arXiv subjects

Fabian J. Theis

Publications and source records attributed to Fabian J. Theis.

At least 19 recordsLinked to original sources

arXiv2026

Same Encoder, Different Winner: A Paired-View Framework for Cell Painting Encoder Evaluation

Vision encoders for Cell Painting are typically ranked by a single evaluation, commonly replicate mean average precision (mAP). We introduce CP-BG-Bench, a paired-view evaluation framework that holds the central cell fixed across four matched views (raw crop C, segmented S, and density-augmented variants CD and SD), ablating or augmenting surrounding pixels as a controlled intervention. Instantiating the framework on three datasets (JUMP-CP, RxRx1, RxRx3-core) and three encoders (DINOv3 ViT-B/16, OpenPhenom, SubCell) under four community-standard protocols (replicate mAP, scIB batch integration, CellProfiler feature prediction, cross-batch perturbation recall), we find that the four protocols rank the same encoders systematically differently, with disagreements decomposing along three axes: cell versus background, morphology versus context, and within-study versus across-batch. The largest effect: on RxRx3-core, SubCell with segmented inputs retains 94% of crop replicate mAP but only 32% of crop R@10, so the within-study signal preserved under segmentation is largely non-transferable; density augmentation recovers 84% of the within-study C-to-S gap but only 8% of the cross-batch gap. Segmented views predict CellProfiler features as well as or better than crops on two of three datasets, inverting the replicate-mAP ranking, and the C-to-S gap varies by an order of magnitude across datasets while remaining similar across encoders, indicating that background-driven gain is set by experimental design rather than by the encoder. Single-metric ranking of Cell Painting encoders is therefore sensitive to the protocol used, and protocol disagreements are interpretable as projections onto the three axes the paired-view design exposes. We will release the paired-view datasets, reconstruction pipelines, 36 trained checkpoints, aggregated embeddings, and the full evaluation suite.

cs.CV↗

arXiv2026

Flow-Based Density Ratio Estimation for Intractable Distributions with Applications in Genomics

Estimating density ratios between pairs of intractable data distributions is a core problem in probabilistic modeling, enabling principled comparisons of sample likelihoods under different data-generating processes across conditions. While exact-likelihood models such as normalizing flows offer a promising approach to density ratio estimation, naive evaluations are computationally expensive and prone to discretization errors because they require simulating each distribution's likelihood independently. In this work, we leverage condition-aware flow matching to derive a single dynamical formulation for tracking density ratios along generative trajectories. We demonstrate competitive performance on simulated benchmarks for closed-form ratio estimation, and show that our method supports versatile tasks in single-cell genomics data analysis, where likelihood-based comparisons of cellular states across experimental conditions enable treatment effect estimation and batch correction evaluation.

cs.LG↗

arXiv2026

Interpretable Neural ODEs for Gene Regulatory Network Discovery under Perturbations

Modern high-throughput biological datasets containing thousands of perturbations enable large-scale discovery of causal graphs that represent regulatory interactions between genes. Differentiable causal graphical models and regression-based methods have been developed to infer gene regulatory networks (GRNs) from interventional datasets. However, existing approaches fail to capture the non-linear dynamics of biological processes such as cellular differentiation. To address this limitation, we propose PerturbODE, a novel framework that employs interpretable neural ordinary differential equations (neural ODEs) to model cell state trajectories under perturbations and derive the underlying causal GRN from the neural ODE parameters, enabling downstream simulation of unseen genetic interventions. The GRN is encoded via a single-hidden-layer feedforward network, implicitly grouping genes into interpretable co-regulated modules. We demonstrate PerturbODE's efficacy in GRN inference and extension to perturbation response prediction across both simulated and real overexpression datasets.

cs.LG↗

arXiv2026

Chem-PerturBridge: a harmonized compendium of small molecule perturbation transcriptomic effects

Large perturbation models require training data encompassing chemical, cellular, and assay diversity. Current transcriptomic resources for small-molecule modeling, however, are fragmented across technologies, metadata conventions, controls, doses, and preprocessing pipelines. We introduce Chem-PerturBridge, a harmonized multi-dataset resource comprising over 37k compounds, 136 cellular contexts, and 1.25M transcriptomic samples across eight assay types, with standardized identifiers, metadata, and replicate-aware condition-level effects. We use the resource to evaluate matched-condition agreement across datasets and replicate agreement within datasets. Matched same-compound conditions generally show weak agreement in fine-grained logFC rankings and magnitudes across most dataset pairs, often falling below same-context different-compound baselines. In contrast, logFC direction agreement is substantially more stable and usually exceeds these baselines. We further evaluate Chem-PerturBridge as a pretraining resource for compound representation learning. Under a compound-held-out OP3 evaluation split, embeddings pretrained on Chem-PerturBridge improve over L1000-only embeddings, Morgan fingerprints, and the descriptor-free OP3 baseline across metrics. An extensive molecule-holdout evaluation across 11 datasets further shows that models trained on Chem-PerturBridge outperform or match those that are not. Chem-PerturBridge therefore supports both diagnostic evaluation of cross-dataset signature agreement and model-oriented reuse of heterogeneous perturbation transcriptomic data.

cs.LG↗

arXiv2026

annbatch unlocks terabyte-scale training of biological data in anndata

The scale of biological datasets now routinely exceeds system memory, making data access rather than model computation the primary bottleneck in training machine-learning models. This bottleneck is particularly acute in biology, where widely used community data formats must support heterogeneous metadata, sparse and dense assays, and downstream analysis within established computational ecosystems. Here we present annbatch, a mini-batch loader native to anndata that enables out-of-core training directly on disk-backed datasets. Across single-cell transcriptomics, microscopy and whole-genome sequencing benchmarks, annbatch increases loading throughput by up to an order of magnitude and shortens training from days to hours, while remaining fully compatible with the scverse ecosystem. Annbatch establishes a practical data-loading infrastructure for scalable biological AI, allowing increasingly large and diverse datasets to be used without abandoning standard biological data formats. Github: https://github.com/scverse/annbatch

cs.LG↗

arXiv2026

A learning health system in Neurorehabilitation as a foundation for multimodal patient representation

Neurological disorders represent a growing global health burden requiring long-term, interdisciplinary rehabilitation. Computational neurorehabilitation (compNR) - the use of data-driven and model-based approaches to personalize treatment - offers new opportunities for precision rehabilitation. However, its clinical deployment is limited by fragmented data systems, poor interoperability, and low clinician engagement in model development. We embed the learning health system (LHS) framework in Neurorehabilitation through integration of multimodal data collection, model computation, and clinical visualization that enables clinician-ML collaboration in everyday neurorehabilitation practice. The system facilitates structured digital data capture, secure computational processing, and interoperable visualization of patient trajectories. Through a real-world deployment in stroke rehabilitation, we demonstrate how such an infrastructure bridges the gap between research models and clinical use, showcasing one approach to a translational pathway for compNR.

cs.HC↗

arXiv2026

GPU-accelerated single-cell analysis at scale with rapids-singlecell

Single-cell sequencing technologies reveal cellular heterogeneity at high resolution, advancing our understanding of biological complexity. As datasets start to scale to tens of millions of cells, computational workflows face substantial bottlenecks, with CPU-based analytical pipelines requiring hours or days for routine processing steps like filtering, normalization, and clustering. These scalability limitations fundamentally restrict common interactive data exploration and iterative hypothesis testing. Here we introduce rapids-singlecell, a GPU-accelerated framework that integrates natively with the scverse ecosystem and operates directly on the AnnData data structure, which delivers orders-of-magnitude speedups for single-cell workflows. Built on CuPy arrays and the NVIDIA CUDA-X Data Science (RAPIDS) ecosystem, rapids-singlecell provides near drop-in GPU replacements for core scanpy-based analysis steps. Across standard single-cell workflows such as preprocessing, dimensionality reduction, neighborhood graph construction, clustering, and batch correction, rapids-singlecell achieves speedups of up to several hundred-fold compared to optimized CPU baselines. This reduces analysis time from hours to minutes on standard hardware, while maintaining consistent biological interpretations. These performance improvements make it possible to analyze large data sets in close to real time, without the need for data splitting. Together with real-time parameter tuning and iterative workflows, rapids-singlecell makes interactive large-scale single-cell analysis possible.

q-bio.GN↗

arXiv2025

Modeling Microenvironment Trajectories on Spatial Transcriptomics with NicheFlow

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.

cs.LG↗

arXiv2025

Enforcing Latent Euclidean Geometry in Single-Cell VAEs for Manifold Interpolation

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.

cs.LG↗

arXiv2025

A Foundation Model for Spatial Proteomics

Foundation models have begun to transform image analysis by acting as pretrained generalist backbones that can be adapted to many tasks even when post-training data are limited, yet their impact on spatial proteomics, imaging that maps proteins at single-cell resolution, remains limited. Here, we introduce KRONOS, a foundation model built for spatial proteomics. KRONOS was trained in a self-supervised manner on over 47 million image patches covering 175 protein markers, 16 tissue types, and 8 fluorescence-based imaging platforms. We introduce key architectural adaptations to address the high-dimensional, multi-channel, and heterogeneous nature of multiplex imaging. We demonstrate that KRONOS learns biologically meaningful representations across multiple scales, ranging from cellular and microenvironment to tissue levels, enabling it to address diverse downstream tasks, including cell phenotyping, region classification, and patient stratification. Evaluated across 11 independent cohorts, KRONOS achieves state-of-the-art performance across cell phenotyping, treatment response prediction, and retrieval tasks, and is highly data-efficient. KRONOS also introduces the paradigm of segmentation-free patch-level processing for efficient and scalable spatial proteomics analysis, allowing cross-institutional comparisons, and as an image reverse search engine for spatial patterns. Together, these results position KRONOS as a flexible and scalable tool for spatial proteomics. The model is publicly accessible at https://github.com/mahmoodlab/KRONOS.

cs.CV↗

arXiv2025

A scalable gene network model of regulatory dynamics in single cells

Single-cell data provide high-dimensional measurements of the transcriptional states of cells, but extracting insights into the regulatory functions of genes, particularly identifying transcriptional mechanisms affected by biological perturbations, remains a challenge. Many perturbations induce compensatory cellular responses, making it difficult to distinguish direct from indirect effects on gene regulation. Modeling how gene regulatory functions shape the temporal dynamics of these responses is key to improving our understanding of biological perturbations. Dynamical models based on differential equations offer a principled way to capture transcriptional dynamics, but their application to single-cell data has been hindered by computational constraints, stochasticity, sparsity, and noise. Existing methods either rely on low-dimensional representations or make strong simplifying assumptions, limiting their ability to model transcriptional dynamics at scale. We introduce a Functional and Learnable model of Cell dynamicS, FLeCS, that incorporates gene network structure into coupled differential equations to model gene regulatory functions. Given (pseudo)time-series single-cell data, FLeCS accurately infers cell dynamics at scale, provides improved functional insights into transcriptional mechanisms perturbed by gene knockouts, both in myeloid differentiation and K562 Perturb-seq experiments, and simulates single-cell trajectories of A549 cells following small-molecule perturbations.

q-bio.MN↗

arXiv2025

Embedding computational neurorehabilitation in clinical practice using a modular intelligent health system

A significant and rising proportion of the global population suffer from non-communicable diseases, such as neurological disorders. Neurorehabilitation aims to restore function and independence of neurological patients through providing interdisciplinary therapeutic interventions. Computational neurorehabilitation, an automated simulation approach to dynamically optimize treatment effectivity, is a promising tool to ensure that each patient has the best therapy for their current status. However, computational neurorehabilitation relies on integrated data flows between clinical assessments, predictive models, and healthcare professionals. Current neurorehabilitation practice is limited by low levels of digitalization and low data interoperability. We here propose and demonstrate an embedded intelligent health system that enables detailed digital data collection in a modular fashion, real-time data flows between patients, models, and clinicians, clinical integration, and multi-context capacities, as required for computational neurorehabilitation approaches. We give an outlook on how modern exploratory data analysis tools can be integrated to facilitate model development and knowledge inference from secondary use of observational data this system collects. With this blueprint, we contribute towards the development of integrated computational neurorehabilitation workflows for clinical practice.

cs.SE↗

arXiv2025

Beyond Predictions in Neural ODEs: Identification and Interventions

Spurred by tremendous success in pattern matching and prediction tasks, researchers increasingly resort to machine learning to aid original scientific discovery. Given large amounts of observational data about a system, can we uncover the rules that govern its evolution? Solving this task holds the great promise of fully understanding the causal interactions and being able to make reliable predictions about the system's behavior under interventions. We take a step towards answering this question for time-series data generated from systems of ordinary differential equations (ODEs). While the governing ODEs might not be identifiable from data alone, we show that combining simple regularization schemes with flexible neural ODEs can robustly recover the dynamics and causal structures from time-series data. Our results on a variety of (non)-linear first and second order systems as well as real data validate our method. We conclude by showing that we can also make accurate predictions under interventions on variables or the system itself.

cs.LG↗

arXiv2024

Mixed Models with Multiple Instance Learning

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.

cs.LG↗

arXiv2024

B-Cos Aligned Transformers Learn Human-Interpretable Features

Vision Transformers (ViTs) and Swin Transformers (Swin) are currently state-of-the-art in computational pathology. However, domain experts are still reluctant to use these models due to their lack of interpretability. This is not surprising, as critical decisions need to be transparent and understandable. The most common approach to understanding transformers is to visualize their attention. However, attention maps of ViTs are often fragmented, leading to unsatisfactory explanations. Here, we introduce a novel architecture called the B-cos Vision Transformer (BvT) that is designed to be more interpretable. It replaces all linear transformations with the B-cos transform to promote weight-input alignment. In a blinded study, medical experts clearly ranked BvTs above ViTs, suggesting that our network is better at capturing biomedically relevant structures. This is also true for the B-cos Swin Transformer (Bwin). Compared to the Swin Transformer, it even improves the F1-score by up to 4.7% on two public datasets.

cs.CV↗

arXiv2024

Training Transitive and Commutative Multimodal Transformers with LoReTTa

Training multimodal foundation models is challenging due to the limited availability of multimodal datasets. While many public datasets pair images with text, few combine images with audio or text with audio. Even rarer are datasets that align all three modalities at once. Critical domains such as healthcare, infrastructure, or transportation are particularly affected by missing modalities. This makes it difficult to integrate all modalities into a large pre-trained neural network that can be used out-of-the-box or fine-tuned for different downstream tasks. We introduce LoReTTa (Linking mOdalities with a tRansitive and commutativE pre-Training sTrAtegy) to address this understudied problem. Our self-supervised framework unifies causal modeling and masked modeling with the rules of commutativity and transitivity. This allows us to transition within and between modalities. As a result, our pre-trained models are better at exploring the true underlying joint probability distribution. Given a dataset containing only the disjoint combinations (A, B) and (B, C), LoReTTa can model the relation A <-> C with A <-> B <-> C. In particular, we show that a transformer pre-trained with LoReTTa can handle any mixture of modalities at inference time, including the never-seen pair (A, C) and the triplet (A, B, C). We extensively evaluate our approach on a synthetic, medical, and reinforcement learning dataset. Across different domains, our universal multimodal transformer consistently outperforms strong baselines such as GPT, BERT, and CLIP on tasks involving the missing modality tuple.

cs.AI↗

arXiv2023

To Transformers and Beyond: Large Language Models for the Genome

In the rapidly evolving landscape of genomics, deep learning has emerged as a useful tool for tackling complex computational challenges. This review focuses on the transformative role of Large Language Models (LLMs), which are mostly based on the transformer architecture, in genomics. Building on the foundation of traditional convolutional neural networks and recurrent neural networks, we explore both the strengths and limitations of transformers and other LLMs for genomics. Additionally, we contemplate the future of genomic modeling beyond the transformer architecture based on current trends in research. The paper aims to serve as a guide for computational biologists and computer scientists interested in LLMs for genomic data. We hope the paper can also serve as an educational introduction and discussion for biologists to a fundamental shift in how we will be analyzing genomic data in the future.

q-bio.GN↗

arXiv2023

Causal machine learning for single-cell genomics

Advances in single-cell omics allow for unprecedented insights into the transcription profiles of individual cells. When combined with large-scale perturbation screens, through which specific biological mechanisms can be targeted, these technologies allow for measuring the effect of targeted perturbations on the whole transcriptome. These advances provide an opportunity to better understand the causative role of genes in complex biological processes such as gene regulation, disease progression or cellular development. However, the high-dimensional nature of the data, coupled with the intricate complexity of biological systems renders this task nontrivial. Within the machine learning community, there has been a recent increase of interest in causality, with a focus on adapting established causal techniques and algorithms to handle high-dimensional data. In this perspective, we delineate the application of these methodologies within the realm of single-cell genomics and their challenges. We first present the model that underlies most of current causal approaches to single-cell biology and discuss and challenge the assumptions it entails from the biological point of view. We then identify open problems in the application of causal approaches to single-cell data: generalising to unseen environments, learning interpretable models, and learning causal models of dynamics. For each problem, we discuss how various research directions - including the development of computational approaches and the adaptation of experimental protocols - may offer ways forward, or on the contrary pose some difficulties. With the advent of single cell atlases and increasing perturbation data, we expect causal models to become a crucial tool for informed experimental design.

cs.LG↗