ICML 2025 Papers

De novo peptide sequencing is a critical task in proteomics. However, the performance of current deep learning-based methods is limited by the inherent complexity of mass spectrometry data and the heterogeneous distribution of noise signals, leading to data-specific biases. We present RankNovo, the first deep reranking framework that enhances de novo peptide sequencing by leveraging the complementary strengths of multiple sequencing models. RankNovo employs a list-wise reranking approach, modeling candidate peptides as multiple sequence alignments and utilizing axial attention to extract informative features across candidates. Additionally, we introduce two new metrics, PMD (**P**eptide **M**ass **D**eviation) and RMD (**R**esidual**M**ass **D**eviation), which offer delicate supervision by quantifying mass differences between peptides at both the sequence and residue levels. Extensive experiments demonstrate that RankNovo not only surpasses its base models used to generate training candidates for reranking pre-training, but also sets a new state-of-the-art benchmark. Moreover, RankNovo exhibits strong zero-shot generalization to unseen models—those whose generations were not exposed during training, highlighting its robustness and potential as a universal reranking framework for peptide sequencing. Our work presents a novel reranking strategy that fundamentally challenges existing single-model paradigms and advances the frontier of accurate de novo sequencing. Our source code is provided on GitHub.

Existing biomedical benchmarks do not provide end-to-end infrastructure for training, evaluation, and inference of models that integrate multimodal biological data and a broad range of machine learning tasks in therapeutics. We present PyTDC, an open-source machine-learning platform providing streamlined training, evaluation, and inference software for multimodal biological AI models. PyTDC unifies distributed, heterogeneous, continuously updated data sources and model weights and standardizes benchmarking and inference endpoints. This paper discusses the components of PyTDC's architecture and, to our knowledge, the first-of-its-kind case study on the introduced single-cell drug-target nomination ML task. We find state-of-the-art methods in graph representation learning and domain-specific methods from graph theory perform poorly on this task. Though we find a context-aware geometric deep learning method that outperforms the evaluated SoTA and domain-specific baseline methods, the model is unable to generalize to unseen cell types or incorporate additional modalities, highlighting PyTDC's capacity to facilitate an exciting avenue of research developing multimodal, context-aware, foundation models for open problems in biomedical AI.

Piecewise constant functions describe a variety of real-world phenomena in domains ranging from chemistry to manufacturing. In practice, it is often required to confidently identify the locations of the abrupt changes in these functions as quickly as possible. For this, we introduce a fixed-confidence piecewise constant bandit problem. Here, we sequentially query points in the domain and receive noisy evaluations of the function under bandit feedback. We provide instance-dependent lower bounds for the complexity of change point identification in this problem. These lower bounds illustrate that an optimal method should focus its sampling efforts adjacent to each of the change points, and the number of samples around each change point should be inversely proportional to the magnitude of the change. Building on this, we devise a simple and computationally efficient variant of Track-and-Stop and prove that it is asymptotically optimal in many regimes. We support our theoretical findings with experimental results in synthetic environments demonstrating the efficiency of our method.

Backpropagation is the foundational algorithm for training neural networks and a key driver of deep learning's success. However, its biological plausibility has been challenged due to three primary limitations: weight symmetry, reliance on global error signals, and the dual-phase nature of training, as highlighted by the existing literature. Although various alternative learning approaches have been proposed to address these issues, most either fail to satisfy all three criteria simultaneously or yield suboptimal results. Inspired by the dynamics and plasticity of pyramidal neurons, we propose Dendritic Localized Learning (DLL), a novel learning algorithm designed to overcome these challenges. Extensive empirical experiments demonstrate that DLL satisfies all three criteria of biological plausibility while achieving state-of-the-art performance among algorithms that meet these requirements. Furthermore, DLL exhibits strong generalization across a range of architectures, including MLPs, CNNs, and RNNs. These results, benchmarked against existing biologically plausible learning algorithms, offer valuable empirical insights for future research. We hope this study can inspire the development of new biologically plausible algorithms for training multilayer networks and advancing progress in both neuroscience and machine learning. Our code is available at https://github.com/Lvchangze/Dendritic-Localized-Learning.

Incorporating group symmetries into neural networks has been a cornerstone of success in many AI-for-science applications. Diagonal groups of isometries, which describe the invariance under a simultaneous movement of multiple objects, arise naturally in many-body quantum problems. Despite their importance, diagonal groups have received relatively little attention, as they lack a natural choice of invariant maps except in special cases. We study different ways of incorporating diagonal invariance in neural network ansatze trained via variational Monte Carlo methods, and consider specifically data augmentation, group averaging and canonicalization. We show that, contrary to standard ML setups, in-training symmetrization destabilizes training and can lead to worse performance. Our theoretical and numerical results indicate that this unexpected behavior may arise from a unique computational-statistical tradeoff not found in standard ML analyses of symmetrization. Meanwhile, we demonstrate that post hoc averaging is less sensitive to such tradeoffs and emerges as a simple, flexible and effective method for improving neural network solvers.

Large language models (LLMs) acquire a breadth of information across various domains. However, their computational complexity, cost, and lack of transparency often hinder their direct application for predictive tasks where privacy and interpretability are paramount. In fields such as healthcare, biology, and finance, specialised and interpretable linear models still hold considerable value. In such domains, labelled data may be scarce or expensive to obtain. Well-specified prior distributions over model parameters can reduce the sample complexity of learning through Bayesian inference; however, eliciting expert priors can be time-consuming. We therefore introduce AutoElicit to extract knowledge from LLMs and construct priors for predictive models. We show these priors are informative and can be refined using natural language. We perform a careful study contrasting AutoElicit with in-context learning and demonstrate how to perform model selection between the two methods. We find that AutoElicit yields priors that can substantially reduce error over uninformative priors, using fewer labels, and consistently outperform in-context learning. We show that AutoElicit saves over 6 months of labelling effort when building a new predictive model for urinary tract infections from sensor recordings of people living with dementia.

Motivated by applications in trajectory inference and particle tracking, we introduce **Smooth Schrödinger Bridges**. Our proposal generalizes prior work by allowing the reference process in the multi-marginal Schrödinger Bridge problem to be a smooth Gaussian process, leading to more regular and interpretable trajectories in applications. Though naïvely smoothing the reference process leads to a computationally intractable problem, we identify a class of processes (including the Matérn processes) for which the resulting Smooth Schrödinger Bridge problem can be *lifted* to a simpler problem on phase space, which can be solved in polynomial time. We develop a practical approximation of this algorithm that outperforms existing methods on numerous simulated and real single-cell RNAseq datasets.

The introduction of the Segment Anything Model (SAM) has paved the way for numerous semantic segmentation applications. For several tasks, quantifying the uncertainty of SAM is of particular interest. However, the ambiguous nature of the class-agnostic foundation model SAM challenges current uncertainty quantification (UQ) approaches. This paper presents a theoretically motivated uncertainty quantification model based on a Bayesian entropy formulation jointly respecting aleatoric, epistemic, and the newly introduced task uncertainty. We use this formulation to train USAM, a lightweight post-hoc UQ method. Our model traces the root of uncertainty back to under-parameterised models, insufficient prompts or image ambiguities. Our proposed deterministic USAM demonstrates superior predictive capabilities on the SA-V, MOSE, ADE20k, DAVIS, and COCO datasets, offering a computationally cheap and easy-to-use UQ alternative that can support user-prompting, enhance semi-supervised pipelines, or balance the tradeoff between accuracy and cost efficiency.

Global minimum cut is a fundamental combinatorial optimization problem with wide-ranging applications. Often in practice, these problems are solved repeatedly on families of similar or related instances. However, the de facto algorithmic approach is to solve each instance of the problem from scratch discarding information from prior instances. In this paper, we consider how predictions informed by prior instances can be used to warm-start practical minimum cut algorithms. The paper considers the widely used Karger's algorithm and its counterpart, the Karger-Stein algorithm. Given good predictions, we show these algorithms become near-linear time and have robust performance to erroneous predictions. Both of these algorithms are randomized edge-contraction algorithms. Our natural idea is to probabilistically prioritize the contraction of edges that are unlikely to be in the minimum cut.

Conditional flow matching (CFM) stands out as an efficient, simulation-free approach for training flow-based generative models, achieving remarkable performance for data generation. However, CFM is insufficient to ensure accuracy in learning probability paths. In this paper, we introduce a new partial differential equation characterization for the error between the learned and exact probability paths, along with its solution. We show that the total variation between probability paths is bounded above by a combination of the CFM loss and an associated divergence loss. This theoretical insight leads to the design of a new objective function that simultaneously matches the flow and its divergence. Our new approach improves the performance of the flow-based generative model by a noticeable margin without significantly raising the computational cost. We showcase the advantages of this enhanced training approach over CFM on several important benchmark tasks, including generative modeling for dynamical systems, DNA sequences, and videos.

Likelihood approximations for images are not trivial to compute and can be useful in many applications. We examine the use of Contrastive Language-Image Pre-training (CLIP) to assess the likelihood of images and captions. We introduce Whitened CLIP, a novel transformation of the CLIP latent space via an invertible linear operation. This transformation ensures that each feature in the embedding space has zero mean, unit standard deviation, and no correlation with all other features, resulting in an identity covariance matrix. We show that the whitened embedding statistics can be well approximated by a standard normal distribution, allowing log-likelihood to be estimated using the squared Euclidean norm in the whitened space. The whitening procedure is completely training-free and uses a precomputed whitening matrix, making it extremely fast. We present several preliminary experiments demonstrating the properties and applicability of these likelihood scores to images and captions. Our code is available at github.com/rbetser/W_CLIP/tree/main.

Learning the site-specific distribution of the wireless channel within a particular environment of interest is essential to exploit the full potential of machine learning (ML) for wireless communications and radar applications. Generative modeling offers a promising framework to address this problem. However, existing approaches pose unresolved challenges, including the need for high-quality training data, limited generalizability, and a lack of physical interpretability. To address these issues, we combine the physics-related compressibility of wireless channels with generative modeling, in particular, sparse Bayesian generative modeling (SBGM), to learn the distribution of the underlying physical channel parameters. By leveraging the sparsity-inducing characteristics of SBGM, our methods can learn from compressed observations received by an access point (AP) during default online operation. Moreover, they are physically interpretable and generalize over system configurations without requiring retraining.

We propose TAROT, a targeted data selection framework grounded in Optimal Transport theory. Previous targeted data selection methods primarily rely on influence-based greedy heuristics to enhance domain-specific performance. While effective on limited, unimodal data (i.e., data following a single pattern), these methods struggle as target data complexity increases. Specifically, in multimodal distributions, such heuristics fail to account for multiple inherent patterns, leading to suboptimal data selection. This work identifies two primary limitations: (i) the disproportionate impact of dominant feature components in high-dimensional influence estimation, and (ii) the restrictive linear additive assumptions in greedy selection strategies. To address these challenges, TAROT incorporates whitened feature distance to mitigate dominant feature bias, offering a more reliable measure of data influence. Building on this, TAROT leverages whitened feature distance to quantify and minimize the optimal transport distance between selected data and target domains. Notably, this minimization also facilitates the estimation of optimal selection ratios. We evaluate TAROT across multiple tasks, including semantic segmentation, motion prediction, and instruction tuning. Results consistently show that TAROT outperforms state-of-the-art methods, demonstrating its versatility across various deep learning tasks. Code is available at: https://github.com/vita-epfl/TAROT.

$E(3)$-equivariant neural networks have demonstrated success across a wide range of 3D modelling tasks. A fundamental operation in these networks is the tensor product, which interacts two geometric features in an equivariant manner to create new features. Due to the high computational complexity of the tensor product, significant effort has been invested to optimize the runtime of this operation. For example, Luo et al. (2024) recently proposed the Gaunt tensor product (GTP) which promises a significant speedup. In this work, we provide a careful, systematic analysis of a number of tensor product operations. In particular, we emphasize that different tensor products are not performing the same operation. The reported speedups typically come at the cost of expressivity. We introduce measures of expressivity and interactability to characterize these differences. In addition, we realized the original implementation of GTP can be greatly simplified by directly using a spherical grid at no cost in asymptotic runtime. This spherical grid approach is faster on our benchmarks and in actual training of the MACE interatomic potential by 30\%. Finally, we provide the first systematic microbenchmarks of the various tensor product operations. We find that the theoretical runtime guarantees can differ wildly from empirical performance, demonstrating the need for careful application-specific benchmarking. Code is available at https://github.com/atomicarchitects/PriceofFreedom

Mass spectrometry plays a fundamental role in elucidating the structures of unknown molecules and subsequent scientific discoveries. One formulation of the structure elucidation task is the conditional *de novo* generation of molecular structure given a mass spectrum. Toward a more accurate and efficient scientific discovery pipeline for small molecules, we present DiffMS, a formula-restricted encoder-decoder generative network that achieves state-of-the-art performance on this task. The encoder utilizes a transformer architecture and models mass spectra domain knowledge such as peak formulae and neutral losses, and the decoder is a discrete graph diffusion model restricted by the heavy-atom composition of a known chemical formula. To develop a robust decoder that bridges latent embeddings and molecular structures, we pretrain the diffusion decoder with fingerprint-structure pairs, which are available in virtually infinite quantities, compared to structure-spectrum pairs that number in the tens of thousands. Extensive experiments on established benchmarks show that DiffMS outperforms existing models on *de novo* molecule generation. We provide several ablations to demonstrate the effectiveness of our diffusion and pretraining approaches and show consistent performance scaling with increasing pretraining dataset size. DiffMS code is publicly available at https://github.com/coleygroup/DiffMS.

Quantum control is concerned with the realisation of desired dynamics in quantum systems, serving as a linchpin for advancing quantum technologies and fundamental research. Analytic approaches and standard optimisation algorithms do not yield satisfactory solutions for more complex quantum systems, and especially not for real world quantum systems which are open and noisy. We devise a physics-constrained Reinforcement Learning (RL) algorithm that restricts the space of possible solutions. We incorporate priors about the desired time scales of the quantum state dynamics - as well as realistic control signal limitations - as constraints to the RL algorithm. These constraints improve solution quality and enhance computational scaleability. We evaluate our method on three broadly relevant quantum systems and incorporate real-world complications, arising from dissipation and control signal perturbations. We achieve both higher fidelities - which exceed 0.999 across all systems - and better robustness to time-dependent perturbations and experimental imperfections than previous methods. Lastly, we demonstrate that incorporating multi-step feedback can yield solutions robust even to strong perturbations. Our implementation can be found at: https://github.com/jan-o-e/RL4qcWpc.

Large language models (LLMs) have demonstrated remarkable capabilities in solving complex reasoning tasks, particularly in mathematics. However, the domain of physics reasoning presents unique challenges that have received significantly less attention. Existing benchmarks often fall short in evaluating LLMs’ abilities on the breadth and depth of undergraduate-level physics, underscoring the need for a comprehensive evaluation. To fill this gap, we introduce UGPhysics, a large-scale and diverse benchmark specifically designed to evaluate **U**nder**G**raduate-level **Physics** (**UGPhysics**) reasoning with LLMs. UGPhysics includes 5,520 undergraduate-level physics problems in both English and Chinese across 13 subjects with seven different answer types and four distinct physics reasoning skills, all rigorously screened for data leakage. Additionally, we develop a Model-Assistant Rule-based Judgment (**MARJ**) pipeline specifically tailored for assessing physics problems, ensuring accurate evaluation. Our evaluation of 31 leading LLMs shows that the highest overall accuracy, 49.8% (achieved by OpenAI-o1-mini), emphasizes the need for models with stronger physics reasoning skills, beyond math abilities. We hope UGPhysics, along with MARJ, will drive future advancements in AI for physics reasoning. Codes and data are available at \href{https://github.com/YangLabHKUST/UGPhysics}{https://github.com/YangLabHKUST/UGPhysics}.

Decoding functional magnetic resonance imaging (fMRI) signals into text has been a key challenge in the neuroscience community, with the potential to advance brain-computer interfaces and uncover deeper insights into brain mechanisms. However, existing approaches often struggle with suboptimal predictive performance, limited task variety, and poor generalization across subjects. In response to this, we propose MindLLM, a model designed for subject-agnostic and versatile fMRI-to-text decoding. MindLLM consists of an fMRI encoder and an off-the-shelf LLM. The fMRI encoder employs a neuroscience-informed attention mechanism, which is capable of accommodating subjects with varying input shapes and thus achieves high-performance subject-agnostic decoding. Moreover, we introduce Brain Instruction Tuning (BIT), a novel approach that enhances the model's ability to capture diverse semantic representations from fMRI signals, facilitating more versatile decoding. We evaluate MindLLM on comprehensive fMRI-to-text benchmarks. Results demonstrate that our model outperforms the baselines, improving downstream tasks by $12.0\%$, unseen subject generalization by $24.5\%$, and novel task adaptation by $25.0\%$. Furthermore, the attention patterns in MindLLM provide interpretable insights into its decision-making process.

Submodular functions, defined on continuous or discrete domains, arise in numerous applications. We study the minimization of the difference of submodular (DS) functions, over both domains, extending prior work restricted to set functions. We show that all functions on discrete domains and all smooth functions on continuous domains are DS. For discrete domains, we observe that DS minimization is equivalent to minimizing the difference of two convex (DC) functions, as in the set function case. We propose a novel variant of the DC Algorithm (DCA) and apply it to the resulting DC Program, obtaining comparable theoretical guarantees as in the set function case. The algorithm can be applied to continuous domains via discretization. Experiments demonstrate that our method outperforms baselines in integer compressive sensing and integer least squares.