Trajectory Inference

Understanding cellular trajectories via time-resolved single-cell transcriptomics is vital for studying development, regeneration, and disease. A key challenge is inferring continuous trajectories from discrete snapshots. Biological complexity stems from stochastic cell fate decisions, temporal proliferation changes, and spatial environmental influences. Current methods often use deterministic interpolations treating cells in isolation, failing to capture the probabilistic branching, population shifts, and niche-dependent signaling driving real biological processes. We introduce Manifold Interpolating Optimal-Transport Flow (MIOFlow) 2.0. This framework learns biologically informed cellular trajectories by integrating manifold learning, optimal transport, and neural differential equations. It models three core processes: (1) stochasticity and branching via Neural Stochastic Differential Equations; (2) non-conservative population changes using a learned growth-rate model initialized with unbalanced optimal transport; and (3) environmental influence through a joint latent space unifying gene expression with spatial features like local cell type composition and signaling. By operating in a PHATE-distance matching autoencoder latent space, MIOFlow 2.0 ensures trajectories respect the data's intrinsic geometry. Empirical comparisons show expressive trajectory learning via neural differential equations outperforms existing generative models, including simulation-free flow matching. Validated on synthetic datasets, embryoid body differentiation, and spatially resolved axolotl brain regeneration, MIOFlow 2.0 improves trajectory accuracy and reveals hidden drivers of cellular transitions, like specific signaling niches. MIOFlow 2.0 thus bridges single-cell and spatial transcriptomics to uncover tissue-scale trajectories.

Trajectory inference investigates how to interpolate paths between observed timepoints of dynamical systems, such as temporally resolved population distributions, with the goal of inferring trajectories at unseen times and better understanding system dynamics. Previous work has focused on continuous geometric priors, utilizing data-dependent spatial features to define a Riemannian metric. In many applications, there exists discrete, directed prior knowledge over admissible transitions (e.g. lineage trees in developmental biology). We introduce a Finsler metric that combines geometry with classification and incorporate both types of priors in trajectory inference, yielding improved performance on interpolation tasks in synthetic and real-world data.

This paper investigates whether a single, unified cost function can explain and predict human reaching movements, in contrast with existing approaches that rely on subject- or posture-specific optimization criteria. Using the Minimal Observation Inverse Reinforcement Learning (MO-IRL) algorithm, together with a seven-dimensional set of candidate cost terms, we efficiently estimate time-varying cost weights for a standard planar reaching task. MO-IRL provides orders-of-magnitude faster convergence than bilevel formulations, while using only a fraction of the available data, enabling the practical exploration of time-varying cost structures. Three levels of generality are evaluated: Subject-Dependent Posture-Dependent, Subject-Dependent Posture-Independent, and Subject-Independent Posture-Independent. Across all cases, time-varying weights substantially improve trajectory reconstruction, yielding an average 27% reduction in RMSE compared to the baseline. The inferred costs consistently highlight a dominant role for joint-acceleration regulation, complemented by smaller contributions from torque-change smoothness. Overall, a single subject- and posture-agnostic time-varying cost function is shown to predict human reaching trajectories with high accuracy, supporting the existence of a unified optimality principle governing this class of movements.

Assistive robots offer agency to humans with severe motor impairments. Often, these users control high-DoF robots through low-dimensional interfaces, such as using a 1-D sip-and-puff interface to operate a 6-DoF robotic arm. This mismatch results in having access to only a subset of control dimensions at a given time, imposing unintended and artificial constraints on robot motion. As a result, interface-limited demonstrations embed suboptimal motions that reflect interface restrictions rather than user intent. To address this, we present a trajectory reconstruction algorithm that reasons about task, environment, and interface constraints to lift demonstrations into the robot's full control space. We evaluate our approach using real-world demonstrations of ADL-inspired tasks performed via a 2-D joystick and 1-D sip-and-puff control interface, teleoperating two distinct 7-DoF robotic arms. Analyses of the reconstructed demonstrations and derived control policies show that lifted trajectories are faster and more efficient than their interface-constrained counterparts while respecting user preferences.

In Part I of this companion paper series, we introduced SWIFTraj, a new open-source vehicle trajectory dataset collected using a unmanned aerial vehicle (UAV) swarm. The dataset has two distinctive features. First, by connecting trajectories across consecutive UAV videos, it provides long-distance continuous trajectories, with the longest exceeding 4.5 km. Second, it covers an integrated traffic network consisting of both freeways and their connected urban roads. Obtaining such long-distance continuous trajectories from a UAV swarm is challenging, due to the need for accurate time alignment across multiple videos and the irregular spatial distribution of UAVs. To address these challenges, this paper proposes a novel graph-based approach for connecting vehicle trajectories captured by a UAV swarm. An undirected graph is constructed to represent flexible UAV layouts, and an automatic time alignment method based on trajectory matching cost minimization is developed to estimate optimal time offsets across videos. To associate trajectories of the same vehicle observed in different videos, a vehicle matching table is established using the Hungarian algorithm. The proposed approach is evaluated using both simulated and real-world data. Results from real-world experiments show that the time alignment error is within three video frames, corresponding to approximately 0.1 s, and that the vehicle matching achieves an F1-score of about 0.99. These results demonstrate the effectiveness of the proposed method in addressing key challenges in UAV-based trajectory connection and highlight its potential for large-scale vehicle trajectory collection.

Understanding the continuous evolution of populations from discrete temporal snapshots is a critical research challenge, particularly in fields like developmental biology and systems medicine where longitudinal tracking of individual entities is often impossible. Such trajectory inference is vital for unraveling the mechanisms of dynamic processes. While Schrödinger Bridge (SB) offer a potent framework, their traditional application to pairwise time points can be insufficient for systems defined by multiple intermediate snapshots. This paper introduces Multi-Marginal Schrödinger Bridge Matching (MSBM), a novel algorithm specifically designed for the multi-marginal SB problem. MSBM extends iterative Markovian fitting (IMF) to effectively handle multiple marginal constraints. This technique ensures robust enforcement of all intermediate marginals while preserving the continuity of the learned global dynamics across the entire trajectory. Empirical validations on synthetic data and real-world single-cell RNA sequencing datasets demonstrate the competitive or superior performance of MSBM in capturing complex trajectories and respecting intermediate distributions, all with notable computational efficiency.

Learning the dynamics of a process given sampled observations at several time points is an important but difficult task in many scientific applications. When no ground-truth trajectories are available, but one has only snapshots of data taken at discrete time steps, the problem of modelling the dynamics, and thus inferring the underlying trajectories, can be solved by multi-marginal generalisations of flow matching algorithms. This paper proposes a novel flow matching method that overcomes the limitations of existing multi-marginal trajectory inference algorithms. Our proposed method, ALI-CFM, uses a GAN-inspired adversarial loss to fit neurally parametrised interpolant curves between source and target points such that the marginal distributions at intermediate time points are close to the observed distributions. The resulting interpolants are smooth trajectories that, as we show, are unique under mild assumptions. These interpolants are subsequently marginalised by a flow matching algorithm, yielding a trained vector field for the underlying dynamics. We showcase the versatility and scalability of our method by outperforming the existing baselines on spatial transcriptomics and cell tracking datasets, while performing on par with them on single-cell trajectory prediction. Code: https://github.com/mmacosha/adversarially-learned-interpolants.