Myotonic Dystrophy Health Index: initial evaluation of a disease-specific outcome measure.
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ABSTRACT:
SUBMITTER: Heatwole C
PROVIDER: S-EPMC5551891 | biostudies-literature | 2014 Jun
REPOSITORIES: biostudies-literature
Publications
Myotonic Dystrophy Health Index: initial evaluation of a disease-specific outcome measure.
Heatwole Chad C Bode Rita R Johnson Nicholas N Dekdebrun Jeanne J Dilek Nuran N Heatwole Mark M Hilbert James E JE Luebbe Elizabeth E Martens William W Mcdermott Michael P MP Rothrock Nan N Thornton Charles C Vickrey Barbara G BG Victorson David D Moxley Richard R
Muscle & nerve 20140601 6
<h4>Introduction</h4>In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI).<h4>Methods</h4>Initially we partnered with 278 myotonic dystrophy type-1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test-retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differ ...[more]
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Project description:The Myotonic Dystrophy Health Index (MDHI) is a disease-specific patient-reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with myotonic dystrophy type-1 (DM1).We conducted a cross-sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient-reported outcome measures.MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures.Patient-reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients.
| S-EPMC4979973 | biostudies-literature
Project description:Introduction: Myotonic dystrophy type 2 (DM2) lacks disease-specific, validated, motor outcome measures (OMs), and patients' reported outcomes (PROs). This represents a limit for the monitoring of disease progression and treatment response. Our aim was to identify the most appropriate OMs to be translated in clinical practice and clinical trials on DM2. This study has been registered on clinicaltrials.gov NCT03603171 (https://clinicaltrials.gov/ct2/show/NCT03603171). Methods: Sixty-six patients with genetically confirmed DM2 underwent a baseline and a follow-up visit after 1 year. The tested OMs included: hand opening time, pressure pain threshold (PPT), manual muscle testing (MMT), hand held dynamometry (HHD), scale for the assessment and rating of ataxia (SARA), quantitative motor function test (QMFT), gait stairs Gowers chair (GSGC), 30-s sit to stand test, functional index 2 (FI-2) and 6MWT. The PROs included DM1-Active-C, Rasch-built Pompe-specific activity scale (R-Pact), fatigue and daytime sleepiness (FDSS), brief pain inventory short form (BPI-sf), myotonia behavior scale (MBS), and the McGill pain questionnaire. Results: All patients completed the MBS and the results correlated well with the hand-opening time. The PPT showed a low reliability, no correlation with pain questionnaires, and did not differentiate patients with or without myalgia. Both muscle strength assessments, MMT and HHD, showed good construct validity. The QMFT showed an acceptable ceiling effect (14.5%), good convergent and differential validity and performed overall better than GSGC. The SARA score showed high flooring effect and is not useful in DM2. 6MWT proved a valid outcome measure in DM2. The 30-s sit to stand is a feasible test with good convergent validity, showing a flooring effect of 20% as it cannot be used in more severely affected patients. The FI-2 is time-consuming and has a high ceiling effect. At the 1-year visit the only assessments able to detect a worsening of DM2 were HHD, QMFT, and 6MWT, which are the most sensitive to change, and therefore clinically meaningful OMs in DM2. Conclusion: The clinical meaningful motor outcome measures that best depict the multifaceted phenotype of DM2 and its slow progression are MBS, MMT, or HHD (depending on the clinical setting), QMFT, and the 6MWT.
| S-EPMC7186332 | biostudies-literature
Project description:ObjectivesDefining clinically relevant outcome measures for myotonic dystrophy type 1 (DM1) that can be valid and feasible for different phenotypes has proven problematic. The Outcome Measures for Myotonic Dystrophy (OMMYD) group proposed a battery of functional outcomes: 6-minute walk test, 30 seconds sit and stand test, timed 10 m walk test, timed 10 m walk/run test, and nine-hole peg test. This, however, required a large-scale investigation, METHODS: A cohort of 213 patients enrolled in the natural history study, PhenoDM1, was analyzed in cross-sectional analysis and subsequently 98 patients were followed for longitudinal analysis. We aimed to assess: (1) feasibility and best practice; (2) intra-session reliability; (3) validity; and (4) behavior over time, of these tests.ResultsOMMYD outcomes proved feasible as 96% of the participants completed at least one trial for all tests and more than half (n = 113) performed all three trials of each test. Body mass index and disease severity associate with functional capacity. There was a significant difference between the first and second trials of each test. There was a moderate to strong correlation between these functional outcomes and muscle strength, disease severity and patient-reported outcomes. All outcomes after 1 year detected a change in functional capacity except the nine-hole peg test.ConclusionsThese tests can be used as a battery of outcomes or independently based on the shown overlapping psychometric features and strong cross-correlations. Due to the large and heterogeneous sample of this study, these results can serve as reference values for future studies.
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Project description:INTRODUCTION:We developed an evaluator-administered functional facioscapulohumeral muscular dystrophy composite outcome measure (FSHD-COM) comprising patient-identified areas of functional burden for future clinical trials. METHODS:We performed a prospective observational study of 41 patients with FSHD at 2 sites. The FSHD-COM includes functional assessment of the legs, shoulders and arms, trunk, hands, and balance/mobility. We determined the test-retest reliability and convergent validity compared to established FSHD disease metrics. RESULTS:The FSHD-COM demonstrated excellent test-retest reliability (intraclass correlation coefficient [ICC] 0.96; subscale ICC range, 0.90-0.94). Cross-sectional associations between the FSHD-COM and disease duration, clinical severity, and strength were moderate to strong (Pearson correlation coefficient range |0.51-0.92|). DISCUSSION:The FSHD-COM is a disease-relevant, functional composite outcome measure suitable for future FSHD clinical trials that shows excellent test-retest reliability and cross-sectional associations to disease measures. Future directions include determining multisite reliability, sensitivity to change, and the minimal clinically important change in the FSHD-COM. Muscle Nerve, 2018.
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Project description:ObjectiveThe objective of this cross-sectional, observational study was to investigate the disease burden of myotonic dystrophy type 1 (DM1), a disabling muscle disorder.MethodsAdults with DM1 were recruited as part of the PhenoDM1 study from Newcastle University (Newcastle upon Tyne, UK). Disease burden data were recorded through the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. Results were examined by sex and clinical variables [e.g. the six-minute walk test (6MWT), the Mini Mental State Examination, and estimated progenitor and modal allele CTG repeat length].ResultsOur sample consisted of 60 patients with DM1 (mean age: 45 years; 45% female). Muscle weakness and fatigue constituted the two most common disease manifestations, reported by 93% and 90% of patients, respectively, followed by muscle locking (73%). Most patients (> 55%) reported feeling anxious/worried, depressed, frustrated, and/or having low confidence/self-esteem, 23% and 33% indicated substantial impairment of daily and leisure activities, respectively, and 47% did not work as a consequence of the disease. Estimated progenitor CTG length corrected by age correlated surprisingly well with INQoL scores. Differences by sex were generally minor.ConclusionWe show that DM1 is associated with a substantial disease burden resulting in impairment across many different domains of patients' lives, emphasizing the need for a holistic approach to medical management. Our results also show that the INQoL records relevant information about patients with DM1, but that further investigation of the psychometric properties of the scale is needed for meaningful interpretation of instrument scores.
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Project description:To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2).In a discovery cohort, we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects, we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM-associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides to reduce levels of toxic RNA.Forty-two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM-specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue.Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy.
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Project description:The discovery of reliable and sensitive blood biomarkers is useful for the diagnosis, monitoring and potential future therapy of diseases. Recently, microRNAs (miRNAs) have been identified in blood circulation and might have the potential to be used as biomarkers for several diseases and clinical conditions. Myotonic Dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy primarily characterized by muscle myotonia, weakness and atrophy. Previous studies have shown an association between miRNAs and DM1 in muscle tissue and, recently, in plasma. The aim of this study was to detect and assess muscle-specific miRNAs as potential biomarkers of DM1 muscle wasting, an important parameter in the disease's natural history. Disease stable or progressive DM1 patients with muscle weakness and wasting were recruited and enrolled in the study. RNA isolated from participants' serum was used to assess miRNA levels. Results suggest that the levels of muscle-specific miRNAs are correlated with the progression of muscle wasting and weakness observed in the DM1 patients. Specifically, miR-1, miR-133a, miR133b and miR-206 serum levels were found elevated in DM1 patients with progressive muscle wasting compared to disease stable DM1 patients. Based on these results, we propose that muscle-specific miRNAs might be useful molecular biomarkers for monitoring the progress of muscle atrophy in DM1 patients.
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Project description:Myotonic dystrophy (DM) is the most common muscular dystrophy in adults. Dominantly inherited CTG and CCTG repeat expansions in DMPK and CNBP genes cause DM type 1 (DM1) and 2 (DM2), respectively. These genetic defects lead to the abnormal splicing of different mRNA transcripts, which are thought to be responsible for the multiorgan involvement of these diseases. In ours and others' experience, cancer frequency in patients with DM appears to be higher than in the general population or non-DM muscular dystrophy cohorts. There are no specific guidelines regarding malignancy screening in these patients, and the general consensus is that they should undergo the same cancer screening as the general population. Here, we review the main studies that investigated cancer risk (and cancer type) in DM cohorts and those that researched potential molecular mechanisms accounting for DM carcinogenesis. We propose some evaluations to be considered as malignancy screening in patients with DM, and we discuss DM susceptibility to general anesthesia and sedatives, which are often needed for the management of cancer. This review underscores the importance of monitoring the adherence of patients with DM to malignancy screenings and the need to design studies that determine whether they would benefit from a more intensified cancer screening than the general population.
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Project description:Background: Central nervous system involvement in myotonic dystrophy type 1 (DM1) is associated with cognitive deficits, impaired social performance and excessive somnolence, which greatly impact quality of life. With the advent of clinical trials in DM1, there is a pressing need to identify outcome measures for quantification of central symptoms that are feasible and valid. In this context, we sought to evaluate neuropsychological and self-reported measures currently recommended by expert consensus, with particular reference to their specificity for central nervous system involvement in a moderate-sized DM1 cohort. Methods: Forty-five adults with DM1 and 20 controls completed neuropsychology assessments and symptom questionnaires. Those without contraindication also underwent MRI brain, from which global gray matter volume and white matter lesion volume were quantified. CTG repeat was measured by small pool PCR, and was screened for the presence of variant repeat sequences. Results: The neuropsychology test battery was well tolerated and detected impairment across various domains in the DM1 group vs. controls. Large effect sizes in the Stroop and Trail Making Tests were however attenuated by correction for basic speed, which could be influenced by dysarthria and upper limb weakness, respectively. Low mood was strongly associated with increased self-reporting of central symptoms, including cognitive impairment. Conversely, self-reported cognitive impairment did not generally predict poorer performance in neuropsychology assessments, and there was a trend toward greater self-reporting of low mood and cognitive problems in those with milder white matter change on MRI. Global gray matter volume correlated with performance in several neuropsychology assessments in a multivariate model with age and sex, while white matter lesion volume was associated with executive dysfunction reported by a proxy. Screening for variant repeats was positive in three individuals, who reported mild muscle symptoms. Conclusions: Identification of outcome measures with good specificity for brain involvement in DM1 is challenging, since complex cognitive assessments may be compromised by peripheral muscle weakness and self-reported questionnaires may be influenced by mood and insight. This highlights the need for further large, longitudinal studies to identify and validate objective measures, which may include imaging biomarkers and cognitive measures not influenced by motor speed.
| S-EPMC6176265 | biostudies-literature
Project description:ObjectivesThis study was to determine whether the BILAG2004-Pregnancy Index (BILAG2004-P) has construct/criterion validity and is sensitive to change.MethodsThis was an observational multicentre study that recruited pregnant SLE patients. Data were collected on disease activity [using the BILAG2004-P and Physician Global Assessment (PGA)], investigations and therapy at each assessment. The overall BILAG2004-P score as determined by the highest score achieved by any system was used in the analysis. Cross-sectional analysis was used for construct and criterion validity. The comparison was with C3, C4 and anti-dsDNA for construct validity, while it was with change in therapy and PGA in criterion validity. Sensitivity to change was assessed by determining the relationship between the change in BILAG2004-P and the change in therapy between two consecutive visits.ResultsA total of 97 patients with 112 pregnancies were recruited. There were 610 assessments available for construct/criterion validity analysis (98.2% of pregnancies had more than one assessment) and 497 observations for sensitivity to change analysis. Increasing BILAG2004-P scores were associated with low C3. The active BILAG2004-P score (grade A or B) was associated with an increase in therapy and the PGA of active disease. There was an increasing likelihood of higher overall scores with an increase in therapy and the PGA of active disease. In the sensitivity to change analysis, an increase in the BILAG2004-P score was associated with an increase in therapy and inversely associated with a decrease in therapy. A decrease in the BILAG2004-P score was associated with a decrease in therapy and inversely associated with an increase in therapy.ConclusionThe BILAG2004-P has criterion validity and is sensitive to change.
| S-EPMC9585949 | biostudies-literature