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Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data

Data augmentation has become a de facto component of deep learning-based medical image segmentation methods. Most data augmentation techniques used in medical imaging focus on spatial and intensity transformations to improve the diversity of training images. They are often designed at the image level, augmenting the full image, and do not pay attention to specific abnormalities within the image. Here, we present LesionMix, a novel and simple lesion-aware data augmentation method. It performs augmentation at the lesion level, increasing the diversity of lesion shape, location, intensity and load distribution, and allowing both lesion populating and inpainting. Experiments on different modalities and different lesion datasets, including four brain MR lesion datasets and one liver CT lesion dataset, demonstrate that LesionMix achieves promising performance in lesion image segmentation, outperforming several recent Mix-based data augmentation methods. The code will be released at https://github.com/dogabasaran/lesionmix., Comment: 13 pages, 5 figures, 4 tables, MICCAI DALI Workshop 2023

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-media

Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand–receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.

Cardiovascular disease, the leading cause of death globally, is an age-related disease. Understanding the morphological and functional changes of the heart during ageing is a key scientific question, the answer to which will help us define important risk factors of cardiovascular disease and monitor disease progression. In this work, we propose a novel conditional generative model to describe the changes of 3D anatomy of the heart during ageing. The proposed model is flexible and allows integration of multiple clinical factors (e.g. age, gender) into the generating process. We train the model on a large-scale cross-sectional dataset of cardiac anatomies and evaluate on both cross-sectional and longitudinal datasets. The model demonstrates excellent performance in predicting the longitudinal evolution of the ageing heart and modelling its data distribution. The codes are available at https://github.com/MengyunQ/AgeHeart.

Understanding the intensity characteristics of brain lesions is key for defining image-based biomarkers in neurological studies and for predicting disease burden and outcome. In this work, we present a novel foreground-based generative method for modelling the local lesion characteristics that can both generate synthetic lesions on healthy images and synthesize subject-specific pseudo-healthy images from pathological images. Furthermore, the proposed method can be used as a data augmentation module to generate synthetic images for training brain image segmentation networks. Experiments on multiple sclerosis (MS) brain images acquired on magnetic resonance imaging (MRI) demonstrate that the proposed method can generate highly realistic pseudo-healthy and pseudo-pathological brain images. Data augmentation using the synthetic images improves the brain image segmentation performance compared to traditional data augmentation methods as well as a recent lesion-aware data augmentation technique, CarveMix. The code will be released at https://github.com/dogabasaran/lesion-synthesis., Comment: 13 pages, 6 figures, 2022 MICCAI SASHIMI (Simulation and Synthesis in Medical Imaging) Workshop paper

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart–brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

In the recent years, convolutional neural networks have transformed the field of medical image analysis due to their capacity to learn discriminative image features for a variety of classification and regression tasks. However, successfully learning these features requires a large amount of manually annotated data, which is expensive to acquire and limited by the available resources of expert image analysts. Therefore, unsupervised, weakly-supervised and self-supervised feature learning techniques receive a lot of attention, which aim to utilise the vast amount of available data, while at the same time avoid or substantially reduce the effort of manual annotation. In this paper, we propose a novel way for training a cardiac MR image segmentation network, in which features are learnt in a self-supervised manner by predicting anatomical positions. The anatomical positions serve as a supervisory signal and do not require extra manual annotation. We demonstrate that this seemingly simple task provides a strong signal for feature learning and with self-supervised learning, we achieve a high segmentation accuracy that is better than or comparable to a U-net trained from scratch, especially at a small data setting. When only five annotated subjects are available, the proposed method improves the mean Dice metric from 0.811 to 0.852 for short-axis image segmentation, compared to the baseline U-net., Comment: Accepted by MICCAI 2019

Background: The trend towards large-scale studies including population imaging poses new challenges in terms of quality control (QC). This is a particular issue when automatic processing tools, e.g. image segmentation methods, are employed to derive quantitative measures or biomarkers for later analyses. Manual inspection and visual QC of each segmentation isn't feasible at large scale. However, it's important to be able to automatically detect when a segmentation method fails so as to avoid inclusion of wrong measurements into subsequent analyses which could lead to incorrect conclusions. Methods: To overcome this challenge, we explore an approach for predicting segmentation quality based on Reverse Classification Accuracy, which enables us to discriminate between successful and failed segmentations on a per-cases basis. We validate this approach on a new, large-scale manually-annotated set of 4,800 cardiac magnetic resonance scans. We then apply our method to a large cohort of 7,250 cardiac MRI on which we have performed manual QC. Results: We report results used for predicting segmentation quality metrics including Dice Similarity Coefficient (DSC) and surface-distance measures. As initial validation, we present data for 400 scans demonstrating 99% accuracy for classifying low and high quality segmentations using predicted DSC scores. As further validation we show high correlation between real and predicted scores and 95% classification accuracy on 4,800 scans for which manual segmentations were available. We mimic real-world application of the method on 7,250 cardiac MRI where we show good agreement between predicted quality metrics and manual visual QC scores. Conclusions: We show that RCA has the potential for accurate and fully automatic segmentation QC on a per-case basis in the context of large-scale population imaging as in the UK Biobank Imaging Study., Comment: 14 pages, 7 figures, Journal of Cardiovascular Magnetic Resonance

Background: The timed 25-foot walk (T25FW) is widely used as a clinic performance measure, but has yet to be directly validated against gait speed in the home environment. Objectives: To develop an accurate method for remote assessment of walking speed and to test how predictive the clinic T25FW is for real-life walking. Methods: An AX3-Axivity tri-axial accelerometer was positioned on 32 MS patients (Expanded Disability Status Scale [EDSS] 0-6) in the clinic, who subsequently wore it at home for up to 7 days. Gait speed was calculated from these data using both a model developed with healthy volunteers and individually personalized models generated from a machine learning algorithm. Results: The healthy volunteer model predicted gait speed poorly for more disabled people with MS. However, the accuracy of individually personalized models was high regardless of disability (R-value = 0.98, p-value = 1.85 × 10-22). With the latter, we confirmed that the clinic T25FW is strongly predictive of the maximum sustained gait speed in the home environment (R-value = 0.89, p-value = 4.34 × 10-8). Conclusion: Remote gait monitoring with individually personalized models is accurate for patients with MS. Using these models, we have directly validated the clinical meaningfulness (i.e., predictiveness) of the clinic T25FW for the first time. © 2018 Supratak, Datta, Gafson, Nicholas, Guo and Matthews.

This paper proposes a practical approach to addressing limitations posed by using of single-channel electroencephalography (EEG) for sleep stage classification. EEG-based characterizations of sleep stage progression contribute the diagnosis and monitoring of the many pathologies of sleep. Several prior reports explored ways of automating the analysis of sleep EEG and of reducing the complexity of the data needed for reliable discrimination of sleep stages at lower cost in the home. However, these reports have involved recordings from electrodes placed on the cranial vertex or occiput, which are both uncomfortable and difficult to position. Previous studies of sleep stage scoring that used only frontal electrodes with a hierarchical decision tree motivated this paper, in which we have taken advantage of rectifier neural network for detecting hierarchical features and long short-term memory network for sequential data learning to optimize classification performance with single-channel recordings. After exploring alternative electrode placements, we found a comfortable configuration of a single-channel EEG on the forehead and have shown that it can be integrated with additional electrodes for simultaneous recording of the electro-oculogram. Evaluation of data from 62 people (with 494 hours sleep) demonstrated better performance of our analytical algorithm than is available from existing approaches with vertex or occipital electrode placements. Use of this recording configuration with neural network deconvolution promises to make clinically indicated home sleep studies practical. © 2001-2011 IEEE.

Segmentation of image sequences is an important task in medical image analysis, which enables clinicians to assess the anatomy and function of moving organs. However, direct application of a segmentation algorithm to each time frame of a sequence may ignore the temporal continuity inherent in the sequence. In this work, we propose an image sequence segmentation algorithm by combining a fully convolutional network with a recurrent neural network, which incorporates both spatial and temporal information into the segmentation task. A key challenge in training this network is that the available manual annotations are temporally sparse, which forbids end-to-end training. We address this challenge by performing non-rigid label propagation on the annotations and introducing an exponentially weighted loss function for training. Experiments on aortic MR image sequences demonstrate that the proposed method significantly improves both accuracy and temporal smoothness of segmentation, compared to a baseline method that utilises spatial information only. It achieves an average Dice metric of 0.960 for the ascending aorta and 0.953 for the descending aorta., Comment: Accepted for publication by MICCAI 2018

NeuroNet is a deep convolutional neural network mimicking multiple popular and state-of-the-art brain segmentation tools including FSL, SPM, and MALPEM. The network is trained on 5,000 T1-weighted brain MRI scans from the UK Biobank Imaging Study that have been automatically segmented into brain tissue and cortical and sub-cortical structures using the standard neuroimaging pipelines. Training a single model from these complementary and partially overlapping label maps yields a new powerful "all-in-one", multi-output segmentation tool. The processing time for a single subject is reduced by an order of magnitude compared to running each individual software package. We demonstrate very good reproducibility of the original outputs while increasing robustness to variations in the input data. We believe NeuroNet could be an important tool in large-scale population imaging studies and serve as a new standard in neuroscience by reducing the risk of introducing bias when choosing a specific software package., Comment: International conference on Medical Imaging with Deep Learning (MIDL) 2018

The effectiveness of a cardiovascular magnetic resonance (CMR) scan depends on the ability of the operator to correctly tune the acquisition parameters to the subject being scanned and on the potential occurrence of imaging artefacts such as cardiac and respiratory motion. In the clinical practice, a quality control step is performed by visual assessment of the acquired images: however, this procedure is strongly operator-dependent, cumbersome and sometimes incompatible with the time constraints in clinical settings and large-scale studies. We propose a fast, fully-automated, learning-based quality control pipeline for CMR images, specifically for short-axis image stacks. Our pipeline performs three important quality checks: 1) heart coverage estimation, 2) inter-slice motion detection, 3) image contrast estimation in the cardiac region. The pipeline uses a hybrid decision forest method - integrating both regression and structured classification models - to extract landmarks as well as probabilistic segmentation maps from both long- and short-axis images as a basis to perform the quality checks. The technique was tested on up to 3000 cases from the UK Biobank as well as on 100 cases from the UK Digital Heart Project, and validated against manual annotations and visual inspections performed by expert interpreters. The results show the capability of the proposed pipeline to correctly detect incomplete or corrupted scans (e.g. on UK Biobank, sensitivity and specificity respectively 88% and 99% for heart coverage estimation, 85% and 95% for motion detection), allowing their exclusion from the analysed dataset or the triggering of a new acquisition.

Functional connectivity has emerged as a promising approach to study the functional organisation of the brain and to define features for prediction of brain state. The most widely used method for inferring functional connectivity is Pearson-s correlation, but it cannot differentiate direct and indirect effects. This disadvantage is often avoided by computing the partial correlation between two regions controlling all other regions, but this method suffers from Berkson-s paradox. Some advanced methods, such as regularised inverse covariance, have been applied. However, these methods usually depend on some parameters. Here we propose use of minimum partial correlation as a parameter-free measure for the skeleton of functional connectivity in functional magnetic resonance imaging (fMRI). The minimum partial correlation between two regions is the minimum of absolute values of partial correlations by controlling all possible subsets of other regions. Theoretically, there is a direct effect between two regions if and only if their minimum partial correlation is non-zero under faithfulness and Gaussian assumptions. The elastic PC-algorithm is designed to efficiently approximate minimum partial correlation within a computational time budget. The simulation study shows that the proposed method outperforms others in most cases and its application is illustrated using a resting-state fMRI dataset from the human connectome project. © 2017, The Author(s).

Motivation: TranSMART has a wide range of functionalities for translational research and a large user community, but it does not support imaging data. In this context, imaging data typically includes 2D or 3D sets of magnitude data and metadata information. Imaging data may summarise complex feature descriptions in a less biased fashion than user defined plain texts and numeric numbers. Imaging data also is contextualised by other data sets and may be analysed jointly with other data that can explain features or their variation. Results: Here we describe the tranSMART-XNAT Connector we have developed. This connector consists of components for data capture, organisation and analysis. Data capture is responsible for imaging capture either from PACS system or directly from an MRI scanner, or from raw data files. Data are organised in a similar fashion as tranSMART and are stored in a format that allows direct analysis within tranSMART. The connector enables selection and download of DICOM images and associated resources using subjects' clinical phenotypic and genotypic criteria. © The Author 2016. Published by Oxford University Press. All rights reserved.

Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix® HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies

Cardiovascular magnetic resonance (CMR) imaging is a standard imaging modality for assessing cardiovascular diseases (CVDs), the leading cause of death globally. CMR enables accurate quantification of the cardiac chamber volume, ejection fraction and myocardial mass, providing information for diagnosis and monitoring of CVDs. However, for years, clinicians have been relying on manual approaches for CMR image analysis, which is time consuming and prone to subjective errors. It is a major clinical challenge to automatically derive quantitative and clinically relevant information from CMR images. Deep neural networks have shown a great potential in image pattern recognition and segmentation for a variety of tasks. Here we demonstrate an automated analysis method for CMR images, which is based on a fully convolutional network (FCN). The network is trained and evaluated on a large-scale dataset from the UK Biobank, consisting of 4,875 subjects with 93,500 pixelwise annotated images. The performance of the method has been evaluated using a number of technical metrics, including the Dice metric, mean contour distance and Hausdorff distance, as well as clinically relevant measures, including left ventricle (LV) end-diastolic volume (LVEDV) and end-systolic volume (LVESV), LV mass (LVM); right ventricle (RV) end-diastolic volume (RVEDV) and end-systolic volume (RVESV). By combining FCN with a large-scale annotated dataset, the proposed automated method achieves a high performance on par with human experts in segmenting the LV and RV on short-axis CMR images and the left atrium (LA) and right atrium (RA) on long-axis CMR images., Comment: Accepted for publication by Journal of Cardiovascular Magnetic Resonance

We developed a machine learning methodology for automatic sleep stage scoring. Our time-frequency analysis-based feature extraction is fine-tuned to capture sleep stage-specific signal features as described in the American Academy of Sleep Medicine manual that the human experts follow. We used ensemble learning with an ensemble of stacked sparse autoencoders for classifying the sleep stages. We used class-balanced random sampling across sleep stages for each model in the ensemble to avoid skewed performance in favor of the most represented sleep stages, and addressed the problem of misclassification errors due to class imbalance while significantly improving worst-stage classification. We used an openly available dataset from 20 healthy young adults for evaluation. We used a single channel of EEG from this dataset, which makes our method a suitable candidate for longitudinal monitoring using wearable EEG in real-world settings. Our method has both high overall accuracy (78%, range 75–80%), and high mean (Formula presented.) -score (84%, range 82–86%) and mean accuracy across individual sleep stages (86%, range 84–88%) over all subjects. The performance of our method appears to be uncorrelated with the sleep efficiency and percentage of transitional epochs in each recording. © 2015, The Author(s).

Objective: Functional parcellation of the cerebral cortex is variable across different subjects or between cognitive states. Ignoring individual-or state-dependent variations in the functional parcellation may lead to inaccurate representations of individual functional connectivity, limiting the precision of interpretations of differences in individual connectivity profiles. However, it is difficult to infer the individual-level variations due to the relatively low robustness of methods for parcellation of individual subjects. Methods: We propose a method called 'joint K-means' to robustly parcellate the cerebral cortex using functional magnetic resonance imaging (fMRI) data for contrasts between two states or subjects that intended to characterize variance in individual functional parcellations. The key idea of the proposed method is to jointly infer parcellations in contrasted datasets by iterative descent, while constraining the similarity of the two pathways in searches for local minima to reduce spurious variations. Results: Parcellations of resting-state fMRI datasets from the Human Connectome Project show that the similarity of parcellations for an individual subject studied on two sessions is greater than that between different subjects. Differences in parcellations between subjects are nonuniformly distributed across the cerebral cortex, with clusters of higher variance in the prefrontal, lateral temporal, and occipito-parietal cortices. This pattern is reproducible across sessions, between groups, and using different numbers of parcels. Conclusion: The individual-level variations inferred by the proposed method are plausible and consistent with the previously reported functional connectivity variability. Significance: The proposed method is a promising tool for investigating relationships between the cerebral functional organization and behavioral differences. © 2016 IEEE.

Long-term electroencephalogram (EEG) is important for seizure detection, sleep monitoring and etc. In-the- ear EEG device makes such recording robust to noise and privacy protected (invisible to other people). However, the state-of-art techniques suffer from various drawbacks such as customization for specific users, manufacturing difficulties and short life cycle. To address these issues, we proposed silvered glass silicone based in-the-ear electrode which can be manufactured using conventional compression moulding. The material and in-the-ear EEG are evaluated separately, showing that the proposed method is durable, low-cost and easy-to-make. © 2016 IEEE.

This paper proposes a practical approach to addressing limitations posed by use of single active electrodes in applications for sleep stage classification. Electroencephalography (EEG)-based characterizations of sleep stage progression contribute the diagnosis and monitoring of the many pathologies of sleep. Several prior reports have explored ways of automating the analysis of sleep EEG and of reducing the complexity of the data needed for reliable discrimination of sleep stages in order to make it possible to perform sleep studies at lower cost in the home (rather than only in specialized clinical facilities). However, these reports have involved recordings from electrodes placed on the cranial vertex or occiput, which can be uncomfortable or difficult for subjects to position. Those that have utilized single EEG channels which contain less sleep information, have showed poor classification performance. We have taken advantage of Rectifier Neural Network for feature detection and Long Short-Term Memory (LSTM) network for sequential data learning to optimize classification performance with single electrode recordings. After exploring alternative electrode placements, we found a comfortable configuration of a single-channel EEG on the forehead and have shown that it can be integrated with additional electrodes for simultaneous recording of the electroocuolgram (EOG). Evaluation of data from 62 people (with 494 hours sleep) demonstrated better performance of our analytical algorithm for automated sleep classification than existing approaches using vertex or occipital electrode placements. Use of this recording configuration with neural network deconvolution promises to make clinically indicated home sleep studies practical., Comment: THIS ARTICLE HAS BEEN PUBLISHED IN IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING

We used convolutional neural networks (CNNs) for automatic sleep stage scoring based on single-channel electroencephalography (EEG) to learn task-specific filters for classification without using prior domain knowledge. We used an openly available dataset from 20 healthy young adults for evaluation and applied 20-fold cross-validation. We used class-balanced random sampling within the stochastic gradient descent (SGD) optimization of the CNN to avoid skewed performance in favor of the most represented sleep stages. We achieved high mean F1-score (81%, range 79-83%), mean accuracy across individual sleep stages (82%, range 80-84%) and overall accuracy (74%, range 71-76%) over all subjects. By analyzing and visualizing the filters that our CNN learns, we found that rules learned by the filters correspond to sleep scoring criteria in the American Academy of Sleep Medicine (AASM) manual that human experts follow. Our method's performance is balanced across classes and our results are comparable to state-of-the-art methods with hand-engineered features. We show that, without using prior domain knowledge, a CNN can automatically learn to distinguish among different normal sleep stages., Comment: 12 pages

Comparing serially acquired fMRI scans is a typical way to detect functional brain changes in different conditions. However, this approach introduces additional variation on physical and physiological conditions, which results in substantial noise. To improve sensitivity and accuracy of signal detection in such highly noisy fMRI data, potentially important information should be incorporated. Here we propose a new significance indicator, the critical regularization value (CR-value), which detects significantly changed voxels by taking both the magnitude of the voxel-wise signal variation and spatial smoothness into account. The CR-value allows voxels that survive in a stronger sparse constraint to be considered as more significant. We demonstrate our method using a simulation dataset and a real fMRI dataset collected from the previous study. The results show that CR-value more accurately detects the true activation than GLM P-value, Posterior Probability Maps (PPM) and the Threshold Free Cluster Enhancement (TFCE) in noisy datasets. © 2015 IEEE.

Functional connectivity, a data-driven modelling of spontaneous fluctuations in activity in spatially segregated brain regions, has emerged as a promising approach to generate hypotheses and features for prediction. The most widely used method for inferring functional connectivity is full correlation, but it cannot differentiate direct and indirect effects. This disadvantage is often avoided by fully partial correlation, but this method suffers from Berkson’s paradox. Some advanced methods, such as regularised inverse covariance and Bayes nets, have been applied. However, the connectivity inferred by these methods usually depends on crucial parameters. This paper suggests minimum partial correlation as a parameter-free measure of functional connectivity in fMRI. An algorithm, called elastic PC-algorithm, is designed to approximately calculate minimum partial correlation. Our experimental results show that the proposed method is more accurate than full correlation, fully partial correlation, regularised inverse covariance, network deconvolution algorithm and global silencing algorithm in most cases. © Springer International Publishing Switzerland 2015.

Brain magnetic resonance imaging is widely used as a diagnostic and monitoring tool in multiple sclerosis and provides a non-invasive, sensitive and reproducible way to track the disease. Topological characteristics relating to the distribution and shape of lesions are recognized as important neuroradiological markers in the diagnosis of multiple sclerosis, although these have been much less well characterized quantitatively than have traditional measures such as T2 hyperintense or T1 hypointense lesion volumes. Here, we used voxel-level 3 T magnetic resonance imaging T1-weighted scans to reconstruct the 3D topology of lesions in 284 subjects with multiple sclerosis and tested whether this is a heritable phenotype. To this end, we extracted the genotypes from a published genome-wide association study on these same individuals and searched for genetic associations with lesion load, shape and topological distribution. Lesion probability maps were created to identify frequently affected areas and to assess the overall distribution of T1 lesions in the subject population as a whole. We then developed an original algorithm to cluster adjacent lesional voxels (cluxels) in each subject and tested whether cluxel topology was significantly associated with any single-nucleotide polymorphism in our data set. To focus on patterns of lesion distribution, we computed the first 10 principal components. Although principal component 1 correlated with lesion load, none of the remaining orthogonal components correlated with any other known variable. We then conducted genome-wide association studies on each of these and found 31 significant associations (false discovery rate <0.01) with principal component 8, which represents a mode of variation of lesion topology in the population. The majority of the loci can be linked to genes related to immune cell function and to myelin and neural growth; some (SYK, MYT1L, TRAPPC9, SLITKR6 and RIC3) have been previously associated with the dist

Background Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed. Methods We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool. Results In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On th

Background: Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed.Methods: We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool.Results: In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility.

Medical imaging has enormous potential for early disease prediction, but is impeded by the difficulty and expense of acquiring data sets before symptom onset. UK Biobank aims to address this problem directly by acquiring high-quality, consistently acquired imaging data from 100,000 predominantly healthy participants, with health outcomes being tracked over the coming decades. The brain imaging includes structural, diffusion and functional modalities. Along with body and cardiac imaging, genetics, lifestyle measures, biological phenotyping and health records, this imaging is expected to enable discovery of imaging markers of a broad range of diseases at their earliest stages, as well as provide unique insight into disease mechanisms. We describe UK Biobank brain imaging and present results derived from the first 5,000 participants' data release. Although this covers just 5% of the ultimate cohort, it has already yielded a rich range of associations between brain imaging and other measures collected by UK Biobank.

UK Biobank is a large-scale prospective epidemiological study with all data accessible to researchers worldwide. It is currently in the process of bringing back 100,000 of the original participants for brain, heart and body MRI, carotid ultrasound and low-dose bone/fat x-ray. The brain imaging component covers 6 modalities (T1, T2 FLAIR, susceptibility weighted MRI, Resting fMRI, Task fMRI and Diffusion MRI). Raw and processed data from the first 10,000 imaged subjects has recently been released for general research access. To help convert this data into useful summary information we have developed an automated processing and QC (Quality Control) pipeline that is available for use by other researchers. In this paper we describe the pipeline in detail, following a brief overview of UK Biobank brain imaging and the acquisition protocol. We also describe several quantitative investigations carried out as part of the development of both the imaging protocol and the processing pipeline.

Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix® HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies