Objectives: We propose a novel imputation method tailored for Electronic Health Records (EHRs) with structured and sporadic missingness. Such missingness frequently arises in the integration of heterogeneous EHR datasets for downstream clinical applications. By addressing these gaps, our method provides a practical solution for integrated analysis, enhancing data utility and advancing the understanding of population health. Materials and Methods: We begin by demonstrating structured and sporadic missing mechanisms in the integrated analysis of EHR data. Following this, we introduce a novel imputation framework, Macomss, specifically designed to handle structurally and heterogeneously occurring missing data. We establish theoretical guarantees for Macomss, ensuring its robustness in preserving the integrity and reliability of integrated analyses. To assess its empirical performance, we conduct extensive simulation studies that replicate the complex missingness patterns observed in real-world EHR systems, complemented by validation using EHR datasets from the Duke University Health System (DUHS). Results: Simulation studies show that our approach consistently outperforms existing imputation methods. Using datasets from three hospitals within DUHS, Macomss achieves the lowest imputation errors for missing data in most cases and provides superior or comparable downstream prediction performance compared to benchmark methods. Conclusions: We provide a theoretically guaranteed and practically meaningful method for imputing structured and sporadic missing data, enabling accurate and reliable integrated analysis across multiple EHR datasets. The proposed approach holds significant potential for advancing research in population health.
High-dimensional linear regression is a fundamental tool in modern statistics, particularly when the number of predictors exceeds the sample size. The classical Lasso, which relies on the squared loss, performs well under Gaussian noise assumptions but often deteriorates in the presence of heavy-tailed errors or outliers commonly encountered in real data applications such as genomics, finance, and signal processing. To address these challenges, we propose a novel robust regression method, termed Heavy Lasso, which incorporates a loss function inspired by the Student's t-distribution within a Lasso penalization framework. This loss retains the desirable quadratic behavior for small residuals while adaptively downweighting large deviations, thus enhancing robustness to heavy-tailed noise and outliers. Heavy Lasso enjoys computationally efficient by leveraging a data augmentation scheme and a soft-thresholding algorithm, which integrate seamlessly with classical Lasso solvers. Theoretically, we establish non-asymptotic bounds under both $\ell_1$ and $\ell_2 $ norms, by employing the framework of localized convexity, showing that the Heavy Lasso estimator achieves rates comparable to those of the Huber loss. Extensive numerical studies demonstrate Heavy Lasso's superior performance over classical Lasso and other robust variants, highlighting its effectiveness in challenging noisy settings. Our method is implemented in the R package heavylasso available on Github.
The pursuit of universal black-box optimization (BBO) algorithms is a longstanding goal. However, unlike domains such as language or vision, where scaling structured data has driven generalization, progress in offline BBO remains hindered by the lack of unified representations for heterogeneous numerical spaces. Thus, existing offline BBO approaches are constrained to single-task and fixed-dimensional settings, failing to achieve cross-domain universal optimization. Recent advances in language models (LMs) offer a promising path forward: their embeddings capture latent relationships in a unifying way, enabling universal optimization across different data types possible. In this paper, we discuss multiple potential approaches, including an end-to-end learning framework in the form of next-token prediction, as well as prioritizing the learning of latent spaces with strong representational capabilities. To validate the effectiveness of these methods, we collect offline BBO tasks and data from open-source academic works for training. Experiments demonstrate the universality and effectiveness of our proposed methods. Our findings suggest that unifying language model priors and learning string embedding space can overcome traditional barriers in universal BBO, paving the way for general-purpose BBO algorithms. The code is provided at https://github.com/lamda-bbo/universal-offline-bbo.
Kernel-based hypothesis tests offer a flexible, non-parametric tool to detect high-order interactions in multivariate data, beyond pairwise relationships. Yet the scalability of such tests is limited by the computationally demanding permutation schemes used to generate null approximations. Here we introduce a family of permutation-free high-order tests for joint independence and partial factorisations of $d$ variables. Our tests eliminate the need for permutation-based approximations by leveraging V-statistics and a novel cross-centring technique to yield test statistics with a standard normal limiting distribution under the null. We present implementations of the tests and showcase their efficacy and scalability through synthetic datasets. We also show applications inspired by causal discovery and feature selection, which highlight both the importance of high-order interactions in data and the need for efficient computational methods.
We introduce an approach to topic modelling with document-level covariates that remains tractable in the face of large text corpora. This is achieved by de-emphasizing the role of parameter estimation in an underlying probabilistic model, assuming instead that the data come from a fixed but unknown distribution whose statistical functionals are of interest. We propose combining a convex formulation of non-negative matrix factorization with standard regression techniques as a fast-to-compute and useful estimate of such a functional. Uncertainty quantification can then be achieved by reposing non-parametric resampling methods on top of this scheme. This is in contrast to popular topic modelling paradigms, which posit a complex and often hard-to-fit generative model of the data. We argue that the simple, non-parametric approach advocated here is faster, more interpretable, and enjoys better inferential justification than said generative models. Finally, our methods are demonstrated with an application analysing covariate effects on discourse of flavours attributed to Canadian beers.
Computational inverse problems for biomedical simulators suffer from limited data and relatively high parameter dimensionality. This often requires sensitivity analysis, where parameters of the model are ranked based on their influence on the specific quantities of interest. This is especially important for simulators used to build medical digital twins, as the amount of data is typically limited. For expensive models, such as blood flow models, emulation is employed to expedite the simulation time. Parameter ranking and fixing using sensitivity analysis are often heuristic, though, and vary with the specific application or simulator used. The present study provides an innovative solution to this problem by leveraging polynomial chaos expansions (PCEs) for both multioutput global sensitivity analysis and formal parameter identifiability. For the former, we use dimension reduction to efficiently quantify time-series sensitivity of a one-dimensional pulmonary hemodynamics model. We consider both Windkessel and structured tree boundary conditions. We then use PCEs to construct profile-likelihood confidence intervals to formally assess parameter identifiability, and show how changes in experimental design improve identifiability. Our work presents a novel approach to determining parameter identifiability and leverages a common emulation strategy for enabling profile-likelihood analysis in problems governed by partial differential equations.
The field of controllable image generation has seen significant advancements, with various architectures improving generation layout consistency with control signals. However, contemporary methods still face challenges in bridging the semantic gap between input text prompts with sparse semantics and the target images, often over-relying on low-level control signals to infer regional details. To address this challenge, we propose ControlThinker, a novel framework that employs a "comprehend-then-generate" paradigm. Firstly, by incentivizing the visual reasoning capability of a MLLM, latent semantics from control images are mined to enrich text prompts. This enriched semantic understanding then seamlessly aids in image generation without the need for additional complex modifications. To further tackle the uncertainty arising from the ambiguity of control images, we encourage broader exploration of reasoning trajectories and select the optimal one using a metric-based output reward model (ORM). Extensive experimental results demonstrate that ControlThinker effectively mitigates the semantic gap between raw text prompts and target images, resulting in improved visual quality and semantic consistency across a wide range of benchmarks. The code and models are available at https://github.com/Maplebb/ControlThinker.
Graph Neural Networks (GNNs) have recently been found to excel in histopathology. However, an important histopathological task, where GNNs have not been extensively explored, is the classification of glomeruli health as an important indicator in nephropathology. This task presents unique difficulties, particularly for the graph construction, i.e., the identification of nodes, edges, and informative features. In this work, we propose a pipeline composed of different traditional and machine learning-based computer vision techniques to identify nodes, edges, and their corresponding features to form a heterogeneous graph. We then proceed to propose a novel heterogeneous GNN architecture for glomeruli classification, called HIEGNet, that integrates both glomeruli and their surrounding immune cells. Hence, HIEGNet is able to consider the immune environment of each glomerulus in its classification. Our HIEGNet was trained and tested on a dataset of Whole Slide Images from kidney transplant patients. Experimental results demonstrate that HIEGNet outperforms several baseline models and generalises best between patients among all baseline models. Our implementation is publicly available at https://github.com/nklsKrmnn/HIEGNet.git.
Recent advanced large reasoning models (LRMs) leverage extended chain-of-thought (CoT) reasoning to solve complex tasks, achieving state-of-the-art performance. Despite their success, we identify a critical issue: a substantial portion of simple tasks solved by LRMs can also be addressed by non-reasoning LLMs using significantly fewer tokens, indicating the complex reasoning may not always be necessary. To address this, we systematically analyze the reasoning trajectories of LRMs and present a method utilizing identified paradigms and LLM-Judge to classify these trajectories as either Redundant Reasoning or Essential Reasoning. And we introduce OThink-R1, a method that prunes redundant reasoning steps while preserving logical validity. OThink-R1 dynamically employs the non-thinking mode (fast-thinking) for straightforward problems while engaging in deliberate thinking (slow-thinking) for complex problems. Experiments across mathematical and question-answering tasks demonstrate that OThink-R1 reduces reasoning redundancy by almost 23\% on average without compromising accuracy, offering practical guidelines for efficient reasoning models. The code is available at https://github.com/AgenticIR-Lab/OThink-R1.
Despite recent advances in protein-ligand structure prediction, deep learning methods remain limited in their ability to accurately predict binding affinities, particularly for novel protein targets dissimilar from the training set. In contrast, physics-based binding free energy calculations offer high accuracy across chemical space but are computationally prohibitive for large-scale screening. We propose a hybrid approach that approximates the accuracy of physics-based methods by training target-specific neural networks on molecular dynamics simulations of the protein in complex with random small molecules. Our method uses force matching to learn an implicit free energy landscape of ligand binding for each target. Evaluated on six proteins, our approach achieves competitive virtual screening performance using 100-500 $\mu$s of MD simulations per target. Notably, this approach achieves state-of-the-art early enrichment when using the true pose for active compounds. These results highlight the potential of physics-informed learning for virtual screening on novel targets. We publicly release the code for this paper at https://github.com/molecularmodelinglab/lfm under the MIT license.
Despite recent progress in text-to-image (T2I) generation, existing models often struggle to faithfully capture user intentions from short and under-specified prompts. While prior work has attempted to enhance prompts using large language models (LLMs), these methods frequently generate stylistic or unrealistic content due to insufficient grounding in visual semantics and real-world composition. Inspired by recent advances in reasoning for language model, we propose RePrompt, a novel reprompting framework that introduces explicit reasoning into the prompt enhancement process via reinforcement learning. Instead of relying on handcrafted rules or stylistic rewrites, our method trains a language model to generate structured, self-reflective prompts by optimizing for image-level outcomes. The tailored reward models assesse the generated images in terms of human preference, semantic alignment, and visual composition, providing indirect supervision to refine prompt generation. Our approach enables end-to-end training without human-annotated data. Experiments on GenEval and T2I-Compbench show that RePrompt significantly boosts spatial layout fidelity and compositional generalization across diverse T2I backbones, establishing new state-of-the-art results.
Object detectors have achieved remarkable performance in many applications; however, these deep learning models are typically designed under the i.i.d. assumption, meaning they are trained and evaluated on data sampled from the same (source) distribution. In real-world deployment, however, target distributions often differ from source data, leading to substantial performance degradation. Domain Generalisation (DG) seeks to bridge this gap by enabling models to generalise to Out-Of-Distribution (OOD) data without access to target distributions during training, enhancing robustness to unseen conditions. In this work, we examine the generalisability and robustness of state-of-the-art object detectors under real-world distribution shifts, focusing particularly on spatial domain shifts. Despite the need, a standardised benchmark dataset specifically designed for assessing object detection under realistic DG scenarios is currently lacking. To address this, we introduce Real-World Distribution Shifts (RWDS), a suite of three novel DG benchmarking datasets that focus on humanitarian and climate change applications. These datasets enable the investigation of domain shifts across (i) climate zones and (ii) various disasters and geographic regions. To our knowledge, these are the first DG benchmarking datasets tailored for object detection in real-world, high-impact contexts. We aim for these datasets to serve as valuable resources for evaluating the robustness and generalisation of future object detection models. Our datasets and code are available at https://github.com/RWGAI/RWDS.
Single-cell omics technologies have transformed our understanding of cellular diversity by enabling high-resolution profiling of individual cells. However, the unprecedented scale and heterogeneity of these datasets demand robust frameworks for data integration and annotation. The Cell Ontology (CL) has emerged as a pivotal resource for achieving FAIR (Findable, Accessible, Interoperable, and Reusable) data principles by providing standardized, species-agnostic terms for canonical cell types - forming a core component of a wide range of platforms and tools. In this paper, we describe the wide variety of uses of CL in these platforms and tools and detail ongoing work to improve and extend CL content including the addition of transcriptomically defined types, working closely with major atlasing efforts including the Human Cell Atlas and the Brain Initiative Cell Atlas Network to support their needs. We cover the challenges and future plans for harmonising classical and transcriptomic cell type definitions, integrating markers and using Large Language Models (LLMs) to improve content and efficiency of CL workflows.
Generative modeling aims to produce new random examples from an unknown target distribution, given access to a finite collection of examples. Among the leading approaches, denoising diffusion probabilistic models (DDPMs) construct such examples by mapping a Brownian motion via a diffusion process driven by an estimated score function. In this work, we first provide empirical evidence that DDPMs are robust to constant-variance noise in the score evaluations. We then establish finite-sample guarantees in Wasserstein-2 distance that exhibit two key features: (i) they characterize and quantify the robustness of DDPMs to noisy score estimates, and (ii) they achieve faster convergence rates than previously known results. Furthermore, we observe that the obtained rates match those known in the Gaussian case, implying their optimality.
Computational modeling of the brain has become a key part of understanding how the brain clears metabolic waste, but patient-specific modeling on a significant scale is still out of reach with current methods. We introduce a novel approach for leveraging model order reduction techniques in computational models of brain geometries to alleviate computational costs involved in numerical simulations. Using image registration methods based on magnetic resonance imaging, we compute inter-brain mappings which allow previously computed solutions on other geometries to be mapped on to a new geometry. We investigate this approach on two example problems typical of modeling of glymphatic function, applied to a dataset of 101 MRI of human patients. We discuss the applicability of the method when applied to a patient with no known neurological disease, as well as a patient diagnosed with idiopathic Normal Pressure Hydrocephalus displaying significantly enlarged ventricles
Pathogen genome data offers valuable structure for spatial models, but its utility is limited by incomplete sequencing coverage. We propose a probabilistic framework for inferring genetic distances between unsequenced cases and known sequences within defined transmission chains, using time-aware evolutionary distance modeling. The method estimates pairwise divergence from collection dates and observed genetic distances, enabling biologically plausible imputation grounded in observed divergence patterns, without requiring sequence alignment or known transmission chains. Applied to highly pathogenic avian influenza A/H5 cases in wild birds in the United States, this approach supports scalable, uncertainty-aware augmentation of genomic datasets and enhances the integration of evolutionary information into spatiotemporal modeling workflows.
Proteins are fundamental to biology, executing diverse functions through complex physicochemical interactions, and they hold transformative potential across medicine, materials science, and environmental applications. Protein Language Models (pLMs) aim to unlock insights from the vast space of unlabeled protein sequences by learning rich, semantic representations from primary sequences via masked language modeling. However, these models typically exhibit limited generative capacity. In this work, we introduce the Diffusion Sequence Model (DSM), a novel pLM trained with masked diffusion to enable both high-quality representation learning and generative protein design. DSM builds upon the ESM2 architecture by incorporating a masked forward diffusion process inspired by the LLaDA framework. After training, DSM is capable of generating diverse, biomimetic sequences that align with expected amino acid compositions, secondary structures, and predicted functions, even with 90\% token corruption. Furthermore, DSM's learned representations match or exceed those of similarly sized pLMs on downstream tasks. We also introduce DSM(ppi), a variant fine-tuned to generate protein binders by attending to target sequences. We demonstrate DSM(ppi)'s effectiveness on the challenging Bench-tested Binder Benchmark (BenchBB), where both DSM and DSM(ppi) produce candidates with superior predicted binding affinity compared to known binders. Our results establish masked diffusion as a powerful paradigm for unifying protein representation and generation in a single framework.
Machine learning has promised to change the landscape of laboratory chemistry, with impressive results in molecular property prediction and reaction retro-synthesis. However, chemical datasets are often inaccessible to the machine learning community as they tend to require cleaning, thorough understanding of the chemistry, or are simply not available. In this paper, we introduce a novel dataset for yield prediction, providing the first-ever transient flow dataset for machine learning benchmarking, covering over 1200 process conditions. While previous datasets focus on discrete parameters, our experimental set-up allow us to sample a large number of continuous process conditions, generating new challenges for machine learning models. We focus on solvent selection, a task that is particularly difficult to model theoretically and therefore ripe for machine learning applications. We showcase benchmarking for regression algorithms, transfer-learning approaches, feature engineering, and active learning, with important applications towards solvent replacement and sustainable manufacturing.
Deciphering protein function remains a fundamental challenge in protein representation learning. The task presents significant difficulties for protein language models (PLMs) due to the sheer volume of functional annotation categories and the highly imbalanced distribution of annotated instances across biological ontologies. Inspired by the remarkable success of reinforcement learning from human feedback (RLHF) in large language model (LLM) alignment, we propose AnnoDPO, a novel multi-modal framework for protein function prediction that leverages Direct Preference Optimization (DPO) to enhance annotation learning. Our methodology addresses the dual challenges of annotation scarcity and category imbalance through preference-aligned training objectives, establishing a new paradigm for biological knowledge integration in protein representation learning.
Understanding how the brain learns may be informed by studying biologically plausible learning rules. These rules, often approximating gradient descent learning to respect biological constraints such as locality, must meet two critical criteria to be considered an appropriate brain model: (1) good neuroscience task performance and (2) alignment with neural recordings. While extensive research has assessed the first criterion, the second remains underexamined. Employing methods such as Procrustes analysis on well-known neuroscience datasets, this study demonstrates the existence of a biologically plausible learning rule -- namely e-prop, which is based on gradient truncation and has demonstrated versatility across a wide range of tasks -- that can achieve neural data similarity comparable to Backpropagation Through Time (BPTT) when matched for task accuracy. Our findings also reveal that model architecture and initial conditions can play a more significant role in determining neural similarity than the specific learning rule. Furthermore, we observe that BPTT-trained models and their biologically plausible counterparts exhibit similar dynamical properties at comparable accuracies. These results underscore the substantial progress made in developing biologically plausible learning rules, highlighting their potential to achieve both competitive task performance and neural data similarity.