Correction: Viral escape-inspired framework for structure-guided dual bait protein biosensor design
by Yee Chuen Teoh, Mohammed Sakib Noor, Sina Aghakhani, Jack Girton, Guiping Hu, Ratul Chowdhury
Academic Intelligence · Curated Daily
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by Yee Chuen Teoh, Mohammed Sakib Noor, Sina Aghakhani, Jack Girton, Guiping Hu, Ratul Chowdhury
Vision-Language models (VLMs) reliability in medical diagnosis is challenged by trust-undermining hallucinations. Existing hallucination detection approaches mainly focus on identifying factual inconsistencies between generated text and reference data. While some studies analyze where models attend in images, they seldom verify whether such attention truly reflects the visual evidence supporting the generated text. To address this gap, we propose Co}unter-Evidence Verification (CoEV), a training-free plug-and-play framework that detects and corrects hallucinations through evidence-based factual consistency verification. CoEV performs bidirectional verification between textual assertions and visual evidence, testing whether each statement is supported by its corresponding evidence region, and assigns each statement into a four-quadrant diagnostic map capturing combinations of text factuality and visual grounding. CoEV detects hallucinated content and serves as a post hoc refinement tool, correcting hallucinations without retraining. Extensive experiments on four medical datasets show that CoEV combats hallucinations in VLMs.For hallucination detection, CoEV consistently outperforms existing methods, improving average PR-AUC and ROC-AUC by 3.0% and 3.9% absolute points respectively, with notable gains of up to 18.5% in specific VQA scenarios. For hallucination correction, it improves Micro-F1 by up to 12.5%, reduces hallucination rates by over 11.9% on medical report generation, and also boosts medical VQA accuracy. These results show that CoEV enables reliable detection and correction of hallucinations, providing clinicians with dependable, evidence-based cues for diagnosis. Code will be released upon acceptance.
arXiv:2606.14975v1 Announce Type: cross Abstract: How the wiring and functional organization of cortex shape recurrent computation remains a central question in both neuroscience and machine learning. Here, we leverage data released through the Machine Intelligence from Cortical Networks (MICrONS) program–a functional connectomics resource spanning multiple areas of mouse visual cortex, in which dense calcium imaging is co-registered with high-resolution electron microscopy reconstruction from the same animal–to build biologically grounded recurrent neural networks. Using neuronal spatial coordinates, anatomical connectivity, and function-derived relationships from nearly 12,000 coregistered excitatory neurons, we initialize recurrent weights and impose communication-aware spatial constraints during learning. Across three cognitive decision-making tasks, networks constrained by cortical structure and function consistently outperform baseline and partially constrained models. Functional weight initialization provides the largest gain, while real spatial embedding yields robust additional improvements across conditions. These biologically grounded networks also develop low-entropy, modular, and small-world organization, and retain strong performance even when recurrence is restricted to positive weights. Together, our results show that the machinery of cortex–its geometry, wiring, and functional structure–can be harnessed as a powerful inductive basis for building recurrent networks that learn more effectively while converging toward key organizational principles of biological computation.
arXiv:2606.13034v1 Announce Type: new Abstract: We present a quantum algorithm for random number generation that achieves a provable quadratic speedup over classical Markov chain mixing, building on the Diaconis-Shahshahani Fourier analysis of the top-to-random card shuffle. The algorithm integrates three quantum primitives into a unified mixing circuit: the Quantum Fourier Transform (QFT), which diagonalizes the Markov transition operator; controlled phase rotations, which encode the shuffle eigenvalue spectrum; and the Grover diffusion operator, which acts as a quantum analogue of the Aldous-Diaconis strong uniform stopping time by reflecting amplitudes about their mean at each iteration. For an n-qubit register, the mixing time is O(\sqrt{n \log n}) iterations. Extending to m qudits of local dimension d reduces this to O(\sqrt{\log_d N}) iterations, where N = d^m, compared to the classical O(n \log n) bound. The qudit formulation further reduces QFT circuit depth from O(\log^2 N) to O(\log_d^2 N) gates per layer by encoding the same N-state space using m = \log_d N subsystems instead of \log_2 N qubits. We validate both variants on IBM superconducting hardware.
arXiv:2606.16286v1 Announce Type: cross Abstract: Flow Matching (FM) is a powerful approach for behavior cloning in multimodal action spaces [Jiang et al., 2025], but because it is not trained to directly maximize expected return, there is still room to improve how FM policies act at test time. This work investigates whether a learned world model can improve FM policies by enabling Model Predictive Path Integral (MPPI) planning over candidate action sequences proposed by the policy. Building on TD-MPC2 [Hansen et al., 2024], I introduce FlowMPC, a framework that combines an imitation-learned FM policy with a learned world model for test-time planning in ManiSkill manipulation tasks [Tao et al., 2025]. Across PickCube and PickSingleYCB, adding the world model improved performance over the FM policy alone, with especially clear gains in end-of-episode success. These results suggest that world-model-based planning can effectively complement flow-based imitation policies without modifying the FM training objective.
arXiv:2509.10303v2 Announce Type: replace-cross Abstract: Online reinforcement learning (RL) approaches have demonstrated strong performance on Job Shop Scheduling (JSP) and Flexible JSP (FJSP) problems by learning scheduling policies through direct interaction with simulated environments. However, these methods often require extensive training interactions, limiting their sample efficiency and practical applicability. Motivated by this challenge, we introduce Conservative Discrete Quantile Actor-Critic (CDQAC), an offline RL algorithm that learns effective scheduling policies directly from static, suboptimal datasets. CDQAC couples a quantile-based critic with delayed policy updates to estimate the return distribution of machine-operation pairs. Extensive experiments on JSP and FJSP benchmarks demonstrate that CDQAC consistently outperforms the data-generating heuristics, surpasses state-of-the-art offline and online RL baselines, and is highly sample efficient, requiring only 1 to 5% of the original dataset to learn high-quality policies. Our analysis suggests that, in scheduling, offline RL performance is governed mainly by state-action coverage rather than the quality of individual trajectories. Scheduling couples a dense reward aligned with the makespan objective with equal-length trajectories across heuristics, enabling effective learning from a broad range of behaviors. Consistent with this observation, datasets generated by a simple random heuristic with broader coverage let it outperform policies trained on datasets produced by stronger heuristics such as Genetic Algorithms.
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.
arXiv:2606.17013v1 Announce Type: cross Abstract: The well known phenomenon of exploding and vanishing gradients in deep neural networks is analyzed using multiplicative ergodic theory. The effect of adding a residual connection is explained in this context. Specifically, a characterization of Liapunov exponents due to Furstenberg and Kifer is exploited in order to make a precise statement about the Liapunov spectrum and the effect of residual connections on it.
Incremental Learning (IL) for Open-ended Image-to-Text Generation (OpenITG) enables models to continuously generate accurate, contextually relevant text for new images while preserving previously acquired knowledge. Unlike prior studies, this paper addresses a more practical scenario in which the predominant category of visual data shifts over time as environments evolve. In this context, we introduce a new notion of continual alignment, which incrementally adapts the alignment module within pre-trained VLMs to preserve high-quality cross-modal representations. Based on this idea, we propose Efficient Continual Alignment (ECA), a novel exemplar-free IL approach for OpenITG. The key challenge is enabling the model to acquire new, task-specific features while minimizing interference with the established alignment without accessing raw data from previous tasks. To address this, ECA employs three core mechanisms: a Mixture of Query (MoQ) module that adapts task-specific query tokens, a Fisher Dynamic Expansion (FeDEx) that dynamically expands model structure based on a Fisher Information Matrix (FIM)-based metric, and an embedding dictionary with Dictionary Replay (DR) to retain past knowledge. To evaluate ECA's performance, we construct four new IL OpenITG benchmarks that better reflect real-world scenarios. Experimental results demonstrate that ECA significantly mitigates catastrophic forgetting and improves IL performance compared to baseline methods. Code and benchmarks are available at https://github.com/Snowball0823/ECA.
The GOOSE 2D Fine-Grained Semantic Segmentation Challenge at the ICRA 2026 Workshop on Field Robotics evaluates dense semantic segmentation of off-road imagery over a fine-grained taxonomy of 64 classes and 11 evaluated non-void coarse categories. We present the first-place solution to this challenge. Our solution comprises two complementary improvements: (a) a network-level design that combines a self-supervised DINOv3 ViT-L/16 backbone, a ViT-Adapter, and a Mask2Former mask-classification decoder, together with a coarse-category auxiliary loss on the global [CLS] token; and (b) an inference-time aggregation strategy based on multi-scale and horizontal-flip test-time augmentation and an ensemble of the top three checkpoints selected using Codabench scores. Our method achieves an official composite score of 76.57%, consisting of 69.32% fine-class mIoU and 83.81% category-level mIoU, and ranks first on the final phase leaderboard: www.codabench.org/competitions/14257/#/results-tab.
Dynamic Flux Balance Analysis (DFBA) enables simulation of microbial culture dynamics under changing environmental conditions, but remains computationally expensive for tasks such as parameter calibration and fermentation optimization when applied using genome-scale metabolic models (GEMs). To address this challenge, we introduce Dynamic Flux Vector Balancing (DFVB), a reformulation of DFBA that solves an equivalent problem using a pre-computed, sparse basis of flux solutions that reduces the dimensionality of the internal optimization problem without information loss. Notably, DFVB provides a compact, interpretable representation of flux states that can readily identify dynamically inactive pathways and enable simulation-based automatic metabolic network reduction. We showed that DFVB produces the same culture dynamics as DFBA across multiple model scales and conditions, and identifies inactive reactions more accurately than Flux Variability Analysis (FVA) when compared to transcriptomic data profiles. Furthermore, computational performance analyses demonstrated that integrating DFVB with solver warm-start strategies and model reduction enhances computational efficiency relative to DFBA, yielding up to 3-fold reductions in simulation time for large-scale metabolic models. Finally, kinetic parameter estimation of culture dynamics with DFVB in two fermentation scenarios using a large-scale yeast GEM reached equal or higher prediction fidelity and narrower confidence intervals than DFBA, indicating improved parameter identifiability and robustness. Together, these results position DFVB as a scalable, robust, and biologically coherent framework for dynamic metabolic modeling, easing the integration of GEMs for culture dynamics simulation.
Recent video diffusion models have achieved impressive capabilities as large-scale generative world models. However, these models often struggle with fine-grained physical consistency, exhibiting physically implausible dynamics over time. In this work, we present Phys4D, a pipeline for learning physics-consistent 4D world representations from video diffusion models. Phys4D adopts a three-stage training paradigm that progressively lifts appearance-driven video diffusion models into physics-consistent 4D world representations. We first bootstrap robust geometry and motion representations through large-scale pseudo-supervised pretraining, establishing a foundation for 4D scene modeling. We then perform physics-grounded supervised fine-tuning using simulation-generated data, enforcing temporally consistent 4D dynamics. Finally, we apply simulation-grounded reinforcement learning to correct residual physical violations that are difficult to capture through explicit supervision. To evaluate fine-grained physical consistency beyond appearance-based metrics, we introduce a set of 4D world consistency evaluation that probe geometric coherence, motion stability, and long-horizon physical plausibility. Experimental results demonstrate that Phys4D substantially improves fine-grained spatiotemporal and physical consistency compared to appearance-driven baselines, while maintaining strong generative performance. Our project page is available at https://sensational-brioche-7657e7.netlify.app/
While Large Language Model (LLM) based Automatic Speech Recognition (ASR) enables seamless multilingual use, models often misidentify the output language, compromising transcription fidelity and downstream application quality. To preserve flexibility and code-switching capabilities, we propose a soft prompting approach that hints at potential spoken languages without strictly constraining the output. We formally define this challenge as a lack of language adherence, introduce a novel metric to quantify violations, and evaluate three mitigation strategies: (1) zero-shot prompting for robust guidance under uncertainty, (2) supervised fine-tuning (SFT) to improve prompt adherence, and (3) Chain-of-Thought (CoT) reasoning to enforce adherence during decoding. We present a comparative analysis of these methods across multiple languages, evaluating effectiveness in reducing the language violation while maintaining overall ASR performance. Finally, we discuss trade-offs to guide strategy selection under various compute constraints.
arXiv:2606.15922v1 Announce Type: new Abstract: We develop a comprehensive, gauge-covariant geometric framework for non-Hermitian quantum systems in the quasi-Hermitian regime, that is, the region of parameter space where the non-Hermitian Hamiltonian admits a real spectrum and a positive-definite metric operator. We build this framework by elevating the Dyson map to a central geometric object. This map is the transformation that converts a non-Hermitian Hamiltonian into an equivalent Hermitian one. From it we construct the Dyson connection and decompose it into Hermitian and anti-Hermitian parts, identified respectively as {\it stretching } and {\it rotation } components. This decomposition cleanly separates the genuine physical metric deformations from the unitary gauge redundancies. Working with manifestly gauge-covariant states, we then derive the complex non-Hermitian Berry phase and the quantum geometric tensor (QGT), and show that the non-Hermitian geometric curvature originates from the non-commutativity of the stretching components at the operator level. We further analyse the geometric singularities near an exceptional point (EP) and uncover a distinct hierarchy of divergences. For a general two-level non-Hermitian model, the quantum metric tensor (QMT) exhibits a leading-order divergence $\sim |\epsilon_\mu|^{-2}$, while the Berry curvature shows a weaker, subleading divergence $\sim |\epsilon_\mu|^{-3/2}$, with $\epsilon_\mu$ denoting the parameter displacement from the EP along an individual parameter axis $\mu$. Finally, we examine physical realizations of this model, including the non-Hermitian Su–Schrieffer–Heeger (SSH) and Hatano–Nelson (HN) models, where exact analytical results confirm the predicted critical scaling laws and illustrate the metric-deformation-driven non-Hermitian geometries.
arXiv:2504.21072v3 Announce Type: replace-cross Abstract: The expansion of text-to-image diffusion models has raised concerns about harmful outputs, from fabricated depictions of public figures to sexually explicit imagery. To mitigate such risks, prior work has proposed concept erasure methods that aim to sever unwanted concepts from the model via fine-tuning, yet it remains unclear whether these approaches truly remove all links to the harmful concept or merely conceal superficial connections. In this work, we reveal a critical vulnerability, the Erasure Evasion Backdoor (EEB): an adversary binds a backdoor trigger to a concept slated for removal, and this malicious link survives subsequent erasure. We show that both black-box and white-box adversaries can instantiate this threat. Across six state-of-the-art erasure methods, including robust ones that explicitly search for alternative representations of the target concept, EEB consistently exposes harmful content: up to 82% success against celebrity-identity unlearning, up to 94% for object erasure, and up to 16 times amplification of explicit-content exposure. While EEB uncovers a blind spot in current erasure methods, it also provides a diagnostic tool for stress-testing future concept erasure techniques.
Vision-language models (VLMs) can produce confident visual answers even when the required visual evidence is missing, blank, or unrelated to the question. This failure mode, recently described as mirage (mirage2026), is especially concerning in medical and document VQA, where a plausible but visually ungrounded answer may be mistaken for image-based evidence. We study the complementary problem of pre-release mirage detection: given an image-question pair, determine whether the VLM should answer or abstain before generation. To that end, we propose a novel model-agnostic Text-Conditioned Layer-wise Internal Alignment (TC-LIA) method that probes patch-token representations across the layers of a CLIP ViT-H/14 vision encoder. The key idea is to project layer-wise image patch tokens into the final CLIP embedding space and measure their similarity with the question embedding, thereby tracking whether question-relevant visual evidence emerges across vision layers. TC-LIA summarizes this alignment trajectory using final image-text cosine similarity, late-layer top-k patch-text alignment, early-to-late gain, and layer-wise slope. These features are combined with pixel-statistic based blank/noise detection, zero-shot domain routing, and structured VLM self-assessment in an ensemble. Across five VQA domains with related, unrelated-real, and blank/noise inputs, and across twelve VLM backbones, Qwen2.5-VL-32B achieves the highest three-class detection accuracy of 94.7% with a 3.0% mirage rate, while Qwen2.5-VL-72B achieves 94.6% accuracy with a lower 2.8% mirage rate. Baseline mirage rates span 21.7-66.6%.
arXiv:2602.14913v2 Announce Type: replace Abstract: Conformal prediction (CP) offers distribution-free marginal coverage guarantees under an exchangeability assumption, but these guarantees can fail if the data distribution shifts. We analyze the use of pseudo-calibration as a tool to counter this performance loss under a bounded label-conditional covariate shift model. Using tools from domain adaptation, we derive a lower bound on target coverage in terms of the source-domain loss of the classifier and a Wasserstein measure of the shift. Using this result, we provide a method to design pseudo-calibrated sets that inflate the conformal threshold by a slack parameter to keep target coverage above a prescribed level. Finally, we propose a source-tuned pseudo-calibration algorithm that interpolates between hard pseudo-labels and randomized labels as a function of classifier uncertainty. Numerical experiments show that our bounds qualitatively track pseudo-calibration behavior and that the source-tuned scheme mitigates coverage degradation under distribution shift while maintaining nontrivial prediction set sizes.
arXiv:2606.20104v1 Announce Type: cross Abstract: Perception for action suggests that representations of the world should be shaped not by visual fidelity alone, but by their relevance for actions. At the same time, latent JEPA-style world models advocate learning compact predictive states from high-dimensional observations to facilitate the prediction of future states, but end-to-end training of these models is nontrivial because representations may collapse if our only goal is to construct a latent state that is easy to predict. We introduce a sensorimotor world model (SMWM): a latent world model trained end-to-end with inverse dynamics regularization. This single regularizer addresses both issues: it prevents representation collapse and induces action-aligned representations. By forcing latent states to preserve information about the action underlying a transition, it biases the model toward the controllable degrees of freedom of the environment while discarding uncontrollable distractors. This yields stable latent world models trained from offline, reward-free trajectories, without frozen encoders, exponential moving averages, or complex latent regularizers. Empirically, SMWM learns compact, interpretable latent spaces and enables competitive planning performance across simple 2D and 3D control tasks.
Physically based rendering (PBR) material estimation is a fundamental appearance decomposition task with broad applications in virtual content creation, relighting, and digital human rendering. However, estimating PBR materials from a single human image remains highly ill-posed, since illumination, geometry, and reflectance are heavily entangled in the observed appearance. To mitigate this ambiguity, we propose HAFMat, a hybrid-prior-guided framework for single-image human material estimation. Our method introduces guidance maps that encode complementary cues, including appearance, body geometry, structure, and prior material predictions from pre-trained models. A key observation is that these guidance cues are heterogeneous: some cues mainly provide texture-level constraints, while others convey higher-level semantic information. To exploit this property, we design a Multi-layer Adaptive Feature Fusion Mechanism, which adaptively fuses guidance features with decoder features at different stages. This design enables texture-dominant and semantic-dominant cues to guide material decoding at appropriate levels, leading to more accurate and physically plausible material estimation. Extensive experiments on both synthetic and real data demonstrate that our method achieves state-of-the-art performance in material estimation and downstream relighting.
Generating high-quality Physics Word Problems (PWPs) that are novel, complex, and solvable remains a challenging and underexplored problem in educational content generation. Existing approaches, many adapted from Math Word Problem (MWP) generation, often produce ambiguous, unsolvable, or structurally simple questions with limited linguistic diversity. We introduce ARVRE (Agentic Retrieval Value Reinforced Equation-chain), a two-stage framework for generating diverse and mathematically valid PWPs. In the first stage, a form of offline temporal-difference learning is used to construct valid chains of physics equations, while an agentic retrieval-augmented generation (RAG) framework dynamically selects topic-specific concepts and vocabulary. This design enables explicit control over problem structure and difficulty. In the second stage, a Large Language Model (LLM) converts the equation chain and retrieved concepts into a natural-language physics question. By grounding generation in valid equation chains, our method preserves mathematical correctness while promoting linguistic diversity and contextual richness. Human and automated evaluations demonstrate that ARVRE generates PWPs that are more complex, novel, and solvable than those produced by existing approaches. These results highlight the potential of combining reinforcement learning, retrieval, and LLMs for reliable generation of educational physics content.
arXiv:2506.08764v3 Announce Type: replace Abstract: Deep neural networks are known to suffer from exploding or vanishing gradients as depth increases, a phenomenon closely tied to the spectral behavior of the input-output Jacobian. Prior work has identified critical initialization schemes that ensure Jacobian stability, but these analyses are typically restricted to fully connected networks with i.i.d. weights. In this work, we go significantly beyond these limitations: we establish a general stability theorem for deep neural networks that accommodates sparsity (such as that introduced by pruning) and non-i.i.d., weakly correlated weights (e.g. induced by training). Our results rely on recent advances in random matrix theory, and provide rigorous guarantees for spectral stability in a much broader class of network models. This extends the theoretical foundation for initialization schemes in modern neural networks with structured and dependent randomness.
arXiv:2606.13311v1 Announce Type: cross Abstract: Contextual anomaly detection aims to identify abnormal behavior conditional on context variables, but practical deployments often face highly imbalanced context distributions where rare regimes can be critical information. Under such frequency bias, context-conditioned models can produce unstable decisions and excessive false alarms in rare contexts. We propose Rarity-Gated Feature-wise Linear Modulation (RGFiLM), a rarity-aware conditioning module that combines feature-wise modulation (i.e., context-conditioned scaling and shifting of hidden features) with a gate controlled by a data-driven rarity score. The rarity score is estimated from the empirical distribution of context variables and regulates how strongly context modulates intermediate representations: the gate becomes more decisive under rare contexts while remaining conservative under frequent contexts. We evaluate RGFiLM on maritime trajectory anomaly detection using AIS motion sequences with ERA5 environmental context in an environment-sensitive detour scenario. When instantiated in a sequential anomaly scoring pipeline, RGFiLM achieves the best mean F1–False Positive Rate (FPR) trade-off among the compared context-agnostic and context-conditioned methods. These results suggest that explicitly accounting for context rarity is an effective approach for reducing false alarms in context-sensitive anomaly detection.
This work presents RepWAM, a representation-centric world action model (WAM) built on representation visual-action tokenizers. Existing WAMs typically inherit reconstruction-oriented video tokenizers from pretrained video generation models. Although these tokenizers preserve visual fidelity, pixel reconstruction alone provides limited guidance for learning instruction-following dynamics that connect future prediction with robot control. To address this, we explore a semantic visual-action latent space for representation-centric world action modeling. Specifically, we train a representation visual-action tokenizer that maps visual inputs into aligned visual and latent action tokens. We then pretrain our WAM to jointly model future visual states and the latent actions that connect them under language instructions, followed by adaptation to real robot trajectories for closed-loop manipulation. Experiments on real-world manipulation tasks and simulation benchmarks show that RepWAM delivers strong performance across diverse manipulation settings, while ablations highlight the value of semantic visual-action tokenization over reconstruction-oriented alternatives. These results establish representation visual-action tokenization as a promising foundation for world action models and a step toward generalist robot policies. Code and weights will be available at https://github.com/wdrink/RepWAM.
arXiv:2606.16933v1 Announce Type: cross Abstract: Reinforcement learning (RL) systems often degrade when operating conditions differ from those previously encountered, reflecting distributional shifts in the underlying data-generating process. Such shifts may occur between training and evaluation, as in In-Distribution (ID) and Out-of-Distribution (OOD) generalization, or within non-stationary settings where environment dynamics evolve over time. However, the formal relationship between these views remains unclear, and existing work mainly focuses on mitigation rather than the causal origin of shift within the agent-environment interaction. This work develops a unified causal-origin taxonomy that characterizes sources of distributional shift in RL and relates ID/OOD generalization to non-stationary settings. We transfer the classical dataset-shift principle from supervised learning to RL by reformulating distributional shift in terms of the generative interaction process. Using a Partially Observable Markov Decision Process (POMDP), we decompose the interaction into structural components, including the state distribution, observation process, policy, reward, and transition dynamics, together with the shifted-time boundary. The proposed taxonomy distinguishes internal, agent-driven, and external, environment-driven, distributional shifts. The shifted-time boundary perspective further characterizes explicit, implicit, and hybrid shifts. This formulation unifies ID/OOD generalization and non-stationarity as structured changes in the underlying process. We also introduce an evaluation framework for measuring shift impact and adaptation through performance degradation and recovery metrics. By grounding distributional shift in the causal-origin structure of RL, this work supports systematic analysis of robustness under distributional shift.
Abstract Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex and incompletely understood molecular mechanisms. Understanding circulating proteins associated with RA may improve understanding of disease biology and clarify its pathological links with cardiometabolic comorbidities. Methods A proteome-wide two-sample Mendelian randomisation (MR) drug target analysis was conducted using plasma proteins measured in 54,219 participants from the UK Biobank Pharma Proteomics Project as exposures and RA and cardiometabolic diseases as the outcomes. Summary statistics for RA included 53,663 cases and 1,070,200 controls. Colocalisation analysis was performed to confirm shared single causal variants and prioritise RA proteins supported by both MR and colocalisation. The prioritised proteins were then evaluated in the Accelerating Medicines Partnership RA Phase II synovial single-cell dataset for cell-type expression patterns. Druggability was then assessed followed by analysis of genetic overlap between RA-associated proteins and cardiometabolic diseases. Results 37 plasma proteins had a causal effect on RA risk, supported by combined evidence from MR and conditional colocalisation. In synovial tissue, TPPP3, RARRES2, AKAP12, and GGT5 were predominantly expressed in stromal and endothelial cell clusters. Druggability assessment identified IFNGR2, IL6R, CD40, and FCGR2B as Tier 1 targets. However, several biologically relevant proteins, including RARRES2, AKAP12, TPPP3, and SNX2, had limited available druggability data. Genetic overlap analysis demonstrated shared protein signals between RA and cardiovascular diseases, including overlap of RARRES2 and TPPP3 with coronary artery disease (CAD) and FCGR2B with atrial fibrillation (AF). To approximate the therapeutic effect of target inhibition, the direction of effect estimates for proteins showing overlap between RA-CAD and RA-AF was reversed. Conclusion This study identified circulating proteins involved in RA pathogenesis and reveals shared mechanisms between RA and cardiovascular diseases. While some proteins showed clear translational potential targets, several prioritised proteins had limited available druggability information and could not be confidently classified. Addressing these gaps may help identify new targets relevant to RA management. Future work should also use phenome-wide MR studies to evaluate potential on-target adverse effects of protein inhibition across RA-CAD and RA-AF.