# DRIFT: Disentangled Responsive-Invariant Flow Transport for Single-Cell Perturbation Prediction

arXiv: https://arxiv.org/abs/2609.35106 · HTML: https://mlsanity.com/paper/2609.35106/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 25 of its 71 references that are in the map.
- First posted on arXiv 28 Sep 2026.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 25 of 25)

- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [Sinkhorn Distances: Lightspeed Computation of Optimal Transportation Distances](https://mlsanity.com/paper/1306.0895/) (2013)
- [Challenging Common Assumptions in the Unsupervised Learning of Disentangled Representations](https://mlsanity.com/paper/1811.12359/) (2018)
- [Improving and generalizing flow-based generative models with minibatch optimal transport](https://mlsanity.com/paper/2302.00482/) (2023)
- [MINE: Mutual Information Neural Estimation](https://mlsanity.com/paper/1801.04062/) (2018)
- [Variational Autoencoders and Nonlinear ICA: A Unifying Framework](https://mlsanity.com/paper/1907.04809/) (2019)
- [Self-Supervised Learning with Data Augmentations Provably Isolates Content from Style](https://mlsanity.com/paper/2106.04619/) (2021)
- [Towards a Definition of Disentangled Representations](https://mlsanity.com/paper/1812.02230/) (2018)
- [Unsupervised Feature Extraction by Time-Contrastive Learning and Nonlinear ICA](https://mlsanity.com/paper/1605.06336/) (2016)
- [CLUB: A Contrastive Log-ratio Upper Bound of Mutual Information](https://mlsanity.com/paper/2006.12013/) (2020)
- [Disentanglement via Mechanism Sparsity Regularization: A New Principle for Nonlinear ICA](https://mlsanity.com/paper/2107.10098/) (2021)
- [Invariant Representations without Adversarial Training](https://mlsanity.com/paper/1805.09458/) (2018)
- [ICE-BeeM: Identifiable Conditional Energy-Based Deep Models Based on Nonlinear ICA](https://mlsanity.com/paper/2002.11537/) (2020)
- [Disentanglement by Nonlinear ICA with General Incompressible-flow Networks (GIN)](https://mlsanity.com/paper/2001.04872/) (2020)
- [Identifiability Guarantees for Causal Disentanglement from Soft Interventions](https://mlsanity.com/paper/2307.06250/) (2023)
- [Self-supervised learning of Split Invariant Equivariant representations](https://mlsanity.com/paper/2302.10283/) (2023)
- [Unsupervised Learning of Group Invariant and Equivariant Representations](https://mlsanity.com/paper/2202.07559/) (2022)
- [Modelling Cellular Perturbations with the Sparse Additive Mechanism Shift Variational Autoencoder](https://mlsanity.com/paper/2311.02794/) (2023)
- [Learning Causal Representations of Single Cells via Sparse Mechanism Shift Modeling](https://mlsanity.com/paper/2211.03553/) (2022)
- [GENOT: Entropic (Gromov) Wasserstein Flow Matching with Applications to Single-Cell Genomics](https://mlsanity.com/paper/2310.09254/) (2023)
- [Dynamic Conditional Optimal Transport through Simulation-Free Flows](https://mlsanity.com/paper/2404.04240/) (2024)
- [Predicting Cellular Responses with Variational Causal Inference and Refined Relational Information](https://mlsanity.com/paper/2210.00116/) (2022)
- [scDFM: Distributional Flow Matching Model for Robust Single-Cell Perturbation Prediction](https://mlsanity.com/paper/2602.07103/) (2026)
- [What Makes a Representation Good for Single-Cell Perturbation Prediction?](https://mlsanity.com/paper/2605.19343/) (2026)
- [Beyond Independent Genes: Learning Module-Inductive Representations for Single-Cell Gene Perturbation Prediction](https://mlsanity.com/paper/2602.04901/) (2026)

## Abstract (arXiv)

Predicting cellular responses to perturbations is a central problem in cellular biology, with broad applications in systems biology and drug discovery. This task is challenging because cellular responses can be complex and cell-state dependent, intrinsic cell-to-cell variability can be confounded with perturbation effects, and destructive single-cell RNA sequencing precludes paired measurements of the same cell before and after treatment. Flow matching transports control cells to perturbed states flexibly, but acting on the full cell state can confound perturbation effects with pre-existing cell-to-cell variability. Disentangled approaches separate responsive from invariant components, but model perturbations through prescribed mechanisms, such as latent shifts or graph edits, limiting their flexibility. We address both limitations in a unified framework. A variational encoder disentangles each cell into an invariant block, capturing state unaffected by the perturbation, and a responsive block, capturing state it changes, through conditional priors and an information-theoretic invariance constraint. Conditional flow matching transports only the responsive block, conditioned on the perturbation and invariant state, yielding a flexible, data-driven model of perturbation effects without confounding pre-existing variability. Across several benchmarks, our method outperforms the strongest published method in settings involving combinatorial and unseen perturbation prediction.