RESUMO
Variant detection from long-read genome sequencing (lrGS) has proven to be considerably more accurate and comprehensive than variant detection from short-read genome sequencing (srGS). However, the rate at which lrGS can increase molecular diagnostic yield for rare disease is not yet precisely characterized. We performed lrGS using Pacific Biosciences "HiFi" technology on 96 short-read-negative probands with rare disease that were suspected to be genetic. We generated hg38-aligned variants and de novo phased genome assemblies, and subsequently annotated, filtered, and curated variants using clinical standards. New disease-relevant or potentially relevant genetic findings were identified in 16/96 (16.7%) probands, eight of which (8/96, 8.33%) harbored pathogenic or likely pathogenic variants. Newly identified variants were visible in both srGS and lrGS in nine probands (~9.4%) and resulted from changes to interpretation mostly from recent gene-disease association discoveries. Seven cases included variants that were only interpretable in lrGS, including copy-number variants, an inversion, a mobile element insertion, two low-complexity repeat expansions, and a 1 bp deletion. While evidence for each of these variants is, in retrospect, visible in srGS, they were either: not called within srGS data, were represented by calls with incorrect sizes or structures, or failed quality-control and filtration. Thus, while reanalysis of older data clearly increases diagnostic yield, we find that lrGS allows for substantial additional yield (7/96, 7.3%) beyond srGS. We anticipate that as lrGS analysis improves, and as lrGS datasets grow allowing for better variant frequency annotation, the additional lrGS-only rare disease yield will grow over time.
RESUMO
RESUMEN Antecedentes: La prueba de lanzadera incremental ha sido empleada para determinar la capacidad física en pacientes con enfermedad renal crónica. Sin embargo, su aplicabilidad y reproducibilidad ha sido poco estudiada en pacientes bajo tratamiento de hemodiálisis. El objetivo de este estudio fue evaluar el rendimiento y reproducibilidad de la prueba de lanzadera incremental en pacientes con enfermedad renal crónica en hemodiálisis. Material y métodos: Se incluyeron pacientes con enfermedad renal crónica en diálisis y sujetos sin enfermedad renal crónica. Cada individuo realizó dos pruebas de lanzadera incremental con un intervalo de 30 minutos. Se registró la distancia recorrida, velocidad máxima, frecuencia cardiaca y el esfuerzo percibido. La reproducibilidad se analizó mediante el cálculo del coeficiente de correlación intraclase y el error estándar de la media. Mediante el método de Bland-Altman, se calculó la discordancia de la distancia recorrida y la frecuencia cardiaca pico. Además, se calculó el cambio mínimo detectable para todos los parámetros de la prueba de lanzadera incremental. Un valor de p=<0,05 se consideró significativo. Resultados: 68 sujetos entraron al estudio (34 pacientes con enfermedad renal crónica y 34 sujetos en el grupo control). Los pacientes con enfermedad renal crónica caminaron una menor distancia recorrida respecto al grupo control (-40%; p=<0,0001). En ambos grupos, se encontró una excelente confiabilidad test/retest en todas las medidas de resultado (cálculo del coeficiente de correlación intraclase >0,80). Los registros del error estándar de medición y cambio mínimo detectable para la distancia recorrida fueron de 26,0 m y 72,1 m, respectivamente. El método de Bland-Altman para la distancia recorrida mostró una diferencia media de -0,9 m con límites de concordancia entre 65,5 y -63,7 m. Conclusión: Los pacientes con enfermedad renal crónica en hemodiálisis presentan un menor rendimiento durante la prueba de lanzadera incremental comparado con individuos sin enfermedad renal crónica. Las medidas de resultado de la prueba de lanzadera incremental presentan una alta reproducibilidad test/retest a corto plazo en este grupo de pacientes.
ABSTRACT Introduction: The Incremental Shuttle Walk Test has been used to determine physical capacity in patients with chronic kidney disease. However, its applicability and reproducibility have seldom been studied in hemodialysis patients. The objective of this study was to evaluate the performance and reproducibility of the incremental shuttle walk test in patients with chronic kidney disease on hemodialysis. Methods: Patients with chronic kidney disease on dialysis and subjects without chronic kidney disease were included. Each individual performed two Incremental Shuttle Walk Test with an interval of 30 minutes. We recorded the distance traveled, maximum speed, heart rate and perceived effort. Reproducibility was analyzed by calculating the intraclass correlation coefficient and the standard error of the mean. Using the Bland-Altman analysis, we calculated the discrepancy of the distance traveled and the peak heart rate. The minimum detectable change was also calculated for all parameters of the incremental shuttle walk test. A value of p=<0.05 was considered significant. Results: 68 subjects entered the study (34 were patients with chronic kidney disease, and 34 subjects constituted the control group). Patients with chronic kidney disease walked a shorter distance than those in the control group (-40%; p=<0.0001). In both groups, excellent test-retest reliability was found in all outcome measurements (intraclass correlation coefficient calculation >0.80). The standard error of measurement and the minimum detectable change for the distance traveled were 26.0 m and 72.1 m, respectively. The Bland-Altman analysis for the distance traveled showed a mean difference of -0.9 m with limits of agreement between 65.5 and -63.7 m. Conclusion: Patients with chronic kidney disease on hemodialysis show lower performance during the incremental shuttle walk test, compared to individuals without chronic kidney disease. The outcome measurements of the Incremental Shuttle Walk Test show high test-retest reproducibility in the short run in this group of patients.
RESUMO
OBJECTIVE: Respiratory muscle weakness is a functional repercussion of chronic lung disease (CLD). The objective of this study was to assess the effects of home-based respiratory muscle training (RMT) in children and adolescents with CLD or neuromuscular disease (NMD). METHODS: This was a quasi-experimental study involving children and adolescents with CLD or NMD. Before and after 6 months of home-based RMT, we measured respiratory muscle strength (MIP and MEP), PEF, and peak cough flow (PCF). We made statistical comparisons between the pre-RMT and post-RMT values, as well as evaluating the correlation between the duration and effect of RMT. RESULTS: The study included 29 patients, with a mean age of 12 years (range, 5-17 years), of whom 18 (62.1%) were male. The CLD group comprised 11 patients (37.9%), and the NMD group comprised 18 (62.1%). The mean duration of the RMT was 60 weeks (range, 46-90 weeks) in the CLD group and 39 weeks (range, 24-89 weeks) in the NMD group. In comparison with the pre-RMT values, the post-RMT values for MIP and MEP were significantly higher in both groups, whereas those for PEF and PCF were significantly higher only in the NMD group. We found no correlation between the duration and the effect of RMT. CONCLUSIONS: Home-based RMT appears to be an effective strategy for increasing respiratory muscle strength in children and adolescents with CLD or NMD, although it increased the ability to cough effectively only in those with NMD.
OBJETIVO: A fraqueza muscular respiratória é uma repercussão funcional da doença pulmonar crônica (DPC). O objetivo deste estudo foi avaliar os efeitos do treinamento muscular respiratório (TMR) domiciliar em crianças e adolescentes com DPC ou doença neuromuscular (DNM). MÉTODOS: Estudo quasi-experimental com crianças e adolescentes com DPC ou DNM. Foram medidos a força muscular respiratória (PEmáx e PImáx) e o pico de fluxo da tosse (PFT) antes e depois de 6 meses de TMR domiciliar. Foram realizadas comparações estatísticas entre valores pré- e pós-TMR e foram avaliadas as correlações entre a duração e o efeito do TMR. RESULTADOS: Foram incluídos no estudo 29 pacientes, com média de idade de 12 anos (variação, 5-17 anos), dos quais 18 (62,1%) eram meninos. O grupo DPC consistiu em 11 pacientes (37,9%) e o grupo DNM, em 18 (62,1%). A média da duração do TMR foi de 60 semanas (variação, 46-90 semanas) no grupo DPC e de 39 semanas (variação, 24-89 semanas) no grupo DNM. Em comparação com os valores pré-TMR, os valores pós-TMR para PImáx e PEmáx foram significativamente maiores nos dois grupos, enquanto aqueles para PFE e PFT foram significativamente maiores apenas no grupo DNM. Não houve correlações entre a duração e o efeito do TMR. CONCLUSÕES: O TMR domiciliar parece ser uma estratégia eficaz para o aumento da força muscular respiratória em crianças e adolescentes com DPC ou DNM, embora aumente efetivamente a capacidade de tosse somente naqueles com DNM.
Assuntos
Exercícios Respiratórios , Pneumopatias/fisiopatologia , Força Muscular/fisiologia , Doenças Neuromusculares/fisiopatologia , Músculos Respiratórios/fisiologia , Adolescente , Resistência das Vias Respiratórias/fisiologia , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Masculino , Contração Muscular/fisiologia , Exercícios de Alongamento Muscular , Testes de Função RespiratóriaRESUMO
OBJECTIVE: Respiratory muscle weakness is a functional repercussion of chronic lung disease (CLD). The objective of this study was to assess the effects of home-based respiratory muscle training (RMT) in children and adolescents with CLD or neuromuscular disease (NMD). METHODS: This was a quasi-experimental study involving children and adolescents with CLD or NMD. Before and after 6 months of home-based RMT, we measured respiratory muscle strength (MIP and MEP), PEF, and peak cough flow (PCF). We made statistical comparisons between the pre-RMT and post-RMT values, as well as evaluating the correlation between the duration and effect of RMT. RESULTS: The study included 29 patients, with a mean age of 12 years (range, 5-17 years), of whom 18 (62.1%) were male. The CLD group comprised 11 patients (37.9%), and the NMD group comprised 18 (62.1%). The mean duration of the RMT was 60 weeks (range, 46-90 weeks) in the CLD group and 39 weeks (range, 24-89 weeks) in the NMD group. In comparison with the pre-RMT values, the post-RMT values for MIP and MEP were significantly higher in both groups, whereas those for PEF and PCF were significantly higher only in the NMD group. We found no correlation between the duration and the effect of RMT. CONCLUSIONS: Home-based RMT appears to be an effective strategy for increasing respiratory muscle strength in children and adolescents with CLD or NMD, although it increased the ability to cough effectively only in those with NMD. .
OBJETIVO: A fraqueza muscular respiratória é uma repercussão funcional da doença pulmonar crônica (DPC). O objetivo deste estudo foi avaliar os efeitos do treinamento muscular respiratório (TMR) domiciliar em crianças e adolescentes com DPC ou doença neuromuscular (DNM). MÉTODOS: Estudo quasi-experimental com crianças e adolescentes com DPC ou DNM. Foram medidos a força muscular respiratória (PEmáx e PImáx) e o pico de fluxo da tosse (PFT) antes e depois de 6 meses de TMR domiciliar. Foram realizadas comparações estatísticas entre valores pré- e pós-TMR e foram avaliadas as correlações entre a duração e o efeito do TMR. RESULTADOS: Foram incluídos no estudo 29 pacientes, com média de idade de 12 anos (variação, 5-17 anos), dos quais 18 (62,1%) eram meninos. O grupo DPC consistiu em 11 pacientes (37,9%) e o grupo DNM, em 18 (62,1%). A média da duração do TMR foi de 60 semanas (variação, 46-90 semanas) no grupo DPC e de 39 semanas (variação, 24-89 semanas) no grupo DNM. Em comparação com os valores pré-TMR, os valores pós-TMR para PImáx e PEmáx foram significativamente maiores nos dois grupos, enquanto aqueles para PFE e PFT foram significativamente maiores apenas no grupo DNM. Não houve correlações entre a duração e o efeito do TMR. CONCLUSÕES: O TMR domiciliar parece ser uma estratégia eficaz para o aumento da força muscular respiratória em crianças e adolescentes com DPC ou DNM, embora aumente efetivamente a capacidade de tosse somente naqueles com DNM. .