arXiv subjects

Theofanis Karaletsos

Publications and source records attributed to Theofanis Karaletsos.

At least 19 recordsLinked to original sources

arXiv2026

Calibrated Test-Time Guidance for Bayesian Inference

Test-time guidance is a widely used mechanism for steering pretrained diffusion models toward outcomes specified by a reward function. Existing approaches, however, focus on maximizing reward rather than sampling from the true Bayesian posterior, leading to miscalibrated inference. In this work, we show that common test-time guidance methods do not recover the correct posterior distribution and identify the structural approximations responsible for this failure. We then propose consistent alternative estimators that enable calibrated sampling from the Bayesian posterior. We significantly outperform previous methods on a set of Bayesian inference tasks, and set a new state-of-the-art PSNR in black hole image reconstruction.

cs.LG↗

arXiv2026

Assessing Sample Quality in Conditional Generation under Compositional Shift

Conditional generators provide a natural tool for controllable generation, including settings where the desired condition is a new composition of observed attributes or experimental factors. In many applications, especially in scientific domains, such models are attractive to explore conditions for which real samples are rare, expensive, or not yet observed. However, this creates a circularity for evaluation: standard conditional quality metrics require a reference target distribution, but in the extrapolative regime that distribution is unavailable by definition. We address this problem with a post-hoc, per-sample trust score for assessing conditional samples using only the training distribution. The score combines two estimable quantities: global realism, measuring compatibility with the real data manifold, and attribute-wise faithfulness, measuring whether a sample is closer to the requested attributes than to plausible alternatives. We show that the score can recover meaningful comparisons across extrapolated generations, under a mild coverage condition on the observed attributes. These comparisons enable effective filtering, ranking, and abstention of generations and can be used directly on off-the-shelf pretrained models. In biological imaging, selected samples preserve real morphological structure better and improve downstream predictive performance, while similar gains are observed on controlled vision benchmarks. Finally, we show how the score can be applied during generation, enabling abstention before full decoding. Code is available at https://github.com/berkerdemirel/faithful-cond-gen.

cs.LG↗

arXiv2026

Scalable Single-Cell Gene Expression Generation with Latent Diffusion Models

Computational modeling of single-cell gene expression is crucial for understanding cellular processes, but generating realistic expression profiles remains a major challenge. This difficulty arises from the count nature of gene expression data and complex latent dependencies among genes. Existing generative models often impose artificial gene orderings or rely on shallow neural network architectures. We introduce a scalable latent diffusion model for single-cell gene expression data, which we refer to as scLDM, that respects the fundamental exchangeability property of the data. Our VAE uses fixed-size latent variables leveraging a unified Multi-head Cross-Attention Block (MCAB) architecture, which serves dual roles: permutation-invariant pooling in the encoder and permutation-equivariant unpooling in the decoder. We enhance this framework by replacing the Gaussian prior with a latent diffusion model using Diffusion Transformers and linear interpolants, enabling high-quality generation with multi-conditional classifier-free guidance. We show its superior performance in a variety of experiments for both observational and perturbational single-cell data, as well as downstream tasks like cell-level classification.

stat.ML↗

arXiv2026

Toward Identifiable Sparse Autoencoders

Recently, sparse autoencoders (SAEs) have emerged as an attractive tool for interpreting and interacting with representations in practical neural networks. While it is common empirical folklore, we also show theoretically that SAEs are highly unstable: different training runs are likely to produce different concept dictionaries and sparse codes. We characterize the model properties that hinder the stability of real-world SAEs, and address each of these problems through minimal changes to the architecture and training procedure. Together, these changes yield two versions of an \textbf{i}dentifiable SAE (iSAE), a variant of the standard TopK SAE with lower reconstruction error and improved stability. We explain this improvement theoretically by connecting SAEs with traditional dictionary learning approaches, and show that the dictionaries learned in practice satisfy an approximate restricted isometry condition, rendering the corresponding sparse codes in those models near-identifiable.

cs.LG↗

arXiv2026

Position: agentic AI orchestration should be Bayes-consistent

LLMs excel at predictive tasks and complex reasoning tasks, but many high-value deployments rely on decisions under uncertainty, for example, which tool to call, which expert to consult, or how many resources to invest. While the usefulness and feasibility of Bayesian approaches remain unclear for LLM inference, this position paper argues that the control layer of an agentic AI system (that orchestrates LLMs and tools) is a clear case where Bayesian principles should shine. Bayesian decision theory provides a framework for agentic systems that can help to maintain beliefs over task-relevant latent quantities, to update these beliefs from observed agentic and human-AI interactions, and to choose actions. Making LLMs themselves explicitly Bayesian belief-updating engines remains computationally intensive and conceptually nontrivial as a general modeling target. In contrast, this paper argues that coherent decision-making requires Bayesian principles at the orchestration level of the agentic system, not necessarily the LLM agent parameters. This paper articulates practical properties for Bayesian control that fit modern agentic AI systems and human-AI collaboration, and provides concrete examples and design patterns to illustrate how calibrated beliefs and utility-aware policies can improve agentic AI orchestration.

cs.AI↗

arXiv2026

Statistical and structural identifiability in representation learning

Representation learning models exhibit a surprising stability in their internal representations. Whereas most prior work treats this stability as a single property, we formalize it as two distinct concepts: statistical identifiability (consistency of representations across runs) and structural identifiability (alignment of representations with some unobserved ground truth). Recognizing that perfect pointwise identifiability is generally unrealistic for modern representation learning models, we propose new model-agnostic definitions of statistical and structural near-identifiability of representations up to some error tolerance $ε$. Leveraging these definitions, we prove a statistical $ε$-near-identifiability result for the representations of models with nonlinear decoders, generalizing existing identifiability theory beyond last-layer representations in e.g. generative pre-trained transformers (GPTs) to near-identifiability of the intermediate representations of a broad class of models including (masked) autoencoders (MAEs) and supervised learners. Although these weaker assumptions confer weaker identifiability, we show that independent components analysis (ICA) can resolve much of the remaining linear ambiguity for this class of models, and validate and measure our near-identifiability claims empirically. With additional assumptions on the data-generating process, statistical identifiability extends to structural identifiability, yielding a simple and practical recipe for disentanglement: ICA post-processing of latent representations. On synthetic benchmarks, this approach achieves state-of-the-art disentanglement using a vanilla autoencoder. With a foundation model-scale MAE for cell microscopy, it disentangles biological variation from technical batch effects, substantially improving downstream generalization.

cs.LG↗

arXiv2026

Learning Explicit Single-Cell Dynamics Using ODE Representations

Modeling the dynamics of cellular differentiation is fundamental to advancing the understanding and treatment of diseases associated with this process, such as cancer. With the rapid growth of single-cell datasets, this has also become a particularly promising and active domain for machine learning. Current state-of-the-art models, however, rely on computationally expensive optimal transport preprocessing and multi-stage training, while also not discovering explicit gene interactions. To address these challenges we propose Cell-Mechanistic Neural Networks (Cell-MNN), an encoder-decoder architecture whose latent representation is a locally linearized ODE governing the dynamics of cellular evolution from stem to tissue cells. Cell-MNN is fully end-to-end (besides a standard PCA pre-processing) and its ODE representation explicitly learns biologically consistent and interpretable gene interactions. Empirically, we show that Cell-MNN achieves competitive performance on single-cell benchmarks, surpasses state-of-the-art baselines in scaling to larger datasets and joint training across multiple datasets, while also learning interpretable gene interactions that we validate against the TRRUST database of gene interactions.

cs.LG↗

arXiv2026

Parallel Token Prediction for Language Models

Autoregressive decoding in language models is inherently slow, generating only one token per forward pass. We propose Parallel Token Prediction (PTP), a general-purpose framework for predicting multiple tokens in a single model call. PTP moves the source of randomness from post-hoc sampling to random input variables, making future tokens deterministic functions of those inputs and thus jointly predictable in a single forward pass. We prove that a single PTP call can represent arbitrary dependencies between tokens. PTP is trained by distilling an existing model or through inverse autoregressive training without a teacher. Experimentally, PTP achieves a 2.4x speedup on a diverse-task speculative decoding benchmark. We provide code and checkpoints at https://github.com/mandt-lab/ptp.

cs.CL↗

arXiv2025

How Well Do LLMs Understand Drug Mechanisms? A Knowledge + Reasoning Evaluation Dataset

Two scientific fields showing increasing interest in pre-trained large language models (LLMs) are drug development / repurposing, and personalized medicine. For both, LLMs have to demonstrate factual knowledge as well as a deep understanding of drug mechanisms, so they can recall and reason about relevant knowledge in novel situations. Drug mechanisms of action are described as a series of interactions between biomedical entities, which interlink into one or more chains directed from the drug to the targeted disease. Composing the effects of the interactions in a candidate chain leads to an inference about whether the drug might be useful or not for that disease. We introduce a dataset that evaluates LLMs on both factual knowledge of known mechanisms, and their ability to reason about them under novel situations, presented as counterfactuals that the models are unlikely to have seen during training. Using this dataset, we show that o4-mini outperforms the 4o, o3, and o3-mini models from OpenAI, and the recent small Qwen3-4B-thinking model closely matches o4-mini's performance, even outperforming it in some cases. We demonstrate that the open world setting for reasoning tasks, which requires the model to recall relevant knowledge, is more challenging than the closed world setting where the needed factual knowledge is provided. We also show that counterfactuals affecting internal links in the reasoning chain present a much harder task than those affecting a link from the drug mentioned in the prompt.

cs.CL↗

arXiv2025

A Roadmap for Predictive Human Immunology

For over a century, immunology has masterfully discovered and dissected the components of our immune system, yet its collective behavior remains fundamentally unpredictable. In this perspective, we argue that building on the learnings of reductionist biology and systems immunology, the field is poised for a third revolution. This new era will be driven by the convergence of purpose-built, large-scale causal experiments and predictive, generalizable AI models. Here, we propose the Predictive Immunology Loop as the unifying engine to harness this convergence. This closed loop iteratively uses AI to design maximally informative experiments and, in turn, leverages the resulting data to improve dynamic, in silico models of the human immune system across biological scales, culminating in a Virtual Immune System. This engine provides a natural roadmap for addressing immunology's grand challenges, from decoding molecular recognition to engineering tissue ecosystems. It also offers a framework to transform immunology from a descriptive discipline into one capable of forecasting and, ultimately, engineering human health.

q-bio.OT↗

arXiv2025

MorphGen: Controllable and Morphologically Plausible Generative Cell-Imaging

Simulating in silico cellular responses to interventions is a promising direction to accelerate high-content image-based assays, critical for advancing drug discovery and gene editing. To support this, we introduce MorphGen, a state-of-the-art diffusion-based generative model for fluorescent microscopy that enables controllable generation across multiple cell types and perturbations. To capture biologically meaningful patterns consistent with known cellular morphologies, MorphGen is trained with an alignment loss to match its representations to the phenotypic embeddings of OpenPhenom, a state-of-the-art biological foundation model. Unlike prior approaches that compress multichannel stains into RGB images -- thus sacrificing organelle-specific detail -- MorphGen generates the complete set of fluorescent channels jointly, preserving per-organelle structures and enabling a fine-grained morphological analysis that is essential for biological interpretation. We demonstrate biological consistency with real images via CellProfiler features, and MorphGen attains an FID score over 35% lower than the prior state-of-the-art MorphoDiff, which only generates RGB images for a single cell type. Code is available at https://github.com/czi-ai/MorphGen.

q-bio.QM↗

arXiv2025

A path towards AI-scale, interoperable biological data

Biology is at the precipice of a new era where AI accelerates and amplifies the ability to study how cells operate, organize, and work as systems, revealing why disease happens and how to correct it. Organizations globally are prioritizing AI to accelerate basic research, drug discovery, personalized medicine, and synthetic biology. However, despite these opportunities, scientific data have proven a bottleneck, and progress has been slow and fragmented. Unless the scientific community takes a technology-led, community-focused approach to scaling and harnessing data, we will fail to capture this opportunity to drive new insights and biological discovery. The data bottleneck presents a unique paradox. It is increasingly simple to generate huge data volumes, thanks to expanding imaging datasets and plummeting sequencing costs, but scientists lack standards and tooling for large biological datasets, preventing integration into a multimodal foundational dataset that unlocks generalizable models of cellular and tissue function. This contradiction highlights two interrelated problems: abundant data that's difficult to manage, and a lack of data resources with necessary quality and utility to realize AI's potential in biology. Science must forge a collective approach enabling distributed contributions to combine into cohesive, powerful datasets transcending individual purposes. Here, we present a technological and data generation roadmap for scaling scientific impact. We outline AI's opportunity, mechanisms to scale data generation, the need for multi-modal measurements, and means to pool resources, standardize approaches, and collectively build the foundation enabling AI's full potential in biological discovery.

q-bio.OT↗

arXiv2025

Variational Control for Guidance in Diffusion Models

Diffusion models exhibit excellent sample quality, but existing guidance methods often require additional model training or are limited to specific tasks. We revisit guidance in diffusion models from the perspective of variational inference and control, introducing Diffusion Trajectory Matching (DTM) that enables guiding pretrained diffusion trajectories to satisfy a terminal cost. DTM unifies a broad class of guidance methods and enables novel instantiations. We introduce a new method within this framework that achieves state-of-the-art results on several linear, non-linear, and blind inverse problems without requiring additional model training or specificity to pixel or latent space diffusion models. Our code will be available at https://github.com/czi-ai/oc-guidance

cs.LG↗

arXiv2024

How to Build the Virtual Cell with Artificial Intelligence: Priorities and Opportunities

The cell is arguably the most fundamental unit of life and is central to understanding biology. Accurate modeling of cells is important for this understanding as well as for determining the root causes of disease. Recent advances in artificial intelligence (AI), combined with the ability to generate large-scale experimental data, present novel opportunities to model cells. Here we propose a vision of leveraging advances in AI to construct virtual cells, high-fidelity simulations of cells and cellular systems under different conditions that are directly learned from biological data across measurements and scales. We discuss desired capabilities of such AI Virtual Cells, including generating universal representations of biological entities across scales, and facilitating interpretable in silico experiments to predict and understand their behavior using virtual instruments. We further address the challenges, opportunities and requirements to realize this vision including data needs, evaluation strategies, and community standards and engagement to ensure biological accuracy and broad utility. We envision a future where AI Virtual Cells help identify new drug targets, predict cellular responses to perturbations, as well as scale hypothesis exploration. With open science collaborations across the biomedical ecosystem that includes academia, philanthropy, and the biopharma and AI industries, a comprehensive predictive understanding of cell mechanisms and interactions has come into reach.

q-bio.QM↗

arXiv2024

Adjusting Pretrained Backbones for Performativity

With the widespread deployment of deep learning models, they influence their environment in various ways. The induced distribution shifts can lead to unexpected performance degradation in deployed models. Existing methods to anticipate performativity typically incorporate information about the deployed model into the feature vector when predicting future outcomes. While enjoying appealing theoretical properties, modifying the input dimension of the prediction task is often not practical. To address this, we propose a novel technique to adjust pretrained backbones for performativity in a modular way, achieving better sample efficiency and enabling the reuse of existing deep learning assets. Focusing on performative label shift, the key idea is to train a shallow adapter module to perform a Bayes-optimal label shift correction to the backbone's logits given a sufficient statistic of the model to be deployed. As such, our framework decouples the construction of input-specific feature embeddings from the mechanism governing performativity. Motivated by dynamic benchmarking as a use-case, we evaluate our approach under adversarial sampling, for vision and language tasks. We show how it leads to smaller loss along the retraining trajectory and enables us to effectively select among candidate models to anticipate performance degradations. More broadly, our work provides a first baseline for addressing performativity in deep learning.

cs.LG↗

arXiv2024

Position: Bayesian Deep Learning is Needed in the Age of Large-Scale AI

In the current landscape of deep learning research, there is a predominant emphasis on achieving high predictive accuracy in supervised tasks involving large image and language datasets. However, a broader perspective reveals a multitude of overlooked metrics, tasks, and data types, such as uncertainty, active and continual learning, and scientific data, that demand attention. Bayesian deep learning (BDL) constitutes a promising avenue, offering advantages across these diverse settings. This paper posits that BDL can elevate the capabilities of deep learning. It revisits the strengths of BDL, acknowledges existing challenges, and highlights some exciting research avenues aimed at addressing these obstacles. Looking ahead, the discussion focuses on possible ways to combine large-scale foundation models with BDL to unlock their full potential.

cs.LG↗

arXiv2024

Channel Vision Transformers: An Image Is Worth 1 x 16 x 16 Words

Vision Transformer (ViT) has emerged as a powerful architecture in the realm of modern computer vision. However, its application in certain imaging fields, such as microscopy and satellite imaging, presents unique challenges. In these domains, images often contain multiple channels, each carrying semantically distinct and independent information. Furthermore, the model must demonstrate robustness to sparsity in input channels, as they may not be densely available during training or testing. In this paper, we propose a modification to the ViT architecture that enhances reasoning across the input channels and introduce Hierarchical Channel Sampling (HCS) as an additional regularization technique to ensure robustness when only partial channels are presented during test time. Our proposed model, ChannelViT, constructs patch tokens independently from each input channel and utilizes a learnable channel embedding that is added to the patch tokens, similar to positional embeddings. We evaluate the performance of ChannelViT on ImageNet, JUMP-CP (microscopy cell imaging), and So2Sat (satellite imaging). Our results show that ChannelViT outperforms ViT on classification tasks and generalizes well, even when a subset of input channels is used during testing. Across our experiments, HCS proves to be a powerful regularizer, independent of the architecture employed, suggesting itself as a straightforward technique for robust ViT training. Lastly, we find that ChannelViT generalizes effectively even when there is limited access to all channels during training, highlighting its potential for multi-channel imaging under real-world conditions with sparse sensors. Our code is available at https://github.com/insitro/ChannelViT.

cs.CV↗

arXiv2024

Compositional Deep Probabilistic Models of DNA Encoded Libraries

DNA-Encoded Library (DEL) has proven to be a powerful tool that utilizes combinatorially constructed small molecules to facilitate highly-efficient screening assays. These selection experiments, involving multiple stages of washing, elution, and identification of potent binders via unique DNA barcodes, often generate complex data. This complexity can potentially mask the underlying signals, necessitating the application of computational tools such as machine learning to uncover valuable insights. We introduce a compositional deep probabilistic model of DEL data, DEL-Compose, which decomposes molecular representations into their mono-synthon, di-synthon, and tri-synthon building blocks and capitalizes on the inherent hierarchical structure of these molecules by modeling latent reactions between embedded synthons. Additionally, we investigate methods to improve the observation models for DEL count data such as integrating covariate factors to more effectively account for data noise. Across two popular public benchmark datasets (CA-IX and HRP), our model demonstrates strong performance compared to count baselines, enriches the correct pharmacophores, and offers valuable insights via its intrinsic interpretable structure, thereby providing a robust tool for the analysis of DEL data.

q-bio.QM↗