An official website of the United States government
Abstract BackgroundCells progressing from an early state to a developed state give rise to lineages in cell differentiation. Knowledge of these lineages is central to developmental biology. Each biological lineage corresponds to a trajectory in a dynamical system. Emerging single-cell technologies such as single-cell RNA sequencing can capture molecular abundance in diverse cell types in a developing tissue. Many computational methods have been developed to infer trajectories from single-cell data. However, to our knowledge, none of the existing methods address the problem of determining the existence of a trajectory in observed data before attempting trajectory inference. ResultsWe introduce a method to identify the existence of a trajectory using three graph-based statistics. A permutation test is utilized to calculate the empirical distribution of the test statistic under the null hypothesis that a trajectory does not exist. Finally, ap-value is calculated to quantify the statistical significance for the presence of trajectory in the data. ConclusionsOur work contributes new statistics to assess the level of uncertainty in trajectory inference to increase the understanding of biological system dynamics.
more »
« less
Joint trajectory inference for single-cell genomics using deep learning with a mixture prior
Trajectory inference methods are essential for analyzing the developmental paths of cells in single-cell sequencing datasets. It provides insights into cellular differentiation, transitions, and lineage hierarchies, helping unravel the dynamic processes underlying development and disease progression. However, many existing tools lack a coherent statistical model and reliable uncertainty quantification, limiting their utility and robustness. In this paper, we introduce VITAE (Variational Inference for Trajectory by AutoEncoder), a statistical approach that integrates a latent hierarchical mixture model with variational autoencoders to infer trajectories. The statistical hierarchical model enhances the interpretability of our framework, while the posterior approximations generated by our variational autoencoder ensure computational efficiency and provide uncertainty quantification of cell projections along trajectories. Specifically, VITAE enables simultaneous trajectory inference and data integration, improving the accuracy of learning a joint trajectory structure in the presence of biological and technical heterogeneity across datasets. We show that VITAE outperforms other state-of-the-art trajectory inference methods on both real and synthetic data under various trajectory topologies. Furthermore, we apply VITAE to jointly analyze three distinct single-cell RNA sequencing datasets of the mouse neocortex, unveiling comprehensive developmental lineages of projection neurons. VITAE effectively reduces batch effects within and across datasets and uncovers finer structures that might be overlooked in individual datasets. Additionally, we showcase VITAE’s efficacy in integrative analyses of multiomic datasets with continuous cell population structures.
more »
« less
- Award ID(s):
- 2113646
- PAR ID:
- 10553794
- Publisher / Repository:
- Proceedings of the National Academy of Sciences
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 121
- Issue:
- 37
- ISSN:
- 0027-8424
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
apid 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.more » « less
-
Learning explicit and implicit patterns in human trajectories plays an important role in many Location-Based Social Networks (LBSNs) applications, such as trajectory classification (e.g., walking, driving, etc.), trajectory-user linking, friend recommendation, etc. A particular problem that has attracted much attention recently – and is the focus of our work – is the Trajectory-based Social Circle Inference (TSCI), aiming at inferring user social circles (mainly social friendship) based on motion trajectories and without any explicit social networked information. Existing approaches addressing TSCI lack satisfactory results due to the challenges related to data sparsity, accessibility and model efficiency. Motivated by the recent success of machine learning in trajectory mining, in this paper we formulate TSCI as a novel multi-label classification problem and develop a Recurrent Neural Network (RNN)-based framework called DeepTSCI to use human mobility patterns for inferring corresponding social circles. We propose three methods to learn the latent representations of trajectories, based on: (1) bidirectional Long Short-Term Memory (LSTM); (2) Autoencoder; and (3) Variational autoencoder. Experiments conducted on real-world datasets demonstrate that our proposed methods perform well and achieve significant improvement in terms of macro-R, macro-F1 and accuracy when compared to baselines.more » « less
-
Abstract Inferring gene regulatory networks (GRNs) from single-cell data is challenging due to heuristic limitations. Existing methods also lack estimates of uncertainty. Here we present Probabilistic Matrix Factorization for Gene Regulatory Network Inference (PMF-GRN). Using single-cell expression data, PMF-GRN infers latent factors capturing transcription factor activity and regulatory relationships. Using variational inference allows hyperparameter search for principled model selection and direct comparison to other generative models. We extensively test and benchmark our method using real single-cell datasets and synthetic data. We show that PMF-GRN infers GRNs more accurately than current state-of-the-art single-cell GRN inference methods, offering well-calibrated uncertainty estimates.more » « less
-
Semi-implicit graph variational auto-encoder (SIG-VAE) is proposed to expand the flexibility of variational graph auto-encoders (VGAE) to model graph data. SIG-VAE employs a hierarchical variational framework to enable neighboring node sharing for better generative modeling of graph dependency structure, together with a Bernoulli-Poisson link decoder. Not only does this hierarchical construction provide a more flexible generative graph model to better capture real-world graph properties, but also does SIG-VAE naturally lead to semi-implicit hierarchical variational inference that allows faithful modeling of implicit posteriors of given graph data, which may exhibit heavy tails, multiple modes, skewness, and rich dependency structures. SIG-VAE integrates a carefully designed generative model, well suited to model real-world sparse graphs, and a sophisticated variational inference network, which propagates the graph structural information and distribution uncertainty to capture complex posteriors. SIG-VAE clearly outperforms a simple combination of VGAE with variational inference, including semi-implicit variational inference~(SIVI) or normalizing flow (NF), which does not propagate uncertainty in its inference network, and provides more interpretable latent representations than VGAE does. Extensive experiments with a variety of graph data show that SIG-VAE significantly outperforms state-of-the-art methods on several different graph analytic tasks.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1073/pnas.2316256121
