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01.
arXiv (CS.LG) 2026-06-15

Concatenated Matrix SVD: Compression Bounds, Incremental Approximation, and Error-Constrained Clustering

arXiv:2601.11626v2 Announce Type: replace-cross Abstract: Large collections of matrices arise throughout modern machine learning, signal processing, and scientific computing, where they are commonly compressed by concatenation followed by truncated singular value decomposition (SVD). This strategy enables parameter sharing and efficient reconstruction and has been widely adopted across domains ranging from multi-view learning and signal processing to neural network compression. However, it leaves a fundamental question unanswered: which matrices can be safely concatenated and compressed together under explicit reconstruction error constraints? Existing approaches rely on heuristic or architecture-specific grouping and provide no principled guarantees on the resulting SVD approximation error. In the present work, we introduce a theory-driven framework for compression-aware clustering of matrices under SVD compression constraints. Our analysis establishes new spectral bounds for horizontally concatenated matrices, deriving global upper bounds on the optimal rank-$r$ SVD reconstruction error from lower bounds on singular value growth. The first bound follows from Weyl-type monotonicity under blockwise extensions, while the second leverages singular values of incremental residuals to yield tighter, per-block guarantees. We further develop an efficient approximate estimator based on incremental truncated SVD that tracks dominant singular values without forming the full concatenated matrix. Therefore, we propose three clustering algorithms that merge matrices only when their predicted joint SVD compression error remains below a user-specified threshold. The algorithms span a trade-off between speed, provable accuracy, and scalability, enabling compression-aware clustering with explicit error control.

02.
arXiv (CS.CL) 2026-06-18

Are LLMs Ready to Assist Physicians? PhysAssistBench for Interactive Doctor-Patient-EHR Assistance

The most plausible near-term role of medical LLMs is to assist rather than replace physicians, yet current evaluations often test isolated capabilities: clinical knowledge, EHR system interaction, or patient communication. Physician assistance instead requires coordinating these capabilities within the same interaction, where physicians issue underspecified requests, patients describe symptoms ambiguously, and EHR systems demand precise tool use. We introduce PhysAssistBench, a benchmark for interactive doctor-patient-EHR assistance. Built from real MIMIC-IV cases, PhysAssistBench uses a scalable pipeline to construct agentic patients: interactive, record-grounded agents that turn static EHR records into multi-turn clinical scenarios while preserving clinical factuality. PhysAssistBench provides a curated bilingual evaluation set of 1,296 manually reviewed and physician-validated turns. Experiments with leading LLMs show that current models remain unreliable in this setting, which exposes a key bottleneck for clinical LLMs: reliable assistance requires coordination across knowledge, communication, and systems, not isolated gains in any of them.

04.
arXiv (quant-ph) 2026-06-16

Diagonal-Budgeted Trotterization for Efficient Quantum Hamiltonian Simulation

arXiv:2606.16959v1 Announce Type: new Abstract: Efficient classical simulation of quantum Hamiltonian dynamics is often bottlenecked by exponential state growth and the overhead of generic sparse linear algebra. We introduce diagonal-budgeted Trotterization, a structure-aware strategy that decomposes Hamiltonians into factors preserving diagonal sparsity while tightly controlling fidelity loss. Our implementation, HamSim, utilizes a compact diagonal-sparse data layout and specialized C++/CUDA kernels to bypass the overheads of generic formats like CSR. By leveraging SIMD vectorization, multithreading, and GPU acceleration, HamSim achieves high performance across heterogeneous architectures. Benchmarks on the HamLib suite show that HamSim significantly outperforms Qiskit-Aer. On CPUs, HamSim attains speedups of $182$–$1,269\times$ on optimization instances (TSP, MaxCut) and $4.8$–$841\times$ on physical models (TFIM, Heisenberg). On GPUs, it achieves up to $178\times$ speedup for $12$–$16$ qubit problems. Unlike traditional Trotterization, HamSim maintains near-perfect fidelity without requiring exponential steps. This demonstrates that diagonal-aware numerical kernels provide a scalable foundation for high-fidelity classical Hamiltonian simulation.

05.
arXiv (CS.CV) 2026-06-11

FOCUS on Contamination: Hydrology-Informed Noise-Aware Learning for Geospatial PFAS Mapping

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants with significant public health impacts, yet large-scale monitoring remains severely limited due to the high cost and logistical challenges of field sampling. The lack of samples leads to difficulty simulating their spread with physical models and limited scientific understanding of PFAS transport in surface waters. Yet, rich geospatial and satellite-derived data describing land cover, hydrology, and industrial activity are widely available. We introduce FOCUS, a geospatial deep learning framework for PFAS contamination mapping that integrates sparse PFAS observations with large-scale environmental context, including priors derived from hydrological connectivity, land cover, source proximity, and sampling distance. These priors are integrated into a principled, noise-aware loss, yielding a robust training objective under sparse labels. Across extensive ablations, robustness analyses, and real-world validation, FOCUS consistently outperforms baselines including sparse segmentation, Kriging, and pollutant transport simulations, while preserving spatial coherence and scalability over large regions. Our results demonstrate how AI can support environmental science by providing screening-level risk maps that prioritize follow-up sampling and help connect potential sources to surface-water contamination patterns in the absence of complete physical models.

06.
medRxiv (Medicine) 2026-06-24

Digital exclusion and mental health in UK Armed Forces veterans: findings from the Veterans Digital Needs Study

Background: Public services are increasingly delivered through digital platforms. Although digital health may improve access and scalability, they may also widen inequalities for people who lack reliable access, confidence, skills, affordability or trust. Objective: This study examined the prevalence of self-reported digital exclusion among UK veterans and assessed its association with depression, anxiety and loneliness. Methods: A cross-sectional online survey was conducted between July 2025 and March 2026. Participants were UK Armed Forces veterans and resident in the UK. The survey collected sociodemographic, military service, digital access and health data. Self-reported digital exclusion was defined as reporting feeling excluded or disadvantaged due to lack of digital access or skills. Probable depression, anxiety and loneliness were assessed using the PHQ-2, GAD-2 and three-item UCLA Loneliness Scale, respectively. Associations between digital exclusion and each outcome were examined using adjusted multivariable logistic regression. Results: Of 1,911 responses received, 1,607 were included after data quality exclusions. Among participants with valid responses to the primary digital exclusion item, 553 (41.7%) reported digital exclusion. Digital exclusion was more common among females, younger veterans and those with lower household income. Probable depression, anxiety and loneliness were more prevalent among digitally excluded participants than among non-excluded participants. In adjusted models, self-reported digital exclusion was associated with higher odds of probable depression (AOR 1.38; 95% CI 1.04 to 1.83; p=0.028), probable anxiety (AOR 1.63, 95% CI 1.23 to 2.16; p

07.
arXiv (CS.LG) 2026-06-15

Structured Noise Adaptation for Sequential Bayesian Filtering with Embedded Latent Transfer Operators

arXiv:2606.14195v1 Announce Type: new Abstract: Kalman filters based on the Embedded Latent Transfer Operators (ELTO) emerge as novel statistical tools for sequential state estimation. However, a critical limitation stems from their use of simplified noise models, which fail to dynamically adapt to non-stationary processes. To address this limitation, we introduce an ELTO-based Bayesian filtering approach with a new structured parameterization for the filter's noise model. This parameterization enables structured noise adaptation, which couples the data-driven learning of an optimal time-invariant noise model with dynamic parameter adaptation that responds to changes in dynamics within non-stationary processes. Empirical results show that our structured noise adaptation improves the filter's dynamic state estimation performance in noisy, time-varying environments.

09.
arXiv (quant-ph) 2026-06-11

Exact Dynamics of Topological Order Across a CDW–SPT Transition

arXiv:2606.11303v1 Announce Type: cross Abstract: We investigate the nonequilibrium dynamics of a one-dimensional interacting system across a transition from a charge-density-wave (CDW) phase to a symmetry-protected topological (SPT) phase. Starting from a CDW initial state, we study both sudden quenches and slow ramps into the SPT regime. While the CDW order melts under both protocols, the fate of topological order is sharply different. Following a sudden quench, long-range SPT order does not emerge because the post-quench state contains a finite density of excitations above the topological ground state. In contrast, slow ramps allow the system to follow the instantaneous ground state away from the critical region, enabling the buildup of SPT order with deviations governed by Kibble-Zurek defect production. The dynamics is solvable via a unitary mapping to a quadratic fermionic Hamiltonian, allowing us to compute the Loschmidt echo, correlation functions, and string correlator. The Loschmidt rate function exhibits cusps signaling dynamical quantum phase transitions, while the correlation dynamics reveal the contrasting mechanisms governing quenches and ramps across the transition. These results demonstrate that entering the topological regime is not sufficient for the emergence of topological order; the decisive factor is the suppression of excitation production during the evolution.

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

Quantum Machine Learning for Industrial Applications

arXiv:2606.14822v1 Announce Type: cross Abstract: Recent advances in Machine Learning have transformed numerous industrial sectors, yet classical paradigms face fundamental limitations: rapidly growing data volumes, rising computational costs, significant energy consumption, and the physical scaling limits of conventional hardware architectures. Quantum computing has emerged as a promising computational paradigm to address these challenges, giving rise to the field of Quantum Machine Learning (QML). In this thesis, the theoretical foundations of QML are investigated, with a focus on near-term and future practical applications. Three central challenges are addressed: the trainability of variational quantum circuits, their expressivity, and their resistance to efficient classical simulation. The trainability of Hamming-weight preserving variational quantum circuits is first studied, and theoretical guarantees are established that resolve an open conjecture on the absence of barren plateaus for this circuit family. Subspace-preserving QML algorithms are then introduced, including photonic circuits and quantum convolutional neural networks, and are designed to mimic classical ML subroutines while offering polynomial quantum advantage. Finally, variational quantum circuits are analyzed as quantum Fourier models, and a framework is derived to jointly characterize expressivity and trainability, from which conditions are obtained under which quantum models provably separate from their classical counterparts. These contributions are intended to advance the theoretical roadmap for harnessing near-term and future quantum technologies in real-world applications.

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

GENEB: Why Genomic Models Are Hard to Compare

Progress in genomic foundation models is difficult to assess due to fragmented benchmarks, incompatible evaluation protocols, and task-specific reporting. As a result, claims of superiority or generality across models are often not directly comparable. We introduce GENEB, a large-scale diagnostic benchmark that evaluates frozen representations from 40 genomic foundation models across 100 tasks spanning 13 functional categories under a unified probing-based protocol, including few-shot regimes. GENEB enables controlled comparison across model scale, architecture, tokenization, and pretraining data while explicitly exposing task-level trade-offs. Our analysis shows that aggregate leaderboards are unstable: model rankings vary sharply across task categories, scale provides only modest and inconsistent gains, and architectural and pretraining alignment frequently outweigh parameter count. These results highlight limitations of current evaluation practices and position GENEB as a reference framework for principled comparison and category-aware model selection in genomic machine learning.

12.
arXiv (CS.CL) 2026-06-19

Disentangling Linguistic Relatedness from Task Alignment in Cross-Lingual Transfer

We study cross-lingual transfer by fine-tuning seven large language models (4B–671B parameters) on Arabic and evaluating zero-shot reading comprehension on Semitic languages and non-Semitic controls. Across dense and Mixture-of-Experts architectures, we find no evidence of Semitic-specific transfer: models with weak baselines improve dramatically across all languages, while strong-baseline models show only marginal gains regardless of language family. A chain-of-thought ablation reinforces this finding – the same models that benefit most from fine-tuning benefit equally from inference-time reasoning, suggesting both mechanisms address task-format alignment rather than cross-lingual knowledge transfer.

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

LEAP: Layer-skipping Efficiency via Adaptive Progression for Vision Transformer Distillation

Vision Foundation Models (VFMs) with Vision Transformer (ViT) backbones, such as DINOv2, have become essential for downstream tasks like object recognition and semantic segmentation. The immense computational requirements of backbones often necessitate distillation into smaller architectures for edge deployment. Feature-based knowledge distillation (KD) often suffers from the teacher-student gap; the student struggles to imitate teacher's complex feature map due to its limited capacity. To mitigate this bottleneck, we propose LEAP: Layer-skipping Efficiency via Adaptive Progression, a training curriculum for ViT feature-based knowledge distillation. By utilizing the teacher's intermediate feature maps as a sequence of progressively more difficult targets, our curriculum allows the student to build a foundational representation before tackling higher-level abstractions. Our results demonstrate that this paradigm significantly accelerates convergence through adaptive difficulty selection across various student model sizes and dataset scales. With our curriculum, the LEAP-distilled ViT-S achieves 90.1% accuracy on ImageNet-100, a +12.24% improvement compared with baseline. On ImageNet-1K, LEAP achieves +3.84% and +7.75% improvement for the instance retrieval task on the Oxford and Paris datasets, respectively. Furthermore, the curriculum enables 25.1% savings in training FLOPs and 21% savings in training time on ImageNet-100 by implementing early-stopping for teacher inference during the initial stages of training. Code is available at https://github.com/KevinZ0217/LEAP

14.
arXiv (CS.CL) 2026-06-12

From Passive Generation to Investigation: A Proactive Scientific Peer Review Agent

Large language models (LLMs) have shown promise in automating scientific peer review. However, existing approaches often struggle to generate in-depth reviews supported by concrete evidence. We argue that a key limitation is the lack of flexibility to proactively investigate suspicious parts of a paper based on accumulated evidence, as human reviewers do. In this paper, we explore how to enable an LLM-based review agent to perform such proactive investigation. We find that this can be naturally formulated as a Markov Decision Process (MDP), and propose ProReviewer, a scientific peer review agent that proactively reviews a paper guided by a maintained, structured review log. The structured review log serves as a workspace for the agent to track evidence and intermediate findings collected during review. Experiments show that ProReviewer with an 8B backbone, trained by supervised fine-tuning and optimized by reinforcement learning, achieves the highest average score across five quality dimensions, outperforming prompt-based methods with much larger frontier LLMs by up to 39% and the strongest fine-tuned baseline by 16% relatively. It also attains the highest win rates against baselines in human evaluation.

15.
arXiv (CS.CV) 2026-06-12

OmniDirector: General Multi-Shot Camera Cloning without Cross-Paired Data

Cloning camera motion from reference videos is an important task in video generation, as videos provide intuitive and precise control. Existing methods either directly use parametric representations that fail to handle multi-shot generation or synthesize cross-paired data, which suffer from data scarcity, resulting in poor performance in complicated camera motion cloning. To address these issues, we introduce a general camera motion representation that encodes cameras as grid motion videos. This camera grid represents the camera parameters visually and supports the integration of diverse trajectories for multi-shot video generation. Building upon this, we propose OmniDirector, a unified framework trained on a million-scale camera grid-video pairs that coordinates characters, actions, and cameras to provide director-level control for multimodal diffusion transformers. Furthermore, we design a novel hierarchical prompt expansion agent that harmoniously integrates different control signals by systematically describing camera motion and visual content through understanding signal relationships. Extensive experiments demonstrate the superior performance and outstanding controllability of our framework. Project page: https://ymlinfeng.github.io/OmniDirector.github.io/

16.
arXiv (CS.AI) 2026-06-15

Federated Causal Inference from Multi-Site Observational Data via Propensity Score Aggregation

arXiv:2505.17961v4 Announce Type: replace-cross Abstract: Causal inference typically assumes centralized access to individual-level data. Yet, in practice, data are often decentralized across multiple sites, making centralization infeasible due to privacy, logistical, or legal constraints. We address this problem by estimating the Average Treatment Effect (ATE) from decentralized observational data via a Federated Learning (FL) approach, allowing inference through the exchange of aggregate statistics rather than individual-level data. We propose a novel method to estimate propensity scores via a federated weighted average of local scores using Membership Weights (MW), defined as probabilities of site membership conditional on covariates. MW can be flexibly estimated with parametric or non-parametric classification models using standard FL algorithms. The resulting propensity scores are used to construct Federated Inverse Propensity Weighting (Fed-IPW) and Augmented IPW (Fed-AIPW) estimators. In contrast to meta-analysis methods, which fail when any site violates positivity, our approach exploits heterogeneity in treatment assignment across sites to improve overlap. We show that Fed-IPW and Fed-AIPW perform well under site-level heterogeneity in sample sizes, treatment mechanisms, and covariate distributions. Theoretical analysis and experiments on simulated and real-world data demonstrate clear advantages over meta-analysis and related approaches.

17.
arXiv (CS.AI) 2026-06-19

Repurposing a Speech Classifier for Guided Diffusion-Based Speech Generation

arXiv:2606.20457v1 Announce Type: cross Abstract: Classifier guidance is a way to control diffusion generation by using a noise-conditioned classifier to steer the sampling process toward a target class. One drawback of classifier guidance is that it requires two separately trained models: a classifier and a diffusion model. We therefore study a more compact alternative in which a conventionally trained speech classifier is repurposed as the backbone for diffusion generation. Starting from a frozen noise-conditioned classifier in log-Mel space, we attach a lightweight subnetwork that reuses intermediate classifier representations and train only this subnetwork under a Denoising Score Matching objective. Our work shows that a pretrained classifier can be repurposed for conditional generation, providing an appealing bridge between discriminative modeling and conditional speech synthesis resulting in high speech quality within a single-backbone model, with reduced memory footprint and computational cost.

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

Riemannian MeanFlow for One-Step Generation on Manifolds

arXiv:2603.10718v3 Announce Type: replace Abstract: Flow Matching enables simulation-free training of generative models on Riemannian manifolds, yet sampling typically still relies on numerically integrating a probability-flow ODE. We propose Riemannian MeanFlow (RMF), extending MeanFlow to manifold-valued generation where velocities lie in location-dependent tangent spaces. RMF defines an average-velocity field via parallel transport and derives a Riemannian MeanFlow identity that links average and instantaneous velocities for intrinsic supervision. We make this identity practical in a log-map tangent representation, avoiding trajectory simulation and heavy geometric computations. For stable optimization, we decompose the RMF objective into two terms and apply conflict-aware multi-task learning to mitigate gradient interference. RMF also supports conditional generation via classifier-free guidance. Experiments on spheres, tori, SO(3), and SE(3) demonstrate competitive one-step sampling with improved quality-efficiency trade-offs and substantially reduced sampling cost.

19.
bioRxiv (Bioinfo) 2026-06-18

ScriptManager: a platform for scalable and reproducible high-resolution analysis of genomics datasets

Background: The growing diversity of genomic and epigenomic assays has driven a parallel expansion in data formats, analysis workflows, and figure-generation tools. However, tools for analyzing data and assembling publication-quality figures are often specialized to a specific assay, dramatically limiting their interoperability and reproducibility. Results: We present the v1.0 release of ScriptManager, a Java-based framework for modular and reproducible analysis and visualization workflows of genomics and epigenomics data. Unlike existing tools specialized for individual assay types, ScriptManager provides a unified and extensible framework for cross-assay visualization and workflow reproducibility. The v1.0 release adds novel analytical modules, GUI session logging, automated unit and integration testing, tutorials, and expanded documentation. It also integrates with the broader reproducibility ecosystem through Singularity containers, Anaconda packaging, and Galaxy XML wrappers. We demonstrate ScriptManager's TagPileup scaling from local single-core execution to a 10,305-job analysis distributed across the Open Science Grid (OSG), with the full workload completing in

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

MERGE: Minimal Expression-Replacement GEneralization Test for Natural Language Inference

As many benchmarks have become saturated, it has become increasingly important to create new datasets that evaluate the generalization capacity of current state-of-the-art models in reasoning. However, designing high-quality reasoning datasets is challenging, as their manual construction is costly, and their automatic generation is unreliable, often leading to synthetic data with limited scope. In this paper, we propose the Minimal Expression-Replacement GEneralization (MERGE) test that evaluates the robustness of reasoning models against non-adversarial variants of existing evaluation datasets. We automatically obtain high-quality variants from the original instances with Minimal Expression REplacement (MERE) generation, which uses Masked Language Models (MLMs) and safeguarding filters. We apply the MERGE test to Natural Language Inference (NLI), a popular task of reasoning. We generate new NLI datasets from two widely used existing ones with the MERE generation and use them to evaluate multiple strong NLI models. The results indicate that both LLMs and fine-tuned NLI models generalize poorly: they struggle to consistently and correctly classify variants minimally different in form and reasoning from the original ones. Further, we also analyze how certain aspects in variant generation, such as the word class and the source MLMs, affect model performance.

21.
arXiv (CS.AI) 2026-06-15

The Weight Norm Sets the Grokking Timescale: A Causal Delay Law

arXiv:2606.13753v1 Announce Type: cross Abstract: Grokking is the delayed onset of generalization in neural networks, arising long after they fit the training data. Whether the weight norm causes this delay is disputed: some studies report a critical norm at the transition, others observe grokking with no fixed norm at all. We settle this by intervening on the norm during training rather than only observing it. Under free training with weight decay, networks grok when the weight norm reaches a value Wc that varies little across seeds and learning rates (CV 1 to 2 percent) and grows with the modular base as a power law. When we instead clamp the norm to a fixed multiple rho of Wc and hold it there, the network still groks, but the delay follows T_grok proportional to exp(alpha rho). One exponent, alpha near 7.5, fits this delay across four moduli (R^2 = 0.996). Over the swept ranges the held norm moves the delay by about 19x and the learning rate by only about 2x, and holding the norm above Wc slows grokking rather than preventing it. A final LayerNorm removes the dependence by decoupling weight scale from the network function; without it the exponential law returns. This pinned-norm delay is the exponential counterpart to the logarithmic delay predicted for a freely contracting norm.

22.
arXiv (CS.AI) 2026-06-12

Intelligence as Managed Autonomy: Failure, Escalation, and Governance for Agentic AI Systems

arXiv:2605.27628v2 Announce Type: replace Abstract: As autonomous and agentic AI systems scale in robotic and human-machine environments, managing hallucination and persistent but unjustified action remains an open challenge. Rather than attributing these failures solely to model or alignment limitations, this paper explores the architectural vulnerability of unbounded autonomy - the presumption that an agent should continue operating regardless of rising uncertainty. It introduces a theory of managed autonomy that defines intelligent behavior through the formal capacity to detect epistemic drift, suspend reasoning, attempt recovery, and ultimately surrender control when reliability diminishes. We instantiate this theory via the SMARt (Self-Managing Multi-tier Autonomous Reasoning with Regulated/Revoked transitions) model, a four-layer framework featuring Stable, Meta-cognitive, Assisted, and Regulated states. By developing a timed, guarded Petri net formulation, we establish theoretically bounded properties for the system, demonstrating how architecture can formally mandate escalation, constrain invalid outputs, and ensure governance reachability under specified conditions. We further analyze how incorporating domain-specific trigger sets across varied operational settings (e.g., healthcare, robotics, etc.) can systematically preserve safety, assuming completeness and soundness criteria are met. Because these triggers are designed to be adaptive, the SMARt model accommodates the safe, controlled expansion of an agent's operational scope over time. We conclude that formalizing failure management within the autonomy lifecycle is a crucial step toward realizing reliable and governed artificial intelligence.

23.
arXiv (CS.CL) 2026-06-24

CAVEWOMAN: How Large Language Models Behave Under Linguistic Input and Output Compression

"Talk short. Drop grammar. Save token." This caveman style is widely promoted as a way to cut inference cost, but whether it actually saves anything depends on which channel (the user's prompt or the model's response) is being compressed. We present Cavewoman, a two-channel evaluation protocol that scores every generation on task accuracy, realized per-item cost, and reference-text agreement against the model's unconstrained reference. We evaluate eight models on five datasets at five reduction levels, with both channels measured on the same items. Output compression cuts realized cost on most API models (1.4-2.4x per model, up to 3x in the best case) and on all four open-weight models under public-tier pricing. Input compression has the opposite effect, a strict lose-lose: it raises net cost rather than lowering it (~1.15x on the five-benchmark mean, up to 1.8x on the worst dataset and 2.7x under stronger compression), because models compensate with longer responses even as accuracy collapses. Under the same setting, surface text diverges from the unconstrained reference: on the non-reasoning models, roughly half of all generations are correct yet their surface text no longer entails the model's own unconstrained baseline generation. The divergence survives length-controlled re-scoring, multiple-comparisons correction, and replication under complementary semantic measures. Code and data are available at https://github.com/danielle34/cavewoman.

24.
bioRxiv (Bioinfo) 2026-06-15

Multi-platform reassessment of human mitochondrial DNA methylation reveals signals consistent with technical artifacts

The existence and functional relevance of mitochondrial DNA methylation remain controversial. Here, we systematically profiled cytosine methylation and hydroxymethylation across human brain and blood tissues spanning healthy and malignant states using orthogonal sequencing approaches that avoid chemical conversion during library preparation. While nuclear DNA exhibited canonical methylation patterns, mitochondrial DNA consistently showed negligible signal, indistinguishable from background technical noise. By mapping cytosine-guanine sites between mitochondrial DNA and nuclear-embedded mitochondrial sequences, we demonstrate the potential of these nuclear counterparts to confound not only cytosine methylation but also hydroxymethylation measurements, corroborating and extending prior findings implicating nuclear contamination as a potential source of apparent mitochondrial epigenetic signals. Additional technical factors that inflate apparent mtDNA methylation signals were identified, including sequence context biases, flow cell chemistries, and coverage-dependent discrepancies between the heavy and light strands. Collectively, these results provide convergent evidence against the presence of biologically meaningful cytosine methylation or hydroxymethylation in mitochondrial DNA. These findings caution against interpreting apparent mtDNA methylation signals in human adult tissues as meaningful without rigorous orthogonal validation and comprehensive consideration of technical and analytical confounding factors.

25.
PLOS Computational Biology 2026-06-24

Variable selection-combined causal mediation analysis for continuous treatments with application to large-dimensional biomedical data

Authors:

by Yajing Zhou, Kecheng Wei, Yahang Liu, Zhaoyang Li, Chen Huang, Guoyou Qin, Yongfu Yu Substantial progress has been made in the area of causal inference utilizing large-scale data, among which the estimation of causal mediation effects has attracted a lot of attention. However, existing large-dimensional causal inference primarily focuses on total effects or typical causal mediation effects under binary variable settings, placing less emphasis on large-scale covariate selection with continuous treatment and mediator. To address this, we propose a weighted semiparametric estimation framework that integrates the generalized outcome-adaptive LASSO method into generalized propensity score modeling to achieve estimation of causal mediation effects under continuous variable settings. Simulation results show that our proposed method outperforms other regularization-based methods in selection accuracy and estimation efficiency, which is achieved by incorporating outcome-related key variables and excluding noise covariates. From the perspective of achieving a stable balance between efficiency and bias, as well as high-dimensional information filtering, our method may serve as a compelling alternative that balances estimation efficiency with model interpretability and inferential robustness. We further conduct a real-world application based on the UK Biobank database, quantifying the causal mediation effects of apolipoprotein B levels within the association between potential diabetes risk and cancer incidence using large-scale healthcare and medical data.