Abstract

The role of non-coding RNAs in neuropsychiatric disorders (NPDs) is an emerging field of study. The long non-coding RNAs (lncRNAs) are shown to sponge the microRNAs (miRNAs) from interacting with their target mRNAs. Investigating the sponge activity of lncRNAs in NPDs will provide further insights into biological mechanisms and help identify disease biomarkers. In this study, a large-scale inference of the lncRNA-related miRNA sponge network of pan-neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BD), was carried out using brain transcriptomic (RNA-Seq) data. The candidate miRNA sponge modules were identified based on the co-expression pattern of non-coding RNAs, sharing of miRNA binding sites, and sensitivity canonical correlation. miRNA sponge modules are associated with chemical synaptic transmission, nervous system development, metabolism, immune system response, ribosomes, and pathways in cancer. The identified modules showed similar and distinct gene expression patterns depending on the neuropsychiatric condition. The preservation of miRNA sponge modules was shown in the independent brain and blood-transcriptomic datasets of NPDs. We also identified miRNA sponging lncRNAs that may be potential diagnostic biomarkers for NPDs. Our study provides a comprehensive resource on miRNA sponging in NPDs.

Abstract

During healthy ageing, the brain networks undergo various topological and functional alterations. Previous studies have shown that the dedifferentiation of the functional modules could be one of the hallmarks of large-scale brain networks and alterations through the lifespan. This modular organiza- tion and alterations may be critically linked to a variety of neurodegenerative disorders and cognitive deficits encountered during ageing. In spite of accumulating evidence based on tracking static functional connectivity (FC) and modularity in characterizing dedifferentiation associated with ageing, there is a gap in understanding the brain dynamics of modular segregation and integration through the lifespan. Using the Cam-CAN dataset (young: 18-44, mean 32 years, old: 65-88, mean 75 years), we characterize the modular reorganization using dynamic measures like flexibility, to find characteristic nodes that make up the stable core and flexible periphery in the young and old age groups. In this study, we hypothesize that the nodes that exhibit higher flexibility in the older age groups will be negatively correlated with modularity since these nodes ‘compensate’ for the functional integration while ensuring that the segregation is efficient. Our results demonstrate that the regions from the Default Mode network (DMN) show a negative correlation with modularity in the old age groups. Further, nodes from Limbic, SensoriMotor (SMN) and Salience networks show a positive correlation with modularity. These networks that are responsible for higher-order cognitive functions, e.g., decision making, attentional control, cognitive flexibility are found to make up a stable core as evidenced by their low flexibility scores. We also trained various classifiers using node flexibility scores as features for the binary (young vs old) classification task. Support Vector Machine (SVM) with Gaussian kernel trained on a reduced-dimensional feature set gave the best classification results. The features (nodes) that are found to be important for classification concur with those identified through the data-driven network measures based analysis. In summary, we anticipate that these findings can help identify the regions that are responsible for the reorganization

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder predominantly found in children. The current behavior-based diagnosis of ASD is arduous and requires expertise. Therefore, it is appealing to develop an accurate computer-aided tool for diagnosing ASD. Although resting-state functional magnetic resonance imaging (rsfMRI) has proven to be successful in capturing the neural organization of the brain, automated detection of ASD using rsfMRI scans is a challenging task due to heterogeneity in the dataset and limited sample size. This paper proposes a Multilayer Perceptron (MLP) based classification model with auto encoder pretraining for classifying ASD from Typically Developing (TD) using rsfMRI scans obtained from the ABIDE-1 dataset. Our model achieves new state-of-the-art performance on the ABIDE-1 dataset with a 10-fold cross-validation accuracy of 74.82%. Further, we use the Integrated Gradients (IG) and DeepLIFT techniques to identify the correlations between brain regions that contribute most to the classification task. Our analysis identifies the following regions, Left Lingual Gyrus, Right Insula Lobe, Right Cuneus, Right Middle Frontal Gyrus, Left Superior Temporal Gyrus to be associated with ASD. Interestingly, these regions in the brain are primarily responsible for social cognition, language, attention, decision making and visual processing, which are known to be altered in ASD.

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. Aberrant production and aggregation of amyloid beta (Ab) peptide into plaques is a frequent feature of AD, but therapeutic approaches targeting Ab accumulation fail to inhibit disease progression. The approved cholinesterase inhibitor drugs are symptomatic treatments. During human brain development, the progenitor cells differentiate into neurons and switch to a postmitotic state. However, cell cycle re-entry often precedes loss of neurons. We developed mathematical models of multiple routes leading to cell cycle re-entry in neurons that incorporate the crosstalk between cell cycle, neuronal, and apoptotic signaling mechanisms. We show that the integration of multiple feedback loops influences disease severity making the switch to pathological state irreversible. We observe that the transcriptional changes associated with this transition are also character- istics of the AD brain. We propose that targeting multiple arms of the feedback loop may bring about disease-modifying effects in AD

Abstract

Histopathology image analysis is widely accepted as a gold standard for cancer diagnosis. The Cancer Genome Atlas (TCGA) contains large repositories of histopathology whole slide images spanning several organs and subtypes. However, not much work has gone into analyzing all the organs and subtypes and their similarities. Our work attempts to bridge this gap by training deep learning models to classify cancer vs. normal patches for 11 subtypes spanning seven organs (9,792 tissue slides) to achieve high classification performance. We used these models to investigate their performances in the test set of other organs (cross-organ inference). We found that every model had a good cross-organ inference accuracy when tested on breast, colorectal, and liver cancers. Further, high accuracy is observed between models trained on the cancer subtypes originating from the same organ (kidney and lung). We also validated these performances by showing the separability of cancer and normal samples in a high-dimensional feature space. We further hypothesized that the high cross-organ inferences are due to shared tumor morphologies among organs. We validated the hypothesis by showing the overlap in the Gradient-weighted Class Activation Mapping (GradCAM) visualizations and similarities in the distributions of nuclei features present within the high-attention regions.

Abstract

The variability of clinical course and prognosis of COVID-19 highlights the necessity of patient sub-group risk stratification based on clinical data. In this study, clinical data from a cohort of Indian COVID-19 hospitalized patients is used to develop risk stratification and mortality prediction models. We analyzed a set of 70 clinical parameters including physiological and hematological for developing machine learning models to identify biomarkers. We also compared the Indian and Wuhan cohort, and analyzed the role of steroids. A bootstrap averaged ensemble of Bayesian networks was also learned to construct an explainable model for discovering actionable influences on mortality and days to outcome. We discovered blood parameters, diabetes, co-morbidity and SpO2 levels as important risk stratification features, whereas mortality prediction is dependent only on blood parameters. XGboost and logistic regression model yielded the best performance on risk stratification and mortality prediction, respectively (AUC score 0.83, AUC score 0.92). Blood coagulation parameters (ferritin, D-Dimer and INR), immune and inflammation parameters IL6, LDH and Neutrophil (%) are common features for both risk and mortality prediction. Compared with Wuhan patients, Indian patients with extreme blood parameters indicated higher survival rate. Analyses of medications suggest that a higher proportion of survivors and mild patients who were administered steroids had extreme neutrophil and lymphocyte percentages. The ensemble averaged Bayesian network structure revealed serum ferritin to be the mos

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system of the patient starts attacking healthy tissues of the body. Lupus Nephritis (LN) refers to the inflammation of kidney tissues resulting in renal failure due to these attacks. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) has released a classification system based on various patterns observed during renal injury in SLE. Traditional methods require meticulous pathological assessment of the renal biopsy and are time-consuming. Recently, computational techniques have helped to alleviate this issue by using virtual microscopy or Whole Slide Imaging (WSI). With the use of deep learning and modern computer vision techniques, we propose a pipeline that is able to automate the process of 1) detection of various glomeruli patterns present in these whole slide images and 2) classification of each image using the extracted glomeruli features.

Abstract

Histopathology image analysis is widely accepted as a gold standard for cancer diagnosis. The Cancer Genome Atlas (TCGA) contains large repositories of histopathology whole slide images spanning across several organs and subtypes. However, not much work has gone into analysis of all the organs and subtypes and their similarities. Our work attempts to bridge this gap by training deep learning models to classify cancer vs normal patches for 11 subtypes spanning 7 organs (9792 tissue slides) to achieve near-perfect classification performance. We used these models to investigate their performances in the test set of other organs (cross organ inference). We found that every model had a good cross organ inference accuracy when tested on breast, colorectal and liver cancers. Further, a high accuracy is observed between models trained on the cancer subtypes originating from same organ (kidney and lung). We also validated these performances by showing the separability of cancer and normal samples in a high dimensional feature space. We further hypothesized that the high cross organ inferences are due to shared tumor morphologies among organs. We validated the hypothesis by showing the overlap in the Gradient-weighted Class Activation Mapping (GradCAM) visualizations and similarities in the distributions of nuclei geometrical features present within the high attention regions. Keywords: TCGA, histopathology, cancer classification, cross-organ inference, deep learning, tissue morphology, class activation map.

Abstract

Owing to the large dimensions of the histopathology whole slide images (WSI), visually searching for clinically significant regions (patches) is a tedious task for a medical expert. Sequential analysis of several such images further increases the workload resulting in poor diagnosis. A major impediment towards automating this task using deep learning models is that it requires a huge chunk of laboriously annotated data in the form of WSI patches. Our work suggests a novel CNN-based, expert feedback-driven interactive learning technique to mitigate this issue. The proposed method seeks to acquire labels of the most informative patches in small increments with multiple feedback rounds to maximize the throughput. It requires the expert to query a patch of interest from one slide and provide feedback to a set of unlabelled patches chosen using the proposed sampling strategy from a ranked list. The experiments on a large patient cohort of colorectal cancer histological patches (100K images with nine classes of tissues) show a significant reduction (≈ 95%) in the amount of labelled data required to achieve state-of theart results when compared to other existing interactive learning methods (35% − 50%). We also demonstrate the utility of the proposed technique to assist a WSI tumor segmentation annotation task using the ICIAR breast cancer challenge dataset (≈ 12.5K patches per slide). The proposed technique reduces the scanning and searching area to about 2% of the total area of WSI (by seeking labels of ≈ 250 informative patches only) and achieves segmentation outputs with 85% IOU. Thus our work helps avoid the routine procedure of exhaustive scanning and searching during annotation and diagnosis in general.

Abstract

The advent of digital pathology presents opportunities for computer vision for fast, accurate, and objective solutions for histopathological images and aid in knowledge discovery. This work uses deep learning to predict genomic biomarkers - TP53 mutation, PIK3CA mutation, ER status, PR status, HER2 status, and intrinsic subtypes, from breast cancer histopathology images. Furthermore, we attempt to understand the underlying morphology as to how these genomic biomarkers manifest in images. Since gene sequencing is expensive, not always available, or even feasible, predicting these biomarkers from images would help in diagnosis, prognosis, and effective treatment planning. We outperform the existing works with a minimum improvement of 0.02 and a maximum of 0.13 AUROC scores across all tasks. We also gain insights that can serve as hypotheses for further experimentations, including the presence of lymphocytes and karyorrhexis. Moreover, our fully automated workflow can be extended to other tasks across other cancer subtypes.