Exploring outcome measures for adults with myotonic dystrophy type 1

PhD ThesisMyotonic Dystrophy type 1 (DM1) is a multisystem progressive disorder with high heterogeneity. Novel emerging therapies require assessment tools that can effectively assess the effects of an intervention. The Outcome Measures in 5 Myotonic Dystrophy (OMMYD) Consortium has proposed a battery of functional outcome measures (FOM) identified as relevant for clinical trials in DM1. However, due to the variable nature of the disease and a scarcity of resources, there is a lack of systematic research that properly explores the use of these FOM. The current study examined three of these FOM and one extra related to 10 patients’ daily life performance. These are: (1) the ten-meters walk test; (2) the ten-meters walk/run test; (3) the 30-seconds sit and stand test; and, (4) a tri-axial accelerometer. By exploring the reliability, validity and responsiveness of these outcomes, we aimed to establish reference values and standard methodologies that could serve as guidance for clinical trials in DM1. A cohort of DM1 adults 15 screened for the two largest-to-date trials in DM1 (OPTIMSITIC and PHENO-DM1) were examined in relation to a set of pre-specified assessments and disease-burden scores. The results of this thesis supply disease-specific evidence of their validity, reliability and feasibility. The FOM, have shown to be psychometrically robust measures of functionality in DM1 and to be feasible for 20 clinical trials; they can provide a picture of patients’ muscle strength and perceived mobility and participation in life. The accelerometer can objectively quantify joints accelerations when walking at different speeds and summarise a DM1 patient’s habitual physical activity. The final choice of an outcome measure for a clinical trial in DM1 should be guided by disease domain that an intervention 25 is likely to impact on; but, a disease-specific study like this one will reduce the burden of protocol design whilst providing evidence supporting the decision-making process.the Medical Research Council Centre for Neuromuscular Diseases, Consejo Nacional de Ciencia y Tecnologia of Mexico and the Barbour Foundation.

Functional impairment in patients with myotonic dystrophy type 1 can be assessed by an ataxia rating scale (SARA)

Myotonic dystrophy type 1 (DM1) is not characterised by ataxia per se; however, DM1 and ataxia patients show similar disturbances in movement coordination often experiencing walking and balance difficulties, although caused by different underlying pathologies. This study aims to investigate the use of a scale previously described for the assessment and rating of ataxia (SARA) with the hypothesis that it could have utility in DM1 patients as a measure of disease severity and risk of falling. Data from 54 DM1 patients were pulled from the PHENO-DM1 natural history study for analysis. Mean SARA score in the DM1 population was 5.45 relative to the maximum score of eight. A flooring effect (score 0) was observed in mild cases within the sample. Inter-rater and test–retest reliability was high with intraclass coefficients (ICC) of 0.983 and 1.00, respectively. Internal consistency was acceptable as indicated by a Cronbach’s alpha of 0.761. Component analysis revealed two principle components. SARA correlated with: (1) all measures of muscle function tested, including quantitative muscle testing of ankle dorsiflexion (r = −0.584*), the 6 min walk test (r = −0.739*), 10 m walk test (r = 0.741*), and the nine hole peg test (r = 0.602*) and (2) measures of disease severity/burden, such as MIRS (r = 0.718*), MDHI (r = 0.483*), and DM1-Activ (r = −0.749*) (*p < 0.001). The SARA score was predicted by an interaction between modal CTG repeat length and age at sampling (r = 0.678, p = 0.003). A score of eight or above predicted the use of a walking aid with a sensitivity of 100% and a specificity of 85.7%. We suggest that further research is warranted to ascertain whether SARA or components of SARA are useful outcome measures for clinical trials in DM1. As a tool, it can be used for gathering information about disease severity/burden and helping to identify patients in need of a walking aid, and can potentially be applied in both research and healthcare settings

Disease burden of myotonic dystrophy type 1

Objective: The objective of this cross-sectional, observational study was to investigate the disease burden of myotonic dystrophy type 1 (DM1), a disabling muscle disorder. Methods: Adults 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]. Results: Our 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. Conclusion: We 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

Change over time in ability to perform activities of daily living in myotonic dystrophy type 1

Objective: The objective of this longitudinal, observational study was to investigate change over time in ability to perform activities of daily living in myotonic dystrophy type 1 (DM1). Methods: Adults with genetically confirmed DM1 were recruited as part of the PhenoDM1 study in the UK. Data on activities of daily living were recorded through the DM1-ActivC at baseline and a follow-up visit after 12 (± 3) months. A subset of patients had advanced genetic testing to determine the size of the progenitor allele. Results: Our sample comprised 150 patients with DM1 (mean age: 45 years; 52% female). Mean follow-up was 383 days. Mean DM1-ActivC total score at baseline was 71.24 (95% confidence interval 67.77–74.71) and at the follow-up visit 69.04 (65.54–72.54). Approximately 43% of patients had a lower score at the follow-up visit (indicating a decreased ability to perform activities of daily living), 24% a higher score (indicating an increased ability), and 33% the same score at baseline and follow-up. The mean annual change in the DM1-ActivC total score, estimated at − 2.06 (− 3.54 to − 0.59), was significantly related to patients’ baseline score, but not sex, disease duration, timed test results, or cytosine-thymine-guanine repeat length. Conclusions: Change over time in ability to perform activities of daily living as recorded through the DM1-ActivC varies substantially between patients with DM1. Our data contribute to the understanding of the natural evolution of the disease, and should be helpful to inform the design of future trials based on the DM1-ActivC

Aplicación de Lean Six Sigma para la mejora del proceso de trabajos de grado en una Institución de Educación Superior

Despite the advances in the implementation of improvement projects in Higher Education Institutions (HEIs), these have been carried out without following a general specific model that defines a clear procedure for their subsequent implementation in this type of organizations, which differs from industries where the Lean Six Sigma (LSS) methodology was created. The HEI have the degree work process to issue the certificate of the library, but this process is taking longer than expected. For this reason, the present research aims to design the improvement project through the LSS model for the aforementioned process. Applying this methodology, it was possible to diagnose the current state of the process, as well as to identify the needs of the interested parties. Finally, an action plan was proposed that would allow continuous improvement of the process aligned to provide quality, effectiveness and service to the process. From the application of these strategies, it is expected to reduce the delivery time of the process by up to 54%, increasing the Value Added indicator from 8% to 17% and increasing the First Pass Yield index by up to 40%.A pesar de los avances en la implementación de proyectos de mejora en Instituciones de Educación Superior (IES), estos se han realizado sin seguir un modelo especifico general que defina un procedimiento claro para su implementación exitosa en este tipo de organizaciones, que difieren de las industrias en donde fue creada la metodología Lean Six Sigma (LSS). Las IES tienen diferentes procesos cómo el de revisión de trabajos de grado para otorgar el paz y salvo de biblioteca, el cual está tardando más de lo esperado. Por tal razón, la presente investigación tiene como objetivo diseñar el proyecto de mejora a través del modelo LSS para el proceso mencionado. A partir de la aplicación de esta metodología, se logró diagnosticar el estado actual del proceso, así mismo, identificar las necesidades de los interesados. Finalmente, se propuso un plan de acción que permitiera el mejoramiento continuo del  proceso alineado a brindar calidad, efectividad y servicio al proceso. A partir de la aplicación de estas estrategias se espera reducir el lead time del proceso hasta un 54% aumentando el indicador de Valor Agregado de 8% a 17% e  incrementado el índice First Pass Yield hasta un 40%. &nbsp

The UK myotonic dystrophy patient registry: facilitating and accelerating clinical research

Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy worldwide with complex, multi-systemic, and progressively worsening symptoms. There is currently no treatment for this inherited disorder and research can be challenging due to the rarity and variability of the disease. The UK Myotonic Dystrophy Patient Registry is a patient self-enrolling online database collecting clinical and genetic information. For this cross-sectional “snapshot” analysis, 556 patients with a confirmed diagnosis of DM1 registered between May 2012 and July 2016 were included. An almost even distribution was seen between genders and a broad range of ages was present from 8 months to 78 years, with the largest proportion between 30 and 59 years. The two most frequent symptoms were fatigue and myotonia, reported by 79 and 78% of patients, respectively. The severity of myotonia correlated with the severity of fatigue as well as mobility impairment, and dysphagia occurred mostly in patients also reporting myotonia. Men reported significantly more frequent severe myotonia, whereas severe fatigue was more frequently reported by women. Cardiac abnormalities were diagnosed in 48% of patients and more than one-third of them needed a cardiac implant. Fifteen percent of patients used a non-invasive ventilation and cataracts were removed in 26% of patients, 65% of which before the age of 50 years. The registry’s primary aim was to facilitate and accelerate clinical research. However, these data also allow us to formulate questions for hypothesis-driven research that may lead to improvements in care and treatment

Aplicación de Lean Six Sigma para la mejora del proceso de trabajos de grado en una Institución de Educación Superior

Despite the advances in the implementation of improvement projects in Higher Education Institutions (HEIs), these have been carried out without following a general specific model that defines a clear procedure for their subsequent implementation in this type of organizations, which differs from industries where the Lean Six Sigma (LSS) methodology was created. The HEI have the degree work process to issue the certificate of the library, but this process is taking longer than expected. For this reason, the present research aims to design the improvement project through the LSS model for the aforementioned process. Applying this methodology, it was possible to diagnose the current state of the process, as well as to identify the needs of the interested parties. Finally, an action plan was proposed that would allow continuous improvement of the process aligned to provide quality, effectiveness and service to the process. From the application of these strategies, it is expected to reduce the delivery time of the process by up to 54%, increasing the Value Added indicator from 8% to 17% and increasing the First Pass Yield index by up to 40%.A pesar de los avances en la implementación de proyectos de mejora en Instituciones de Educación Superior (IES), estos se han realizado sin seguir un modelo especifico general que defina un procedimiento claro para su implementación exitosa en este tipo de organizaciones, que difieren de las industrias en donde fue creada la metodología Lean Six Sigma (LSS). Las IES tienen diferentes procesos cómo el de revisión de trabajos de grado para otorgar el paz y salvo de biblioteca, el cual está tardando más de lo esperado. Por tal razón, la presente investigación tiene como objetivo diseñar el proyecto de mejora a través del modelo LSS para el proceso mencionado. A partir de la aplicación de esta metodología, se logró diagnosticar el estado actual del proceso, así mismo, identificar las necesidades de los interesados. Finalmente, se propuso un plan de acción que permitiera el mejoramiento continuo del  proceso alineado a brindar calidad, efectividad y servicio al proceso. A partir de la aplicación de estas estrategias se espera reducir el lead time del proceso hasta un 54% aumentando el indicador de Valor Agregado de 8% a 17% e  incrementado el índice First Pass Yield hasta un 40%. &nbsp

Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort

To evaluate the role of genetic variation at the locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial.We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats.We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed test = -3.7, = 0.0019).Careful characterization of the CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials

Associations Between Variant Repeat Interruptions and Clinical Outcomes in Myotonic Dystrophy Type 1

Objective: To assess the association between variant repeat (VR) interruptions in patients with myotonic dystrophy type 1 (DM1) and clinical symptoms and outcome measures after cognitive behavioral therapy (CBT) intervention. Methods: Adult patients with DM1 were recruited within the OPTIMISTIC trial (NCT02118779). Disease-related history, current clinical symptoms and comorbidities, functional assessments, and disease- and health-related questionnaires were obtained at baseline and after 5 and 10 months. After genetic analysis, we assessed the association between the presence of VR interruptions and clinical symptoms' long-term outcomes and compared the effects of CBT in patients with and without VR interruptions. Core trial outcome measures analyzed were: 6-minute walking test, DM1-Activ-C, Checklist Individual Strength Fatigue Score, Myotonic Dystrophy Health Index, McGill-Pain questionnaire, and Beck Depression inventory—fast screen. Blood samples for DNA testing were obtained at the baseline visit for determining CTG length and detection of VR interruptions. Results: VR interruptions were detectable in 21/250 patients (8.4%)—12 were assigned to the standard-of-care group (control group) and 9 to the CBT group. Patients with VR interruptions were significantly older when the first medical problem occurred and had a significantly shorter disease duration at baseline. We found a tendency toward a milder disease severity in patients with VR interruptions, especially in ventilation status, mobility, and cardiac symptoms. Changes in clinical outcome measures after CBT were not associated with the presence of VR interruptions. Conclusions: The presence of VR interruptions is associated with a later onset of the disease and a milder phenotype. However, based on the OPTIMISTIC trial data, the presence of VR interruptions was not associated with significant changes on outcome measures after CBT intervention. Trial Registration: Information ClinicalTrials.gov NCT02118779