Alessandro Palma

Jan P. Engelmann, Alessandro Palma, Jakub M. Tomczak et al.

Predicting patient features from single-cell data can help identify cellular states implicated in health and disease. Linear models and average cell type expressions are typically favored for this task for their efficiency and robustness, but they overlook the rich cell heterogeneity inherent in single-cell data. To address this gap, we introduce MixMIL, a framework integrating Generalized Linear Mixed Models (GLMM) and Multiple Instance Learning (MIL), upholding the advantages of linear models while modeling cell state heterogeneity. By leveraging predefined cell embeddings, MixMIL enhances computational efficiency and aligns with recent advancements in single-cell representation learning. Our empirical results reveal that MixMIL outperforms existing MIL models in single-cell datasets, uncovering new associations and elucidating biological mechanisms across different domains.

Alessandro Palma, Till Richter, Hanyi Zhang et al.

Generative modeling of single-cell RNA-seq data is crucial for tasks like trajectory inference, batch effect removal, and simulation of realistic 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.

Kristiyan Sakalyan, Alessandro Palma, Filippo Guerranti et al.

Understanding the evolution of cellular microenvironments in spatiotemporal data is essential for deciphering tissue development and disease progression. While experimental techniques like spatial transcriptomics now enable high-resolution mapping of tissue organization across space and time, current methods that model cellular evolution operate at the single-cell level, overlooking the coordinated development of cellular states in a tissue. We introduce NicheFlow, a flow-based generative model that infers the temporal trajectory of cellular microenvironments across sequential spatial slides. By representing local cell neighborhoods as point clouds, NicheFlow jointly models the evolution of cell states and spatial coordinates using optimal transport and Variational Flow Matching. Our approach successfully recovers both global spatial architecture and local microenvironment composition across diverse spatiotemporal datasets, from embryonic to brain development.

Alessandro Palma, Sergei Rybakov, Leon Hetzel et al.

Latent space interpolations are a powerful tool for navigating deep generative models in applied settings. An example is single-cell RNA sequencing, where existing methods model cellular state transitions as latent space interpolations with variational autoencoders, often assuming linear shifts and Euclidean geometry. However, unless explicitly enforced, linear interpolations in the latent space may not correspond to geodesic paths on the data manifold, limiting methods that assume Euclidean geometry in the data representations. We introduce FlatVI, a novel training framework that regularises the latent manifold of discrete-likelihood variational autoencoders towards Euclidean geometry, specifically tailored for modelling single-cell count data. By encouraging straight lines in the latent space to approximate geodesic interpolations on the decoded single-cell manifold, FlatVI enhances compatibility with downstream approaches that assume Euclidean latent geometry. Experiments on synthetic data support the theoretical soundness of our approach, while applications to time-resolved single-cell RNA sequencing data demonstrate improved trajectory reconstruction and manifold interpolation.