Rapid growth of high-dimensional datasets in fields such as single-cell RNA sequencing and spatial genomics has led to unprecedented opportunities for scientific discovery, but it also presents unique computational and statistical challenges. Traditional methods struggle with geometry-aware data generation, interpolation along meaningful trajectories, and transporting populations via feasible paths. To address these issues, we introduce Geometry-Aware Generative Autoencoder (GAGA), a novel framework that combines extensible manifold learning with generative modeling. GAGA constructs a neural network embedding space that respects the intrinsic geometries discovered by manifold learning and learns a novel warped Riemannian metric on the data space. This warped metric is derived from both the points on the data manifold and negative samples off the manifold, allowing it to characterize a meaningful geometry across the entire latent space. Using this metric, GAGA can uniformly sample points on the manifold, generate points along geodesics, and interpolate between populations across the learned manifold. GAGA shows competitive performance in simulated and real-world datasets, including a 30% improvement over SOTA in single-cell population-level trajectory inference.

The rapidly growing field of single-cell transcriptomic sequencing (scRNAseq) presents challenges for data analysis due to its massive datasets. A common method in manifold learning consists in hypothesizing that datasets lie on a lower dimensional manifold. This allows to study the geometry of point clouds by extracting meaningful descriptors like curvature. In this work, we will present Adaptive Local PCA (AdaL-PCA), a data-driven method for accurately estimating various notions of intrinsic curvature on data manifolds, in particular principal curvatures for surfaces. The model relies on local PCA to estimate the tangent spaces. The evaluation of AdaL-PCA on sampled surfaces shows state-of-the-art results. Combined with a PHATE embedding, the model applied to single-cell RNA sequencing data allows us to identify key variations in the cellular differentiation.

We introduce a new intrinsic measure of local curvature on point-cloud data called diffusion curvature. Our measure uses the framework of diffusion maps, including the data diffusion operator, to structure point cloud data and define local curvature based on the laziness of a random walk starting at a point or region of the data. We show that this laziness directly relates to volume comparison results from Riemannian geometry. We then extend this scalar curvature notion to an entire quadratic form using neural network estimations based on the diffusion map of point-cloud data. We show applications of both estimations on toy data, single-cell data, and on estimating local Hessian matrices of neural network loss landscapes.

We propose a new fast method of measuring distances between large numbers of related high dimensional datasets called the Diffusion Earth Mover’s Distance (EMD). We model the datasets as distributions supported on common data graph that is derived from the affinity matrix computed on the combined data. In such cases where the graph is a discretization of an underlying Riemannian closed manifold, we prove that Diffusion EMD is topologically equivalent to the standard EMD with a geodesic ground distance. Diffusion EMD can be computed in {Õ}(n) time and is more accurate than similarly fast algorithms such as tree-based EMDs. We also show Diffusion EMD is fully differentiable, making it amenable to future uses in gradient-descent frameworks such as deep neural networks. Finally, we demonstrate an application of Diffusion EMD to single cell data collected from 210 COVID-19 patient samples at Yale New Haven Hospital. Here, Diffusion EMD can derive distances between patients on the manifold of cells at least two orders of magnitude faster than equally accurate methods. This distance matrix between patients can be embedded into a higher level patient manifold which uncovers structure and heterogeneity in patients. More generally, Diffusion EMD is applicable to all datasets that are massively collected in parallel in many medical and biological systems.