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02.
arXiv (quant-ph) 2026-06-25

High-sensitivity and high-resolution collaborative determination of birefringence coefficient using weak measurement

arXiv:2504.15571v2 Announce Type: replace-cross Abstract: Precise nanofilm birefringence characterization is essential for high-sensitivity polarization response and strong anti-interference detection in photodetectors. We present a high-sensitivity and high-resolution birefringence coefficient determination system for nm-level membranes based on weak measurement, addressing the sensitivity-resolution trade-off. A tunable bandwidth light source is exploited to achieve simultaneous and complementary measurements of momentum (P-pointer) and intensity (I-pointer), enabling calibration-free operation across various bandwidths, and to realize high-precision phase difference monitoring of the measured membranes. This method maps the birefringence effect to a weak-value amplified signal of spectral shift and light intensity. The optimal resolution, achieved at a spectral width of 6 nm, is $1.12 \times 10^{-8}$ RIU, while the optimal sensitivity is achieved when the light source is a narrow-linewidth coherent laser, reaching 4710 mV/RIU. The linear range of the system covers a broad birefringence coefficient range for crystals, from $10^{-6}$ to 0.1. Furthermore, the auxiliary optical path eliminates substrate interference, achieving a detection limit of birefringence coefficient as low as $10^{-8}$ RIU. This approach, characterized by high precision, high sensitivity, and strong robustness, provides an effective solution for the detection of optical nano-thin membrane parameters.

03.
arXiv (CS.CV) 2026-06-25

VENI: Variational Encoder for Natural Illumination

Inverse rendering is an ill-posed problem, but priors such as illumination priors can help simplify it. Existing work either disregards the spherical and rotation-equivariant nature of illumination environments or does not provide a well-behaved latent space. We propose a rotation-equivariant variational autoencoder that models natural illumination on the sphere without relying on 2D projections. To preserve the SO(2)-equivariance of environment maps, we use a novel Vector Neuron Vision Transformer (VN-ViT) as encoder and a rotation-equivariant conditional neural field as decoder. In the encoder, we reduce the equivariance from SO(3) to SO(2) using a novel SO(2)-equivariant fully connected layer, an extension of Vector Neurons. We show that our SO(2)-equivariant fully connected layer outperforms standard Vector Neurons when used in our SO(2)-equivariant model. Compared to previous methods, our variational autoencoder enables smoother interpolation in latent space and offers a more well-behaved latent space.

04.
arXiv (CS.LG) 2026-06-15

Shuttling Compiler for Trapped-Ion Quantum Computers Based on Large Language Models

arXiv:2512.18021v3 Announce Type: replace-cross Abstract: We present the first shuttling compiler based on large language models (LLMs) for trapped-ion quantum computers, where qubits are shuttled between segments for gate execution and qubit storage. We fine-tune pre-trained LLMs on examples from linear and branched one-dimensional shuttling architectures. Thus, we obtain a layout-independent compilation strategy that learns the required shuttling operations directly from data. Using benchmark circuits with up to 16 qubits, such fine-tuned LLMs can now generate valid schedules for shuttling architectures. Notably, we also obtain a valid schedule for a previously unseen four-way junction layout. This demonstrates that trained LLMs can generalize to layouts not encountered during training. For various architectures, LLM-based schedules improve upon state-of-the-art baseline compiler results, reducing the shuttling effort by up to 15%.

05.
arXiv (CS.AI) 2026-06-17

Patients With Personality: Realistic Patient Simulation through Controlled Diversity and Selective Disclosure

arXiv:2606.17441v1 Announce Type: cross Abstract: Simulating realistic patient interactions is a key requirement to testing clinical applications of LLMs at scale without time-consuming and expensive user studies. However, existing approaches often lack realism and controllability, often oversharing information unprompted, and failing to capture the wide variability of patient behavior. Here, we introduce PatientsWithPersonality (PWP), a patient simulation framework that generates realistic yet diverse virtual patient responses through explicit personality parametrization over a latent patient state. Grounded in HEXACO, a six-dimensional personality space used to quantify and parameterize human behavioral traits, our approach enables fine-grained control over conversational style, cooperativeness, and information disclosure within a unified framework. In a clinician evaluation, PWP is judged nearly as realistic as recorded human actors and clearly ahead of prior simulators, while being flagged as "too informative" far less often. Conditioning on HEXACO axes yields personas whose configured traits are recoverable by both clinicians and an autorater, span a substantially wider behavioral footprint than the closest baseline, and prevent oversharing. Altogether, our framework paves the way for more accurate and informative LLM benchmarking through our realistic and steerable patient simulator.

06.
arXiv (quant-ph) 2026-06-25

Forced Gap Post-Selection for Quantum LDPC Codes and their Operations

arXiv:2605.20346v2 Announce Type: replace Abstract: We develop a simple and general post-selection strategy for high-rate quantum codes that is transferrable across decoders. After an initial baseline run, the decoder is re-run once per logical observable, and forced in these latter runs to provide a solution where the given observable has the complementary outcome. Shots are rejected that find logically complementary solutions with similar likelihoods compared to the baseline. Using the Relay-BP decoder, we benchmark the strategy on the $72$-qubit and $144$-qubit bivariate bicycle codes, as well as surgery gadgets for the latter. In comparison to previous post-selection strategies, our results offer an improved logical error rate by over a factor of $4$ on the same circuit and physical error rate, and at the same rate of post-selection. Our strategies are also lightweight, relying only on FPGA-friendly belief propagation, whereas the previous best used repeated rounds of a high-latency BP-OSD decoder.

07.
arXiv (CS.CL) 2026-06-16

Know Your Limits : On the Faithfulness of LLMs as Solvers and Autoformalizers in Legal Reasoning

Large Language Models (LLMs) achieve strong performance on reasoning tasks, but whether this reflects faithful logical inference or heuristic approximation remains unclear. We study this question in legal entailment by comparing three paradigms, including pure LLM classification, LLM-based Formal Reasoning, and solver-based Formal Reasoning using the Z3 SMT solver, on a re-annotated subset of ContractNLI across five LLMs. Our re-annotation reveals a systematic and measurable gap between pragmatic legal interpretation and strict formal entailment, where a substantial proportion of legally sound inferences are not formally grounded without additional unstated assumptions. While introducing formal structure improves accuracy, with LLM-based Formal Reasoning achieving the highest benchmark performance, we show that this gain does not imply faithful reasoning. We identify three recurring failure modes: scope laundering, where LLMs report solver-inconsistent classifications without executing the underlying formal reasoning, producing conclusions that appear logically grounded but are not; implicit constraint blindness, where LLMs overlook logical constraints present in formal representations; and program synthesis failures, where LLMs generate incorrect Z3 code despite structured prompting. Critically, scope laundering persists across all models, raising serious concerns about the faithfulness of LLM-based formal reasoning as a proxy for symbolic execution. These results reveal a fundamental gap between benchmark accuracy and logical faithfulness.

08.
arXiv (quant-ph) 2026-06-17

Split-Head Quantum Generative Adversarial Network for Crystalline Material Discovery

arXiv:2606.17852v1 Announce Type: new Abstract: The discovery of novel crystalline materials is a critical challenge in computational materials science, often limited by the spatial representation limitations and mode collapse typical of classical generative models. Traditionally, developing Quantum GANs for continuous 3D space is hindered by the limited capacity of near-term hardware. To overcome this, we adapt a physics-informed "split-head" architecture right from the quantum trunk to explicitly decouple macroscopic lattice bounds from microscopic atomic coordinates, significantly maximizing resource efficiency. This study disentangles the contributions of quantum circuits from these architectural priors by evaluating a Split-Head Quantum Generative Adversarial Network against an architecture-matched classical ablation model. Evaluated on the highly constrained Mg-Mn-O system, the results reveal a highly nuanced performance dichotomy between the advanced models. The architecture-matched classical ablation model demonstrated superior thermodynamic precision. Conversely, the integration of quantum circuits in the SH-QGAN drove unparalleled structural breadth and latent space exploration, more than doubling the ablation's geometric validity and successfully generating novel, metastable candidates converging on the Mg2MnO4 stoichiometry. These findings clarify that while architectural separation of cell and atom generation drives strict thermodynamic precision, quantum feature mapping independently provides the spatial diversity necessary to overcome mode collapse. Both mechanisms offer distinct, complementary enhancements for the generative discovery of advanced materials.

09.
medRxiv (Medicine) 2026-06-18

Rare Coding Variants Reveal Distinct Genetic Architectures Across Multidimensional Sleep Phenotypes

Sleep and circadian traits have been widely studied using common variants, but the contribution of rare coding variation remains unclear. We analyzed rare coding variants in 397,065 whole-exome sequenced UK Biobank participants across 36 sleep phenotypes from self-report, diagnoses, sleep medication use and accelerometry, and meta-analyzed results with 171,536 whole-genome sequenced All of Us participants of diverse ancestries, with replication in the Mass General Brigham Biobank (N = 31,275). We identified 260 genes associated with sleep phenotypes, including novel associations with sleep medication use in 29 genes and 24 out of 29 have not previously been reported with any sleep phenotypes. We observed modest but significant rare variant heritability and strong genetic correlations between sleep medication use, insomnia and fatigue. Temporal gene expression trajectory analyses indicate that genes associated with self-reported sleep traits show constant high prenatal expression, whereas genes linked to sleep medication phenotypes exhibit peak expression in the late prenatal period. These findings highlight distinct biological mechanisms captured by different measurement sources of sleep phenotypes and reveal rare-variant-informed targets for therapeutic discovery.

10.
arXiv (CS.LG) 2026-06-19

Flow Matching for Efficient and Scalable Data Assimilation

arXiv:2508.13313v4 Announce Type: replace-cross Abstract: Data assimilation (DA) estimates a dynamical system's state from noisy observations. Recent generative models like the ensemble score filter (EnSF) improve DA in high-dimensional nonlinear settings but are computationally expensive. We introduce the ensemble flow filter (EnFF), a training-free, flow matching (FM)-based framework that accelerates sampling and offers flexibility in flow design. EnFF uses Monte Carlo estimators for the marginal flow field, localized guidance for observation assimilation, and utilizes a novel flow path that exploits the Bayesian DA formulation. It generalizes classical filters such as the bootstrap particle filter and ensemble Kalman filter. Experiments on high-dimensional benchmarks demonstrate EnFF's improved cost-accuracy tradeoffs and scalability, highlighting FM's potential for efficient, scalable DA. Code is available at https://github.com/Utah-Math-Data-Science/Data-Assimilation-Flow-Matching.

11.
medRxiv (Medicine) 2026-06-22

Histologically validated diffusion MRI signatures of neuroinflammation and neurodegeneration in Alzheimer disease

Noninvasive neuroinflammation measurement remains a major barrier for Alzheimer disease (AD) therapeutics. We present generalized diffusion basis spectrum imaging (g-DBSI), a diffusion MRI framework that decomposes the tissue signal into biologically interpretable microstructural compartments. In postmortem Knight ADRC brains, g-DBSI-derived restricted isotropic fraction (RIF) and restricted anisotropic fraction (RAF) mapped cellularity and neurofilament density, while their ratio (RIF/RAF) tracked inflammatory cell density and peri-plaque amyloid-beta with higher specificity and regional consistency than RIF alone. In 112 living Knight ADRC participants stratified by PET amyloid, g-DBSI metrics showed amyloid-dependent trajectories: in low-amyloid individuals, RIF and RAF rose together with amyloid, consistent with early neuropil expansion and glial elaboration, whereas in high-amyloid individuals, RIF/RAF increased, and RAF declined, indicating established neuroinflammatory remodeling and neurofilament loss. CSF proteomics linked RIF/RAF to glia-enriched immune and vascular pathways, supporting g-DBSI as a clinically compatible MRI biomarker of neuroinflammation and neurodegeneration in AD.

12.
Nature (Science) 2026-06-10

The Amazon can be saved — with concerted action inside and outside Brazil

作者: 未知作者

As deforestation in the Amazon falls, fresh evidence shows that the rainforest can withstand global warming, but only if there is a worldwide effort to stop cutting it down. As deforestation in the Amazon falls, fresh evidence shows that the rainforest can withstand global warming, but only if there is a worldwide effort to stop cutting it down.

13.
arXiv (quant-ph) 2026-06-16

Noise-Adaptive Predictive Dynamical Decoupling

arXiv:2606.15769v1 Announce Type: new Abstract: Protecting quantum coherence against realistic environmental noise remains one of the fundamental obstacles to scalable quantum technologies. We develop a noise-adaptive dynamical decoupling framework that combines analytical open-quantum-system modeling with machine-learning-based forecasting for a qubit interacting with random telegraph noise. Unlike conventional dynamical decoupling protocols based on fixed pulse schedules, the proposed approach continuously forecasts short-time coherence evolution and adaptively applies control pulses according to the instantaneous noise dynamics. We investigate stationary and non-stationary environments spanning both Markovian and non-Markovian regimes. Numerical simulations demonstrate that the machine-learning-assisted adaptive control strategy substantially outperforms conventional periodic dynamical decoupling while using a comparable number of control pulses. The improvement becomes particularly pronounced in non-Markovian and non-stationary regimes, where memory effects, coherence revivals, and temporally evolving noise strongly limit the effectiveness of static pulse protocols. These results establish predictive machine-learning-assisted dynamical decoupling as a promising and scalable framework for adaptive quantum control in realistic noisy quantum devices.

14.
arXiv (quant-ph) 2026-06-17

Closest Accessible Symmetry reduction: a tool for Hamiltonian interpolation analysis

arXiv:2606.18161v1 Announce Type: new Abstract: We introduce a framework for analysing the spectrum of Hamiltonian interpolations without heavily relying on discretising the interpolation parameter. The method is based on the concept of accessible symmetries: a problem-class-dependent family of certifiable reflections that induce bipartitions of the Hilbert space. At each step, the interpolation Hamiltonian is projected onto the sectors of the accessible symmetry that is closest to being satisfied, yielding a hierarchy of weakly coupled pseudo-eigenspaces together with explicit residual couplings between them. We show that this representation captures qualitative signatures of quantum phase transitions, provides estimates of their location, and offers insights into their nature. The quality of the approximation is controlled by the compatibility between the accessible symmetry family and the problem instance. Although motivated in spirit by adiabatic quantum computation, our approach applies more broadly to the study of Hamiltonian phase diagrams, providing a new perspective on the spectral reorganisation of many-body quantum systems.

15.
arXiv (quant-ph) 2026-06-25

A Contactless Heat Engine Driven by Nonreciprocal Fluctuation-Induced Torques

arXiv:2606.25053v1 Announce Type: new Abstract: We describe a contactless heat engine in which quantum and thermal electromagnetic fluctuations act as the working medium. The setup consists of two concentric cylinders held at different temperatures. The inner cylinder stably levitates within the outer one due to repulsive nonequilibrium Casimir forces. The chirality of the setup is broken by using nonreciprocal dielectric materials, akin to application of a magnetic field along the common cylinder axis. Using Rytov fluctuational electrodynamics, we show that heat transfer and torque can be expressed in terms of an angular-momentum-resolved heat flux density, $\Phi_n(\omega)$: each exchanged photon carries energy $\hbar \omega$ and angular momentum $\hbar n$. In reciprocal media contributions from modes $n$ and $-n$ cancel and there is no net torque; nonreciprocity breaks this symmetry and powers rotation of the inner cylinder. Even in the absence of contact, electromagnetic fluctuations produce a frictional torque opposing rotation that we compute. This enables computation of characteristic steady state rotations, and estimation of the engine efficiency (which remains bounded by the Carnot limit). The cylindrical setup provides a natural realization of fluctuation-induced angular-momentum transfer and a possible route toward nanoscale contactless engines.

17.
arXiv (CS.CV) 2026-06-16

Track2View: 4D-Consistent Camera-Controlled Video Generation via Paired 3D Point Tracks

Re-rendering an existing video from a novel camera viewpoint requires the output to follow the prescribed camera trajectory while preserving the appearance and dynamics of the original scene across every frame. Existing methods rely on per-frame pose embeddings, noisy point-cloud renderings, or implicit learned correspondences, none of which provides an explicit, temporally continuous link between source and target pixels. We propose Track2View, which conditions a video diffusion transformer on paired 3D point tracks: sparse trajectories of scene points projected into both the source and target camera views. These tracks provide explicit spatiotemporal correspondences that are temporally continuous by construction, encoding what content should appear where and when. At the core of Track2View is a dual-view track conditioner that transfers visual context from source to target view through parameter-free geometric operations and learned temporal aggregation, ensuring generalization to arbitrary camera trajectories without memorizing specific motions. We further introduce a data curation pipeline that extracts one-to-one track correspondences by running a 3D point tracker on temporally concatenated multi-camera view pairs. On a 400-video benchmark spanning static and dynamic scenes, Track2View achieves state-of-the-art results across visual quality, view synchronization, and camera accuracy, reducing rotation error by 30-65% and translation error by 61-72% relative to leading baselines. Project page is available at this https URL: https://qjizhi.github.io/track2view

18.
bioRxiv (Bioinfo) 2026-06-18

Elucidating the Design Space of Generative Models for Single-Cell Perturbation Prediction

Next-token prediction has produced predictable scaling in language, but the recipe presumes a sequence of tokens with a meaningful order. Single-cell RNA-seq counts have no natural gene ordering, so applying the recipe directly to raw expression fails under an ill-suited left-to-right bias. We instead ask whether a learned latent can supply the structure the recipe needs. We introduce texttt{ExpressionVAE} (eVAE), a discrete-latent perturbation model that compresses each cell into a short sequence of discrete codes through a finite-scalar-quantization (FSQ) bottleneck and trains a perturbation-conditioned discrete prior over those codes. On Replogle and Parse~1M, eVAE sets a new state of the art on every distributional metric and leads on most cell-eval perturbation metrics, with Fr'echet distance and $mathrm{MMD}^2$ roughly $3$ to $20times$ lower than the strongest continuous-latent baseline. Swapping the prior between autoregressive and masked discrete diffusion leaves performance near-identical, isolating the gain to the discrete latent itself rather than the prior family. A decoder-head ablation then exposes a single design axis, the richness of the predictive distribution at inference, that splits the standard metrics into two groups, variance-sensitive and mean-sensitive, which move in opposite directions along the axis. Finally, on a held-out CRISPRi reversion benchmark of $1{,}732$ perturbations under inflammatory cytokine stress, the frozen eVAE encoder outperforms UMAP and differential expression and matches scGPT on perturbation ranking at a fraction of the data.

19.
arXiv (CS.AI) 2026-06-24

Representation Interventions Enable Lifelong Knowledge Memory Control in LLMs

arXiv:2511.20892v4 Announce Type: replace Abstract: Large language models (LLMs) often produce incorrect or outdated content after being employed. Efficient and accurate knowledge updates without costly retraining are a major challenge. This problem is particularly challenging in lifelong settings, where complex, unstructured knowledge must coexist without interference. We introduce RILKE (Representation Intervention for Lifelong KnowledgE Control), a robust and scalable method that treats knowledge control as interventions within the model's representation space. Leveraging representation-space expressiveness, we identify two key properties enabling RILKE to achieve fine-grained control over complex, unstructured knowledge while maintaining general utility with frozen base weights. During training, RILKE learns paraphrase-robust and edit-localized modules that limit each update to a low-dimensional subspace to minimize cross-edit interference. At inference, a query-adaptive router selects the appropriate module to guide the model's generation. Across LLaMA and Qwen models, RILKE scales effectively to large-scale benchmarks, demonstrating high edit success and strong paraphrase generalization while preserving general utility with modest memory overhead. These results show RILKE is an effective and scalable solution for lifelong knowledge control in LLMs.

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

Scalable Deep Unfolding of Conic Optimizers

arXiv:2606.13825v1 Announce Type: cross Abstract: Deep unfolding (DU) accelerates iterative optimizers by introducing learnable components and training them through unrolled iterations, but extending DU to the large-scale semidefinite programs (SDPs) common in robotics has remained limited. Unrolling a full-update conic solver such as COSMO exposes two obstacles that prior work on learned conic solvers has not: backpropagating through the per-iteration linear-system solve incurs memory quadratic in the problem size once the coefficient matrix is formed explicitly, and backpropagating through the positive semidefinite (PSD) cone projection becomes numerically unstable when eigenvalues coincide. We address the first obstacle with a matrix-free implicit differentiation rule that operates entirely through matrix-vector products, reducing memory from $O(n^2)$ to $O(n)$ and enabling backpropagation at scales where direct factorization runs out of memory. We address the second with a backward rule based on the Dalečkii–Krein representation of the Fréchet derivative, which remains well-defined under repeated eigenvalues. Together these make it possible to learn lightweight hyperparameter policies and warm-starts for a full-update conic solver. We evaluate on nonlinear covariance steering problems solved via sequential convex programming (SCP), as well as standalone SDPs and second-order cone programs ranging from max-cut and Lovász $\vartheta$ SDPs to robust estimation and control problems. The learned policies outperform state-of-the-art solvers across all problems, and can provide up to a 50$\times$ speedup depending on the class. When used as a subroutine in SCP, the learned approach delivers over a 30$\times$ speedup compared to COSMO.

21.
arXiv (math.PR) 2026-06-17

Persistence diagrams of random triangular matrices over finite fields

arXiv:2606.17895v1 Announce Type: cross Abstract: Let us consider a random infinite lower triangular matrix, where the entries on and below the diagonal are i.i.d. uniform random elements of a fixed finite field. We investigate the evolution of the span of the first $n$ rows of this matrix as $n$ grows. Many properties of this evolving subspace can be captured with the help of the verbose persistence diagram, which is a standard tool in stochastic topology and topological data analysis. We give an explicit formula for the distribution of the persistence diagram. We prove a law of large numbers for the distribution of lifetimes. We also describe the fluctuations of the persistent Betti numbers.

22.
arXiv (CS.LG) 2026-06-18

Quantifying and Auditing LLM Evaluation via Positive–Unlabeled Learning

arXiv:2606.19057v1 Announce Type: cross Abstract: Large Language Models (LLMs) are increasingly used as judges for scalable evaluation, yet such LLM–as–a–Judge systems exhibit systematic biases that are decoupled from semantic quality, most notably verbosity bias. Meanwhile, human supervision is costly and typically selective, yielding reliable positive judgments but leaving most outputs unlabelled and potentially mixed in quality. We formulate LLM evaluation under selective human supervision as a positive–unlabelled learning problem and propose a geometric auditing framework based on Partial Optimal Transport. By aligning a small set of human–verified positives with a reliable subset of unlabelled outputs in a fixed embedding space, our method identifies human–consistent preferences and corrects biased judges without retraining. Experiments demonstrate improved alignment with human preferences, increased robustness to presentation biases, and interpretable confidence estimates, offering a scalable and statistically grounded alternative to existing LLM–as–a–judge pipelines.

23.
arXiv (CS.AI) 2026-06-12

Generativism: Toward a Learning Theory for the Age of Generative Artificial Intelligence

arXiv:2606.12441v1 Announce Type: cross Abstract: The four dominant learning theories of behaviorism, cognitivism, constructivism, and connectivism show significant conceptual limitations as generative artificial intelligence (AI) proliferates in educational settings. These frameworks were formulated before the emergence of AI systems capable of generating, synthesizing, and reasoning about knowledge. This article critically examines each learning theory and identifies assumptions challenged by generative AI's affordances. Drawing on research in distributed cognition, extended mind, human-AI collaboration, AI literacy, cognitive offloading, and metacognition, the article proposes Generativism as a learning theory for the generative AI age. Generativism posits that learning increasingly occurs through the iterative co-construction of knowledge between human learners and AI systems. The proposed framework is organized around four principles: epistemic partnership, distributed agency, generative literacy, and adaptive metacognition. The framework offers a foundation for rethinking instructional design, learning, assessment, and expertise development in contexts where generative AI plays an integral role in cognition.

24.
arXiv (CS.LG) 2026-06-24

Subtyping patients with chronic disease using longitudinal BMI patterns

arXiv:2111.05385v3 Announce Type: replace Abstract: Obesity is a major health problem, increasing the risk of various major chronic diseases, such as diabetes, cancer, and stroke. While the role of obesity identified by cross-sectional BMI recordings has been heavily studied, the role of BMI trajectories is much less explored. In this study, we use a machine-learning approach to subtype individuals' risk of developing 18 major chronic diseases by using their BMI trajectories extracted from a large and geographically diverse EHR dataset capturing the health status of around two million individuals for a period of six years. We define nine new interpretable and evidence-based variables based on the BMI trajectories to cluster the patients into subgroups using the k-means clustering method. We thoroughly review each cluster's characteristics in terms of demographic, socioeconomic, and physiological measurement variables to specify the distinct properties of the patients in the clusters. In our experiments, the direct relationship of obesity with diabetes, hypertension, Alzheimer's, and dementia has been re-established and distinct clusters with specific characteristics for several of the chronic diseases have been found to be conforming or complementary to the existing body of knowledge.

25.
medRxiv (Medicine) 2026-06-23

Novel loci and multi-omics risk models for rheumatoid arthritis through a million-participant genome-wide association meta-analysis

Rheumatoid arthritis (RA) remains incompletely understood, limiting targeted prevention. In this work, genome-wide association study meta-analyses were performed for RA and seropositive RA, comprising approximately one million participants of European ancestry. Eight and six novel genomic risk loci were defined for RA and seropositive RA, and candidate causal genes were identified, highlighting relevant biological pathways, including established immune pathways and estrogen metabolism. Novel disease-specific polygenic risk scores (PRSs) were constructed, enhancing predictive performance over clinical risk factors (incremental C-statistics of 2.7 and 5.1 for RA and seropositive RA, respectively). In parallel, integrating metabolomic data into high-dimensional models enhanced risk stratification over models based on clinical risk factors and genomics, particularly for seropositive RA, where the hazard ratio of the highest decile increased from 4.869 to 5.697. These findings expand the understanding of genetic factors underlying RA and support the value of including PRSs in risk assessment, while suggesting metabolomic integration may further enhance risk stratification, particularly for seropositive RA.