Literature mining discerns latent disease-gene relationships.

MOTIVATION: Dysregulation of a gene's function, either due to mutations or impairments in regulatory networks, often triggers pathological states in the affected tissue. Comprehensive mapping of these apparent gene-pathology relationships is an ever-daunting task, primarily due to genetic pleiotropy and lack of suitable computational approaches. With the advent of high throughput genomics platforms and community scale initiatives such as the Human Cell Landscape project, researchers have been able to create gene expression portraits of healthy tissues resolved at the level of single cells. However, a similar wealth of knowledge is currently not at our finger-tip when it comes to diseases. This is because the genetic manifestation of a disease is often quite diverse and is confounded by several clinical and demographic covariates. RESULTS: To circumvent this, we mined ∼18 million PubMed abstracts published till May 2019 and automatically selected ∼4.5 million of them that describe roles of particular genes in disease pathogenesis. Further, we fine-tuned the pretrained bidirectional encoder representations from transformers (BERT) for language modeling from the domain of natural language processing to learn vector representation of entities such as genes, diseases, tissues, cell-types, etc., in a way such that their relationship is preserved in a vector space. The repurposed BERT predicted disease-gene associations that are not cited in the training data, thereby highlighting the feasibility of in silico synthesis of hypotheses linking different biological entities such as genes and conditions. AVAILABILITY AND IMPLEMENTATION: PathoBERT pretrained model: https://github.com/Priyadarshini-Rai/Pathomap-Model. BioSentVec-based abstract classification model: https://github.com/Priyadarshini-Rai/Pathomap-Model. Pathomap R package: https://github.com/Priyadarshini-Rai/Pathomap.

Memory-efficient semantic segmentation of large microscopy images using graph-based neural networks.

We present a graph neural network (GNN)-based framework applied to large-scale microscopy image segmentation tasks. While deep learning models, like convolutional neural networks (CNNs), have become common for automating image segmentation tasks, they are limited by the image size that can fit in the memory of computational hardware. In a GNN framework, large-scale images are converted into graphs using superpixels (regions of pixels with similar color/intensity values), allowing us to input information from the entire image into the model. By converting images with hundreds of millions of pixels to graphs with thousands of nodes, we can segment large images using memory-limited computational resources. We compare the performance of GNN- and CNN-based segmentation in terms of accuracy, training time and required graphics processing unit memory. Based on our experiments with microscopy images of biological cells and cell colonies, GNN-based segmentation used one to three orders-of-magnitude fewer computational resources with only a change in accuracy of $-2\;%$ to $+0.3\;%$. Furthermore, errors due to superpixel generation can be reduced by either using better superpixel generation algorithms or increasing the number of superpixels, thereby allowing for improvement in the GNN framework's accuracy. This trade-off between accuracy and computational cost over CNN models makes the GNN framework attractive for many large-scale microscopy image segmentation tasks in biology.

A Comprehensive Evaluation of Generalizability of Deep Learning-Based Hi-C Resolution Improvement Methods.

Hi-C is a widely used technique to study the 3D organization of the genome. Due to its high sequencing cost, most of the generated datasets are of a coarse resolution, which makes it impractical to study finer chromatin features such as Topologically Associating Domains (TADs) and chromatin loops. Multiple deep learning-based methods have recently been proposed to increase the resolution of these datasets by imputing Hi-C reads (typically called upscaling). However, the existing works evaluate these methods on either synthetically downsampled datasets, or a small subset of experimentally generated sparse Hi-C datasets, making it hard to establish their generalizability in the real-world use case. We present our framework-Hi-CY-that compares existing Hi-C resolution upscaling methods on seven experimentally generated low-resolution Hi-C datasets belonging to various levels of read sparsities originating from three cell lines on a comprehensive set of evaluation metrics. Hi-CY also includes four downstream analysis tasks, such as TAD and chromatin loops recall, to provide a thorough report on the generalizability of these methods. We observe that existing deep learning methods fail to generalize to experimentally generated sparse Hi-C datasets, showing a performance reduction of up to 57%. As a potential solution, we find that retraining deep learning-based methods with experimentally generated Hi-C datasets improves performance by up to 31%. More importantly, Hi-CY shows that even with retraining, the existing deep learning-based methods struggle to recover biological features such as chromatin loops and TADs when provided with sparse Hi-C datasets. Our study, through the Hi-CY framework, highlights the need for rigorous evaluation in the future. We identify specific avenues for improvements in the current deep learning-based Hi-C upscaling methods, including but not limited to using experimentally generated datasets for training.

The Utility of PET/CT for the Diagnosis of Periosteal Chondrosarcoma in a Patient With Maffucci's Syndrome.

Maffucci's syndrome is a rare congenital nonhereditary syndrome with less than 300 cases having been reported in the United States. It is characterized by multiple enchondromas, hemangiomas, and rarely lymphangiomas. Enchondromas may undergo malignant transformation to chondrosarcomas. Surveillance plays a vital role in detecting early malignant transformation. Fluorodeoxyglucose (FDG) PET/CT, although falling out of favor, may be utilized as an imaging modality by physicians to determine such transformation, allowing for timely management and intervention. In this report, we share our experience with such a case.

Gene expression based inference of cancer drug sensitivity.

Inter and intra-tumoral heterogeneity are major stumbling blocks in the treatment of cancer and are responsible for imparting differential drug responses in cancer patients. Recently, the availability of high-throughput screening datasets has paved the way for machine learning based personalized therapy recommendations using the molecular profiles of cancer specimens. In this study, we introduce Precily, a predictive modeling approach to infer treatment response in cancers using gene expression data. In this context, we demonstrate the benefits of considering pathway activity estimates in tandem with drug descriptors as features. We apply Precily on single-cell and bulk RNA sequencing data associated with hundreds of cancer cell lines. We then assess the predictability of treatment outcomes using our in-house prostate cancer cell line and xenografts datasets exposed to differential treatment conditions. Further, we demonstrate the applicability of our approach on patient drug response data from The Cancer Genome Atlas and an independent clinical study describing the treatment journey of three melanoma patients. Our findings highlight the importance of chemo-transcriptomics approaches in cancer treatment selection.