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01.
arXiv (CS.LG) 2026-06-18

Estimating carbon pools in the European Shelf sea environment: replacing reanalysis by model-informed machine learning?

Authors:

arXiv:2508.10178v3 Announce Type: replace-cross Abstract: Shelf seas are important for the economy and the carbon cycle, but shelf sea observations for carbon pools are often sparse, or highly uncertain. An alternative can be provided by carbon reanalyses (whether assimilating proxy variables, such as chlorophyll-$a$, or directly carbon), but these are often expensive to run. We propose to use a computationally cheap ensemble of neural networks (i.e. deep ensemble) to learn the relationship between the directly observable (atmospheric, riverine and ocean) variables and marine carbon pools from a coupled physics-biogeochemistry model. The deep ensemble was trained on a North-West European Shelf (NWES) physical-biogeochemistry model free run simulation. After training, the deep ensemble was run using inputs from the NWES reanalysis instead of the free run, demonstrating that it can efficiently predict several NWES carbon pools (e.g., detritus, zooplankton, heterotrophic bacteria) in much better agreement with the reanalysis than the free run, while also providing uncertainty information. We further show that the deep ensemble performs similarly well when it is driven directly by the observations assimilated into the reanalysis, with the limitation that carbon pools can then be predicted only at the observed locations and times. We focus on explainability of the results and demonstrate potential use of the deep ensembles for future climate what-if scenarios. We suggest that model-informed machine learning presents a viable alternative to expensive reanalyses and could complement observations, wherever they are missing and/or highly uncertain.

02.
arXiv (CS.AI) 2026-06-11

Agents All the Way Down; A Methodology for Building Custom AI Agents from Substrate to Production

arXiv:2606.11869v1 Announce Type: cross Abstract: Custom AI agents areagents that live inside their own application, talk to their own data and tools, enforce their own security boundaries, and carry their own brand and audit trail. What separates them from the general-purpose tier is fit, not capability: each is built for one job, by the engineer who will maintain it. No published practice sets out how to build one end to end. The pieces are everywhere (function-calling APIs, the Model Context Protocol, code agents to pair with), but the practice that chains them lives in podcasts, blogs, and leaked system prompts. This paper writes that practice down as a methodology, Agents All the Way Down: two preconditions crossed once and kept, then three practices repeated for the agent's life. The preconditions are (P1) Substrate, the LLM as a software component, framed as tools, then system, then messages under prompt-caching; and (P2) Building blocks: function calling, MCP, CLI orchestration, the liteshell pattern, the agent loop, skills, characters, hooks, and scaffolding. The practices are (P3) prototype with a general-purpose agent; (P4) harvest, fold, and ship the result as a CLI, the Turtle pattern; and (P5) agent-tests-agent, in which a general-purpose agent drives it through behavioural scenarios, a complement to classical testing, not a replacement. The working loop is P3 to P4 to P5 and back, and one corollary falls out for free: multi-agent orchestration is just CLI composition. The methodology is framework-free by construction. It was distilled from the AAC, a custom agent for the open-source LAMB platform, built in about ten days by one developer with an AI pair-programmer and in production . We present it as a transferable practice, independent of any language or framework.

03.
arXiv (CS.CL) 2026-06-11

Debiasing Without Protected Attributes: Latent Concept Erasure from Textual Profiles

Most fairness research in NLP assumes direct access to protected attributes such as gender, race, or nationality. In practice, however, such information is often unavailable due to privacy constraints, missing metadata, or legal restrictions, even though models may infer it from indirect textual cues. This raises a key question: can debiasing succeed without direct access to sensitive attributes? We propose H-SAL, which performs post-hoc concept and attribute erasure using self-description text as an implicit debiasing signal. To support this setting, we introduce a multi-domain Stack Exchange-based fairness benchmark for helpfulness prediction that includes both explicit and implicit signals, enabling comparison between standard debiasing with protected labels and debiasing without access to sensitive information. Across encoder and decoder-only language models, we find that implicit self-description often matches or outperforms explicit-label-based debiasing. Our results broaden representation-level fairness research and provide a new benchmark for studying debiasing under realistic data constraints.

04.
medRxiv (Medicine) 2026-06-23

Shared Polygenic Architecture Across Arteriopathies: An Integrative Cross-Trait Analysis

Background: Non-monogenic arteriopathies are often classified as distinct entities according to the arterial territory involved, yet they share clinical features and may co-occur in the same individual. This pattern suggests shared susceptibility across anatomically distinct arteriopathies, potentially driven by common biological and genetic mechanisms. Methods: We investigated the shared genetic architecture of five arteriopathies (cervical artery dissection (CeAD), intracranial aneurysm (IA), spontaneous coronary artery dissection (SCAD), aortic aneurysm and dissection (AAD), and fibromuscular dysplasia (FMD)) using LD score regression, Association analysis based on SubSETs (ASSET), pairwise Multi-Trait Analysis of Genome-wide association summary statistics (MTAG), pleiotropy mapping and Mendelian randomization (MR) to identify shared loci and prioritise candidate causal genes. Results: LD score regression identified significant positive genetic correlations between CeAD-SCAD (rg = 0.64), IA-AAD (rg = 0.33), IA-SCAD (rg = 0.37), CeAD-AAD (rg = 0.56) and SCAD-AAD (rg = 0.20). ASSET identified 37 shared independent loci, and in MTAG analyses, one novel locus was identified for CeAD and SCAD (SLC39A8) and one for IA (FGF5). 13 loci showed strong cross-trait colocalization, including PHACTR1, LRP1, and CDKN2B-AS1. Using the Genotype-Phenotype Map, we found that arteriopathy-associated variants colocalized with blood pressure- and migraine-related traits, while many showed effect directions opposite to those observed for coronary artery disease. Proteome-wide MR identified 67 circulating proteins associated with at least one trait, including ECM1 and SHISA5 for CeAD and FGF5 for IA, with 17 supported by colocalization. Transcriptome-wide MR identified 204 colocalized tissue?specific signals, of which, 14 were shared across multiple traits. Enrichment analyses implicated pathways related to vascular development, smooth muscle cell function, extracellular matrix organization, and TGF-? signaling. Conclusions: These findings support shared genetic architecture across anatomically distinct arteriopathies, implicating pathways involved in vascular structure and prioritising therapeutic targets for future mechanistic investigation.

05.
arXiv (CS.LG) 2026-06-16

Unsupervised Learning for Missing Modalities in Multimodal Learning

arXiv:2606.15743v1 Announce Type: new Abstract: This paper addresses the missing-modality challenge in multi-modal learning by introducing Unsupervised Learning for Missing Modalities in Multi-Modal Learning (UL4M4), a flexible framework that imputes missing feature embeddings in a task-independent manner before supervised prediction. We propose modality-specific normalization and a novel partial-modality distance metric to enable fair clustering of incomplete observations, capturing cross-modal structures while preserving scale-invariance across varying dimensionalities and modality counts. Cluster centers from this unsupervised stage guide an iterative greedy imputation process for any missing modalities during training or inference, supporting arbitrary numbers of modalities and arbitrary missing patterns per sample. The imputation module is lightweight, uses frozen encoders, and decouples from the downstream task, allowing easy integration with any fusion/prediction architecture. Extensive experiments under diverse and highly incomplete regimes demonstrate UL4M4's robustness, achieving, to the best of our knowledge, the first consistent F1-Micro scores above 0.7 on challenging missing configurations even when more than 50\% of modality slots are missing. Results are also stable across cluster sizes and significantly outperform state-of-the-art baselines. Code is available here: https://github.com/h-ismkhan/Multimodal-Learning-with-Missing-Modalities-via-Unsupervised-Learning.

06.
Nature (Science) 2026-06-10

Confirmation that bryozoan animals were present during the Cambrian explosion

Authors: Unknown Author

Bryozoans are marine invertebrates that live in colonies and have long been considered absent from the Cambrian explosion — a rapid evolutionary event that began around 538 million years ago. Newly discovered fossils from the Cambrian period reveal that the bryozoan phylum had already diversified by this time. Fossils of two forms of bryozoans show evidence of soft tissue still preserved inside their mineralized skeletons.

07.
arXiv (CS.LG) 2026-06-18

Stealthy World Model Manipulation via Data Poisoning

arXiv:2606.18697v1 Announce Type: new Abstract: Model-based learning agents use learned world models to predict future states, plan actions, and adapt to new environments. However, the process of updating world models from collected experience creates a training-time attack surface: adversarially poisoned fine-tuning trajectories can manipulate the learned dynamics and thereby corrupt downstream planning. In this paper, we propose SWAAP, the first two-stage data poisoning framework for learned world models. In the first stage, SWAAP identifies a harmful target world model that induces low-return behavior under planning while remaining close to clean dynamics, using first-order bilevel optimization enabled by a transition-gradient theorem. In the second stage, SWAAP realizes this target through stealth-constrained gradient matching, modifying only a limited fraction of fine-tuning transition targets so that the induced training gradients steer the victim model toward the adversarial target, while a prediction-error regularizer encourages the poisoned targets to remain close to the world model's natural approximation error. To assess attack stealthiness, we evaluate defenses and detectability across three stages of the poisoning pipeline: pre-training detection of poisoned transitions, robust training during fine-tuning, and test-time monitoring of the resulting world model. Across diverse continuous-control tasks, SWAAP causes substantial performance degradation while keeping poisoned transitions close to clean data and evading the evaluated non-adaptive residual/CUSUM/TRIM-style defenses. These results reveal a practical vulnerability in world-model adaptation pipelines and highlight the need for robustness methods that protect both world-model training data and learned dynamics.

08.
arXiv (CS.LG) 2026-06-16

LoComposition: Terrain-Adaptive Energy-Efficient Quadruped Locomotion without Gait Priors

arXiv:2606.15896v1 Announce Type: cross Abstract: Learning-based quadrupedal locomotion typically relies on complex reward formulations that entangle task specification, operational limits, gait preference, and terrain adaptation within a single optimization objective. We instead treat these functions through distinct mechanisms: rewards for task specification, constraints for operational limits, energy minimization for gait preference, and exteroceptive perception for adapting energy use to terrain difficulty. We show that these components jointly enable efficient, terrain-adaptive locomotion, and that removing each component exposes a distinct failure mode. Our formulation removes explicit gait priors (including air-time, contact-count, and foot-clearance targets) in favor of emergent behavior. Compared to a conventional complex-reward baseline, our formulation achieves comparable terrain traversal while reducing cost of transport by 56% and operational-limit violations by 96%. The resulting policies transfer zero-shot to a physical Unitree Go2 using LiDAR-based elevation mapping. Project website with videos: https://tinyurl.com/locomposition.

09.
arXiv (CS.AI) 2026-06-12

AgentRivet: an automated system for producing Rivet routines from journal publications

arXiv:2606.13535v1 Announce Type: cross Abstract: Particle physics collider experiments provide Rivet routines as part of the analysis preservation strategy for model-independent measurements. Rivet is a C++ toolkit that allow new theoretical models to be compared to the measurements, thus aiding the development and tuning of Monte Carlo event generators as well as searches for physics beyond the Standard Model. However, analysis coverage is known to be incomplete, with only 39% of measurements having documented and publicly available Rivet routines. In this article, we design and implement an automated workflow based on Large Language Models with the goal of providing the missing routines. This multi-step workflow, referred to as AgentRivet, extracts the physics analysis information from published papers and writes the missing Rivet routines, with intermediate code- and physics- reviews as part of an autonomous quality control. We report the results obtained using commercial Large Language Models, provided by OpenAI, Anthropic, and Google, for two recent measurements from the ATLAS and CMS experiments. We find that AgentRivet produces competent Rivet routines with few syntax errors. The physics fidelity of the routines is reasonable and follows the explanations given in the relevant publications. Nevertheless, physics-implementation issues do arise and are investigated using the artefacts produced by AgentRivet. The majority of physics implementation issues arise from subtle-but-ambiguous definitions in the given publication, although some models struggle to implement complex observables even when clear definitions are given.

10.
arXiv (CS.AI) 2026-06-16

AgentFairBench: Do LLM Agents Discriminate When They Act?

arXiv:2606.16723v1 Announce Type: new Abstract: Large language model (LLM) agents increasingly take actions (screening applicants, recommending credit, triaging patients), yet fairness for LLMs is still measured by grading answers. We introduce AgentFairBench, a cheap, reproducible, multi-domain benchmark for demographic disparity in the actions of LLM agents. Grounded in a companion framework, the Bias Conduction Framework (BCF, restated here), it spans three regulator-anchored domains: hiring, lending, and medical triage. Synthetic, demographic-neutral profiles are evaluated in counterfactual matched sets that vary only a name-coded race x gender signal (in the Bertrand Mullainathan tradition), under four agent scaffolds of increasing agency (direct, chain-of-thought, multi-agent deliberation, tool-augmented). A NumPy-only harness computes counterfactual flip rate, mean absolute score difference (MASD), action-rate disparity, and tool-invocation disparity, with bootstrap confidence intervals, paired tests, and false-discovery-rate control, for single-digit dollars per model. A live leaderboard with a held-out private split and a contamination canary admits external models by submission. Our pilot (864 decisions plus a test-retest replication) carries a methodological lesson: comparing a six-group score spread against a two-run noise difference overstates disparity by ~ 2.4X through statistic arity alone. Against an arity matched noise floor and an omnibus group test, claude haiku 4 5 shows no demographic effect above sampling noise (0 of 120 pairwise and 0 of 9 omnibus contrasts survive correction); a planted-bias test confirms the instrument detects disparity when present. The contribution is a sound, sensitive, adoption-ready instrument, the arity matched null methodology, and open artifacts to scale it. Code, data, and harness are released under open licenses, with an anonymized review artifact.

11.
arXiv (CS.CV) 2026-06-12

JointEdit3D: Feed-Forward 3D Scene Editing in a Unified Latent Space

Existing 3D scene editing methods typically rely on per-scene optimization over explicit 3D representations or cascaded edit-and-reconstruct pipelines, resulting in high test-time cost, limited 3D awareness, and structural inconsistencies. To couple appearance synthesis and geometry prediction during editing, we build on a unified RGB-geometry reconstruction-generation latent space and adapt it to feed-forward 3D scene editing. The resulting framework, JointEdit3D, performs asymmetric latent inpainting by observing only a single edited RGB reference latent and generating the remaining RGB views and edited geometry latent under source-scene anchoring. JointEdit3D introduces a dedicated SceneAnchor Branch to inject source-scene structure without forcing direct copying, and adopts edit/background-aware losses to balance edited-region fidelity with unedited-content preservation. To address the lack of paired resources for standardized 3D scene editing evaluation, we introduce SceneEdit3D-15K, a dataset with 15K paired editing samples and renderer-provided 3D annotations, together with SceneEdit3D-Bench, a curated 100-sample benchmark. Experiments show that JointEdit3D improves edited-region quality and 3D structural completeness over prior baselines while maintaining competitive background preservation.

12.
arXiv (CS.CV) 2026-06-16

Last But Not Least: Boundary Attention CalibratiON for Multimodal KV Cache Compression

Multimodal Large Language Models (MLLMs) achieve strong vision-language reasoning, but long visual contexts enlarge the KV cache and increase decoding latency. Existing compression methods rely on observation window attention for stable token-importance estimation, yet this aggregation can dilute sparse visual evidence and discard answer-critical tokens under aggressive compression. Therefore, we identify last-query attention as a complementary source for recovering such evidence, but its answer-irrelevant signals can mislead retention. We propose BACON, a plug-and-play method that calibrates observation window attention with last-query evidence and suppresses isolated noise via intra-layer coherence and inter-layer persistence. Across diverse benchmarks, models, budgets, and compression methods, BACON improves multimodal KV compression by 7.5% on average under the most aggressive budget, with gains up to 30.9%.

13.
arXiv (CS.LG) 2026-06-17

VISTA: Scale-Aware Visual Navigation via Action History Conditioning

arXiv:2606.17294v1 Announce Type: cross Abstract: Vision Navigation Foundation Models (VNMs) promise end-to-end learned navigation policies capable of zero-shot deployment across diverse embodiments and environments. To maintain generality, many vision-based navigation models predict normalized actions. However, this normalization introduces a critical deployment vulnerability: applying different scaling factors to the same normalized trajectory alters its physical geometry, which degrades navigation performance and increases collision risks. We address this vulnerability by conditioning the model on normalized action histories alongside image observations, providing explicit context on the relationship between the model's predictions and the robot's actual physical displacement. Furthermore, current VNMs often struggle in visually repetitive environments that lack distinct features. To resolve this issue, we integrate a DINOv3 encoder, whose richer representations enable our model to capture both spatial and geometric dimensions between observations. VISTA generalizes robustly to out-of-distribution environments, achieving 100% goal prediction accuracy in zero-shot, real-world deployment in Outdoor, Forest and Office settings, and an average of 95% checkpoints crossed, demonstrating consistent path following in unseen environments.

14.
arXiv (CS.CL) 2026-06-19

Actionable Activation Directions for Detecting and Mitigating Emergent Misalignment Across Language Model Families

Fine-tuning language models on insecure code induces emergent misalignment with poorly understood internal structure. We investigate whether this misalignment corresponds to a causally actionable activation-space direction shared across architectures. Across four instruction-tuned model families (Qwen2.5-1.5B, Gemma-2-2B, Llama-3.2-1B, Ministral-3-3B) finetuned identically, a difference-in-means direction achieves 99.6% separation of aligned and misaligned activations at each model's final layer. Causal steering by subtracting this direction reduces code spillover by 21-51 points, while a secure-code control confirms content specificity. Cross-architecture transfer via ridge regression maps yields large behavioral suppression (up to 46 points) but fails specificity controls as random and orthogonal directions perform comparably. We identify a two-tier specificity structure: within-model directions are causally specific and actionable; cross-model directions are causally real but non-specific. An asymmetric transfer topology emerges, with Gemma and Qwen acting as geometric donors and Llama as a receiver. These findings define the limits of linear cross-architecture correction and recommend within-model probing for auditing.

15.
arXiv (quant-ph) 2026-06-12

Asymmetric quantum steering harvested near a Lorentz-violating BTZ black hole

arXiv:2606.12766v1 Announce Type: cross Abstract: We investigate the harvesting of quantum steering and its directional asymmetry between two Unruh-DeWitt detectors in a Lorentz-violating BTZ black hole spacetime. Since the detectors are located at different radial positions outside the black hole, they experience inequivalent local environments induced by gravitational redshift, causing Alice to undergo stronger effective thermal noise than Bob. Remarkably, we uncover a counterintuitive phenomenon in which the detector subjected to a higher effective temperature exhibits stronger steerability than the other one, revealing a nontrivial inversion of thermal intuition in curved spacetime. Furthermore, quantum steering survives only within a finite window of detector energy gaps and reaches its maximum within an optimal regime. We find that Lorentz violation suppresses steering most strongly near this optimal energy gap, indicating an enhanced sensitivity of maximal correlation extraction to symmetry breaking effects. Our results demonstrate that Lorentz violation acts as a geometric constraint on the quantum information capacity of spacetime, simultaneously restricting both the strength and the directionality of quantum correlations.

16.
arXiv (CS.LG) 2026-06-19

A Solver-Free Training Method for Predict-then-Optimize

arXiv:2606.19587v1 Announce Type: cross Abstract: We propose a scalable method for training prediction (machine learning) models in the predict-then-optimize paradigm, where model outputs serve as coefficients for a subsequent linear optimization task. Directly minimizing the empirical decision regret is intractable for linear programming and combinatorial optimization since the decision mapping is piecewise constant, and the gradients are zero almost everywhere. While existing methods address this by smoothing the differentiation process, they suffer from scalability issues, since a computationally expensive solver call is required for every gradient evaluation. To address this, we propose a decision-focused learning pipeline based on a measure transformation principle, which yields a new surrogate loss that is completely optimization-solver-free during training. We establish theoretical guarantees, including Fisher consistency and excess risk bounds. Empirically, our method achieves decision quality competitive with state-of-the-art methods while reducing training time by orders of magnitude.

17.
PLOS Computational Biology 2026-06-09

Multi-stable oscillations in cortical networks with two classes of inhibition

by Arnab Dey Sarkar, Bard Ermentrout In the classical view of cortical rhythms, interactions between excitatory pyramidal neurons (E) and inhibitory parvalbumin-expressing interneurons (I) are sufficient to generate gamma- and beta-band oscillations. However, it is now well established that multiple inhibitory interneuron subtypes exist and that they play important roles in the generation and modulation of these rhythms. In this paper, we develop a spiking network model consisting of populations of E, I, and an additional interneuron type, somatostatin-expressing neurons (S), which receive excitation from the E cells and inhibit both the E and I populations. The S cells are further modulated by a third inhibitory subtype, vasoactive intestinal peptide (VIP) neurons, which receive inputs from other cortical areas. We reduce the spiking network to a system of nine differential equations that describe the mean membrane potential, firing rate, and synaptic conductance for each population. Using this reduced model, we identify a wide range of parameters that exhibit multiple coexisting rhythms. Employing tools from nonlinear dynamics, we then explore the roles of the two classes of inhibition, as well as VIP modulation, in shaping the properties of these rhythms.

18.
arXiv (CS.CV) 2026-06-11

Image Quality Assessment of Identity Cards Using Measures from Open Face Image Quality

This paper addresses the challenge of assessing image quality in ID cards in remote verification systems by applying capture-related quality measures from the Open Face Image Quality (OFIQ) standard to ID card images. Our preprocessing pipeline includes corner detection, perspective normalization, and comprehensive foreground masking to ensure accurate and unbiased quality measure computation. We evaluate the effectiveness of these measures by analyzing their correlation with the performance of three presentation attack detection (PAD) algorithms across four diverse ID card datasets, where two datasets contain bona fide, i.e. pristine, images and two contain printed mock ID cards. Our results suggest that quality assessment based on some OFIQ measures can significantly improve PAD performance.

19.
arXiv (CS.AI) 2026-06-15

The Perceived Fragility of Explanations in Audio Models: Manipulation of Attribution with Unchanged Predictions

arXiv:2606.14466v1 Announce Type: cross Abstract: This paper investigates the fragility of post-hoc explanation methods in audio deepfake detection. While previous work on explanation manipulation focused on images using standard $L_p$ metrics, we introduce a psychoacoustic framework that optimizes inaudible perturbations to decouple model attributions from final classifications. We evaluate this vulnerability across state-of-the-art architectures under strict prediction-preserving constraints. By evaluating the manipulation cost through domain-specific perceptual audio quality metrics alongside explanation alignment criteria, our framework demonstrates that an adversary can systematically distort automated explanation heatmaps while preserving the predicted deepfake label. Full code available at: https://github.com/cncPomper/Audio-XAI

20.
arXiv (CS.LG) 2026-06-15

Deep Doubly Debiased Longitudinal Effect Estimation with ICE G-Computation

arXiv:2602.12379v2 Announce Type: replace Abstract: Estimating longitudinal treatment effects is essential for sequential decision-making but is challenging due to treatment-confounder feedback. While Iterative Conditional Expectation (ICE) G-computation offers a principled approach, its recursive structure suffers from error propagation, corrupting the learned outcome regression models. We propose D3-Net, a framework that mitigates error propagation in ICE training and then applies a robust final correction. First, to interrupt error propagation during learning, we train the ICE sequence using Sequential Doubly Robust (SDR) pseudo-outcomes, which provide bias-corrected targets for each regression. Second, we employ a multi-task transformer with a covariate simulator head for auxiliary supervision, regularizing representation learning, and a target network to stabilize training dynamics. For the final estimate, we discard the SDR correction and instead use the uncorrected nuisance models to perform Longitudinal Targeted Minimum Loss-Based Estimation (LTMLE) on the original outcomes. This second-stage, targeted debiasing ensures robustness and optimal finite-sample properties. Comprehensive experiments demonstrate that our model, D3-Net, robustly reduces bias and variance across different horizons, counterfactuals, and time-varying confoundings, compared to existing state-of-the-art ICE-based estimators.

21.
arXiv (CS.LG) 2026-06-19

Shifting-based Optimizable Linear Relaxations for General Activation Functions

arXiv:2606.20292v1 Announce Type: new Abstract: The use of neural networks (NNs) is rapidly increasing, including in safety- and security-critical domains. To provide formal guarantees about NN behavior, many verification methods rely on optimizable linear relaxations of activation functions. However, existing techniques depend on hand-crafted relaxations for each activation function. Extension to state-of-the-art activation functions therefore requires substantial manual effort. In contrast, our approach SLiR (Shifting-based Linear Relaxations) is broadly applicable, requiring only a Lipschitz constant or a set of critical points. SLiR parameterizes relaxations by their slope and computes the corresponding offset via a shifting procedure that ensures sound upper and lower bounds over the input domain, enabling efficient optimization while maintaining correctness. Our experiments show that SLiR produces tight relaxations across a wide range of practical activation functions and enables verification of up to 7.8x more properties compared to state-of-the-art methods.

22.
medRxiv (Medicine) 2026-06-11

Dissecting the functional landscape of rare diseases through genomic variation in a heterogeneous cohort of 11,000 patients

Rare diseases (RDs) remain a major diagnostic challenge. Genetic and phenotypic heterogeneity, incomplete knowledge of disease mechanisms, and limitations in variant clinical interpretation leave many patients without a molecular diagnosis. Meanwhile, the growing volume of genomic data generated in clinical practice offers an opportunity to develop data-driven methodologies for exploring disease mechanisms and improving the reanalysis of unsolved cases. We aggregated real-world genomic data from 11,084 unrelated patients with suspected RD. Patients were clinically classified into 122 diseases. We built a multi-disease genomic variant frequency database (FJD-DB), which enabled the development of variant and gene-disease association scores by means of case-control subcohort comparisons across 32 disease groups. Functional enrichment analyses were then used to highlight disease-associated protein domains, pathways, biological processes, and phenotypes. Finally, the resulting knowledge was integrated into a data-driven framework for the guided reanalysis of unsolved RD patients applied to Inherited Retinal Dystrophies (IRD) patients as first use case. FJD-DB contained more than 45 million unique variants, including ~185,000 potentially pathogenic variants. Disease-specific analyses identified disease-associated pathogenic variants and highlighted both established and candidate disease genes. We detected 179 significantly enriched protein domains across 23 diseases, 124 Human Phenotype Ontology terms across 13 diseases, 79 Reactome pathways across 10 diseases, and 72 Gene Ontology biological processes across 8 diseases, revealing highly disease-specific functional signatures. Integration of disease-specific variant, gene, and functional association signals enabled the development of a data-driven framework for guided reanalysis of unsolved RD cases. Applied to more than 1,100 unsolved IRD cases, the framework generated clinically relevant findings in 26 patients, including four molecular diagnoses, seven candidate diagnoses, and 15 cases upgraded from non-informative findings to variants of uncertain significance. Aggregated real-world genomic data can be leveraged to identify disease-associated molecular signals generating novel biological hypotheses. A unified analytical framework provides a scalable strategy for knowledge discovery and guided reanalysis, facilitating the identification of overlooked and potentially novel genetic causes of RDs.

23.
arXiv (CS.LG) 2026-06-15

Adaptive Identification and Modeling of Clinical Pathways with Process Mining

arXiv:2512.03787v2 Announce Type: replace Abstract: Clinical pathways are specialized healthcare plans that model patient treatment procedures. They are developed to provide criteria-based progression and standardize patient treatment, thereby improving care, reducing resource use, and accelerating patient recovery. However, manual modeling of these pathways based on clinical guidelines and domain expertise is difficult and may not reflect the actual best practices for different variations or combinations of diseases. We propose a two-phase modeling method using process mining, which extends the knowledge base of clinical pathways by leveraging conformance checking diagnostics. In the first phase, historical data of a given disease is collected to capture treatment in the form of a process model. In the second phase, new data is compared against the reference model to verify conformance. Based on the conformance checking results, the knowledge base can be expanded with more specific models tailored to new variants or disease combinations. We demonstrate our approach using Synthea, a benchmark dataset simulating patient treatments for SARS-CoV-2 infections with varying COVID-19 complications. The results show that our method enables expanding the knowledge base of clinical pathways with sufficient precision, peaking to 95.62% AUC while maintaining an arc-degree simplicity of 67.11%.

24.
medRxiv (Medicine) 2026-06-17

Multi-strain Probiotics Alter Gut Microbiota and Estrobolome Pathways in Primary Dysmenorrhea

Background: Exact cause of primary dysmenorrhoea is unknown but recent evidence uncovers a potential link between gut dysbiosis and benign gynaecological disorder via disruption of estrobolome. Methods: A randomized controlled trial to investigate the effects of multi-strain oral probiotics on primary dysmenorrhoea has been conducted. This is a secondary analysis comparing the stool microbiome in women with primary dysmenorrhoea and those without (control), and the effects of treatment with probiotics versus placebo. Results: Although microbial richness and evenness were comparable between groups (alpha diversity, p > 0.05), gut microbial community composition differed significantly (Bray Curtis PERMANOVA, p = 0.015), characterised by reduced Bifidobacterium adolescentis and Blautia and enrichment of Faecalibacterium in dysmenorrhoea, alongside condition-specific core taxa. Post-intervention analysis revealed significant shifts in microbial community structure between pre- and post-treatment groups (PERMANOVA, F = 2.11, p = 0.005), with probiotic supplementation inducing more consistent and directed microbiome changes than placebo, without altering alpha diversity (p > 0.05). Functional prediction showed no significant difference in overall beta glucuronidase pathway abundance (p > 0.05); however, dysmenorrhoea was associated with higher abundance of beta glucuronidase producing taxa (MaAsLin2, q < 0.05) that were differentially modulated by probiotic treatment. Conclusion: This discovery provides evidence on the microbial disruption in primary dysmenorrhoea as well as the benefit of probiotics to modulate the intestinal microbiota to improve the condition.

25.
arXiv (CS.CV) 2026-06-16

Sub-Semantic Image Segmentation

Images can be segmented based on visual cues (i.e., texture segmentation) or into objects (i.e., semantic segmentation). We propose a new category of sub-semantic image segmentation that blurs the line between the two. In sub-semantic image segmentation, language is not used to name whole objects. Instead, it is used to partition an image into stable appearance patterns that can be described by language. To do that, we couple a general-purpose vision-language model to SAM 3, a promptable segmentation backbone whose native text pathway can ground rich descriptions into masks. Simple coupling fails for a number of reasons that we identify in the paper, and we overcome them by introducing DETECTURE that resolves three concrete failure modes – language leakage between texture regions, prompt competition inside the segmentation backbone, and semantic distortion at the language-to-mask interface. Since there is no dataset of sub-semantic image segmentation, we introduce one, termed TextureADE. The new dataset is derived from the ADE20K dataset using a system we designed. We compare DETECTURE to a number of baselines and find that it achieves the strongest performance on several datasets using different metrics. Code is available at https://github.com/Scientific-Computing-Lab/TextureDetecture.