend towards normalization of these miRNA between the pre- and post-treatment samples of the systemic trial, which however failed to reach statistical significance. This could possibly be due to the small number of patients and the short duration of these clinical trials.</p><p>Although longer term studies are needed to clarify the relationship between dystrophin restoration following therapeutic intervention and the level of circulating miRNAs, our results indicate that miR-1 and miR-133 can be considered as exploratory biomarkers for monitoring the progression of muscle weakness and indirectly the remaining muscle mass in DMD.</p></div

Correlation analysis between the level of the analysed dystromirs in DMD and the FVC values.

<p>Linear regression analysis between the levels of miR-1, miR-206, miR-31, miR-133a and miR-133b in serum samples and FVC scores in DMD patients showed correlation between the level of miR-1 (p = 0.0034, r² = 0.34) and miR-133b (p = 0.0035, r² = 0.34) with the FVC scores. The data are presented as miRNA copy number per ml normalized to the spiked-in <i>C. elegance</i> miRNA s (<i>cel-miR-54, cel-miR-39, cel-miR-238</i>). Regression lines are also presented.</p