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01.
arXiv (CS.CV) 2026-06-11

Benchmarking Cross-Domain Audio-Visual Deception Detection

Automated deception detection is crucial for assisting humans in accurately assessing truthfulness and identifying deceptive behavior. Conventional contact-based techniques, like polygraph devices, rely on physiological signals to determine the authenticity of an individual's statements. Nevertheless, recent developments in automated deception detection have demonstrated that multimodal features derived from both audio and video modalities may outperform human observers on publicly available datasets. Despite these positive findings, the generalizability of existing audio-visual deception detection approaches across different scenarios remains largely unexplored. To close this gap, we present the first cross-domain audio-visual deception detection benchmark, that enables us to assess how well these methods generalize for use in real-world scenarios. We used widely adopted audio and visual features and different architectures for benchmarking, comparing single-to-single and multi-to-single domain generalization performance. To further exploit the impacts using data from multiple source domains for training, we investigate three types of domain sampling strategies, including domain-simultaneous, domain-alternating, and domain-by-domain for multi-to-single domain generalization evaluation. We also propose an algorithm to enhance the generalization performance by maximizing the gradient inner products between modality encoders, named ``MM-IDGM". Furthermore, we proposed the Attention-Mixer fusion method to improve performance, and we believe that this new cross-domain benchmark will facilitate future research in audio-visual deception detection.

02.
arXiv (CS.AI) 2026-06-19

Frequency-Aware Flow Matching for Continuous and Consistent Robotic Action Generation

arXiv:2606.20135v1 Announce Type: cross Abstract: Flow matching has emerged as a standard paradigm for robotic manipulation owing to its strong expressive power for modelling complex, multimodal action distributions, alongside similar approaches like diffusion policy. However, existing methods rely on discretized action chunks, making them brittle to demonstrations collected at heterogeneous control frequencies and prone to temporally inconsistent actions that degrade control stability. In this paper, we propose Frequency-Aware Flow Matching (FAFM), which outputs continuous, temporally consistent actions. To handle heterogeneous frequency input, we transform discrete action sequences into the frequency domain with the discrete cosine transform (DCT), perform flow matching over the resulting coefficients, and reconstruct continuous actions via cosine basis expansion. To generate temporally consistent actions, we regularize the first-order temporal derivative to promote smooth actions. This corresponds to a Sobolev-type constraint that suppresses high-frequency errors and discourages abrupt action changes. Our FAFM is simple, introduces no additional network parameters and applies to standalone flow-matching policies and vision-language action models. Across synthetic toy benchmark, obstacle avoidance, LapGym, and LIBERO, FAFM improves success rates, multimodal expressivity, motion smoothness, convergence speed, robustness to mechanical bias and mixed-frequency input. These gains are consistent when deployed on a real-world Franka robot. Code available at https://anonymous.4open.science/r/FAFM.

04.
arXiv (CS.LG) 2026-06-16

Generative Modeling on Metric Graphs via Neural Optimal Transport

arXiv:2606.16273v1 Announce Type: cross Abstract: We introduce, to our knowledge, the first deep generative modeling framework for probability distributions continuously supported on compact metric graphs. Given source and target measures on a metric graph, our method embeds the graph into a smooth ambient space, solves an entropic Kantorovich problem via a neural semidual parameterization, and projects generated samples back onto the original graph. We study two embedded geometries: an extrinsic Euclidean realization and the intrinsic tropical Abel–Jacobi embedding into the Jacobian torus. In both cases, the resulting generator is graph-supported by construction. We prove that, in the joint limit of increasing neural expressivity, the learned generator converges weakly to a valid transport coupling between the original graph measures. Empirically, across a range of geometrically distinct graphs, our method matches or improves upon heuristic transport baselines based on discrete graph OT, while scaling more favorably. Finally, we demonstrate scalability on real-world urban mobility data by training our model on one million Uber pickup locations in Manhattan, New York City.

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

Spectral Adaptive Conformal Prediction for Structured Non-Exchangeable Data

arXiv:2606.15950v1 Announce Type: cross Abstract: Conformal prediction gives prediction intervals with finite-sample coverage when the data are exchangeable. Many time-indexed datasets are not exchangeable. They have seasons, recurring regimes, changing frequencies, or other forms of structured dependence. This paper studies a simple way to use that structure. We propose spectral adaptive conformal prediction, a method that forms weighted conformal quantiles using local spectral similarity and then updates the target miscoverage level online. The spectral weights choose calibration residuals that look relevant to the current test point. The adaptive update corrects the long-run miss rate when uncertainty changes over time. We give an approximate coverage result for the fixed spectral weighted quantile and a deterministic long-run calibration result for the adaptive update. Simulations with recurring regimes and slowly changing frequencies, together with three U.S. real-data examples, show that the hybrid method can improve on fixed spectral weighting, while also showing that spectral weighting must be monitored through effective sample size diagnostics.

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

FoundCause: Causal Discovery with Latent Confounders from Observational Data

arXiv:2606.17516v1 Announce Type: cross Abstract: Causal discovery from observational data remains challenging due to the need to recover directed structure and latent confounding without interventions. We propose FoundCause, an amortized causal discovery model trained entirely on synthetic data that maps datasets directly to causal graphs in a single forward pass. By learning from large collections of simulated structural causal models, FoundCause captures transferable statistical patterns that generalize beyond individual datasets. The architecture incorporates several key inductive biases for causal discovery. It uses a permutation-invariant transformer encoder with alternating attention over samples and variables to jointly model cross-variable dependence and per-variable distributions. Pairwise statistical features derived from classical asymmetry measures are injected through statistics-conditioned attention, guiding the model toward known causal signals. A factorized decoder separates edge existence from direction, while a triangular refinement module enables reasoning over higher-order causal motifs such as chains and colliders. In addition, a dedicated confounder module based on learnable latent tokens explicitly models hidden common causes, and the model explicitly handles missing data via its masked input representation. To our knowledge, FoundCause is the first amortized causal discovery approach to explicitly model latent confounding. FoundCause outperforms 11 classical non-amortized methods (e.g., PC, GES, NOTEARS-style optimization) and 4 amortized causal discovery methods on 15 real-world datasets, achieving +9.6% improvement in $F_1$, +1.2% in AUROC, and an 18.9% reduction in structural Hamming distance relative to the strongest non-amortized methods, while performing inference in a single forward pass.

07.
arXiv (CS.CV) 2026-06-24

DDStereo: Efficient Dual Decoder Transformers for Stereo 3D Road Anomaly Detection

Stereo-based 3D object detection still faces two critical safety challenges: real-time performance and open-set generalization. Existing stereo 3D methods typically achieve twice the accuracy of monocular methods but suffer from significantly lower inference speeds, making them unsuitable for real-time applications. Meanwhile, recent advances in open-world detection have introduced open-set and open-vocabulary algorithms in monocular 2D and 3D settings, yet stereo-based open-set detection remains largely unexplored. To bridge this gap, we propose DDStereo, a novel Dual-Decoder Stereo Transformer for real-time open-set 3D object detection. DDStereo features two lightweight decoder branches: one for open-set foreground 2D detection and the other for 3D attribute regression. These decoders share object-level queries to achieve unified target-level alignment. To enhance inference efficiency, we designed a compact disparity feature extractor and a streamlined decoder architecture. Experiments on public stereo 3D benchmarks demonstrate that DDStereo achieves state-of-the-art accuracy under both closed-set and open-set protocols. Notably, our method surpasses existing stereo 3D detectors in inference speed and, for the first time, achieves real-time performance comparable to monocular approaches.

08.
arXiv (CS.CL) 2026-06-12

Layer-Resolved Optimal Transport for Hallucination Detection in NMT and Abstractive Summarization

Optimal transport (OT) has been shown to detect hallucinations in neural machine translation (NMT) by measuring the geometric distance between cross-attention distributions and a reference distribution, without any supervision. We extend this analysis to all six decoder layers of the Fairseq DE-EN model ($N=3{,}414$), showing that Wass-to-Unif and Wass-to-Data are complementary detectors specialised across hallucination types, that detection is concentrated in layers L1–L4 with L5 anti-predictive for subtler types, and that hallucinated translations lack the exploratory attention phase present in correct translations from the first decoding step. We further evaluate whether the geometric signal transfers to abstractive summarization faithfulness detection: our unsupervised OT detector on AggreFact ($N=1{,}116$) achieves $57.2\%$/$57.6\%$ balanced accuracy on CNN/XSum – above chance but substantially below supervised MiniCheck-Flan-T5-L($69.9\%$/$74.3\%$). This gap is principled: unlike NMT hallucinations, unfaithful summaries can attend correctly to source tokens while misrepresenting their content, a failure mode invisible to concentration-based OT metrics by construction. Structural experiments on T5-base confirm consistent decoder organisation across depth, with Layer~3 showing peak concentration and Layer~12 being most critical for generation quality. Together, the results establish OT on cross-attention as a reliable detector when the failure mode is source disengagement, a principled interpretability tool regardless of task, and fundamentally limited when faithfulness failures occur downstream of attention.

09.
arXiv (CS.CL) 2026-06-11

Afrispeech Semantics: Evaluating Audio Semantic Reasoning in Spoken Language Models Across Domains and Accents

Audio language models (ALMs) are increasingly used for speech-based understanding, yet their ability to perform semantic reasoning beyond transcription, Text-to-Audio Retrieval, Captioning, and Question-Answering accuracy remains insufficiently benchmarked. In particular, the effects of accent variation, domain shift, and semantic over-inference on audio reasoning are poorly understood. We evaluate audio language models across five semantic and paralinguistic reasoning tasks: entailment, consistency, plausibility, accent drift, and accent restraint. Collectively, these tasks assess a model's ability to reason over spoken audio as the primary evidence source, including whether a textual hypothesis can be inferred, contradicted, or left undetermined by the audio, whether statements align or conflict with spoken content, whether claims are plausible given the discourse, and whether model predictions remain stable or appropriately constrained across accent variation. These findings highlight critical limitations in current audio reasoning evaluations and hope to provide guidance for more robust and equitable ALM design and assessment

10.
arXiv (CS.CL) 2026-06-12

LoHoSearch: Benchmarking Long-Horizon Search Agents Beyond the Human Difficulty Ceiling

Search agent benchmarks exemplified by BrowseComp have rapidly saturated over the past year, with the strongest models surpassing 90% accuracy. Since these benchmarks are predominantly human-authored, annotators lack a global perspective on entity statistics and cannot systematically maximize search space size and structural complexity. This creates a difficulty ceiling that is hard to break. To address this, we introduce LoHoSearch (Long-Horizon Search Agents), a challenging benchmark comprising 544 human-verified questions across 11 domains. LoHoSearch is constructed via an automated pipeline built upon a knowledge graph covering over 7 million Wikipedia entities, which selects relations with large search spaces and assembles them into structurally complex questions with KG-verified unique answers. Our evaluation demonstrates that even the strongest model achieves only 34.74% accuracy, and existing context management strategies (best +6.8%) yield far smaller gains than on prior benchmarks. LoHoSearch provides a more demanding standard for evaluating long-horizon reasoning and context management in search agents.

11.
arXiv (CS.LG) 2026-06-16

A Penalty Approach for Differentiation Through Black-Box Quadratic Programming Solvers

arXiv:2602.14154v3 Announce Type: replace Abstract: Differentiating through the solution of a quadratic program (QP) is a central problem in differentiable optimization. Most existing approaches differentiate through the Karush–Kuhn–Tucker (KKT) system, but their computational cost and numerical robustness can degrade at scale. To address these limitations, we propose dXPP, a penalty-based differentiation framework that decouples QP solving from differentiation. In the solving step (forward pass), dXPP is solver-agnostic and can leverage any black-box QP solver. In the differentiation step (backward pass), we map the solution to a smooth approximate penalty problem and implicitly differentiate through it, requiring only the solution of a much smaller linear system in the primal variables. This approach bypasses the difficulties inherent in explicit KKT differentiation and significantly improves computational efficiency and robustness. We evaluate dXPP on various tasks, including randomly generated QPs, large-scale sparse projection problems, and a real-world multi-period portfolio optimization task. Empirical results demonstrate that dXPP is competitive with KKT-based differentiation methods and achieves substantial speedups on large-scale problems. Our implementation is open source and available at https://github.com/mmmmmmlinghu/dXPP.

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

Stop the Sampler! Classifier-Based Adaptive Stopping for Sampling Kernels

arXiv:2606.16073v1 Announce Type: new Abstract: Sampling from complex, unnormalized probability densities is a fundamental challenge in Bayesian inference and probabilistic modeling. While Markov chain Monte Carlo (MCMC) methods provide asymptotic guarantees, they often suffer from slow mixing and high computational costs due to fixed or manually tuned trajectory lengths. In this work, we propose a novel framework that treats trajectory termination as a learnable component of the sampling dynamics. By framing MCMC within the theory of non-acyclic generative flow networks (GFlowNets), we train state-dependent neural classifiers to decide when a trajectory has reached a high-density region and should terminate. We theoretically establish the connection between optimal classifiers and the target density via detailed balance conditions and introduce a multilevel training scheme to facilitate exploration in complex geometries. Experimental results across various benchmark densities demonstrate that our approach significantly reduces average trajectory lengths while improving mode coverage and mixing compared to standard MCMC baselines.

13.
arXiv (CS.AI) 2026-06-19

Improving Code-Switching ASR with Code-Mixing Guided Synthetic Speech

arXiv:2606.19381v1 Announce Type: cross Abstract: Code-switch (CS) Automatic Speech Recognition (ASR) remains challenging due to limited availability of high quality CS text-speech pairs for training. Although synthetic data augmentation via Text-to-speech (TTS) has been explored, existing CS TTS approaches primarily optimise reconstruction fidelity and do not explicitly enforce language-boundary consistency, thereby limiting their effectiveness for CS ASR augmentation. This paper proposes a code-mixing guided preference-learning framework that steers synthetic speech generation toward improved code-switching fidelity using the Code Mixing Index (CMI). Experiments on the SEAME Mandarin-English conversational corpus demonstrate that the proposed method enhances the utility of synthetic data for ASR fine-tuning. Specifically, when fine-tuning Whisper Large, the proposed approach reduces Mixed Error Rate (MER) from 12.1%/17.8% to 8.9%/14.2% on the DevMAN and DevSGE sets, respectively.

14.
arXiv (CS.CL) 2026-06-16

Deep Temporal Modeling and Ensemble Fusion for Multimodal Emotion Recognition from Physiological Signals

Physiological stress and emotion recognition are important for health monitoring and affective computing. In this work, we present a comprehensive evaluation of deep learning models such as Long Short-Term Memory (LSTM), Temporal Convolutional Networks (TCN), and Transformer on the WESAD dataset for multimodal affect recognition using wrist and chest sensor signals. We perform ablation studies to assess the individual contributions of each modality by training models on wrist-only and chest-only inputs. In addition, we implement a late-fusion ensemble strategy that combines predictions from all three architectures trained on multimodal input. We also employ early fusion at the sensor level by concatenating wrist and chest signals before feeding them into each model. Our results show that Transformer models consistently achieve the highest accuracy in multimodal settings, while TCN models perform best in the wrist-only configuration. The ensemble method yields the highest overall accuracy (98.91 +/- 0.13%) and macro-F1 score (98.56 +/- 0.17%). These findings demonstrate the effectiveness of sensor fusion and ensemble-based fusion in developing robust systems for physiological emotion recognition.

15.
arXiv (CS.AI) 2026-06-24

Weight-Space Geometry of Offline Reasoning Training

arXiv:2606.23740v1 Announce Type: cross Abstract: Offline reinforcement-learning losses (RFT, RIFT, DFT, Offline GRPO, DPO) are widely used to distill reasoning from large teachers into smaller students, and are typically compared on downstream accuracy alone. We ask whether they are mechanistically distinct or converge to a similar weight update. Training six methods (SFT, RFT, DFT, RIFT, Offline GRPO, DPO) on identical math rollouts from a single base model (Qwen3-4B) with attention-only LoRA, we analyze the resulting deltas via cosine similarity, principal-angle subspace analysis, linear mode connectivity, and CKA. We observe: (i) SFT, RFT, and RIFT have nearly colinear weight deltas (cosine >= 0.97, top-1 principal angle ~7 deg median over 144 modules) and comparable GSM8K accuracy (87-88%, n=1319; pairwise McNemar p >= 0.15); (ii) DFT diverges further in direction than any reward-weighted method despite using the same data; (iii) Offline GRPO adds a substantial component orthogonal to the SFT direction (~67% globally, up to ~86% in late layers) while staying in the SFT loss basin; (iv) DPO sits in a near-orthogonal subspace, shows a mode-connectivity barrier, and collapses late-layer CKA to ~0.46. DPO also reaches the highest accuracy in our protocol on both GSM8K (93.5%, McNemar p < 10^-9 vs. each other method) and AIME26 (30.0% vs. 3.3-10.0%); its training uses a 10x smaller learning rate than the others (the standard convention), so the update-norm and accuracy gaps reflect loss-function and optimizer choices jointly, and a learning-rate-matched DPO comparison is left for future work.

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

Playful Agentic Robot Learning

arXiv:2606.19419v1 Announce Type: cross Abstract: Current agentic robot systems can write executable Code-as-Policy programs, observe feedback, and revise behavior across multiple attempts, but they remain largely task-driven: reusable skills are acquired only after explicit instructions. We study Playful Agentic Robot Learning, where an embodied coding agent uses self-directed play as a continual skill-learning stage before downstream tasks arrive. We introduce RATs, Robotics Agent Teams designed for play-time skill acquisition. During play, RATs proposes novel yet learnable exploratory tasks, plans and executes robot-code policies, verifies intermediate progress, diagnoses failures, retries with dense, step-level feedback, and distills successful executions into a persistent code skill library. At test time, the agent reuses relevant skills from this frozen library to help solve new tasks. Experiments in LIBERO-PRO and MolmoSpaces show that play-learned skills improve held-out downstream tasks over no-play and random-play baselines, with 20.6 and 17.0 percentage-point gains over CaP-Agent0 on LIBERO-PRO and MolmoSpaces, respectively. Moreover, the learned skills can be plugged into other inference-time Code-as-Policy agents by simply retrieving them into the context, improving RoboSuite and real-world transfer by 8.9 and 8.8 points, respectively, without finetuning the underlying model.

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

Learning Credal Ensembles via Distributionally Robust Optimization

arXiv:2602.08470v3 Announce Type: replace Abstract: Credal predictors are models that are aware of epistemic uncertainty and produce a convex set of probabilistic predictions. They offer a principled way to quantify predictive epistemic uncertainty (EU) and have been shown to improve model robustness in various settings. However, most state-of-the-art methods mainly define EU as disagreement caused by random training initializations, which mostly reflects sensitivity to optimization randomness rather than uncertainty from deeper sources. To address this, we define EU as disagreement among models trained with varying relaxations of the i.i.d. assumption between training and test data. Based on this idea, we propose CreDRO, which learns an ensemble of plausible models through distributionally robust optimization. As a result, CreDRO captures EU not only from training randomness but also from meaningful disagreement due to potential distribution shifts between training and test data. Empirical results show that CreDRO consistently outperforms existing credal methods on tasks such as out-of-distribution detection across multiple benchmarks and selective classification in medical applications.

18.
arXiv (CS.AI) 2026-06-15

Metabolic cost of information processing in Poisson variational autoencoders

arXiv:2602.13421v2 Announce Type: replace-cross Abstract: Computation in biological systems is fundamentally energy-constrained, yet standard theories of computation treat energy as freely available. Here, we argue that variational free energy minimization under a Poisson assumption offers a principled path toward an energy-aware theory of computation. Our key observation is that the Kullback-Leibler (KL) divergence term in the Poisson free energy objective becomes proportional to the prior firing rates of model neurons, yielding an emergent metabolic cost term that penalizes high baseline activity. This structure couples an abstract information-theoretic quantity – the *coding rate* – to a concrete biophysical variable – the *firing rate* – which enables a trade-off between coding fidelity and energy expenditure. Such a coupling arises naturally in the Poisson variational autoencoder (P-VAE) – a brain-inspired generative model that encodes inputs as discrete spike counts and recovers a spiking form of *sparse coding* as a special case – but is absent from standard Gaussian VAEs. To demonstrate that this metabolic cost structure is unique to the Poisson formulation, we compare the P-VAE against Grelu-VAE, a Gaussian VAE with ReLU rectification applied to latent samples, which controls for the non-negativity constraint. Across a systematic sweep of the KL term weighting coefficient $\beta$ and latent dimensionality, we find that increasing $\beta$ monotonically increases sparsity and reduces average spiking activity in the P-VAE. In contrast, Grelu-VAE representations remain unchanged, confirming that the effect is specific to Poisson statistics rather than a byproduct of non-negative representations. These results establish Poisson variational inference as a promising foundation for a resource-constrained theory of computation.

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

Curvature-Informed Potential Energy Surface for Protein-Ligand Binding Affinity Prediction

arXiv:2606.14217v1 Announce Type: new Abstract: Accurate prediction of protein-ligand binding affinity is essential for structure-based drug discovery. Recent geometric deep learning methods have achieved promising performance by representing protein-ligand complexes as three-dimensional graphs. However, most existing approaches mainly rely on static interaction geometry from a single bound conformation, while neglecting molecular flexibility and binding-induced conformational changes. To address this limitation, we propose a curvature-informed potential energy surface (CPES) graph neural network for protein-ligand binding affinity prediction, which incorporates physics-informed curvature representations to model conformational flexibility. CPES first derives curvature spectral descriptors from the Hessian of the potential energy surface evaluated at equilibrium configurations, whose eigenvalues define the local principal curvatures of the potential energy surface. It then uses spectral cross-attention to compare the unbound ligand and protein with the bound complex, thereby capturing binding-induced changes in conformational dynamics. In parallel, hierarchical protein-ligand interaction representations are learned from static structural features through geometry-aware message passing, soft clustering, and bidirectional cross-attention. Finally, CPES fuses the curvature-informed dynamic representations with static interaction representations for affinity regression. Extensive evaluations on multiple benchmark datasets demonstrate that CPES achieves improved predictive performance and offers physical interpretability.

20.
arXiv (CS.LG) 2026-06-24

Asymptotic Signal Subspace Recovery in Softmax Attention Models

arXiv:2606.22406v2 Announce Type: replace Abstract: Attention mechanisms have demonstrated remarkable empirical success in identifying relevant information from large collections of tokens, yet the theoretical principles underlying this behavior remain poorly understood. We study a stylized softmax-attention model in which a query vector is learned by stochastic gradient ascent from a collection of informative and nuisance tokens. Exploiting the symmetry of the model, we derive a population objective and characterize the limiting ordinary differential equation governing the learning dynamics. Using tools from stochastic approximation and dynamical systems theory, we establish a rigorous connection between the stochastic learning algorithm and its deterministic limit. Our main result shows that, under suitable high-dimensional scaling assumptions and standard step-size conditions, the learned query converges almost surely to the one-dimensional signal subspace spanned by the latent informative direction. Equivalently, the query asymptotically recovers the latent signal up to the intrinsic sign ambiguity. These results provide a rigorous theoretical foundation for understanding attention mechanisms as signal extraction procedures in high-dimensional noisy environments and offer a dynamical-systems perspective on how attention discovers relevant information in the presence of substantial noise.

21.
arXiv (CS.CL) 2026-06-17

PseudoBench: Measuring How Agentic Auto-Research Fuels Pseudoscience

As Large Language Model based agents enter autonomous scientific research, their ability to resist pseudoscience becomes increasingly important. Otherwise, such systems may rapidly generate plausible yet misleading studies that contaminate academic literature and erode trust in science. We present PseudoBench, an adversarial benchmark for evaluating whether agentic auto-research systems can identify and resist pseudoscientific narratives. PseudoBench contains 200 curated pseudoscientific claim-evidence pairs across five domains and evaluates agents through an end-to-end research pipeline from experiments to writing. Testing seven state-of-the-art agents, we find that current systems readily produce persuasive reports that align with pseudoscientific premises with near-zero refusal rates and the highest resistance of only 27.4%. Stronger agents risk packaging pseudoscience in more sophisticated scientific language, increasing its apparent credibility. These findings reveal an alarming capacity to fuel pseudoscience, calling for scientific alignment before widespread deployment.

22.
arXiv (CS.AI) 2026-06-15

Evidence-Gated LLM Priors for Multi-Objective Bayesian Optimization

arXiv:2606.01730v2 Announce Type: replace Abstract: Large language models (LLMs) are increasingly used as heuristic advisors for black-box optimization, yet their suggestions and self-reported confidence are not necessarily calibrated to downstream objective values. This issue becomes more pronounced in multi-objective Bayesian optimization, where different objectives may require different expert knowledge and where an LLM expert can be useful for one objective but misleading for another. We study how to use LLM-generated expert priors in discrete multi-objective Bayesian optimization without blindly trusting them. We propose an objective-wise reputation-market mechanism that treats each expert-objective pair as a falsifiable prior source. Expert weights are updated online from observed objective feedback, discounted over time, and gated by market-level trust. We then introduce a decoupled counterfactual gate that can use the LLM prior without confidence, use it with confidence, or abstain from the LLM prior entirely. Across controlled synthetic stress tests and three molecule optimization benchmarks with \qwenflash{}-generated expert priors, we find that dynamic objective-wise calibration improves robustness over fixed LLM priors. However, raw LLM confidence is not reliably beneficial: on ESOL, confidence is positively correlated with prediction error; on FreeSolv, confidence can help; and on Lipophilicity, ignoring confidence remains strongest. Our fixed three-arm counterfactual gate improves over the first counterfactual variant on ESOL and FreeSolv, while an attempted margin portfolio exposes a useful negative result: margin selection should be acquisition-aware rather than based only on one-step prior error.

23.
medRxiv (Medicine) 2026-06-22

Cumulative Metabolic Exposure to Hyperglycemia and Risk of Cardiovascular and Limb Events in Peripheral Artery Disease

Background: Although diabetes is a potent risk factor for the development of peripheral artery disease (PAD), the effect of cumulative metabolic exposure to hyperglycemia on risk of cardiovascular or limb events in patients with PAD remains unclear. Methods: The Peripheral Artery Disease: Long-term Survival (PEARLS) is a longitudinal registry of Veterans with newly diagnosed PAD identified using a natural language processing approach. Included patients had ankle brachial index [&le;]0.9 or toe brachial index [&le;]0.7, and no history of lower extremity revascularization or major amputation. Among patients with diabetes in this cohort, we assessed cumulative exposure to hyperglycema based on a 24-month rolling average of hemoglobin (Hgb) A1c values, categorized as [&le;]7%, >7% to [&le;]8%, and >8%. Multivariable Cox regression models evaluated the association between categories of HgbA1c, modeled as a time-varying exposure, and risk of cardiovascular (CV: myocardial infarction or stroke) and limb (chronic limb threatening ischemia [CLTI] or major amputation) events. Results: Among 45,109 patients with new diagnosis of PAD and pre-existing diabetes, the mean HgbA1c at baseline was 7.5%, with nearly one-third (30.4%) having HgbA1c >8%. The mean age was 70.4 years, 19.8% were Black and 4% were Hispanic. Patients with baseline HgbA1c >8% were younger and compared to those with HgbA1c [&le;]7%, more likely to have coronary disease, kidney disease, and obesity. Over a median follow up of 4.2 years, 8,306 (18.4%) patients experienced a CV event, and 8,199 (18.2%) experienced a limb event. The adjusted association between HgbA1c and hazard of CV events was 12% higher in patients exposed to HgbA1c >7% to [&le;]8% (HR 1.12; 95%CI: 1.05-1.18) and 38% higher in those exposed to HgbA1c >8% (HR 1.38; 95%CI: 1.30-1.46), compared to HgbA1c 7% to [&le;]8% (HR 1.20; 95%CI: 1.13-1.28) and HgbA1c >8% (HR 1.60; 95%CI: 1.51-1.70), respectively when compared to HgbA1c [&le;]7%. These findings were consistent in subgroups based on age and severity of PAD. Conclusions: Among diabetic patients with PAD, cumulatiave metabolic exposure to hyperglycemia is associated with a markedly increased risk of clinical events, especially limb events.

24.
bioRxiv (Bioinfo) 2026-06-14

FENNEC: Fine-Tuned Ensemble Neural Networks Accelerate Chemically Modified siRNA Design and Screening

Small interfering RNAs (siRNAs) are a clinically validated therapeutic modality, yet designing potent chemically modified siRNAs remains a costly and iterative process, limited by scarce public data. Computational prediction of siRNA efficacy is therefore essential for rational design and accelerated preclinical development. However, despite the critical role of chemical modifications in therapeutic performance, current state-of-the-art machine learning methods either are not designed to model the chemical diversity of therapeutic siRNAs, or exhibit poor generalization performance. Here, we present FENNEC (Fine-Tuned Ensemble of Neural Networks for siRNA Efficiency Characterization), a machine-learning framework for predicting siRNA activity across chemically diverse design spaces. To support this effort, we curated the largest patent-derived dataset to date of chemically modified siRNAs from 42 patents using OCR-based table extraction and stringent filtering. FENNEC combines temporal convolutional networks with thermodynamic descriptors, experimental covariates, and embeddings from RNA foundation models to capture both local chemical determinants and broader target-context information. Importantly, we show that language-model-derived embeddings provide meaningful higher-order representations of target transcripts, particularly in data-scarce settings. FENNEC achieved robust predictive performance across both gene-level and scaffold-level validation settings, with additional experimental validation on a novel AHSA1-targeting dataset further supporting its generalizability across chemically modified siRNAs. In benchmarking, FENNEC outperformed classical machine-learning and state-of-the-art deep learning models, demonstrating generalization to unseen chemistry. Model interpretation recovered established design principles, including position-specific effects of glycol nucleic acid, 2'-fluoro modifications, and phosphorothioate backbones. Furthermore, in silico perturbation analyses suggest that FENNEC can serve not only as a predictive model, but also as an oracle for the design and optimization of chemically modified siRNAs. Together, our work addresses a key gap in the field by enabling chemically aware deep learning for siRNA design, supported by a large and diverse collection of chemically modified siRNA measurements.

25.
medRxiv (Medicine) 2026-06-15

Data-Driven Stochastic Model for Detecting Patientswith Alzheimer's Disease

Alzheimer s disease (AD) is a critical neurological disorder that causes the brain to shrink and leads to the eventual death of brain cells, adversely affecting a person s ability to function. AD is a fast-growing disease in the United States and was the fifth leading cause of death among Americans 65 years of age or older in 2023. In the United States 6.9 million people aged 65 or older were diagnosed with AD, along with a high rate of undiagnosed patients. Thus, the objective of our study is to develop a real data-driven predictive model to identify a patient with AD based on eight risk factors: Age, Gender, ADAS-Cog13, Entorhinal, Fusiform, Intracranial Volume (ICV), Amyloid-Beta, and Tau Protein, with a high degree of accuracy. The quality of the model was evaluated using well-established and sophisticated statistical measures: the area under the receiver operating characteristic curve, calibration plot, Hosmer-Lemeshow goodness-of-fit test, and K-fold cross-validation. If a patient is given information on the above risk factors, our proposed binary logistic regression model can classify the patient as having AD or not with at least 98% accuracy.