CHeart: A Conditional Spatio-Temporal Generative Model for Cardiac Anatomy.

Two key questions in cardiac image analysis are to assess the anatomy and motion of the heart from images; and to understand how they are associated with non-imaging clinical factors such as gender, age and diseases. While the first question can often be addressed by image segmentation and motion tracking algorithms, our capability to model and answer the second question is still limited. In this work, we propose a novel conditional generative model to describe the 4D spatio-temporal anatomy of the heart and its interaction with non-imaging clinical factors. The clinical factors are integrated as the conditions of the generative modelling, which allows us to investigate how these factors influence the cardiac anatomy. We evaluate the model performance in mainly two tasks, anatomical sequence completion and sequence generation. The model achieves high performance in anatomical sequence completion, comparable to or outperforming other state-of-the-art generative models. In terms of sequence generation, given clinical conditions, the model can generate realistic synthetic 4D sequential anatomies that share similar distributions with the real data. The code and the trained generative model are available at https://github.com/MengyunQ/CHeart.

DeepMesh: Mesh-Based Cardiac Motion Tracking Using Deep Learning.

3D motion estimation from cine cardiac magnetic resonance (CMR) images is important for the assessment of cardiac function and the diagnosis of cardiovascular diseases. Current state-of-the art methods focus on estimating dense pixel-/voxel-wise motion fields in image space, which ignores the fact that motion estimation is only relevant and useful within the anatomical objects of interest, e.g., the heart. In this work, we model the heart as a 3D mesh consisting of epi- and endocardial surfaces. We propose a novel learning framework, DeepMesh, which propagates a template heart mesh to a subject space and estimates the 3D motion of the heart mesh from CMR images for individual subjects. In DeepMesh, the heart mesh of the end-diastolic frame of an individual subject is first reconstructed from the template mesh. Mesh-based 3D motion fields with respect to the end-diastolic frame are then estimated from 2D short- and long-axis CMR images. By developing a differentiable mesh-to-image rasterizer, DeepMesh is able to leverage 2D shape information from multiple anatomical views for 3D mesh reconstruction and mesh motion estimation. The proposed method estimates vertex-wise displacement and thus maintains vertex correspondences between time frames, which is important for the quantitative assessment of cardiac function across different subjects and populations. We evaluate DeepMesh on CMR images acquired from the UK Biobank. We focus on 3D motion estimation of the left ventricle in this work. Experimental results show that the proposed method quantitatively and qualitatively outperforms other image-based and mesh-based cardiac motion tracking methods.

Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; P<0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; P=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M1: 0.86-0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Environmental and genetic predictors of human cardiovascular ageing.

Cardiovascular ageing is a process that begins early in life and leads to a progressive change in structure and decline in function due to accumulated damage across diverse cell types, tissues and organs contributing to multi-morbidity. Damaging biophysical, metabolic and immunological factors exceed endogenous repair mechanisms resulting in a pro-fibrotic state, cellular senescence and end-organ damage, however the genetic architecture of cardiovascular ageing is not known. Here we use machine learning approaches to quantify cardiovascular age from image-derived traits of vascular function, cardiac motion and myocardial fibrosis, as well as conduction traits from electrocardiograms, in 39,559 participants of UK Biobank. Cardiovascular ageing is found to be significantly associated with common or rare variants in genes regulating sarcomere homeostasis, myocardial immunomodulation, and tissue responses to biophysical stress. Ageing is accelerated by cardiometabolic risk factors and we also identify prescribed medications that are potential modifiers of ageing. Through large-scale modelling of ageing across multiple traits our results reveal insights into the mechanisms driving premature cardiovascular ageing and reveal potential molecular targets to attenuate age-related processes.

Phenotyping urban built and natural environments with high-resolution satellite images and unsupervised deep learning.

Cities in the developing world are expanding rapidly, and undergoing changes to their roads, buildings, vegetation, and other land use characteristics. Timely data are needed to ensure that urban change enhances health, wellbeing and sustainability. We present and evaluate a novel unsupervised deep clustering method to classify and characterise the complex and multidimensional built and natural environments of cities into interpretable clusters using high-resolution satellite images. We applied our approach to a high-resolution (0.3 m/pixel) satellite image of Accra, Ghana, one of the fastest growing cities in sub-Saharan Africa, and contextualised the results with demographic and environmental data that were not used for clustering. We show that clusters obtained solely from images capture distinct interpretable phenotypes of the urban natural (vegetation and water) and built (building count, size, density, and orientation; length and arrangement of roads) environment, and population, either as a unique defining characteristic (e.g., bodies of water or dense vegetation) or in combination (e.g., buildings surrounded by vegetation or sparsely populated areas intermixed with roads). Clusters that were based on a single defining characteristic were robust to the spatial scale of analysis and the choice of cluster number, whereas those based on a combination of characteristics changed based on scale and number of clusters. The results demonstrate that satellite data and unsupervised deep learning provide a cost-effective, interpretable and scalable approach for real-time tracking of sustainable urban development, especially where traditional environmental and demographic data are limited and infrequent.

The association between brain volume loss and disability in multiple sclerosis: A systematic review.

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, degenerative disease of the central nervous system that affects approximately 2.8 million people worldwide. Compelling evidence from observational studies and clinical trials indicates a strong association between brain volume loss (BVL) and the accumulation of disability in MS. However, the considerable heterogeneity in study designs and methods of assessment of BVL invites questions concerning the generalizability of the reported findings. Therefore, we conducted this systematic review to characterize the relationship between BVL and physical disability in patients with MS. METHODS: A systematic literature search of MEDLINE and EMBASE databases was performed supplemented by gray literature searches. The following study designs were included: prospective/retrospective cohort, cross-sectional and case-control. Only English language articles published from 2010 onwards were eligible for final inclusion. There were no restrictions on MS subtype, age, or ethnicity. Of the 1620 citations retrieved by the structured searches, 50 publications met our screening criteria and were included in the final data set. RESULTS: Across all BVL measures, there was considerable heterogeneity in studies regarding the underlying study population, the definitions of BVL and image analysis methodologies, the physical disability measure used, the measures of association reported and whether the analysis conducted was univariable or multivariable. A total of 36 primary studies providing data on the association between whole BVL and physical disability in MS collectively suggest that whole brain atrophy is associated with greater physical disability progression in MS patients. Similarly, a total of 15 primary studies providing data on the association between ventricular atrophy and physical disability in MS suggest that ventricular atrophy is associated with greater physical disability progression in MS patients. Along similar lines, the existing evidence based on a total of 13 primary studies suggests that gray matter atrophy is associated with greater physical disability progression in MS patients. Four primary studies suggest that corpus callosum atrophy is associated with greater physical disability progression in MS patients. The majority of the existing evidence (6 primary studies) suggests no association between white matter atrophy and physical disability in MS. It is difficult to assign a relationship between basal ganglia volume loss and physical disability as well as medulla oblongata width and physical disability in MS due to very limited data. CONCLUSION: The evidence gathered from this systematic review, although very heterogeneous, suggests that whole brain atrophy is associated with greater physical disability progression in MS patients. Our review can help define future imaging biomarkers for physical disability progression and treatment monitoring in MS.

Better Together: Data Harmonization and Cross-Study Analysis of Abdominal MRI Data From UK Biobank and the German National Cohort.

OBJECTIVES: The UK Biobank (UKBB) and German National Cohort (NAKO) are among the largest cohort studies, capturing a wide range of health-related data from the general population, including comprehensive magnetic resonance imaging (MRI) examinations. The purpose of this study was to demonstrate how MRI data from these large-scale studies can be jointly analyzed and to derive comprehensive quantitative image-based phenotypes across the general adult population. MATERIALS AND METHODS: Image-derived features of abdominal organs (volumes of liver, spleen, kidneys, and pancreas; volumes of kidney hilum adipose tissue; and fat fractions of liver and pancreas) were extracted from T1-weighted Dixon MRI data of 17,996 participants of UKBB and NAKO based on quality-controlled deep learning generated organ segmentations. To enable valid cross-study analysis, we first analyzed the data generating process using methods of causal discovery. We subsequently harmonized data from UKBB and NAKO using the ComBat approach for batch effect correction. We finally performed quantile regression on harmonized data across studies providing quantitative models for the variation of image-derived features stratified for sex and dependent on age, height, and weight. RESULTS: Data from 8791 UKBB participants (49.9% female; age, 63 ± 7.5 years) and 9205 NAKO participants (49.1% female, age: 51.8 ± 11.4 years) were analyzed. Analysis of the data generating process revealed direct effects of age, sex, height, weight, and the data source (UKBB vs NAKO) on image-derived features. Correction of data source-related effects resulted in markedly improved alignment of image-derived features between UKBB and NAKO. Cross-study analysis on harmonized data revealed comprehensive quantitative models for the phenotypic variation of abdominal organs across the general adult population. CONCLUSIONS: Cross-study analysis of MRI data from UKBB and NAKO as proposed in this work can be helpful for future joint data analyses across cohorts linking genetic, environmental, and behavioral risk factors to MRI-derived phenotypes and provide reference values for clinical diagnostics.

Causality-Inspired Single-Source Domain Generalization for Medical Image Segmentation.

Deep learning models usually suffer from the domain shift issue, where models trained on one source domain do not generalize well to other unseen domains. In this work, we investigate the single-source domain generalization problem: training a deep network that is robust to unseen domains, under the condition that training data are only available from one source domain, which is common in medical imaging applications. We tackle this problem in the context of cross-domain medical image segmentation. In this scenario, domain shifts are mainly caused by different acquisition processes. We propose a simple causality-inspired data augmentation approach to expose a segmentation model to synthesized domain-shifted training examples. Specifically, 1) to make the deep model robust to discrepancies in image intensities and textures, we employ a family of randomly-weighted shallow networks. They augment training images using diverse appearance transformations. 2) Further we show that spurious correlations among objects in an image are detrimental to domain robustness. These correlations might be taken by the network as domain-specific clues for making predictions, and they may break on unseen domains. We remove these spurious correlations via causal intervention. This is achieved by resampling the appearances of potentially correlated objects independently. The proposed approach is validated on three cross-domain segmentation scenarios: cross-modality (CT-MRI) abdominal image segmentation, cross-sequence (bSSFP-LGE) cardiac MRI segmentation, and cross-site prostate MRI segmentation. The proposed approach yields consistent performance gains compared with competitive methods when tested on unseen domains.

Generative myocardial motion tracking via latent space exploration with biomechanics-informed prior.

Myocardial motion and deformation are rich descriptors that characterize cardiac function. Image registration, as the most commonly used technique for myocardial motion tracking, is an ill-posed inverse problem which often requires prior assumptions on the solution space. In contrast to most existing approaches which impose explicit generic regularization such as smoothness, in this work we propose a novel method that can implicitly learn an application-specific biomechanics-informed prior and embed it into a neural network-parameterized transformation model. Particularly, the proposed method leverages a variational autoencoder-based generative model to learn a manifold for biomechanically plausible deformations. The motion tracking then can be performed via traversing the learnt manifold to search for the optimal transformations while considering the sequence information. The proposed method is validated on three public cardiac cine MRI datasets with comprehensive evaluations. The results demonstrate that the proposed method can outperform other approaches, yielding higher motion tracking accuracy with reasonable volume preservation and better generalizability to varying data distributions. It also enables better estimates of myocardial strains, which indicates the potential of the method in characterizing spatiotemporal signatures for understanding cardiovascular diseases.

New lesion segmentation for multiple sclerosis brain images with imaging and lesion-aware augmentation.

Multiple sclerosis (MS) is an inflammatory and demyelinating neurological disease of the central nervous system. Image-based biomarkers, such as lesions defined on magnetic resonance imaging (MRI), play an important role in MS diagnosis and patient monitoring. The detection of newly formed lesions provides crucial information for assessing disease progression and treatment outcome. Here, we propose a deep learning-based pipeline for new MS lesion detection and segmentation, which is built upon the nnU-Net framework. In addition to conventional data augmentation, we employ imaging and lesion-aware data augmentation methods, axial subsampling and CarveMix, to generate diverse samples and improve segmentation performance. The proposed pipeline is evaluated on the MICCAI 2021 MS new lesion segmentation challenge (MSSEG-2) dataset. It achieves an average Dice score of 0.510 and F 1 score of 0.552 on cases with new lesions, and an average false positive lesion number n FP of 0.036 and false positive lesion volume V FP of 0.192 mm 3 on cases with no new lesions. Our method outperforms other participating methods in the challenge and several state-of-the-art network architectures.

Automated imaging-based abdominal organ segmentation and quality control in 20,000 participants of the UK Biobank and German National Cohort Studies.

Large epidemiological studies such as the UK Biobank (UKBB) or German National Cohort (NAKO) provide unprecedented health-related data of the general population aiming to better understand determinants of health and disease. As part of these studies, Magnetic Resonance Imaging (MRI) is performed in a subset of participants allowing for phenotypical and functional characterization of different organ systems. Due to the large amount of imaging data, automated image analysis is required, which can be performed using deep learning methods, e. g. for automated organ segmentation. In this paper we describe a computational pipeline for automated segmentation of abdominal organs on MRI data from 20,000 participants of UKBB and NAKO and provide results of the quality control process. We found that approx. 90% of data sets showed no relevant segmentation errors while relevant errors occurred in a varying proportion of data sets depending on the organ of interest. Image-derived features based on automated organ segmentations showed relevant deviations of varying degree in the presence of segmentation errors. These results show that large-scale, deep learning-based abdominal organ segmentation on MRI data is feasible with overall high accuracy, but visual quality control remains an important step ensuring the validity of down-stream analyses in large epidemiological imaging studies.

Enhancing MR image segmentation with realistic adversarial data augmentation.

The success of neural networks on medical image segmentation tasks typically relies on large labeled datasets for model training. However, acquiring and manually labeling a large medical image set is resource-intensive, expensive, and sometimes impractical due to data sharing and privacy issues. To address this challenge, we propose AdvChain, a generic adversarial data augmentation framework, aiming at improving both the diversity and effectiveness of training data for medical image segmentation tasks. AdvChain augments data with dynamic data augmentation, generating randomly chained photo-metric and geometric transformations to resemble realistic yet challenging imaging variations to expand training data. By jointly optimizing the data augmentation model and a segmentation network during training, challenging examples are generated to enhance network generalizability for the downstream task. The proposed adversarial data augmentation does not rely on generative networks and can be used as a plug-in module in general segmentation networks. It is computationally efficient and applicable for both low-shot supervised and semi-supervised learning. We analyze and evaluate the method on two MR image segmentation tasks: cardiac segmentation and prostate segmentation with limited labeled data. Results show that the proposed approach can alleviate the need for labeled data while improving model generalization ability, indicating its practical value in medical imaging applications.

Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities.

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-ß, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

Genetic and environmental determinants of diastolic heart function.

Diastole is the sequence of physiological events that occur in the heart during ventricular filling and principally depends on myocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processes and is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine learning cardiac motion analysis to measure diastolic functional traits in 39,559 participants of the UK Biobank and perform a genome-wide association study. We identified 9 significant, independent loci near genes that are associated with maintaining sarcomeric function under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes were independent predictors of diastolic function and we found a causal relationship between genetically-determined ventricular stiffness and incident heart failure. Our results provide insights into the genetic and environmental factors influencing diastolic function that are relevant for identifying causal relationships and potential tractable targets.

Precision measurement of cardiac structure and function in cardiovascular magnetic resonance using machine learning.

BACKGROUND: Measurement of cardiac structure and function from images (e.g. volumes, mass and derived parameters such as left ventricular (LV) ejection fraction [LVEF]) guides care for millions. This is best assessed using cardiovascular magnetic resonance (CMR), but image analysis is currently performed by individual clinicians, which introduces error. We sought to develop a machine learning algorithm for volumetric analysis of CMR images with demonstrably better precision than human analysis. METHODS: A fully automated machine learning algorithm was trained on 1923 scans (10 scanner models, 13 institutions, 9 clinical conditions, 60,000 contours) and used to segment the LV blood volume and myocardium. Performance was quantified by measuring precision on an independent multi-site validation dataset with multiple pathologies with n = 109 patients, scanned twice. This dataset was augmented with a further 1277 patients scanned as part of routine clinical care to allow qualitative assessment of generalization ability by identifying mis-segmentations. Machine learning algorithm ('machine') performance was compared to three clinicians ('human') and a commercial tool (cvi42, Circle Cardiovascular Imaging). FINDINGS: Machine analysis was quicker (20 s per patient) than human (13 min). Overall machine mis-segmentation rate was 1 in 479 images for the combined dataset, occurring mostly in rare pathologies not encountered in training. Without correcting these mis-segmentations, machine analysis had superior precision to three clinicians (e.g. scan-rescan coefficients of variation of human vs machine: LVEF 6.0% vs 4.2%, LV mass 4.8% vs. 3.6%; both P < 0.05), translating to a 46% reduction in required trial sample size using an LVEF endpoint. CONCLUSION: We present a fully automated algorithm for measuring LV structure and global systolic function that betters human performance for speed and precision.

Suggestive annotation of brain MR images with gradient-guided sampling.

Machine learning has been widely adopted for medical image analysis in recent years given its promising performance in image segmentation and classification tasks. The success of machine learning, in particular supervised learning, depends on the availability of manually annotated datasets. For medical imaging applications, such annotated datasets are not easy to acquire, it takes a substantial amount of time and resource to curate an annotated medical image set. In this paper, we propose an efficient annotation framework for brain MR images that can suggest informative sample images for human experts to annotate. We evaluate the framework on two different brain image analysis tasks, namely brain tumour segmentation and whole brain segmentation. Experiments show that for brain tumour segmentation task on the BraTS 2019 dataset, training a segmentation model with only 7% suggestively annotated image samples can achieve a performance comparable to that of training on the full dataset. For whole brain segmentation on the MALC dataset, training with 42% suggestively annotated image samples can achieve a comparable performance to training on the full dataset. The proposed framework demonstrates a promising way to save manual annotation cost and improve data efficiency in medical imaging applications.

MulViMotion: Shape-Aware 3D Myocardial Motion Tracking From Multi-View Cardiac MRI.

Recovering the 3D motion of the heart from cine cardiac magnetic resonance (CMR) imaging enables the assessment of regional myocardial function and is important for understanding and analyzing cardiovascular disease. However, 3D cardiac motion estimation is challenging because the acquired cine CMR images are usually 2D slices which limit the accurate estimation of through-plane motion. To address this problem, we propose a novel multi-view motion estimation network (MulViMotion), which integrates 2D cine CMR images acquired in short-axis and long-axis planes to learn a consistent 3D motion field of the heart. In the proposed method, a hybrid 2D/3D network is built to generate dense 3D motion fields by learning fused representations from multi-view images. To ensure that the motion estimation is consistent in 3D, a shape regularization module is introduced during training, where shape information from multi-view images is exploited to provide weak supervision to 3D motion estimation. We extensively evaluate the proposed method on 2D cine CMR images from 580 subjects of the UK Biobank study for 3D motion tracking of the left ventricular myocardium. Experimental results show that the proposed method quantitatively and qualitatively outperforms competing methods.

QU-BraTS: MICCAI BraTS 2020 Challenge on Quantifying Uncertainty in Brain Tumor Segmentation - Analysis of Ranking Scores and Benchmarking Results.

Deep learning (DL) models have provided state-of-the-art performance in various medical imaging benchmarking challenges, including the Brain Tumor Segmentation (BraTS) challenges. However, the task of focal pathology multi-compartment segmentation (e.g., tumor and lesion sub-regions) is particularly challenging, and potential errors hinder translating DL models into clinical workflows. Quantifying the reliability of DL model predictions in the form of uncertainties could enable clinical review of the most uncertain regions, thereby building trust and paving the way toward clinical translation. Several uncertainty estimation methods have recently been introduced for DL medical image segmentation tasks. Developing scores to evaluate and compare the performance of uncertainty measures will assist the end-user in making more informed decisions. In this study, we explore and evaluate a score developed during the BraTS 2019 and BraTS 2020 task on uncertainty quantification (QU-BraTS) and designed to assess and rank uncertainty estimates for brain tumor multi-compartment segmentation. This score (1) rewards uncertainty estimates that produce high confidence in correct assertions and those that assign low confidence levels at incorrect assertions, and (2) penalizes uncertainty measures that lead to a higher percentage of under-confident correct assertions. We further benchmark the segmentation uncertainties generated by 14 independent participating teams of QU-BraTS 2020, all of which also participated in the main BraTS segmentation task. Overall, our findings confirm the importance and complementary value that uncertainty estimates provide to segmentation algorithms, highlighting the need for uncertainty quantification in medical image analyses. Finally, in favor of transparency and reproducibility, our evaluation code is made publicly available at https://github.com/RagMeh11/QU-BraTS.

Boosting the diagnostic power of amyloid-ß PET using a data-driven spatially informed classifier for decision support.

BACKGROUND: Amyloid-ß (Aß) PET has emerged as clinically useful for more accurate diagnosis of patients with cognitive decline. Aß deposition is a necessary cause or response to the cellular pathology of Alzheimer's disease (AD). Usual clinical and research interpretation of amyloid PET does not fully utilise all information regarding the spatial distribution of signal. We present a data-driven, spatially informed classifier to boost the diagnostic power of amyloid PET in AD. METHODS: Voxel-wise k-means clustering of amyloid-positive voxels was performed; clusters were mapped to brain anatomy and tested for their associations by diagnostic category and disease severity with 758 amyloid PET scans from volunteers in the AD continuum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). A machine learning approach based on this spatially constrained model using an optimised quadratic support vector machine was developed for automatic classification of scans for AD vs non-AD pathology. RESULTS: This classifier boosted the accuracy of classification of AD scans to 81% using the amyloid PET alone with an area under the curve (AUC) of 0.91 compared to other spatial methods. This increased sensitivity to detect AD by 15% and the AUC by 9% compared to the use of a composite region of interest SUVr. CONCLUSIONS: The diagnostic classification accuracy of amyloid PET was improved using an automated data-driven spatial classifier. Our classifier highlights the importance of considering the spatial variation in Aß PET signal for optimal interpretation of scans. The algorithm now is available to be evaluated prospectively as a tool for automated clinical decision support in research settings.

Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population. OBJECTIVES: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults. METHODS: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status. RESULTS: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001). CONCLUSIONS: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.