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Spatial transcriptomics (ST) technologies are rapidly becoming the extension of single-cell RNA sequencing (scRNAseq), holding the potential of profiling gene expression at a single-cell resolution while maintaining cellular compositions within a tissue. Having both expression profiles and tissue organization enables researchers to better understand cellular interactions and heterogeneity, providing insight into complex biological processes that would not be possible with traditional sequencing technologies. Data generated by ST technologies are inherently noisy, high-dimensional, sparse, and multi-modal (including histological images, count matrices, etc.), thus requiring specialized computational tools for accurate and robust analysis. However, many ST studies currently utilize traditional scRNAseq tools, which are inadequate for analyzing complex ST datasets. On the other hand, many of the existing ST-specific methods are built upon traditional statistical or machine learning frameworks, which have shown to be sub-optimal in many applications due to the scale, multi-modality, and limitations of spatially resolved data (such as spatial resolution, sensitivity, and gene coverage). Given these intricacies, researchers have developed deep learning (DL)-based models to alleviate ST-specific challenges. These methods include new state-of-the-art models in alignment, spatial reconstruction, and spatial clustering, among others. However, DL models for ST analysis are nascent and remain largely underexplored. In this review, we provide an overview of existing state-of-the-art tools for analyzing spatially resolved transcriptomics while delving deeper into the DL-based approaches. We discuss the new frontiers and the open questions in this field and highlight domains in which we anticipate transformational DL applications. 

Abstract MotivationSingle-cell RNA sequencing (scRNAseq) technologies allow for measurements of gene expression at a single-cell resolution. This provides researchers with a tremendous advantage for detecting heterogeneity, delineating cellular maps or identifying rare subpopulations. However, a critical complication remains: the low number of single-cell observations due to limitations by rarity of subpopulation, tissue degradation or cost. This absence of sufficient data may cause inaccuracy or irreproducibility of downstream analysis. In this work, we present Automated Cell-Type-informed Introspective Variational Autoencoder (ACTIVA): a novel framework for generating realistic synthetic data using a single-stream adversarial variational autoencoder conditioned with cell-type information. Within a single framework, ACTIVA can enlarge existing datasets and generate specific subpopulations on demand, as opposed to two separate models [such as single-cell GAN (scGAN) and conditional scGAN (cscGAN)]. Data generation and augmentation with ACTIVA can enhance scRNAseq pipelines and analysis, such as benchmarking new algorithms, studying the accuracy of classifiers and detecting marker genes. ACTIVA will facilitate analysis of smaller datasets, potentially reducing the number of patients and animals necessary in initial studies. ResultsWe train and evaluate models on multiple public scRNAseq datasets. In comparison to GAN-based models (scGAN and cscGAN), we demonstrate that ACTIVA generates cells that are more realistic and harder for classifiers to identify as synthetic which also have better pair-wise correlation between genes. Data augmentation with ACTIVA significantly improves classification of rare subtypes (more than 45% improvement compared with not augmenting and 4% better than cscGAN) all while reducing run-time by an order of magnitude in comparison to both models. Availability and implementationThe codes and datasets are hosted on Zenodo (https://doi.org/10.5281/zenodo.5879639). Tutorials are available at https://github.com/SindiLab/ACTIVA. Supplementary informationSupplementary data are available at Bioinformatics online. 

Division and label structured population models (DLSPMs) are a class of partial differential equations (PDEs) that have been used to study intracellular dynamics in dividing cells. DLSPMs have improved the understanding of cell proliferation assays involving measurements such as fluorescent label decay, protein production, and prion aggregate amplification. One limitation in using DLSPMs is the significant computational time required for numerical approximations, especially for models with complex biologically relevant dynamics. Here we develop a novel numerical and theoretical framework involving a recursive formulation for a class of DLSPMs. We develop this framework for a population of dividing cells with an arbitrary functional form describing the intracellular dynamics. We found that, compared to previous methods, our framework is faster and more accurate. We illustrate our approach on three common models for intracellular dynamics and discuss the potential impact of our findings in the context of data-driven methods for parameter estimation. 

Abstract Computational models of various facets of hemostasis and thrombosis have increased substantially in the last decade. These models have the potential to make predictions that can uncover new mechanisms within the complex dynamics of thrombus formation. However, these predictions are only as good as the data and assumptions they are built upon, and therefore model building requires intimate coupling with experiments. The objective of this article is to guide the reader through how a computational model is built and how it can inform and be refined by experiments. This is accomplished by answering six questions facing the model builder: (1) Why make a model? (2) What kind of model should be built? (3) How is the model built? (4) Is the model a “good” model? (5) Do we believe the model? (6) Is the model useful? These questions are answered in the context of a model of thrombus formation that has been successfully applied to understanding the interplay between blood flow, platelet deposition, and coagulation and in identifying potential modifiers of thrombin generation in hemophilia A. 

Bleeding frequency and severity within clinical categories of hemophilia A are highly variable and the origin of this variation is unknown. Solving this mystery in coagulation requires the generation and analysis of large data sets comprised of experimental outputs or patient samples, both of which are subject to limited availability. In this review, we describe how a computationally driven approach bypasses such limitations by generating large synthetic patient data sets. These data sets were created with a mechanistic mathematical model, by varying the model inputs, clotting factor, and inhibitor concentrations, within normal physiological ranges. Specific mathematical metrics were chosen from the model output, used as a surrogate measure for bleeding severity, and statistically analyzed for further exploration and hypothesis generation. We highlight results from our recent study that employed this computationally driven approach to identify FV (factor V) as a key modifier of thrombin generation in mild to moderate hemophilia A, which was confirmed with complementary experimental assays. The mathematical model was used further to propose a potential mechanism for these observations whereby thrombin generation is rescued in FVIII-deficient plasma due to reduced substrate competition between FV and FVIII for FXa.