Controllable Diffusion-Based Generation for Multi-Channel Biological Data

Abstract

Biological profiling technologies, such as imaging mass cytometry (IMC) and spatial transcriptomics (ST), generate multi-channel data with strong spatial alignment and complex inter-channel relationships. Modeling such data requires generative frameworks that jointly model spatial structure and inter-channel dependencies and generalize across arbitrary subsets of observed and missing channels. Existing generative models typically assume low-dimensional inputs (e.g., RGB images) and rely on simple conditioning mechanisms that disrupt spatial correspondence and overlook inter-channel dependencies. This work proposes a unified multi-channel diffusion (MCD) framework for controllable generation of structured biological data with complex inter-channel relationships. Our model introduces two key innovations: (1) a hierarchical feature injection mechanism that enables multi-resolution conditioning on spatially aligned observed channels, and (2) two complementary channel attention modules to capture inter-channel relationships and recalibrate latent features. To support flexible conditioning and generalization to arbitrary sets of observed channels, we train the model using a random channel masking strategy, enabling it to reconstruct missing channels given any combination of observed channels as the spatial condition. We demonstrate state-of-the-art performance across both spatial and non-spatial biological data generation tasks, including imputation in spatial proteomics and clinical imaging, as well as gene-to-protein translation in single-cell datasets, and show strong generalizability to unseen conditional configurations.