tGPLVM – a robust nonlinear low-dimensional manifold for single cell RNA-seq data

Modern developments in single-cell sequencing technologies enable broad insights into cellular state. Single-cell RNA sequencing (scRNA-seq) can be used to explore cell types, states, and developmental trajectories to broaden our understanding of cellular heterogeneity in tissues and organs. Analysis of these sparse, high-dimensional experimental results requires dimension reduction. Several methods have been developed to estimate low-dimensional embeddings for filtered and normalized single-cell data. However, methods have yet to be developed for unfiltered and unnormalized count data that estimate uncertainty in the low-dimensional space. Princeton University researchers present a nonlinear latent variable model with robust, heavy-tailed error and adaptive kernel learning to estimate low-dimensional nonlinear structure in scRNA-seq data.

Gene expression in a single cell is modeled as a noisy draw from a Gaussian process in high dimensions from low-dimensional latent positions. This model is called the Gaussian process latent variable model (GPLVM). The developers model residual errors with a heavy-tailed Student’s t-distribution to estimate a manifold that is robust to technical and biological noise found in normalized scRNA-seq data. They compare their approach to common dimension reduction tools across a diverse set of scRNA-seq data sets to highlight this model’s ability to enable important downstream tasks such as clustering, inferring cell developmental trajectories, and visualizing high throughput experiments on available experimental data.

Manifold learning methods on unprocessed CD34+ PBMCs counts

Fig. 6

tGPLVM shows the best separation of expression patterns based on cell state marker genes. Color bars indicate log2(1+Y), where Y represents total counts across genes and cells

Researchers show that an adaptive robust statistical approach to estimate a nonlinear manifold is well suited for raw, unfiltered gene counts from high-throughput sequencing technologies for visualization, exploration, and uncertainty estimation of cell states.

Availability – The pollen data and implementation is available in the tGPLVM repository (

Verma A, Engelhardt BE. (2020) A robust nonlinear low-dimensional manifold for single cell RNA-seq data. BMC Bioinformatics 21(1):324. [article]

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