Aviv Regev

Romain Lopez, Nataša Tagasovska, Stephen Ra et al. · berkeley

Latent variable models such as the Variational Auto-Encoder (VAE) have become a go-to tool for analyzing biological data, especially in the field of single-cell genomics. One remaining challenge is the interpretability of latent variables as biological processes that define a cell's identity. Outside of biological applications, this problem is commonly referred to as learning disentangled representations. Although several disentanglement-promoting variants of the VAE were introduced, and applied to single-cell genomics data, this task has been shown to be infeasible from independent and identically distributed measurements, without additional structure. Instead, recent methods propose to leverage non-stationary data, as well as the sparse mechanism shift assumption in order to learn disentangled representations with a causal semantic. Here, we extend the application of these methodological advances to the analysis of single-cell genomics data with genetic or chemical perturbations. More precisely, we propose a deep generative model of single-cell gene expression data for which each perturbation is treated as a stochastic intervention targeting an unknown, but sparse, subset of latent variables. We benchmark these methods on simulated single-cell data to evaluate their performance at latent units recovery, causal target identification and out-of-domain generalization. Finally, we apply those approaches to two real-world large-scale gene perturbation data sets and find that models that exploit the sparse mechanism shift hypothesis surpass contemporary methods on a transfer learning task. We implement our new model and benchmarks using the scvi-tools library, and release it as open-source software at https://github.com/Genentech/sVAE.

Hugues Van Assel, Edward De Brouwer, Saeed Saremi et al.

Generative modeling and self-supervised representation learning (SSL) optimize structurally different objectives: generative training rewards distributional fidelity, while SSL rewards semantic coherence. Yet recent work repeatedly finds that SSL features improve generative training, though the mechanism of this synergy remains unclear. Here, we study the benefits of SSL in generative modeling in the framework of one-step generation where the role of representation is explicit: frozen SSL features are used to match generated samples to real data. We use the Sinkhorn divergence in that feature space, providing a tractable surrogate for the Wasserstein distance, the population-level discrepancy approximated by Fréchet-style evaluation metrics (such as FID). We find that this objective becomes highly effective when computed in a semantically structured SSL feature space (a 39$\times$ reduction in ImageNet FID). We trace this behavior primarily to matching estimation: semantic SSL features that suppress nuisance reconstruction details induce a more compact geometry, making distribution matching more tractable. As a consequence, the best training SSL features need not match the features used by the evaluation metric. In particular, we show that using Inception as the feature extractor can improve FID while degrading matching stability and sample quality, revealing a form of metric hacking. Using extensive experiments on ImageNet, we identify which SSL feature families lead to best generation performance and show that matching stability is a quantitative criterion for selecting them. Code is available at https://github.com/Genentech/semantic-transport-generation.

Romain Lopez, Jan-Christian Hütter, Jonathan K. Pritchard et al. · berkeley

A common theme in causal inference is learning causal relationships between observed variables, also known as causal discovery. This is usually a daunting task, given the large number of candidate causal graphs and the combinatorial nature of the search space. Perhaps for this reason, most research has so far focused on relatively small causal graphs, with up to hundreds of nodes. However, recent advances in fields like biology enable generating experimental data sets with thousands of interventions followed by rich profiling of thousands of variables, raising the opportunity and urgent need for large causal graph models. Here, we introduce the notion of factor directed acyclic graphs (f-DAGs) as a way to restrict the search space to non-linear low-rank causal interaction models. Combining this novel structural assumption with recent advances that bridge the gap between causal discovery and continuous optimization, we achieve causal discovery on thousands of variables. Additionally, as a model for the impact of statistical noise on this estimation procedure, we study a model of edge perturbations of the f-DAG skeleton based on random graphs and quantify the effect of such perturbations on the f-DAG rank. This theoretical analysis suggests that the set of candidate f-DAGs is much smaller than the whole DAG space and thus may be more suitable as a search space in the high-dimensional regime where the underlying skeleton is hard to assess. We propose Differentiable Causal Discovery of Factor Graphs (DCD-FG), a scalable implementation of -DAG constrained causal discovery for high-dimensional interventional data. DCD-FG uses a Gaussian non-linear low-rank structural equation model and shows significant improvements compared to state-of-the-art methods in both simulations as well as a recent large-scale single-cell RNA sequencing data set with hundreds of genetic interventions.

Xiner Li, Yulai Zhao, Chenyu Wang et al. · princeton

Diffusion models excel at capturing the natural design spaces of images, molecules, DNA, RNA, and protein sequences. However, rather than merely generating designs that are natural, we often aim to optimize downstream reward functions while preserving the naturalness of these design spaces. Existing methods for achieving this goal often require ``differentiable'' proxy models (\textit{e.g.}, classifier guidance or DPS) or involve computationally expensive fine-tuning of diffusion models (\textit{e.g.}, classifier-free guidance, RL-based fine-tuning). In our work, we propose a new method to address these challenges. Our algorithm is an iterative sampling method that integrates soft value functions, which looks ahead to how intermediate noisy states lead to high rewards in the future, into the standard inference procedure of pre-trained diffusion models. Notably, our approach avoids fine-tuning generative models and eliminates the need to construct differentiable models. This enables us to (1) directly utilize non-differentiable features/reward feedback, commonly used in many scientific domains, and (2) apply our method to recent discrete diffusion models in a principled way. Finally, we demonstrate the effectiveness of our algorithm across several domains, including image generation, molecule generation, and DNA/RNA sequence generation. The code is available at \href{https://github.com/masa-ue/SVDD}{https://github.com/masa-ue/SVDD}.

Charlotte Bunne, Yusuf Roohani, Yanay Rosen et al.

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.

Masatoshi Uehara, Yulai Zhao, Chenyu Wang et al. · princeton

This tutorial provides an in-depth guide on inference-time guidance and alignment methods for optimizing downstream reward functions in diffusion models. While diffusion models are renowned for their generative modeling capabilities, practical applications in fields such as biology often require sample generation that maximizes specific metrics (e.g., stability, affinity in proteins, closeness to target structures). In these scenarios, diffusion models can be adapted not only to generate realistic samples but also to explicitly maximize desired measures at inference time without fine-tuning. This tutorial explores the foundational aspects of such inference-time algorithms. We review these methods from a unified perspective, demonstrating that current techniques -- such as Sequential Monte Carlo (SMC)-based guidance, value-based sampling, and classifier guidance -- aim to approximate soft optimal denoising processes (a.k.a. policies in RL) that combine pre-trained denoising processes with value functions serving as look-ahead functions that predict from intermediate states to terminal rewards. Within this framework, we present several novel algorithms not yet covered in the literature. Furthermore, we discuss (1) fine-tuning methods combined with inference-time techniques, (2) inference-time algorithms based on search algorithms such as Monte Carlo tree search, which have received limited attention in current research, and (3) connections between inference-time algorithms in language models and diffusion models. The code of this tutorial on protein design is available at https://github.com/masa-ue/AlignInversePro

Masatoshi Uehara, Xingyu Su, Yulai Zhao et al. · princeton

To fully leverage the capabilities of diffusion models, we are often interested in optimizing downstream reward functions during inference. While numerous algorithms for reward-guided generation have been recently proposed due to their significance, current approaches predominantly focus on single-shot generation, transitioning from fully noised to denoised states. We propose a novel framework for inference-time reward optimization with diffusion models inspired by evolutionary algorithms. Our approach employs an iterative refinement process consisting of two steps in each iteration: noising and reward-guided denoising. This sequential refinement allows for the gradual correction of errors introduced during reward optimization. Besides, we provide a theoretical guarantee for our framework. Finally, we demonstrate its superior empirical performance in protein and cell-type-specific regulatory DNA design. The code is available at \href{https://github.com/masa-ue/ProDifEvo-Refinement}{https://github.com/masa-ue/ProDifEvo-Refinement}.

Shuvom Sadhuka, Drew Prinster, Clara Fannjiang et al.

Agentic AI systems execute a sequence of actions, such as reasoning steps or tool calls, in response to a user prompt. To evaluate the success of their trajectories, researchers have developed verifiers, such as LLM judges and process-reward models, to score the quality of each action in an agent's trajectory. Although these heuristic scores can be informative, there are no guarantees of correctness when used to decide whether an agent will yield a successful output. Here, we introduce e-valuator, a method to convert any black-box verifier score into a decision rule with provable control of false alarm rates. We frame the problem of distinguishing successful trajectories (that is, a sequence of actions that will lead to a correct response to the user's prompt) and unsuccessful trajectories as a sequential hypothesis testing problem. E-valuator builds on tools from e-processes to develop a sequential hypothesis test that remains statistically valid at every step of an agent's trajectory, enabling online monitoring of agents over arbitrarily long sequences of actions. Empirically, we demonstrate that e-valuator provides greater statistical power and better false alarm rate control than other strategies across six datasets and three agents. We additionally show that e-valuator can be used for to quickly terminate problematic trajectories and save tokens. Together, e-valuator provides a lightweight, model-agnostic framework that converts verifier heuristics into decisions rules with statistical guarantees, enabling the deployment of more reliable agentic systems.

Chenyu Wang, Masatoshi Uehara, Yichun He et al.

Recent studies have demonstrated the strong empirical performance of diffusion models on discrete sequences across domains from natural language to biological sequence generation. For example, in the protein inverse folding task, conditional diffusion models have achieved impressive results in generating natural-like sequences that fold back into the original structure. However, practical design tasks often require not only modeling a conditional distribution but also optimizing specific task objectives. For instance, we may prefer protein sequences with high stability. To address this, we consider the scenario where we have pre-trained discrete diffusion models that can generate natural-like sequences, as well as reward models that map sequences to task objectives. We then formulate the reward maximization problem within discrete diffusion models, analogous to reinforcement learning (RL), while minimizing the KL divergence against pretrained diffusion models to preserve naturalness. To solve this RL problem, we propose a novel algorithm, DRAKES, that enables direct backpropagation of rewards through entire trajectories generated by diffusion models, by making the originally non-differentiable trajectories differentiable using the Gumbel-Softmax trick. Our theoretical analysis indicates that our approach can generate sequences that are both natural-like and yield high rewards. While similar tasks have been recently explored in diffusion models for continuous domains, our work addresses unique algorithmic and theoretical challenges specific to discrete diffusion models, which arise from their foundation in continuous-time Markov chains rather than Brownian motion. Finally, we demonstrate the effectiveness of DRAKES in generating DNA and protein sequences that optimize enhancer activity and protein stability, respectively, important tasks for gene therapies and protein-based therapeutics.

Xiner Li, Masatoshi Uehara, Xingyu Su et al.

Diffusion models have shown promising generative capabilities across diverse domains, yet aligning their outputs with desired reward functions remains a challenge, particularly in cases where reward functions are non-differentiable. Some gradient-free guidance methods have been developed, but they often struggle to achieve optimal inference-time alignment. In this work, we newly frame inference-time alignment in diffusion as a search problem and propose Dynamic Search for Diffusion (DSearch), which subsamples from denoising processes and approximates intermediate node rewards. It also dynamically adjusts beam width and tree expansion to efficiently explore high-reward generations. To refine intermediate decisions, DSearch incorporates adaptive scheduling based on noise levels and a lookahead heuristic function. We validate DSearch across multiple domains, including biological sequence design, molecular optimization, and image generation, demonstrating superior reward optimization compared to existing approaches.

Hugues Van Assel, Mark Ibrahim, Tommaso Biancalani et al.

Reconstruction and joint embedding have emerged as two leading paradigms in Self Supervised Learning (SSL). Reconstruction methods focus on recovering the original sample from a different view in input space. On the other hand, joint embedding methods align the representations of different views in latent space. Both approaches offer compelling advantages, yet practitioners lack clear guidelines for choosing between them. In this work, we unveil the core mechanisms that distinguish each paradigm. By leveraging closed form solutions for both approaches, we precisely characterize how the view generation process, e.g. data augmentation, impacts the learned representations. We then demonstrate that, unlike supervised learning, both SSL paradigms require a minimal alignment between augmentations and irrelevant features to achieve asymptotic optimality with increasing sample size. Our findings indicate that in scenarios where these irrelevant features have a large magnitude, joint embedding methods are preferable because they impose a strictly weaker alignment condition compared to reconstruction based methods. These results not only clarify the trade offs between the two paradigms but also substantiate the empirical success of joint embedding approaches on real world challenging datasets.

Romain Lopez, Jan-Christian Huetter, Ehsan Hajiramezanali et al.

Deep Generative Models (DGMs) are versatile tools for learning data representations while adequately incorporating domain knowledge such as the specification of conditional probability distributions. Recently proposed DGMs tackle the important task of comparing data sets from different sources. One such example is the setting of contrastive analysis that focuses on describing patterns that are enriched in a target data set compared to a background data set. The practical deployment of those models often assumes that DGMs naturally infer interpretable and modular latent representations, which is known to be an issue in practice. Consequently, existing methods often rely on ad-hoc regularization schemes, although without any theoretical grounding. Here, we propose a theory of identifiability for comparative DGMs by extending recent advances in the field of non-linear independent component analysis. We show that, while these models lack identifiability across a general class of mixing functions, they surprisingly become identifiable when the mixing function is piece-wise affine (e.g., parameterized by a ReLU neural network). We also investigate the impact of model misspecification, and empirically show that previously proposed regularization techniques for fitting comparative DGMs help with identifiability when the number of latent variables is not known in advance. Finally, we introduce a novel methodology for fitting comparative DGMs that improves the treatment of multiple data sources via multi-objective optimization and that helps adjust the hyperparameter for the regularization in an interpretable manner, using constrained optimization. We empirically validate our theory and new methodology using simulated data as well as a recent data set of genetic perturbations in cells profiled via single-cell RNA sequencing.

Taro Makino, Ji Won Park, Natasa Tagasovska et al.

Real-world datasets often combine data collected under different experimental conditions. This yields larger datasets, but also introduces spurious correlations that make it difficult to model the phenomena of interest. We address this by learning two embeddings to independently represent the phenomena of interest and the spurious correlations. The embedding representing the phenomena of interest is correlated with the target variable $y$, and is invariant to the environment variable $e$. In contrast, the embedding representing the spurious correlations is correlated with $e$. The invariance to $e$ is difficult to achieve on real-world datasets. Our primary contribution is an algorithm called Supervised Contrastive Block Disentanglement (SCBD) that effectively enforces this invariance. It is based purely on Supervised Contrastive Learning, and applies to real-world data better than existing approaches. We empirically validate SCBD on two challenging problems. The first problem is domain generalization, where we achieve strong performance on a synthetic dataset, as well as on Camelyon17-WILDS. We introduce a single hyperparameter $α$ to control the degree of invariance to $e$. When we increase $α$ to strengthen the degree of invariance, out-of-distribution performance improves at the expense of in-distribution performance. The second problem is batch correction, in which we apply SCBD to preserve biological signal and remove inter-well batch effects when modeling single-cell perturbations from 26 million Optical Pooled Screening images.

Aditya Gorla, Hugues Van Assel, Jan-Christian Huetter et al.

We present GROOVE, a semi-supervised multi-modal representation learning approach for high-content perturbation data where samples across modalities are weakly paired through shared perturbation labels but lack direct correspondence. Our primary contribution is GroupCLIP, a novel group-level contrastive loss that bridges the gap between CLIP for paired cross-modal data and SupCon for uni-modal supervised contrastive learning, addressing a fundamental gap in contrastive learning for weakly-paired settings. We integrate GroupCLIP with an on-the-fly backtranslating autoencoder framework to encourage cross-modally entangled representations while maintaining group-level coherence within a shared latent space. Critically, we introduce a comprehensive combinatorial evaluation framework that systematically assesses representation learners across multiple optimal transport aligners, addressing key limitations in existing evaluation strategies. This framework includes novel simulations that systematically vary shared versus modality-specific perturbation effects enabling principled assessment of method robustness. Our combinatorial benchmarking reveals that there is not yet an aligner that uniformly dominates across settings or modality pairs. Across simulations and two real single-cell genetic perturbation datasets, GROOVE performs on par with or outperforms existing approaches for downstream cross-modal matching and imputation tasks. Our ablation studies demonstrate that GroupCLIP is the key component driving performance gains. These results highlight the importance of leveraging group-level constraints for effective multi-modal representation learning in scenarios where only weak pairing is available.

Sukwon Yun, Heming Yao, Burkhard Hoeckendorf et al.

Vision Transformers ($\text{ViTs}$) have become the backbone of vision foundation models, yet their optimization for multi-channel domains - such as cell painting or satellite imagery - remains underexplored. A key challenge in these domains is capturing interactions between channels, as each channel carries different information. While existing works have shown efficacy by treating each channel independently during tokenization, this approach naturally introduces a major computational bottleneck in the attention block - channel-wise comparisons leads to a quadratic growth in attention, resulting in excessive $\text{FLOPs}$ and high training cost. In this work, we shift focus from efficacy to the overlooked efficiency challenge in cross-channel attention and ask: "Is it necessary to model all channel interactions?". Inspired by the philosophy of Sparse Mixture-of-Experts ($\text{MoE}$), we propose MoE-ViT, a Mixture-of-Experts architecture for multi-channel images in $\text{ViTs}$, which treats each channel as an expert and employs a lightweight router to select only the most relevant experts per patch for attention. Proof-of-concept experiments on real-world datasets - JUMP-CP and So2Sat - demonstrate that $\text{MoE-ViT}$ achieves substantial efficiency gains without sacrificing, and in some cases enhancing, performance, making it a practical and attractive backbone for multi-channel imaging.

Weiqi Ji, Bo Yuan, Ciyue Shen et al.

Data-driven dynamic models of cell biology can be used to predict cell response to unseen perturbations. Recent work (CellBox) had demonstrated the derivation of interpretable models with explicit interaction terms, in which the parameters were optimized using machine learning techniques. While the previous work was tested only in a single biological setting, this work aims to extend the range of applicability of this model inference approach to a diversity of biological systems. Here we adapted CellBox in Julia differential programming and augmented the method with adjoint algorithms, which has recently been used in the context of neural ODEs. We trained the models using simulated data from both abstract and biology-inspired networks, which afford the ability to evaluate the recovery of the ground truth network structure. The resulting accuracy of prediction by these models is high both in terms of low error against data and excellent agreement with the network structure used for the simulated training data. While there is no analogous ground truth for real life biological systems, this work demonstrates the ability to construct and parameterize a considerable diversity of network models with high predictive ability. The expectation is that this kind of procedure can be used on real perturbation-response data to derive models applicable to diverse biological systems.

Miriam Shiffman, William T. Stephenson, Geoffrey Schiebinger et al.

Until recently, transcriptomics was limited to bulk RNA sequencing, obscuring the underlying expression patterns of individual cells in favor of a global average. Thanks to technological advances, we can now profile gene expression across thousands or millions of individual cells in parallel. This new type of data has led to the intriguing discovery that individual cell profiles can reflect the imprint of time or dynamic processes. However, synthesizing this information to reconstruct dynamic biological phenomena from data that are noisy, heterogenous, and sparse---and from processes that may unfold asynchronously---poses a complex computational and statistical challenge. Here, we develop a full generative model for probabilistically reconstructing trees of cellular differentiation from single-cell RNA-seq data. Specifically, we extend the framework of the classical Dirichlet diffusion tree to simultaneously infer branch topology and latent cell states along continuous trajectories over the full tree. In tandem, we construct a novel Markov chain Monte Carlo sampler that interleaves Metropolis-Hastings and message passing to leverage model structure for efficient inference. Finally, we demonstrate that these techniques can recover latent trajectories from simulated single-cell transcriptomes. While this work is motivated by cellular differentiation, we derive a tractable model that provides flexible densities for any data (coupled with an appropriate noise model) that arise from continuous evolution along a latent nonparametric tree.

Eran Segal, Dana Pe'er, Aviv Regev et al.

Methods for learning Bayesian network structure can discover dependency structure between observed variables, and have been shown to be useful in many applications. However, in domains that involve a large number of variables, the space of possible network structures is enormous, making it difficult, for both computational and statistical reasons, to identify a good model. In this paper, we consider a solution to this problem, suitable for domains where many variables have similar behavior. Our method is based on a new class of models, which we call module networks. A module network explicitly represents the notion of a module - a set of variables that have the same parents in the network and share the same conditional probability distribution. We define the semantics of module networks, and describe an algorithm that learns a module network from data. The algorithm learns both the partitioning of the variables into modules and the dependency structure between the variables. We evaluate our algorithm on synthetic data, and on real data in the domains of gene expression and the stock market. Our results show that module networks generalize better than Bayesian networks, and that the learned module network structure reveals regularities that are obscured in learned Bayesian networks.