Alexander Tong

2025-09-26

ArXiv (prépublication)

arxiv.org

Amortized Sampling with Transferable Normalizing Flows

Charlie B. Tan

Majdi Hassan

Leon Klein

Saifuddin Syed

Dominique Beaini

Michael M. Bronstein

Kirill Neklyudov

Efficient equilibrium sampling of molecular conformations remains a core challenge in computational chemistry and statistical inference. Cla… (voir plus)ssical approaches such as molecular dynamics or Markov chain Monte Carlo inherently lack amortization; the computational cost of sampling must be paid in full for each system of interest. The widespread success of generative models has inspired interest towards overcoming this limitation through learning sampling algorithms. Despite performing competitively with conventional methods when trained on a single system, learned samplers have so far demonstrated limited ability to transfer across systems. We demonstrate that deep learning enables the design of scalable and transferable samplers by introducing Prose, a 285 million parameter all-atom transferable normalizing flow trained on a corpus of peptide molecular dynamics trajectories up to 8 residues in length. Prose draws zero-shot uncorrelated proposal samples for arbitrary peptide systems, achieving the previously intractable transferability across sequence length, whilst retaining the efficient likelihood evaluation of normalizing flows. Through extensive empirical evaluation we demonstrate the efficacy of Prose as a proposal for a variety of sampling algorithms, finding a simple importance sampling-based finetuning procedure to achieve competitive performance to established methods such as sequential Monte Carlo. We open-source the Prose codebase, model weights, and training dataset, to further stimulate research into amortized sampling methods and finetuning objectives.

2025-09-17

NeurIPS.cc/2025/Conference (poster)

Progressive Inference-Time Annealing of Diffusion Models for Sampling from Boltzmann Densities

Tara Akhound-Sadegh

Jungyoon Lee

Avishek Joey Bose

Valentin De Bortoli

Arnaud Doucet

Michael M. Bronstein

Dominique Beaini

Siamak Ravanbakhsh

Kirill Neklyudov

Sampling efficiently from a target unnormalized probability density remains a core challenge, with relevance across countless high-impact sc… (voir plus)ientific applications. A promising approach towards this challenge is the design of amortized samplers that borrow key ideas, such as probability path design, from state-of-the-art generative diffusion models. However, all existing diffusion-based samplers remain unable to draw samples from distributions at the scale of even simple molecular systems. In this paper, we propose Progressive Inference-Time Annealing (PITA), a novel framework to learn diffusion-based samplers that combines two complementary interpolation techniques: I.) Annealing of the Boltzmann distribution and II.) Diffusion smoothing. PITA trains a sequence of diffusion models from high to low temperatures by sequentially training each model at progressively higher temperatures, leveraging engineered easy access to samples of the temperature-annealed target density. In the subsequent step, PITA enables simulating the trained diffusion model to procure training samples at a lower temperature for the next diffusion model through inference-time annealing using a novel Feynman-Kac PDE combined with Sequential Monte Carlo. Empirically, PITA enables, for the first time, equilibrium sampling of N-body particle systems, Alanine Dipeptide, and tripeptides in Cartesian coordinates with dramatically lower energy function evaluations. Code available at: https://github.com/taraak/pita

2025-09-17

NeurIPS.cc/2025/Conference (spotlight)

Revealing dynamic temporal trajectories and underlying regulatory networks with
<i>Cflows</i>

Manik Kuchroo

Shabarni Gupta

Aarthi Venkat

Chen Liu

Beatriz P. San Juan

Laura Rangel

Brandon Zhu

John G. Lock

Christine L. Chaffer

Smita Krishnaswamy

While single-cell technologies provide snapshots of tumor states, building continuous trajectories and uncovering causative gene regulatory … (voir plus)networks remains a significant challenge. We present Cflows , an AI framework that combines neural ODE networks with Granger causality to infer continuous cell state transitions and gene regulatory interactions from static scRNA-seq data. In a new 5-time point dataset capturing tumorsphere development over 30 days, Cflows reconstructs two types of trajectories leading to tumorsphere formation or apoptosis. Trajectory-based cell-of-origin analysis delineated a novel cancer stem cell profile characterized by CD44 hi EPCAM + CAV1 + , and uncovered a cell cycle–dependent enrichment of tumorsphere-initiating potential in G2/M or S-phase cells. Cflows uncovers ESRRA as a crucial causal driver of the tumor-forming gene regulatory network. Indeed, ESRRA inhibition significantly reduces tumor growth and metastasis in vivo. Cflows offers a powerful framework for uncovering cellular transitions and dynamic regulatory networks from static single-cell data.

2025-08-06

bioRxiv (prépublication)

Efficient Regression-Based Training of Normalizing Flows for Boltzmann Generators

Oscar Davis

Michael Bronstein

Avishek Joey Bose

Simulation-free training frameworks have been at the forefront of the generative modelling revolution in continuous spaces, leading to large… (voir plus)-scale diffusion and flow matching models. However, such modern generative models suffer from expensive inference, inhibiting their use in numerous scientific applications like Boltzmann Generators (BGs) for molecular conformations that require fast likelihood evaluation. In this paper, we revisit classical normalizing flows in the context of BGs that offer efficient sampling and likelihoods, but whose training via maximum likelihood is often unstable and computationally challenging. We propose Regression Training of Normalizing Flows (RegFlow), a novel and scalable regression-based training objective that bypasses the numerical instability and computational challenge of conventional maximum likelihood training in favour of a simple

2025-06-10

ICML.cc/2025/Workshop/GenBio (spotlight)

Multi-Modal and Multi-Attribute Generation of Single Cells with CFGen

Alessandro Palma

Till Richter

Hanyi Zhang

Manuel Lubetzki

Andrea Dittadi

Fabian J. Theis

Generative modeling of single-cell RNA-seq data is crucial for tasks like trajectory inference, batch effect removal, and simulation of real… (voir plus)istic cellular data. However, recent deep generative models simulating synthetic single cells from noise operate on pre-processed continuous gene expression approximations, overlooking the discrete nature of single-cell data, which limits their effectiveness and hinders the incorporation of robust noise models. Additionally, aspects like controllable multi-modal and multi-label generation of cellular data remain underexplored. This work introduces CellFlow for Generation (CFGen), a flow-based conditional generative model that preserves the inherent discreteness of single-cell data. CFGen generates whole-genome multi-modal single-cell data reliably, improving the recovery of crucial biological data characteristics while tackling relevant generative tasks such as rare cell type augmentation and batch correction. We also introduce a novel framework for compositional data generation using Flow Matching. By showcasing CFGen on a diverse set of biological datasets and settings, we provide evidence of its value to the fields of computational biology and deep generative models.

2025-04-22

International Conference on Learning Representations (Accept (Poster))

Steering Masked Discrete Diffusion Models via Discrete Denoising Posterior Prediction

Jarrid Rector-Brooks

Mohsin Hasan

Zhangzhi Peng

Zachary Quinn

Michael Bronstein

Pranam Chatterjee

Avishek Joey Bose

Generative modeling of discrete data underlies important applications spanning text-based agents like ChatGPT to the design of the very buil… (voir plus)ding blocks of life in protein sequences. However, application domains need to exert control over the generated data by steering the generative process - typically via RLHF - to satisfy a specified property, reward, or affinity metric. In this paper, we study the problem of steering Masked Diffusion Models (MDMs), a recent class of discrete diffusion models that offer a compelling alternative to traditional autoregressive models. We introduce Discrete Denoising Posterior Prediction (DDPP), a novel framework that casts the task of steering pre-trained MDMs as a problem of probabilistic inference by learning to sample from a target Bayesian posterior. Our DDPP framework leads to a family of three novel objectives that are all simulation-free, and thus scalable while applying to general non-differentiable reward functions. Empirically, we instantiate DDPP by steering MDMs to perform class-conditional pixel-level image modeling, RLHF-based alignment of MDMs using text-based rewards, and finetuning protein language models to generate more diverse secondary structures and shorter proteins. We substantiate our designs via wet-lab validation, where we observe transient expression of reward-optimized protein sequences.

2025-04-22

International Conference on Learning Representations (Accept (Poster))

The Superposition of Diffusion Models Using the Itô Density Estimator

Marta Skreta

Lazar Atanackovic

Avishek Joey Bose

Kirill Neklyudov

The Cambrian explosion of easily accessible pre-trained diffusion models suggests a demand for methods that combine multiple different pre-t… (voir plus)rained diffusion models without incurring the significant computational burden of re-training a larger combined model. In this paper, we cast the problem of combining multiple pre-trained diffusion models at the generation stage under a novel proposed framework termed superposition. Theoretically, we derive superposition from rigorous first principles stemming from the celebrated continuity equation and design two novel algorithms tailor-made for combining diffusion models in SuperDiff. SuperDiff leverages a new scalable Itô density estimator for the log likelihood of the diffusion SDE which incurs no additional overhead compared to the well-known Hutchinson's estimator needed for divergence calculations. We demonstrate that SuperDiff is scalable to large pre-trained diffusion models as superposition is performed solely through composition during inference, and also enjoys painless implementation as it combines different pre-trained vector fields through an automated re-weighting scheme. Notably, we show that SuperDiff is efficient during inference time, and mimics traditional composition operators such as the logical OR and the logical AND. We empirically demonstrate the utility of using SuperDiff for generating more diverse images on CIFAR-10, more faithful prompt conditioned image editing using Stable Diffusion, as well as improved conditional molecule generation and unconditional de novo structure design of proteins. https://github.com/necludov/super-diffusion

2025-04-22

ICLR (Accept (Spotlight))

Meta Flow Matching: Integrating Vector Fields on the Wasserstein Manifold

Lazar Atanackovic

Xi Zhang

Brandon Amos

Mathieu Blanchette

Leo J. Lee

Yoshua Bengio

Kirill Neklyudov

Numerous biological and physical processes can be modeled as systems of interacting entities evolving continuously over time, e.g. the dynam… (voir plus)ics of communicating cells or physical particles. Learning the dynamics of such systems is essential for predicting the temporal evolution of populations across novel samples and unseen environments. Flow-based models allow for learning these dynamics at the population level - they model the evolution of the entire distribution of samples. However, current flow-based models are limited to a single initial population and a set of predefined conditions which describe different dynamics. We argue that multiple processes in natural sciences have to be represented as vector fields on the Wasserstein manifold of probability densities. That is, the change of the population at any moment in time depends on the population itself due to the interactions between samples. In particular, this is crucial for personalized medicine where the development of diseases and their respective treatment response depend on the microenvironment of cells specific to each patient. We propose Meta Flow Matching (MFM), a practical approach to integrate along these vector fields on the Wasserstein manifold by amortizing the flow model over the initial populations. Namely, we embed the population of samples using a Graph Neural Network (GNN) and use these embeddings to train a Flow Matching model. This gives MFM the ability to generalize over the initial distributions, unlike previously proposed methods. We demonstrate the ability of MFM to improve the prediction of individual treatment responses on a large-scale multi-patient single-cell drug screen dataset.

2025-01-21

International Conference on Learning Representations (poster)

Trajectory Flow Matching with Applications to Clinical Time Series Modeling

Xi Zhang

Yuan Pu

Yuki Kawamura

Andrew Loza

Yoshua Bengio

Dennis L. Shung

2024-10-27

ArXiv (prépublication)

A Computational Framework for Solving Wasserstein Lagrangian Flows

Kirill Neklyudov

Rob Brekelmans

Lazar Atanackovic

Qiang Liu

Alireza Makhzani

The dynamical formulation of the optimal transport can be extended through various choices of the underlying geometry (kinetic energy), and … (voir plus)the regularization of density paths (potential energy). These combinations yield different variational problems (Lagrangians), encompassing many variations of the optimal transport problem such as the Schrödinger bridge, unbalanced optimal transport, and optimal transport with physical constraints, among others. In general, the optimal density path is unknown, and solving these variational problems can be computationally challenging. We propose a novel deep learning based framework approaching all of these problems from a unified perspective. Leveraging the dual formulation of the Lagrangians, our method does not require simulating or backpropagating through the trajectories of the learned dynamics, and does not need access to optimal couplings. We showcase the versatility of the proposed framework by outperforming previous approaches for the single-cell trajectory inference, where incorporating prior knowledge into the dynamics is crucial for correct predictions.

2024-07-07

Proceedings of the 41st International Conference on Machine Learning (publié)

proceedings.mlr.press

ImageFlowNet: Forecasting Multiscale Image-Level Trajectories of Disease Progression with Irregularly-Sampled Longitudinal Medical Images

Chen Liu

Ke Xu

Liangbo L. Shen

Jay Stewart

Jay C. Wang

Lucian V. Del Priore

Smita Krishnaswamy

Advances in medical imaging technologies have enabled the collection of longitudinal images, which involve repeated scanning of the same pat… (voir plus)ients over time, to monitor disease progression. However, predictive modeling of such data remains challenging due to high dimensionality, irregular sampling, and data sparsity. To address these issues, we propose ImageFlowNet, a novel model designed to forecast disease trajectories from initial images while preserving spatial details. ImageFlowNet first learns multiscale joint representation spaces across patients and time points, then optimizes deterministic or stochastic flow fields within these spaces using a position-parameterized neural ODE/SDE framework. The model leverages a UNet architecture to create robust multiscale representations and mitigates data scarcity by combining knowledge from all patients. We provide theoretical insights that support our formulation of ODEs, and motivate our regularizations involving high-level visual features, latent space organization, and trajectory smoothness. We validate ImageFlowNet on three longitudinal medical image datasets depicting progression in geographic atrophy, multiple sclerosis, and glioblastoma, demonstrating its ability to effectively forecast disease progression and outperform existing methods. Our contributions include the development of ImageFlowNet, its theoretical underpinnings, and empirical validation on real-world datasets. The official implementation is available at https://github.com/KrishnaswamyLab/ImageFlowNet.

2024-06-19

ArXiv (prépublication)