Drinking severity mediates the relationship between hypothalamic connectivity and rule-breaking/intrusive behavior differently in young women and men: an exploratory study.

Background: The hypothalamus is a key hub of the neural circuits of motivated behavior. Alcohol misuse may lead to hypothalamic dysfunction. Here, we investigated how resting-state hypothalamic functional connectivities are altered in association with the severity of drinking and clinical comorbidities and how men and women differ in this association. Methods: We employed the data of the Human Connectome Project. A total of 870 subjects were included in data analyses. The severity of alcohol use was quantified for individual subjects with the first principal component (PC1) identified from principal component analyses of all drinking measures. Rule-breaking and intrusive scores were evaluated with the Achenbach Adult Self-Report Scale. We performed a whole-brain regression of hypothalamic connectivities on drinking PC1 in all subjects and men/women separately and evaluated the results at a corrected threshold. Results: Higher drinking PC1 was associated with greater hypothalamic connectivity with the paracentral lobule (PCL). Hypothalamic PCL connectivity was positively correlated with rule-breaking score in men (r=0.152, P=0.002) but not in women. In women but not men, hypothalamic connectivity with the left temporo-parietal junction (LTPJ) was negatively correlated with drinking PC1 (r=-0.246, P<0.001) and with intrusiveness score (r=-0.127, P=0.006). Mediation analyses showed that drinking PC1 mediated the relationship between hypothalamic PCL connectivity and rule-breaking score in men and between hypothalamic LTPJ connectivity and intrusiveness score bidirectionally in women. Conclusions: We characterized sex-specific hypothalamic connectivities in link with the severity of alcohol misuse and its comorbidities. These findings extend the literature by elucidating the potential impact of problem drinking on the motivation circuits.

Deficient sleep, altered hypothalamic functional connectivity, depression and anxiety in cigarette smokers.

Background: Deficient sleep is implicated in nicotine dependence as well as depressive and anxiety disorders. The hypothalamus regulates the sleep-wake cycle and supports motivated behavior, and hypothalamic dysfunction may underpin comorbid nicotine dependence, depression and anxiety. We aimed to investigate whether and how the resting state functional connectivities (rsFCs) of the hypothalamus relate to cigarette smoking, deficient sleep, depression and anxiety. Methods: We used the data of 64 smokers and 198 age- and sex-matched adults who never smoked, curated from the Human Connectome Project. Deficient sleep and psychiatric problems were each assessed with Pittsburgh Sleep Quality Index (PSQI) and Achenbach Adult Self-Report. We processed the imaging data with published routines and evaluated the results at a corrected threshold, all with age, sex, and the severity of alcohol use as covariates. Results: Smokers vs. never smokers showed poorer sleep quality and greater severity of depression and anxiety. In smokers only, the total PSQI score, indicating more sleep deficits, was positively associated with hypothalamic rsFCs with the right inferior frontal/insula/superior temporal and postcentral (rPoCG) gyri. Stronger hypothalamus-rPoCG rsFCs were also associated with greater severity of depression and anxiety in smokers but not never smokers. Additionally, in smokers, the PSQI score completely mediated the relationships of hypothalamus-rPoCG rsFCs with depression and anxiety severity. Conclusions: These findings associate hypothalamic circuit dysfunction to sleep deficiency and severity of depression and anxiety symptoms in adults who smoke. Future studies may investigate the roles of the hypothalamic circuit in motivated behaviors to better characterize the inter-related neural markers of smoking, deficient sleep, depression and anxiety.

Machine Learning of Functional Connectivity to Biotype Alcohol and Nicotine Use Disorders.

BACKGROUND: Magnetic resonance imaging provides noninvasive tools to investigate alcohol use disorder (AUD) and nicotine use disorder (NUD) and neural phenotypes for genetic studies. A data-driven transdiagnostic approach could provide a new perspective on the neurobiology of AUD and NUD. METHODS: Using samples of individuals with AUD (n = 140), individuals with NUD (n = 249), and healthy control participants (n = 461) from the UK Biobank, we integrated clinical, neuroimaging, and genetic markers to identify biotypes of AUD and NUD. We partitioned participants with AUD and NUD based on resting-state functional connectivity (FC) features associated with clinical metrics. A multitask artificial neural network was trained to evaluate the cluster-defined biotypes and jointly infer AUD and NUD diagnoses. RESULTS: Three biotypes-primary NUD, mixed NUD/AUD with depression and anxiety, and mixed AUD/NUD-were identified. Multitask classifiers incorporating biotype knowledge achieved higher area under the curve (AUD: 0.76, NUD: 0.74) than single-task classifiers without biotype differentiation (AUD: 0.61, NUD: 0.64). Cerebellar FC features were important in distinguishing the 3 biotypes. The biotype of mixed NUD/AUD with depression and anxiety demonstrated the largest number of FC features (n = 5), all related to the visual cortex, that significantly differed from healthy control participants and were validated in a replication sample (p < .05). A polymorphism in TNRC6A was associated with the mixed AUD/NUD biotype in both the discovery (p = 7.3 × 10-5) and replication (p = 4.2 × 10-2) sets. CONCLUSIONS: Biotyping and multitask learning using FC features can characterize the clinical and genetic profiles of AUD and NUD and help identify cerebellar and visual circuit markers to differentiate the AUD/NUD group from the healthy control group. These markers support a new growing body of literature.

Deep statistical modelling of nanopore sequencing translocation times reveals latent non-B DNA structures.

MOTIVATION: Non-canonical (or non-B) DNA are genomic regions whose three-dimensional conformation deviates from the canonical double helix. Non-B DNA play an important role in basic cellular processes and are associated with genomic instability, gene regulation, and oncogenesis. Experimental methods are low-throughput and can detect only a limited set of non-B DNA structures, while computational methods rely on non-B DNA base motifs, which are necessary but not sufficient indicators of non-B structures. Oxford Nanopore sequencing is an efficient and low-cost platform, but it is currently unknown whether nanopore reads can be used for identifying non-B structures. RESULTS: We build the first computational pipeline to predict non-B DNA structures from nanopore sequencing. We formalize non-B detection as a novelty detection problem and develop the GoFAE-DND, an autoencoder that uses goodness-of-fit (GoF) tests as a regularizer. A discriminative loss encourages non-B DNA to be poorly reconstructed and optimizing Gaussian GoF tests allows for the computation of P-values that indicate non-B structures. Based on whole genome nanopore sequencing of NA12878, we show that there exist significant differences between the timing of DNA translocation for non-B DNA bases compared with B-DNA. We demonstrate the efficacy of our approach through comparisons with novelty detection methods using experimental data and data synthesized from a new translocation time simulator. Experimental validations suggest that reliable detection of non-B DNA from nanopore sequencing is achievable. AVAILABILITY AND IMPLEMENTATION: Source code is available at https://github.com/bayesomicslab/ONT-nonb-GoFAE-DND.

Convolutional neural network for automated mass segmentation in mammography.

BACKGROUND: Automatic segmentation and localization of lesions in mammogram (MG) images are challenging even with employing advanced methods such as deep learning (DL) methods. We developed a new model based on the architecture of the semantic segmentation U-Net model to precisely segment mass lesions in MG images. The proposed end-to-end convolutional neural network (CNN) based model extracts contextual information by combining low-level and high-level features. We trained the proposed model using huge publicly available databases, (CBIS-DDSM, BCDR-01, and INbreast), and a private database from the University of Connecticut Health Center (UCHC). RESULTS: We compared the performance of the proposed model with those of the state-of-the-art DL models including the fully convolutional network (FCN), SegNet, Dilated-Net, original U-Net, and Faster R-CNN models and the conventional region growing (RG) method. The proposed Vanilla U-Net model outperforms the Faster R-CNN model significantly in terms of the runtime and the Intersection over Union metric (IOU). Training with digitized film-based and fully digitized MG images, the proposed Vanilla U-Net model achieves a mean test accuracy of 92.6%. The proposed model achieves a mean Dice coefficient index (DI) of 0.951 and a mean IOU of 0.909 that show how close the output segments are to the corresponding lesions in the ground truth maps. Data augmentation has been very effective in our experiments resulting in an increase in the mean DI and the mean IOU from 0.922 to 0.951 and 0.856 to 0.909, respectively. CONCLUSIONS: The proposed Vanilla U-Net based model can be used for precise segmentation of masses in MG images. This is because the segmentation process incorporates more multi-scale spatial context, and captures more local and global context to predict a precise pixel-wise segmentation map of an input full MG image. These detected maps can help radiologists in differentiating benign and malignant lesions depend on the lesion shapes. We show that using transfer learning, introducing augmentation, and modifying the architecture of the original model results in better performance in terms of the mean accuracy, the mean DI, and the mean IOU in detecting mass lesion compared to the other DL and the conventional models.

Bi-convex Optimization to Learn Classifiers from Multiple Biomedical Annotations.

The problem of constructing classifiers from multiple annotators who provide inconsistent training labels is important and occurs in many application domains. Many existing methods focus on the understanding and learning of the crowd behaviors. Several probabilistic algorithms consider the construction of classifiers for specific tasks using consensus of multiple labelers annotations. These methods impose a prior on the consensus and develop an expectation-maximization algorithm based on logistic regression loss. We extend the discussion to the hinge loss commonly used by support vector machines. Our formulations form bi-convex programs that construct classifiers and estimate the reliability of each labeler simultaneously. Each labeler is associated with a reliability parameter, which can be a constant, or class-dependent, or varies for different examples. The hinge loss is modified by replacing the true labels by the weighted combination of labelers' labels with reliabilities as weights. Statistical justification is discussed to motivate the use of linear combination of labels. In parallel to the expectation-maximization algorithm for logistic-based methods, efficient alternating algorithms are developed to solve the proposed bi-convex programs. Experimental results on benchmark datasets and three real-world biomedical problems demonstrate that the proposed methods either outperform or are competitive to the state of the art.

Robust large scale prone-supine polyp matching using local features: a metric learning approach.

Computer aided detection (CAD) systems have emerged as noninvasive and effective tools, using 3D CT Colonography (CTC) for early detection of colonic polyps. In this paper, we propose a robust and automatic polyp prone-supine view matching method, to facilitate the regular CTC workflow where radiologists need to manually match the CAD findings in prone and supine CT scans for validation. Apart from previous colon registration approaches based on global geometric information, this paper presents a feature selection and metric distance learning approach to build a pairwise matching function (where true pairs of polyp detections have smaller distances than false pairs), learned using local polyp classification features. Thus our process can seamlessly handle collapsed colon segments or other severe structural artifacts which often exist in CTC, since only local features are used, whereas other global geometry dependent methods may become invalid for collapsed segmentation cases. Our automatic approach is extensively evaluated using a large multi-site dataset of 195 patient cases in training and 223 cases for testing. No external examination on the correctness of colon segmentation topology is needed. The results show that we achieve significantly superior matching accuracy than previous methods, on at least one order-of-magnitude larger CTC datasets.

A two-level approach towards semantic colon segmentation: removing extra-colonic findings.

Computer aided detection (CAD) of colonic polyps in computed tomographic colonography has tremendously impacted colorectal cancer diagnosis using 3D medical imaging. It is a prerequisite for all CAD systems to extract the air-distended colon segments from 3D abdomen computed tomography scans. In this paper, we present a two-level statistical approach of first separating colon segments from small intestine, stomach and other extra-colonic parts by classification on a new geometric feature set; then evaluating the overall performance confidence using distance and geometry statistics over patients. The proposed method is fully automatic and validated using both the classification results in the first level and its numerical impacts on false positive reduction of extra-colonic findings in a CAD system. It shows superior performance than the state-of-art knowledge or anatomy based colon segmentation algorithms.