Background
Genetic heterogeneity is common in inherited cardiac diseases. Next-generation sequencing gene panels are therefore suitable for genetic diagnosis. We describe the results of ...implementation of cardiomyopathy and arrhythmia gene panels in clinical care.
Methods
We present detection rates for variants with unknown (class 3), likely (class 4), and certain (class 5) pathogenicity in cardiogenetic gene panels since their introduction into diagnostics.
Results
In 936 patients tested on the arrhythmia panel, likely pathogenic and pathogenic variants were detected in 8.8% (4.6% class 5; 4.2% class 4), and one or multiple class 3 variants in 34.8%. In 1970 patients tested on the cardiomyopathy panel, likely pathogenic and pathogenic variants were detected in 19.8% (12.0% class 5; 7.9% class 4), and one or multiple class 3 variants in 40.8%. Detection rates of all different classes of variants increased with the increasing number of genes on the cardiomyopathy gene panel. Multiple variants were detected in 11.7% and 28.5% of patients on the arrhythmia and cardiomyopathy panels respectively. In more recent larger versions of the cardiomyopathy gene panel the detection rate of likely pathogenic and pathogenic variants only slightly increased, but was associated with a large increase of class 3 variants.
Conclusion
Overall detection rates (class 3, 4, and 5 variants) in a diagnostic setting are 44% and 61% for the arrhythmia and cardiomyopathy gene panel respectively, with only a small minority of likely pathogenic and pathogenic variants (8.8% and 19.8% respectively). Larger gene panels can increase the detection rate of likely pathogenic and pathogenic variants, but mainly increase the frequency of variants of unknown pathogenicity.
Background
Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions.
Aim
To create a large ...national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research.
Methods
This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing.
Discussion
The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website (
www.acmregistry.nl
) and patient conferences.
In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of ...research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (
D
eterminants
o
f
s
usceptibility
i
n inherited cardiomyopathy: towards novel therapeutic approache
s
) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies. Here we highlight several recent observations from our consortium and collaborators which may ultimately be relevant for clinical practice.
In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early ...treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.
Abstract Congenital hydrocephalus is a common and often disabling disorder. The etiology is very heterogeneous. Little is known about the genetic causes of congenital hydrocephalus. A retrospective ...survey was performed including patients with primary congenital hydrocephalus referred to the Department of Clinical Genetics between 1985 and 2010 by perinatologists, (child) neurologists or pediatricians. Patients with hydrocephalus secondary to other pathology were excluded from this survey. We classified patients with primary congenital hydrocephalus into two main groups: non-syndromic hydrocephalus (NSH) and syndromic hydrocephalus (SH). Seventy-five individuals met the inclusion criteria, comprising 36% (27/75) NSH and 64% (48/75) SH. In 11% (8/75) hydrocephalus was familial. The cause of hydrocephalus was unknown in 81% (61/75), including all patients with NSH. The male–female ratio in this subgroup was 2.6:1, indicating an X-linked factor other than the L1CAM gene. In the group of SH patients, 29% (14/48) had a known cause of hydrocephalus including chromosomal abnormalities, L1 syndrome, Marden–Walker syndrome, Walker–Warburg syndrome and hemifacial microsomia. We performed this survey in order to evaluate current knowledge on the genetic etiology of primary congenital hydrocephalus and to identify new candidate genes or regulatory pathways for congenital hydrocephalus. Recommendations were made concerning the evaluation and genetic workup of patients with primary congenital hydrocephalus. We conclude that further molecular and functional analysis is needed to identify new genetic forms of congenital hydrocephalus.
Abstract
Background/Introduction
Recently, a variant-specific prediction model for PLN p.Arg14del variant carriers was developed to predict individual malignant ventricular arrhythmia (VA) risk to ...inform decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts malignant VA risk from data at diagnosis, but iterative evaluation of malignant VA risk may be warranted considering that the risk factors for malignant VA are progressive.
Purpose
To evaluate the diagnostic performance of the PLN p.Arg14del risk model.
Methods/Results
Date were collected of 278 PLN p.Arg14del variant carriers at 3 year follow-up. This was considered the new baseline for the survival analysis. Patients with history of malignant VA at both baseline and during the first 3 years after baseline were excluded. At 3 year patients were aged 40.1±18.0 year and 40.7% was male. Median left ventricular ejection fraction (LVEF) was 53% and percentage with microvoltages was 10.3. During a median follow-up of 4 years (Interquartile range 1.8–6.5) 31 (11%) carriers experienced malignant VA, defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. Reevaluation of the predictors with the 3 year follow-up data revealed hazard rates that were similar to those in the original PLN p.Arg14del risk model; LVEF per 1% decrease (hazard ratio (HR) 1.10 95% confidence interval (CI), 1.06–1.12; p<0.001), premature ventricular contraction count/24h (HR 1.51 95% CI, 1.15–1.98; p=0.003) and the presence of low-voltage electrocardiogram (HR 12.24 95% CI, 5.21–28.8); p<0.001). Negative T waves did not remain significant as a predictor. The 5-year malignant VA risk was calculated for each variant carrier, after multiple imputation for dealing with incomplete cases, by applying the PLN p.Arg14del risk model to the 3 year follow-up data. Afterwards the cohort was divided into tertiles of predicted risk. This clearly demonstrated the lowest risk tertile having a low malignant VA rate and the highest risk tertile having a high malignant VA rate, which resulted in an optimism-corrected C-statistic of 0.85 (95% CI 0.78–0.92).
Conclusion
The PLN p.Arg14del risk model is valid at 3 year follow-up in PLN p.Arg14del variant carriers with no history of malignant VA and can therefore be used to inform decision-making for primary prevention ICD implantation not merely at diagnosis, but also during follow-up and can be seen as a type of validation in a cohort where no other large cohort is present to perform external validation.
Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): 1. PSIDER: From pluripotent stem cells to prime editing gene therapy for inheritedcardiomyopathies. ZOn-MW.2. PREDICT2: Predicting sudden cardiac arrest. The Dutch Heart Foundation.
Abstract
Background/Introduction
The founder mutation p.Arg14del in the gene encoding phospholamban (PLN) is a known cause of arrhythmogenic cardiomyopathy (ACM) with distinct clinical features, such ...as microvoltages on the ECG and right or left ventricular dysfunction or both. At present, risk stratification for ICD implantation in carriers of this mutation is based on left ventricular ejection fraction and previous ventricular arrhythmia's, which are not specific risk factors for the PLN p.Arg14del cardiomyopathy.
Purpose
Our goal is to develop a mutation specific prediction model for incident malignant ventricular arrhythmia to guide ICD implantation.
Methods
Data were collected from p.Arg14del carriers with no history of malignant VA at baseline, identified between September 2009 and June 2018 in three Dutch university hospitals. Genetic analysis of PLN was performed in a clinical setting in index patients with clinical signs of DCM/ACM, or in family members of p.Arg14del carriers. We collected clinical data from the first cardiac evaluation and follow-ups. Malignant VAs were defined as sustained VA, appropriate ICD intervention or (aborted) sudden cardiac death. A prediction model was developed using Cox Proportional Hazard regression. Candidate baseline predictors were pre specified based on literature and clinical expertise. Age, sex, proband status, sudden cardiac death (SCD) in 1st degree relative, repolarization abnormalities, microvoltages, premature ventricular complexes (PVC) burden on 24hrs Holter monitoring, LVEF and non-sustained ventricular arrhythmias (NSVT) were considered. The multivariable model was fitted using stepwise backward selection based on Akaike's Information Criterion.
Results
We included 440 p.Arg14del carriers with a mean age of 41±18 years and 41% males. During a median follow-up of 4.7 years (IQR 1.7–7.3), 44 incident malignant VA occurred, 20 sustained VAs and 24 appropriate ICD therapies. The multivariable HR's of selected predictors were: 2.2 for minor and 4.5 for major repolarization abnormalities vs no abnormalities (p value respectively 0.06 and 0.01), 2.2 for LVEF <45% (p value 0,1) and 7.7 for >500PVC/24hrs (p value 0.003). Carriers with and without events could be accurately distinguished with this model, with an optimism corrected C-statistic of 0.81. The model calibrated well, with agreement of observed and predicted 5 year malignant VA risk. Risk groups were split into quintiles of predicted risk, figure 1 shows the Kaplan Meier curve of incident malignant VA per risk group. The 5 year risk of incident malignant VA in the lowest 3 quintiles was 0%, 9% in the 4th quintile and 25.2% in the highest quintile.
Conclusion
We created a PLN p.Arg14del mutation specific prediction model to estimate risk of incident malignant VA. With this model a clear distinction between high risk and low risk patients can be made and can be used to guide ICD implantation for primary prevention.
Abstract
Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): PSIDER (ZOn-MW)
PREDICT2 (Hartstichting)
Background
The PLN p.Arg14del risk model is a ...mutation-specific risk model developed to predict individual malignant ventricular arrhythmia (VA) risk to inform decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. While the risk model has proven to be valid, two main points of criticisms remain to be discussed: first, the risk model is only validated at baseline and second, appropriate ICD therapy and sustained ventricular tachycardia (VT) <250 bpm is an imperfect surrogate outcome for SCD.
Purpose
To evaluate the diagnostic performance of the PLN p.Arg14del risk model longitudinal at 3 year follow-up and to reevaluate the predictors regarding SCD.
Methods
Clinical data of 278 PLN p.Arg14del mutation carriers with no history of malignant VA at both baseline and 3 year follow-up were collected. During a median follow-up of 4 years (Interquartile range (IQR) 1.8-6.5), 31 (11%) carriers experienced malignant VA, defined as sustained VA, appropriate ICD intervention, or (aborted) SCD. The reevaluation of the predictors with the 3 year follow up data revealed hazard ratio’s (HR) that were similar to the baseline PLN p.Arg14del risk model for left ventricular ejection fraction (HR 1.10 95% CI, 1.06-1.12, p<0.001), low-voltage ECG (HR 12.24 95% CI, 5.21-28.8, p<0.001) and the PVC count per 24h (HR 1.51 1.15-1.98, p=0.003). The 5-year malignant VA risk was divided into tertiles of predicted risk. The tertiles clearly demonstrated good discrimination between risk group as shown in figure 1 and this resulted in an C-statistic of 0.85 (95% CI 0.78-0.92).
To reevaluate the predictive performance of the PLN p.Arg14del risk model for a more strict surrogate of SCD we redefined the outcome as VT >250 beats per minute sustained (lasting ≥30 seconds) or terminated by ICD, ventricular fibrillation, aborted SCD and SCD. We included 669 PLN p.Arg14del carriers with no presentation or history of sustained VA or (aborted) SCD. During a median follow-up of 4.75 years (IQR 1.9-7.9), 33 (5%) carriers experienced the outcome. Results of the univariable analysis are shown in table 1. The PLN p.Arg14del risk model yielded a C-statistic of 0.75 (95% CI 0.70-0.80). Adding risk factors sex, age and sustained VT <250 bpm did not change its performance.
Conclusion
The PLN p.Arg14del risk model was validated longitudinal at 3 year follow-up and it held its performance with a more strict definition of SCD.
Kaplan Meier, longitudinal validation
Real-Time Lagrangian Traffic State Estimator for Freeways Yufei Yuan; van Lint, J. W. C.; Wilson, R. E. ...
IEEE transactions on intelligent transportation systems,
2012-March, 2012-03-00, 20120301, Letnik:
13, Številka:
1
Journal Article
Recenzirano
Freeway traffic state estimation and prediction are central components in real-time traffic management and information applications. Model-based traffic state estimators consist of a dynamic model ...for the state variables (e.g., a first- or second-order macroscopic traffic flow model), a set of observation equations relating sensor observations to the system state (e.g., the fundamental diagrams), and a data-assimilation technique to combine the model predictions with the sensor observations e.g., the extended Kalman filter (EKF). Commonly, both process and observation models are formulated in Eulerian (space-time) coordinates. Recent studies have shown that this model can be formulated and solved more efficiently and accurately in Lagrangian (vehicle number-time) coordinates. In this paper, we propose a new model-based state estimator based on the EKF technique, in which the discretized Lagrangian Lighthill-Whitham and Richards (LWR) model is used as the process equation, and in which observation models for both Eulerian and Lagrangian sensor data (from loop detectors and vehicle trajectories, respectively) are incorporated. This Lagrangian state estimator is validated and compared with a Eulerian state estimator based on the same LWR model using an empirical microscopic traffic data set from the U.K. The results indicate that the Lagrangian estimator is significantly more accurate and offers computational and theoretical benefits over the Eulerian approach.
This is a report of 148 patients with hematologic malignancies who received an unmanipulated haploidentical bone marrow transplant (BMT), followed by post-transplant high-dose cyclophosphamide ...(PT-CY). All patients received a myeloablative conditioning consisting of thiotepa, busulfan, fludarabine (n=92) or TBI, fludarabine (n=56). The median age was 47 years (17-74); 47 patients were in first remission (CR1), 37 in second remission (CR2) and 64 had an active disease; all patients were first grafts. The diagnosis was acute leukemia (n=75), myelodisplastic syndrome (n=24), myelofibrosis (n=16), high-grade lymphoma (n=15) and others (n=18). GVHD prophylaxis consisted in PT-CY on days +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median day for neutrophil engraftment was day +18 (13-32). The cumulative incidence of grades II-IV acute GVHD was 24%, and of grades III-IV GVHD 10%. The incidence of moderate-severe chronic GVHD was 12%. With a median follow-up for the surviving patients of 313 days (100-1162), the cumulative incidence of transplant-related mortality (TRM) is 13%, and the relapse-related death is 23%. The actuarial 22 months overall survival is 77% for CR1 patients, 49% for CR2 patients and 38% for patients grafted in relapse (P<0.001). Major causes of death were relapse (22%), GVHD (2%) and infections (6%). We confirm our initial results, suggesting that a myeloablative conditioning regimen followed by unmanipulated haploidentical BMT with PT-CY, results in a low risk of acute and chronic GVHD and encouraging rates of TRM and overall survival, also for patients with active disease at the time of transplant.
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