# Doloris: Dual Conditional Diffusion Implicit Bridges with Sparsity Masking Strategy for Unpaired Single-Cell Perturbation Estimation

arXiv: https://arxiv.org/abs/2506.21107 · HTML: https://mlsanity.com/paper/2506.21107/

## Key facts

- Cited by 4 papers in the map (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 10 of its 35 references that are in the map.
- First posted on arXiv 26 Jun 2025.

## 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, 10 of 10)

- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [AnimateDiff: Animate Your Personalized Text-to-Image Diffusion Models without Specific Tuning](https://mlsanity.com/paper/2307.04725/) (2023)
- [Understanding Diffusion Models: A Unified Perspective](https://mlsanity.com/paper/2208.11970/) (2022)
- [Dual Diffusion Implicit Bridges for Image-to-Image Translation](https://mlsanity.com/paper/2203.08382/) (2022)
- [Spatially Resolved Gene Expression Prediction from H&E Histology Images via Bi-modal Contrastive Learning](https://mlsanity.com/paper/2306.01859/) (2023)
- [Predicting Cellular Responses to Novel Drug Perturbations at a Single-Cell Resolution](https://mlsanity.com/paper/2204.13545/) (2022)
- [Modelling Cellular Perturbations with the Sparse Additive Mechanism Shift Variational Autoencoder](https://mlsanity.com/paper/2311.02794/) (2023)
- [Predicting Cellular Responses with Variational Causal Inference and Refined Relational Information](https://mlsanity.com/paper/2210.00116/) (2022)
- [GRAPE: Heterogeneous Graph Representation Learning for Genetic Perturbation with Coding and Non-Coding Biotype](https://mlsanity.com/paper/2505.03853/) (2025)
- [Spatially Resolved Gene Expression Prediction from Histology via Multi-view Graph Contrastive Learning with HSIC-bottleneck Regularization](https://mlsanity.com/paper/2406.12229/) (2024)

## Built on by (most cited first, 4 of 4)

- [scDFM: Distributional Flow Matching Model for Robust Single-Cell Perturbation Prediction](https://mlsanity.com/paper/2602.07103/) (2026)
- [PerturbDiff: Functional Diffusion for Single-Cell Perturbation Modeling](https://mlsanity.com/paper/2602.19685/) (2026)
- [Departures: Distributional Transport for Single-Cell Perturbation Prediction with Neural Schr"odinger Bridges](https://mlsanity.com/paper/2511.13124/) (2025)
- [PopPert: Population-level Joint-Distribution Modeling for Single-Cell Perturbation Prediction](https://mlsanity.com/paper/2609.01357/) (2026)

## Abstract (arXiv)

Estimating single-cell responses across various perturbations facilitates the identification of key genes and enhances drug screening, significantly boosting experimental efficiency. However, single-cell sequencing is a destructive process, making it impossible to capture the same cell's phenotype before and after perturbation. Consequently, data collected under perturbed and unperturbed conditions are inherently unpaired, creating a critical yet unresolved problem in single-cell perturbation modeling. Moreover, the high dimensionality and sparsity of single-cell expression make direct modeling prone to focusing on zeros and neglecting meaningful patterns. To address these problems, we propose a new paradigm for single-cell perturbation modeling. Specifically, we leverage dual diffusion models to learn the control and perturbed distributions separately, and implicitly align them through a shared Gaussian latent space, without requiring explicit cell pairing. Furthermore, we introduce a sparsity masking strategy in which the mask model learns to predict zero-expressed genes, allowing the diffusion model to focus on capturing meaningful patterns among expressed genes and thereby preserving diversity in high-dimensional sparse data. We introduce Doloris, a generative framework that defines a new paradigm for modeling unpaired, high-dimensional, and sparse single-cell perturbation data. It leverages dual conditional diffusion models for separate learning of control and perturbed distributions, complemented by a sparsity masking strategy to enhance prediction of zero-valued genes. The results on publicly available datasets show that our model effectively captures the diversity of single-cell perturbations and achieves state-of-the-art performance. To facilitate reproducibility, we include the code in the supplementary materials.