Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA and deconvolution of the sequencing data with reference to methylation ...profiles of different tissues, we developed a general approach for studying the major tissue contributors to the circulating DNA pool. We tested this method in pregnant women, patients with hepatocellular carcinoma, and subjects following bone marrow and liver transplantation. In most subjects, white blood cells were the predominant contributors to the circulating DNA pool. The placental contributions in the plasma of pregnant women correlated with the proportional contributions as revealed by fetal-specific genetic markers. The graft-derived contributions to the plasma in the transplant recipients correlated with those determined using donor-specific genetic markers. Patients with hepatocellular carcinoma showed elevated plasma DNA contributions from the liver, which correlated with measurements made using tumor-associated copy number aberrations. In hepatocellular carcinoma patients and in pregnant women exhibiting copy number aberrations in plasma, comparison of methylation deconvolution results using genomic regions with different copy number status pinpointed the tissue type responsible for the aberrations. In a pregnant woman diagnosed as having follicular lymphoma during pregnancy, methylation deconvolution indicated a grossly elevated contribution from B cells into the plasma DNA pool and localized B cells as the origin of the copy number aberrations observed in plasma. This method may serve as a powerful tool for assessing a wide range of physiological and pathological conditions based on the identification of perturbed proportional contributions of different tissues into plasma.
Abstract Background Hypertrophic cardiomyopathy (HCM) has been prominently associated with adverse disease complications, including sudden death or heart failure death and a generally adverse ...prognosis, with annual mortality rates of up to 6%. Objectives This study determined whether recent advances in management strategy, including implantable cardioverter-defibrillators (ICDs), heart transplantation, or other therapeutic measures have significantly improved survival and the clinical course of adult HCM patients. Methods We addressed long-term outcomes in 1,000 consecutive adult HCM patients presenting at 30 to 59 years of age (mean 45 ± 8 years) over 7.2 ± 5.2 years of follow-up. Results Of 1,000 patients, 918 (92%) survived to 53 ± 9.2 years of age (range 32 to 80 years) with 91% experiencing no or only mild symptoms at last evaluation. HCM-related death occurred in 40 patients (4% 0.53%/year) at 50 ± 10 years from the following events: progressive heart failure (n = 17); arrhythmic sudden death (SD) (n = 17); and embolic stroke (n = 2). In contrast, 56 other high-risk patients (5.6%) survived life-threatening events, most commonly with ICD interventions for ventricular tachyarrhythmias (n = 33) or heart transplantation for advanced heart failure (n = 18 0.79%/year). SD occurred in patients who declined ICD recommendations, had evaluations before application of prophylactic ICDs to HCM, or were without conventional risk factors. The 5- and 10-year survival rates (confined to HCM deaths) were 98% and 94%, respectively, not different from the expected all-cause mortality in the general U.S. population (p = 0.25). Multivariate independent predictors of adverse outcome were younger age at diagnosis, female sex, and increased left atrial dimension. Conclusions In a large longitudinally assessed adult HCM cohort, we have demonstrated that contemporary management strategies and treatment interventions, including ICDs for SD prevention, have significantly altered the clinical course, now resulting in a low disease-related mortality rate of 0.5%/year and an opportunity for extended longevity.
The aims of this study included performing a meta-analysis of the predictive value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) for adverse events and death in hypertrophic ...cardiomyopathy (HCM).
CMR with LGE can identify areas of myocardial fibrosis; however, controversies remain regarding the independent prognostic importance of LGE-CMR in HCM.
We searched PubMed and Web of Science for studies that investigated the prognostic value of LGE in patients with HCM. Pooled odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated to assess the role of LGE CMR in the risk stratification of HCM.
Seven studies were retrieved from 393 citations for the analysis, of which 2 were eliminated because of overlapping data. In total, 2,993 patients (mean age 54.6 years; median follow-up 36.8 months) were included in the analysis. Meta-analysis showed the presence of LGE was associated with an increased risk for sudden cardiac death (SCD) (OR: 3.41; 95% CI:1.97 to 5.94; p < 0.001), all-cause mortality (OR: 1.80, 95% CI: 1.21 to 2.69; p = 0.004), cardiovascular mortality (OR: 2.93, 95% CI: 1.53 to 5.61; p = 0.001), and a trend for heart failure death (OR: 2.21, 95% CI: 0.84 to 5.80; p = 0.107). Extent of LGE was associated with an increased risk of SCD (HR: 1.56/10% LGE; 95% CI: 1.33 to 1.82; p < 0.0001), heart failure death (HR: 1.61/10% LGE; 95% CI: 1.21 to 2.13; p = 0.001), all-cause mortality (HR: 1.29/10% LGE; 95% CI: 1.09 to 1.51; p = 0.002), and cardiovascular mortality (HR: 1.57/10% LGE; 95% CI: 1.30 to 1.89; p < 0.001). After adjusting for baseline characteristics, the extent of LGE remained strongly associated with the risk of SCD (HR
: 1.36/10% LGE; 95% CI: 1.10 to 1.69; p = 0.005).
Quantitative LGE by CMR exhibited a substantial prognostic value in SCD events prediction, independent of baseline characteristics. Assessment of LGE can be used as an effective tool for risk stratifying patients with HCM.
Abstract Background Left ventricular outflow tract gradients are absent in an important proportion of patients with hypertrophic cardiomyopathy (HCM). However, the natural course of this important ...patient subgroup remains largely unresolved. Objectives The authors systematically employed exercise (stress) echocardiography to define those patients without obstruction to left ventricular outflow at rest and/or under physiological exercise and to examine their natural history and clinical course to create a more robust understanding of this complex disease. Methods We prospectively studied 573 consecutive HCM patients in 3 centers (44 ± 17 years; 66% male) with New York Heart Association functional class I/II symptoms at study entry, including 249 in whom left ventricular outflow tract obstruction was absent both at rest and following physiological exercise (<30 mm Hg; nonobstructive HCM) and retrospectively assembled clinical follow-up data. Results Over a median follow-up of 6.5 years, 225 of 249 nonobstructive patients (90%) remained in classes I/II, whereas 24 (10%) developed progressive heart failure to New York Heart Association functional classes III/IV. Nonobstructive HCM patients were less likely to experience advanced limiting class III/IV symptoms than the 324 patients with outflow obstruction (1.6%/year vs. 7.4%/year rest obstruction vs. 3.2%/year provocable obstruction; p < 0.001). However, 7 nonobstructive patients (2.8%) did require heart transplantation for progression to end stage versus none of the obstructive patients. HCM-related mortality among nonobstructive patients was low (n = 8; 0.5%/year), with 5- and 10-year survival rates of 99% and 97%, respectively, which is not different from expected all-cause mortality in an age- and sex-matched U.S. population (p = 0.15). Conclusions HCM patients with nonobstructive disease appear to experience a relatively benign clinical course, associated with a low risk for advanced heart failure symptoms, other disease complications, and HCM-related mortality, and largely without the requirement for major treatment interventions. A small minority of nonobstructive HCM patients progress to heart transplant.
Risk stratification for sudden death (SD) is an essential component of hypertrophic cardiomyopathy (HC) management, given the proven effectiveness of implantable cardioverter-defibrillators (ICD) for ...preventing SD. Although highly effective in identifying high-risk patients, current stratification algorithms remain incomplete and novel strategies are encouraged. In this regard, reliability of the statistical model to predict SD risk in HC, as recommended by the recent European Society of Cardiology (ESC) guidelines, was retrospectively tested in an independent cohort of 1,629 consecutive patients with HC aged ≥16 years. Of the 1,629 patients, 35 incurred SD events, but only 4 of these (11%) had high predictive risk scores >6%/5 years consistent with an ICD recommendation, and most (60%; n = 21) had scores <4%/5 years that would not justify ICDs. Of 46 high-risk patients with appropriate ICD interventions for ventricular fibrillation/tachycardia, 27 (59%) had low SD risk scores of <4%/5 years, regarded by ESC as insufficient to recommend ICDs, and only 12 (26%) had scores >6%/5 years, considered an ICD indication; 11 of these 12 had already met conventional criteria warranting implantation with 2 to 3 risk markers. Of 414 patients with ICDs but without appropriate interventions, 258 (62%) had low risk scores (<4%/5 years) that would argue against implant. In conclusion, primary risk stratification using the ESC prognostic score applied retrospectively to a large independent HC cohort proved unreliable for prediction of future SD events. Most patients with HC with SD or appropriate ICD interventions were misclassified with low risk scores and therefore would have remained unprotected from arrhythmic SD without ICDs.
Hypertrophic cardiomyopathy (HCM) is prominently associated with risk for sudden death and disease progression, largely in young patients. Whether patients of more advanced age harbor similar risks ...is unresolved, often creating clinical dilemmas, particularly in decisions for primary prevention of sudden death with implantable defibrillators.
We studied 428 consecutive HCM patients presenting at ≥60 years of age and followed for 5.8±4.8 years; 53% were women. Of the 428 patients, 279 (65%) survived to 73±7 years of age (range, 61-96 years), most (n=245, 88%) with no/mild symptoms, including 135 with ≥1 conventional sudden death risk factors and 50 (37%) with late gadolinium enhancement. Over follow-up, 149 (35%) died at 80±8 years of age, mostly from non-HCM-related causes (n=133, 31%), including a substantial proportion from noncardiac disease (n=54). Sixteen patients (3.7%) had HCM-related mortality events (0.64%/y), including embolic stroke (n=6), progressive heart failure or transplantation (n=3), postoperative complications (n=2), and arrhythmic sudden death events (n=5, 1.2% 0.20%/y). All-cause mortality was increased in HCM patients ≥60 years of age compared with an age-matched US general population, predominantly as a result of non-HCM-related diseases (P<0.001; standard mortality ratio, 1.5).
HCM patients surviving into the seventh decade of life are at low risk for disease-related morbidity/mortality, including sudden death, even with conventional risk factors. These data do not support aggressive prophylactic defibrillator implantation at advanced ages in HCM. Other cardiac or noncardiac comorbidities have a greater impact on survival than HCM in older patients.
The total variation (TV) model is attractive in that it is able to preserve sharp attributes in images. However, the restored images from TV-based methods do not usually stay in a given dynamic ...range, and hence projection is required to bring them back into the dynamic range for visual presentation or for storage in digital media. This will affect the accuracy of the restoration as the projected image will no longer be the minimizer of the given TV model. In this paper, we show that one can get much more accurate solutions by imposing box constraints on the TV models and solving the resulting constrained models. Our numerical results show that for some images where there are many pixels with values lying on the boundary of the dynamic range, the gain can be as great as 10.28 decibel in the peak signal-to-noise ratio. One traditional hindrance using the constrained model is that it is difficult to solve. However, in this paper, we propose using the alternating direction method of multipliers (ADMM) to solve the constrained models. This leads to a fast and convergent algorithm that is applicable for both Gaussian and impulse noise. Numerical results show that our ADMM algorithm is better than some state-of-the-art algorithms for unconstrained models in terms of both accuracy and robustness with respect to the regularization parameter. PUBLICATION ABSTRACT
Epstein-Barr virus (EBV) DNA analysis has been shown to be useful for early detection, prognostication, and monitoring of treatment response of nasopharyngeal carcinoma (NPC), and the recent ...literature provides growing evidence of the clinical utility of EBV DNA testing, particularly to inform treatment decisions for NPC patients. Despite the fact that NPC is a rare disease, the NRG Oncology cooperative group has successfully activated a phase 2/3 randomized clinical trial for NPC with international partners and in that process has discovered that the development of a harmonized EBV DNA test is absolutely critical for integration into clinical trials and for future deployment in clinical and central laboratories. In November 2015, the National Cancer Institute (NCI) convened a workshop of international experts in the treatment of NPC and EBV testing to provide a forum for discussing the state of EBV DNA testing and its clinical utility, and to stimulate consideration of future studies and clinical practice guidelines for EBV DNA. This review provides a summary of that discussion.
There are two key issues in successfully solving the image restoration problem: 1) estimation of the regularization parameter that balances data fidelity with the regularity of the solution and 2) ...development of efficient numerical techniques for computing the solution. In this paper, we derive a fast algorithm that simultaneously estimates the regularization parameter and restores the image. The new approach is based on the total-variation (TV) regularized strategy and Morozov's discrepancy principle. The TV norm is represented by the dual formulation that changes the minimization problem into a minimax problem. A proximal point method is developed to compute the saddle point of the minimax problem. By adjusting the regularization parameter adaptively in each iteration, the solution is guaranteed to satisfy the discrepancy principle. We will give the convergence proof of our algorithm and numerically show that it is better than some state-of-the-art methods in terms of both speed and accuracy.
Hyperspectral images often have hundreds of spectral bands of different wavelengths captured by aircraft or satellites that record land coverage. Identifying detailed classes of pixels becomes ...feasible due to the enhancement in spectral and spatial resolution of hyperspectral images. In this work, we propose a novel framework that utilizes both spatial and spectral information for classifying pixels in hyperspectral images. The method consists of three stages. In the first stage, the pre-processing stage, the Nested Sliding Window algorithm is used to reconstruct the original data by enhancing the consistency of neighboring pixels and then Principal Component Analysis is used to reduce the dimension of data. In the second stage, Support Vector Machines are trained to estimate the pixel-wise probability map of each class using the spectral information from the images. Finally, a smoothed total variation model is applied to ensure spatial connectivity in the classification map by smoothing the class probability tensor. We demonstrate the superiority of our method against three state-of-the-art algorithms on six benchmark hyperspectral datasets with 10 to 50 training labels for each class. The results show that our method gives the overall best performance in accuracy even with a very small set of labeled pixels. Especially, the gain in accuracy with respect to other state-of-the-art algorithms increases when the number of labeled pixels decreases, and, therefore, our method is more advantageous to be applied to problems with a small training set. Hence, it is of great practical significance since expert annotations are often expensive and difficult to collect.
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