Spatially-resolved genomic technologies have allowed us to study the physical organization of cells and tissues, and promise an understanding of the local interactions between cells. However, it remains difficult to precisely align spatial observations across slices, samples, scales, individuals, and technologies. Here, we propose a probabilistic model that aligns a set of spatially-resolved genomics and histology slices onto a known or unknown common coordinate system into which the samples are aligned both spatially and in terms of the phenotypic readouts (e.g., gene or protein expression levels, cell density, open chromatin regions). Our method consists of a two-layer Gaussian process: the first layer maps the observed samples' spatial locations into a common coordinate system, and the second layer maps from the common coordinate system to the observed readouts. Our approach also allows for slices to be mapped to a known template coordinate space if one exists. We show that our registration approach enables complex downstream spatially-aware analyses of spatial genomics data at multiple resolutions that are impossible or inaccurate with unaligned data, including an analysis of variance, differential expression across the z-axis, and association tests across multiple data modalities.
High-throughput RNA-sequencing (RNA-seq) technologies are powerful tools for understanding cellular state. Often it is of interest to quantify and summarize changes in cell state that occur between experimental or biological conditions. Differential expression is typically assessed using univariate tests to measure gene-wise shifts in expression. However, these methods largely ignore changes in transcriptional correlation. Furthermore, there is a need to identify the low-dimensional structure of the gene expression shift to identify collections of genes that change between conditions. Here, we propose contrastive latent variable models designed for count data to create a richer portrait of differential expression in sequencing data. These models disentangle the sources of transcriptional variation in different conditions, in the context of an explicit model of variation at baseline. Moreover, we develop a model-based hypothesis testing framework that can test for global and gene subset-specific changes in expression. We test our model through extensive simulations and analyses with count-based gene expression data from perturbation and observational sequencing experiments. We find that our methods can effectively summarize and quantify complex transcriptional changes in case-control experimental sequencing data.
Summary Current tools for multivariate density estimation struggle when the density is concentrated near a non‐linear subspace or manifold. Most approaches require the choice of a kernel, with the multivariate Gaussian kernel by far the most commonly used. Although heavy‐tailed and skewed extensions have been proposed, such kernels cannot capture curvature in the support of the data. This leads to poor performance unless the sample size is very large relative to the dimension of the data. The paper proposes a novel generalization of the Gaussian distribution, which includes an additional curvature parameter. We refer to the proposed class as Fisher–Gaussian kernels, since they arise by sampling from a von Mises–Fisher density on the sphere and adding Gaussian noise. The Fisher–Gaussian density has an analytic form and is amenable to straightforward implementation within Bayesian mixture models by using Markov chain Monte Carlo sampling. We provide theory on large support and illustrate gains relative to competitors in simulated and real data applications.
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