RESUMO
Importance: Congenital long QT syndrome (LQTS) is associated with syncope, ventricular arrhythmias, and sudden death. Half of patients with LQTS have a normal or borderline-normal QT interval despite LQTS often being detected by QT prolongation on resting electrocardiography (ECG). Objective: To develop a deep learning-based neural network for identification of LQTS and differentiation of genotypes (LQTS1 and LQTS2) using 12-lead ECG. Design, Setting, and Participants: This diagnostic accuracy study used ECGs from patients with suspected inherited arrhythmia enrolled in the Hearts in Rhythm Organization Registry (HiRO) from August 2012 to December 2021. The internal dataset was derived at 2 sites and an external validation dataset at 4 sites within the HiRO Registry; an additional cross-sectional validation dataset was from the Montreal Heart Institute. The cohort with LQTS included probands and relatives with pathogenic or likely pathogenic variants in KCNQ1 or KCNH2 genes with normal or prolonged corrected QT (QTc) intervals. Exposures: Convolutional neural network (CNN) discrimination between LQTS1, LQTS2, and negative genetic test results. Main Outcomes and Measures: The main outcomes were area under the curve (AUC), F1 scores, and sensitivity for detecting LQTS and differentiating genotypes using a CNN method compared with QTc-based detection. Results: A total of 4521 ECGs from 990 patients (mean [SD] age, 42 [18] years; 589 [59.5%] female) were analyzed. External validation within the national registry (101 patients) demonstrated the CNN's high diagnostic capacity for LQTS detection (AUC, 0.93; 95% CI, 0.89-0.96) and genotype differentiation (AUC, 0.91; 95% CI, 0.86-0.96). This surpassed expert-measured QTc intervals in detecting LQTS (F1 score, 0.84 [95% CI, 0.78-0.90] vs 0.22 [95% CI, 0.13-0.31]; sensitivity, 0.90 [95% CI, 0.86-0.94] vs 0.36 [95% CI, 0.23-0.47]), including in patients with normal or borderline QTc intervals (F1 score, 0.70 [95% CI, 0.40-1.00]; sensitivity, 0.78 [95% CI, 0.53-0.95]). In further validation in a cross-sectional cohort (406 patients) of high-risk patients and genotype-negative controls, the CNN detected LQTS with an AUC of 0.81 (95% CI, 0.80-0.85), which was better than QTc interval-based detection (AUC, 0.74; 95% CI, 0.69-0.78). Conclusions and Relevance: The deep learning model improved detection of congenital LQTS from resting ECGs and allowed for differentiation between the 2 most common genetic subtypes. Broader validation over an unselected general population may support application of this model to patients with suspected LQTS.
Assuntos
Aprendizado Profundo , Síndrome do QT Longo , Humanos , Feminino , Adulto , Masculino , Estudos Transversais , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Eletrocardiografia , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/complicações , GenótipoRESUMO
3D cell cultures, in particular organoids, are emerging models in the investigation of healthy or diseased tissues. Understanding the complex cellular sociology in organoids requires integration of imaging modalities across spatial and temporal scales. We present a multi-scale imaging approach that traverses millimeter-scale live-cell light microscopy to nanometer-scale volume electron microscopy by performing 3D cell cultures in a single carrier that is amenable to all imaging steps. This allows for following organoids' growth, probing their morphology with fluorescent markers, identifying areas of interest, and analyzing their 3D ultrastructure. We demonstrate this workflow on mouse and human 3D cultures and use automated image segmentation to annotate and quantitatively analyze subcellular structures in patient-derived colorectal cancer organoids. Our analyses identify local organization of diffraction-limited cell junctions in compact and polarized epithelia. The continuum-resolution imaging pipeline is thus suited to fostering basic and translational organoid research by simultaneously exploiting the advantages of light and electron microscopy.
Assuntos
Técnicas de Cultura de Células em Três Dimensões , Microscopia , Organoides , Animais , Humanos , Camundongos , Técnicas de Cultura de Células em Três Dimensões/métodos , Microscopia Eletrônica , Organoides/diagnóstico por imagem , Organoides/fisiologia , Organoides/ultraestrutura , Neoplasias Colorretais/patologiaRESUMO
OBJECTIVE: One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149-1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: MYBPC3 p.Arg502Trp/Gln. METHODS: We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of MYBPC3 c.2149-1G>A. Carriers with this mutation were compared with those from MYBPC3 p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes. RESULTS: MYBPC3 c.2149-1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). MYBPC3 c.2149-1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with MYBPC3 p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups. CONCLUSIONS: MYBPC3 c.2149-1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than MYBPC3 p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes.
Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , DNA/genética , Mutação , Penetrância , Adulto , Idade de Início , Cardiomiopatia Hipertrófica/epidemiologia , Cardiomiopatia Hipertrófica/metabolismo , Proteínas de Transporte/metabolismo , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Miosinas , Linhagem , Estudos Retrospectivos , Distribuição por Sexo , Fatores Sexuais , Espanha/epidemiologiaAssuntos
Cardiopatias Congênitas , Humanos , Cardiopatias Congênitas/fisiopatologia , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico , Masculino , Eletrocardiografia/métodos , Ablação por Cateter/métodos , Sistema de Condução Cardíaco/fisiopatologia , Feminino , Mapeamento Potencial de Superfície Corporal/métodos , Técnicas Eletrofisiológicas Cardíacas/métodos , AdultoRESUMO
No disponible
Assuntos
Humanos , Masculino , Feminino , Adulto , Idoso , Herpes Zoster , Meningite Asséptica , Transplante de CoraçãoAssuntos
Diabetes Mellitus Tipo 2/complicações , Obesidade/complicações , Doenças Vasculares/etiologia , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fatores de Risco , Espanha/epidemiologia , Doenças Vasculares/epidemiologiaRESUMO
No disponible