MarkerMap: nonlinear marker selection for single-cell studies.

Single-cell RNA-seq data allow the quantification of cell type differences across a growing set of biological contexts. However, pinpointing a small subset of genomic features explaining this variability can be ill-defined and computationally intractable. Here we introduce MarkerMap, a generative model for selecting minimal gene sets which are maximally informative of cell type origin and enable whole transcriptome reconstruction. MarkerMap provides a scalable framework for both supervised marker selection, aimed at identifying specific cell type populations, and unsupervised marker selection, aimed at gene expression imputation and reconstruction. We benchmark MarkerMap's competitive performance against previously published approaches on real single cell gene expression data sets. MarkerMap is available as a pip installable package, as a community resource aimed at developing explainable machine learning techniques for enhancing interpretability in single-cell studies.

Hypergraph factorization for multi-tissue gene expression imputation.

Integrating gene expression across tissues and cell types is crucial for understanding the coordinated biological mechanisms that drive disease and characterise homeostasis. However, traditional multitissue integration methods cannot handle uncollected tissues or rely on genotype information, which is often unavailable and subject to privacy concerns. Here we present HYFA (Hypergraph Factorisation), a parameter-efficient graph representation learning approach for joint imputation of multi-tissue and cell-type gene expression. HYFA is genotype-agnostic, supports a variable number of collected tissues per individual, and imposes strong inductive biases to leverage the shared regulatory architecture of tissues and genes. In performance comparison on Genotype-Tissue Expression project data, HYFA achieves superior performance over existing methods, especially when multiple reference tissues are available. The HYFA-imputed dataset can be used to identify replicable regulatory genetic variations (eQTLs), with substantial gains over the original incomplete dataset. HYFA can accelerate the effective and scalable integration of tissue and cell-type transcriptome biorepositories.

In silico tissue generation and power analysis for spatial omics.

As spatially resolved multiplex profiling of RNA and proteins becomes more prominent, it is increasingly important to understand the statistical power available to test specific hypotheses when designing and interpreting such experiments. Ideally, it would be possible to create an oracle that predicts sampling requirements for generalized spatial experiments. However, the unknown number of relevant spatial features and the complexity of spatial data analysis make this challenging. Here, we enumerate multiple parameters of interest that should be considered in the design of a properly powered spatial omics study. We introduce a method for tunable in silico tissue (IST) generation and use it with spatial profiling data sets to construct an exploratory computational framework for spatial power analysis. Finally, we demonstrate that our framework can be applied across diverse spatial data modalities and tissues of interest. While we demonstrate ISTs in the context of spatial power analysis, these simulated tissues have other potential use cases, including spatial method benchmarking and optimization.

Deep learning for bioimage analysis in developmental biology.

Deep learning has transformed the way large and complex image datasets can be processed, reshaping what is possible in bioimage analysis. As the complexity and size of bioimage data continues to grow, this new analysis paradigm is becoming increasingly ubiquitous. In this Review, we begin by introducing the concepts needed for beginners to understand deep learning. We then review how deep learning has impacted bioimage analysis and explore the open-source resources available to integrate it into a research project. Finally, we discuss the future of deep learning applied to cell and developmental biology. We analyze how state-of-the-art methodologies have the potential to transform our understanding of biological systems through new image-based analysis and modelling that integrate multimodal inputs in space and time.

Optimal marker gene selection for cell type discrimination in single cell analyses.

Single-cell technologies characterize complex cell populations across multiple data modalities at unprecedented scale and resolution. Multi-omic data for single cell gene expression, in situ hybridization, or single cell chromatin states are increasingly available across diverse tissue types. When isolating specific cell types from a sample of disassociated cells or performing in situ sequencing in collections of heterogeneous cells, one challenging task is to select a small set of informative markers that robustly enable the identification and discrimination of specific cell types or cell states as precisely as possible. Given single cell RNA-seq data and a set of cellular labels to discriminate, scGeneFit selects gene markers that jointly optimize cell label recovery using label-aware compressive classification methods. This results in a substantially more robust and less redundant set of markers than existing methods, most of which identify markers that separate each cell label from the rest. When applied to a data set given a hierarchy of cell types as labels, the markers found by our method improves the recovery of the cell type hierarchy with fewer markers than existing methods using a computationally efficient and principled optimization.

Causal network inference from gene transcriptional time-series response to glucocorticoids.

Gene regulatory network inference is essential to uncover complex relationships among gene pathways and inform downstream experiments, ultimately enabling regulatory network re-engineering. Network inference from transcriptional time-series data requires accurate, interpretable, and efficient determination of causal relationships among thousands of genes. Here, we develop Bootstrap Elastic net regression from Time Series (BETS), a statistical framework based on Granger causality for the recovery of a directed gene network from transcriptional time-series data. BETS uses elastic net regression and stability selection from bootstrapped samples to infer causal relationships among genes. BETS is highly parallelized, enabling efficient analysis of large transcriptional data sets. We show competitive accuracy on a community benchmark, the DREAM4 100-gene network inference challenge, where BETS is one of the fastest among methods of similar performance and additionally infers whether causal effects are activating or inhibitory. We apply BETS to transcriptional time-series data of differentially-expressed genes from A549 cells exposed to glucocorticoids over a period of 12 hours. We identify a network of 2768 genes and 31,945 directed edges (FDR ≤ 0.2). We validate inferred causal network edges using two external data sources: Overexpression experiments on the same glucocorticoid system, and genetic variants associated with inferred edges in primary lung tissue in the Genotype-Tissue Expression (GTEx) v6 project. BETS is available as an open source software package at https://github.com/lujonathanh/BETS.

Sparse multi-output Gaussian processes for online medical time series prediction.

BACKGROUND: For real-time monitoring of hospital patients, high-quality inference of patients' health status using all information available from clinical covariates and lab test results is essential to enable successful medical interventions and improve patient outcomes. Developing a computational framework that can learn from observational large-scale electronic health records (EHRs) and make accurate real-time predictions is a critical step. In this work, we develop and explore a Bayesian nonparametric model based on multi-output Gaussian process (GP) regression for hospital patient monitoring. METHODS: We propose MedGP, a statistical framework that incorporates 24 clinical covariates and supports a rich reference data set from which relationships between observed covariates may be inferred and exploited for high-quality inference of patient state over time. To do this, we develop a highly structured sparse GP kernel to enable tractable computation over tens of thousands of time points while estimating correlations among clinical covariates, patients, and periodicity in patient observations. MedGP has a number of benefits over current methods, including (i) not requiring an alignment of the time series data, (ii) quantifying confidence regions in the predictions, (iii) exploiting a vast and rich database of patients, and (iv) inferring interpretable relationships among clinical covariates. RESULTS: We evaluate and compare results from MedGP on the task of online prediction for three patient subgroups from two medical data sets across 8,043 patients. We find MedGP improves online prediction over baseline and state-of-the-art methods for nearly all covariates across different disease subgroups and hospitals. CONCLUSIONS: The MedGP framework is robust and efficient in estimating the temporal dependencies from sparse and irregularly sampled medical time series data for online prediction. The publicly available code is at https://github.com/bee-hive/MedGP .

netNMF-sc: leveraging gene-gene interactions for imputation and dimensionality reduction in single-cell expression analysis.

Single-cell RNA-sequencing (scRNA-seq) enables high-throughput measurement of RNA expression in single cells. However, because of technical limitations, scRNA-seq data often contain zero counts for many transcripts in individual cells. These zero counts, or dropout events, complicate the analysis of scRNA-seq data using standard methods developed for bulk RNA-seq data. Current scRNA-seq analysis methods typically overcome dropout by combining information across cells in a lower-dimensional space, leveraging the observation that cells generally occupy a small number of RNA expression states. We introduce netNMF-sc, an algorithm for scRNA-seq analysis that leverages information across both cells and genes. netNMF-sc learns a low-dimensional representation of scRNA-seq transcript counts using network-regularized non-negative matrix factorization. The network regularization takes advantage of prior knowledge of gene-gene interactions, encouraging pairs of genes with known interactions to be nearby each other in the low-dimensional representation. The resulting matrix factorization imputes gene abundance for both zero and nonzero counts and can be used to cluster cells into meaningful subpopulations. We show that netNMF-sc outperforms existing methods at clustering cells and estimating gene-gene covariance using both simulated and real scRNA-seq data, with increasing advantages at higher dropout rates (e.g., >60%). We also show that the results from netNMF-sc are robust to variation in the input network, with more representative networks leading to greater performance gains.

Statistical tests for detecting variance effects in quantitative trait studies.

Motivation: Identifying variants, both discrete and continuous, that are associated with quantitative traits, or QTs, is the primary focus of quantitative genetics. Most current methods are limited to identifying mean effects, or associations between genotype or covariates and the mean value of a quantitative trait. It is possible, however, that a variant may affect the variance of the quantitative trait in lieu of, or in addition to, affecting the trait mean. Here, we develop a general methodology to identify covariates with variance effects on a quantitative trait using a Bayesian heteroskedastic linear regression model (BTH). We compare BTH with existing methods to detect variance effects across a large range of simulations drawn from scenarios common to the analysis of quantitative traits. Results: We find that BTH and a double generalized linear model (dglm) outperform classical tests used for detecting variance effects in recent genomic studies. We show BTH and dglm are less likely to generate spurious discoveries through simulations and application to identifying methylation variance QTs and expression variance QTs. We identify four variance effects of sex in the Cardiovascular and Pharmacogenetics study. Our work is the first to offer a comprehensive view of variance identifying methodology. We identify shortcomings in previously used methodology and provide a more conservative and robust alternative. We extend variance effect analysis to a wide array of covariates that enables a new statistical dimension in the study of sex and age specific quantitative trait effects. Availability and implementation: https://github.com/b2du/bth. Supplementary information: Supplementary data are available at Bioinformatics online.

Bayesian nonparametric discovery of isoforms and individual specific quantification.

Most human protein-coding genes can be transcribed into multiple distinct mRNA isoforms. These alternative splicing patterns encourage molecular diversity, and dysregulation of isoform expression plays an important role in disease etiology. However, isoforms are difficult to characterize from short-read RNA-seq data because they share identical subsequences and occur in different frequencies across tissues and samples. Here, we develop BIISQ, a Bayesian nonparametric model for isoform discovery and individual specific quantification from short-read RNA-seq data. BIISQ does not require isoform reference sequences but instead estimates an isoform catalog shared across samples. We use stochastic variational inference for efficient posterior estimates and demonstrate superior precision and recall for simulations compared to state-of-the-art isoform reconstruction methods. BIISQ shows the most gains for low abundance isoforms, with 36% more isoforms correctly inferred at low coverage versus a multi-sample method and 170% more versus single-sample methods. We estimate isoforms in the GEUVADIS RNA-seq data and validate inferred isoforms by associating genetic variants with isoform ratios.