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01.
arXiv (CS.LG) 2026-06-16

Time-Varying Audio Effect Modeling by End-to-End Adversarial Training

arXiv:2512.15313v2 Announce Type: replace-cross Abstract: Deep learning has become a standard approach for the modeling of audio effects, yet strictly black-box modeling remains problematic for time-varying systems. Unlike time-invariant effects, training models on devices with internal modulation typically requires the recording or extraction of control signals to ensure the time-alignment required by standard loss functions. This paper introduces a Generative Adversarial Network (GAN) framework to model such effects using only input-output audio recordings, without requiring a modulation signal extraction. We propose a convolutional-recurrent architecture trained via a two-stage strategy: an initial adversarial phase allows the model to learn the distribution of the modulation behavior without strict phase constraints, followed by a supervised fine-tuning phase where a State Prediction Network (SPN) estimates the initial internal states required to synchronize the model with the target. Additionally, a new metric based on chirp-train signals is developed to quantify modulation accuracy. Experiments modeling a vintage hardware phaser demonstrate the method's ability to capture time-varying dynamics in a fully black-box context.

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

How Transparent is DiffusionGemma?

arXiv:2606.20560v1 Announce Type: cross Abstract: LLM reasoning transparency is a critical affordance for understanding model decisions, mitigating misuse and misalignment, and debugging surprising model behaviors. However, DiffusionGemma performs a larger fraction of its computation in a continuous latent space; does this make its reasoning less transparent? We study this question by decomposing transparency into two components: variable transparency, whether we understand intermediate snapshots of a model's computational state; and algorithmic transparency, whether we can use these snapshots to reconstruct the process by which the model arrived at its outputs. Naively, DiffusionGemma has poor variable transparency: its opaque serial depth, the amount of serial computation that occurs in between interpretable model states, seems at first 28.6X higher than the corresponding autoregressive Gemma 4 model. However, we show that we can map the information flowing between denoising steps through an interpretable token bottleneck with no decrease in downstream performance. Treating these intermediate states as interpretable reduces the opaque serial depth to just 1.1X that of Gemma 4. Algorithmic transparency is harder for diffusion models than for autoregressive models because all token predictions in the canvas can change at every denoising step, giving the model the power to implement complicated distributed algorithms during the denoising process. To begin bridging this gap, we conduct a suite of interpretability case studies, uncovering initial evidence of novel diffusion-specific phenomena such as non-chronological reasoning, token and sequence smearing, and intermediate-context reasoning. Finally, we test monitorability, a key application of transparency that measures whether model outputs are useful for downstream tasks. We find that DiffusionGemma is similarly monitorable to Gemma 4.

03.
arXiv (CS.AI) 2026-06-15

TabKD: Tabular Knowledge Distillation through Interaction Diversity of Learned Feature Bins

arXiv:2603.15481v2 Announce Type: replace-cross Abstract: Data-free knowledge distillation enables model compression without original training data, critical for privacy-sensitive tabular domains. However, existing methods does not perform well on tabular data because they do not explicitly address feature interactions, the fundamental way tabular models encode predictive knowledge. We identify interaction diversity, systematic coverage of feature combinations, as an essential requirement for effective tabular distillation. To operationalize this insight, we propose TabKD, which learns adaptive feature bins aligned with teacher decision boundaries, then generates synthetic queries that maximize pairwise interaction coverage. Across 4 benchmark datasets and 4 teacher architectures, TabKD achieves highest student-teacher agreement in 14 out of 16 configurations, outperforming 5 state-of-the-art baselines. We further show that interaction coverage strongly correlates with distillation quality, validating our core hypothesis. Our work establishes interaction-focused exploration as a principled framework for tabular model extraction.

04.
arXiv (CS.CL) 2026-06-12

S-GBT: Smooth Growth Bound Tensor for Certified Robustness Against Word Substitution Attacks in NLP

Despite recent progress in Natural Language Processing (NLP), models remain vulnerable to word substitution attacks. Most existing defenses focus on first order sensitivity and measure how much the output changes when the input is slightly perturbed. However, they ignore how this sensitivity evolves, which is described by curvature. When gradients vary sharply, models can still fail. This paper introduces the Smooth Growth Bound Tensor (S-GBT), a second order method that bounds the Hessian element-wise, for which we provide formal theoretical proofs on the resulting robustness bounds. A regularization term is added during training to minimize these bounds. This yields tighter certified robustness against word substitution attacks. The change in the output under word substitution is bounded by both a linear term and a quadratic term. S-GBT is derived for two architectures: Long Short-Term Memory (LSTM) and Convolutional Neural Networks (CNN). The method is integrated directly into the training objective. Its effectiveness is evaluated on multiple benchmark datasets. The results show that combining first and second order regularization improves certified robust accuracy by up to 23.4% compared to prior methods, while clean accuracy remains competitive. These findings indicate that controlling both the gradient and its variation is a promising direction for building more robust models.

05.
arXiv (quant-ph) 2026-06-17

Induced Resource Theories and Harvesting via Quantum Probes

arXiv:2606.17287v1 Announce Type: new Abstract: We consider scenarios in which a quantum system with a well-defined resource theory is used as a probe to interact with an environment, such as a quantum field, for which a resource-theoretic description is absent or incomplete. We clarify if and how the harvesting of a resource in the probe can tell us about the state of the environment. This is particularly ambiguous when the probe-environment interaction is not a free operation, or the concept of such free operations cannot be defined altogether. We propose a framework and precise conditions under which it becomes possible to interpret resource generation on the probe as evidence of resources in the environment, thereby introducing an effective notion of resources for the latter. Our results clarify in which sense resources can be said to be harvested from the environment and provide a systematic way to analyse such processes beyond fully controlled resource-theoretic settings. More generally, this work may provide a step towards a more general understanding of the interplay of different quantum resources.

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

A Multi-level Analysis of Factors Associated with Student Performance: A Machine Learning Approach to the SAEB Microdata

arXiv:2510.22266v3 Announce Type: replace-cross Abstract: Identifying the factors that influence student performance in basic education is a central challenge for formulating effective public policies in Brazil. This study introduces a multi-level machine learning approach to classify the proficiency of 9th-grade and high school students using microdata from the System of Assessment of Basic Education (SAEB). Our model uniquely integrates four data sources: student socioeconomic characteristics, teacher professional profiles, school indicators, and principal management profiles. A comparative analysis of four ensemble algorithms confirmed the superiority of a Random Forest model, which achieved 90.2% accuracy and an Area Under the Curve (AUC) of 96.7%. To move beyond prediction, we applied Explainable AI (XAI) using SHAP, which revealed that the school's average socioeconomic level is the most dominant predictor, demonstrating that systemic factors have a greater impact than individual characteristics in isolation. The primary conclusion is that academic performance is a systemic phenomenon deeply tied to the school's ecosystem. This study provides a data-driven, interpretable tool to inform policies aimed at promoting educational equity by addressing disparities between schools.

07.
arXiv (CS.CV) 2026-06-12

On the Reliability of Cue Conflict and Beyond

Understanding how neural networks rely on visual cues offers a human-interpretable view of their internal decision processes. The cue-conflict benchmark has been influential in probing shape-texture preference and in motivating the insight that stronger, human-like shape bias is often associated with improved in-domain performance. However, we find that the current stylization-based instantiation can yield unstable and ambiguous bias estimates. Specifically, stylization may not reliably instantiate perceptually valid and separable cues nor control their relative informativeness, ratio-based bias can obscure absolute cue sensitivity, and restricting evaluation to preselected classes can distort model predictions by ignoring the full decision space. Together, these factors can confound preference with cue validity, cue balance, and recognizability artifacts. We introduce REFINED-BIAS, an integrated dataset and evaluation framework for reliable and interpretable shape-texture bias diagnosis. REFINED-BIAS constructs balanced, human- and model- recognizable cue pairs using explicit definitions of shape and texture, and measures cue-specific sensitivity over the full label space via a ranking-based metric, enabling fairer cross-model comparisons. Across diverse training regimes and architectures, REFINED-BIAS enables fairer cross-model comparison, more faithful diagnosis of shape and texture biases, and clearer empirical conclusions, resolving inconsistencies that prior cue-conflict evaluations could not reliably disambiguate.

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

Machine Learning and the Random Walk Puzzle: Forecasting the CAD/USD Exchange Rate with Expanding Window Evaluation and SHAP Interpretability

arXiv:2606.15058v1 Announce Type: new Abstract: This study examines whether machine learning (ML) models can outperform the naive random walk benchmark in forecasting the monthly USD/CAD exchange rate. Using daily data from the Bank of Canada spanning January 2017 to May 2026, resampled into 113 monthly observations, five ML models are evaluated: linear regression, random forest, gradient boosting, XGBoost, and AdaBoost. These models are benchmarked against the naive random walk model and exponential smoothing with Holt-Winters seasonality (ETS). All models are evaluated using an expanding-window framework to maintain strict out-of-sample integrity, and forecast-accuracy differences are assessed using the Diebold-Mariano (DM) test. Structural break detection identifies four significant breakpoints in the series, corresponding to the escalation of the US-China trade war in 2018, the COVID-19 economic recovery in 2020, the peak of the Bank of Canada rate-hiking cycle in 2022, and the start of the Bank of Canada rate-cutting cycle in 2024. SHAP, or Shapley Additive Explanations, analysis is applied to interpret the drivers of the best-performing ML model. The results show that the naive random walk model remains a formidable benchmark. Linear regression is the only model that statistically outperforms the naive random walk model, with a DM statistic of 3.0585 and a p value of 0.0071, whereas the ML ensemble models show only marginal differences. Random Forest with an expanding-window framework achieves the lowest MAPE of 1.17 percent among all models except the random walk. SHAP analysis confirms that short-term lags, particularly lag1 and lag2, and recent rolling means dominate predictions, consistent with the near-random-walk behavior of exchange rates.

09.
arXiv (CS.LG) 2026-06-17

On Randomized Algorithms in Online Strategic Classification

arXiv:2602.06257v2 Announce Type: replace Abstract: Online strategic classification studies settings in which agents strategically modify their features to obtain favorable predictions. For example, given a classifier that determines loan approval based on credit scores, applicants may open or close credit cards and bank accounts to obtain a positive prediction. The learning goal is to achieve low mistake or regret bounds despite such behavior. While randomized algorithms have the potential to offer advantages to the learner in strategic settings, they have been largely underexplored. In the realizable setting, no lower bound is known for randomized algorithms, and existing lower bound constructions for deterministic learners can be circumvented by randomization. In the agnostic setting, the best known regret upper bound is $O(T^{3/4}\log^{1/4}T|\mathcal H|)$, which is far from the standard online learning rate of $O(\sqrt{T\log|\mathcal H|})$. In this work, we provide refined bounds for online strategic classification in both settings; our bounds depend on the Littlestone dimension $\mathrm{Ldim}(\mathcal H)$ of the hypothesis class $\mathcal H$ and the maximum degree $\Delta$ of the manipulation graph. In the realizable setting, we extend, for $T > \mathrm{Ldim}(\mathcal H) \Delta^2$, the existing lower bound $\Omega(\mathrm{Ldim}(\mathcal H) \Delta)$ for deterministic learners to all learners. This yields the first lower bound that applies to randomized learners. We then provide the first randomized learner that improves the known (deterministic) upper bound of $O(\mathrm{Ldim}(\mathcal H) \cdot \Delta \log \Delta)$. In the agnostic setting, we give an improper randomized learner that improves the regret upper bound to $O(\sqrt{T\log|\mathcal H|})$, matching the standard online learning rate. We also show a larger lower bound for all proper learning rules, demonstrating that improperness is necessary to achieve the optimal rate.

10.
bioRxiv (Bioinfo) 2026-06-20

MIRATS framework: Normative multiscale characterization of brain regulatory systems across sex and age using multimodal MRI

作者:

Deep brain systems involved in arousal, autonomic regulation, sensory integration, and homeostatic control remain underrepresented in conventional whole-brain neuroimaging frameworks. In particular, diencephalic and brainstem nuclei are often insufficiently represented in cortex-centered analyses, limiting the normative references needed to interpret systems-level variation in health and disease. To address this gap, we developed a unified multiscale framework with explicit representation of deep nuclei. By integrating cerebral, cerebellar, diencephalic, and brainstem atlases in standard space, we constructed a 220-region whole-brain parcellation and extracted complementary features at three analytical scales: nodal properties, edge-wise connectivity, and persistent-homology-based topological descriptors. We applied this framework to healthy adults from the Human Connectome Project-Aging cohort to characterize normative multiscale organization and test sex- and age-related variation. Applied to this cohort, our framework revealed pronounced heterogeneity across anatomical systems. Brainstem and diencephalic nuclei showed multiscale feature profiles distinct from those of cerebral and cerebellar regions across nodal, edge-wise, and higher-order topological scales. Sex comparisons identified selective differences across different scales, whereas age modeling revealed widespread but feature- and system-dependent variation across adulthood. Together, these findings show that normative whole-brain organization in this deep-system-aware space is structured by system-specific rather than globally uniform patterns. These findings establish a normative multiscale framework for characterizing brainstem-diencephalic-cerebellar-cerebral organization in healthy adults and provide a quantitative reference for future translational studies of disease-related abnormalities in deep regulatory systems.

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

Pareto Q-Learning with Reward Machines

arXiv:2606.19134v1 Announce Type: cross Abstract: We present Pareto Q-Learning with Reward Machines (PQLRM), a multi-objective reinforcement learning algorithm for tasks whose reward structure is specified by a set of reward machines (RMs). PQLRM combines Pareto Q-Learning (PQL), which maintains sets of vector-valued Q-estimates to approximate the Pareto front, with enhancements from Q-Learning with Reward Machines (QRM), which exploits the factored automaton structure of the reward signal. This yields a multi-policy algorithm that remains sample-efficient under non-Markovian, RM-encoded rewards. Experimental trials show that PQLRM converges faster than a naive PQL baseline applied to the cross-product MDP and can synthesize Pareto-optimal policies that QRM cannot.

12.
arXiv (math.PR) 2026-06-16

Atypical Decay Rates for Atypical Heights in Random Recursive Trees

arXiv:2604.20139v2 Announce Type: replace Abstract: We establish the large deviation probabilities for the height of random recursive trees, revealing polynomial upper-tail decay and stretched-exponential lower-tail decay. Remarkably, the lower tail features an atypical prefactor that grows to infinity more slowly than any $n$-fold iterated logarithm.

13.
arXiv (CS.AI) 2026-06-11

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

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

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

SafeSpec: Fast and Safe LLM via Dynamic Reflective Sampling

arXiv:2606.19755v1 Announce Type: cross Abstract: Speculative inference accelerates large language model (LLM) decoding but provides no inherent safety guarantees. Existing safety defenses are largely incompatible with speculative inference: they either introduce additional computation or disrupt the draft-verify mechanism, negating acceleration benefits. This reveals a fundamental incompatibility between current safety methods and speculative decoding. We propose SafeSpec, a safety-aware speculative inference framework that integrates risk estimation directly into the verification process. SafeSpec attaches a lightweight latent safety head to the target model to jointly evaluate semantic validity and safety in a single forward pass. When unsafe generations are detected, SafeSpec applies rollback and safety-guided reflective multi-sampling to recover safe continuations rather than terminating generation. We model jailbreak attacks as distributional shifts over generative trajectories, where adversarial prompts increase the probability of harmful continuations without eliminating safe ones. Under this model, SafeSpec performs risk-aware trajectory recovery within the speculative decoding process. Across multiple models and adversarial benchmarks, SafeSpec achieves a substantially improved safety-efficiency trade-off. On Qwen3-32B, SafeSpec reduces attack success rates by 15% while preserving a 2.06x inference speedup on benign workloads, demonstrating that speculative acceleration and inference-time safety can be jointly optimized.

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

An Empirical Analysis of Optimization Dynamics and Sparsity Boundaries in Large-Scale Pedestrian Attribute Recognition

Pedestrian Attribute Recognition (PAR) is critical for video surveillance, enabling forensic search and re-identification systems. Extreme class imbalance remains a fundamental obstacle when merging PETA and PA-100K into a 109,000-image composite corpus, where minority attributes have positive sample fractions below 1%. This causes standard BCE optimization to suppress rare traits, a phenomenon we term the majority negative class cheating trap. We present a systematic ablation of Multi-Label Focal Loss hyperparameters (alpha and gamma) on a ResNet-18 backbone. A calibrated configuration (alpha=0.50, gamma=2.0) achieves a Macro F1-score of 62.32%, matching BCE baseline while preserving superior hard-example mining and convergence dynamics. Our approach uses pure loss-function engineering with zero computational overhead for edge deployment. We identify the Sparsity Wall, a hard boundary where positive sample fractions below 0.1% make global loss reweighting ineffective, requiring instance-level intervention.

17.
arXiv (CS.CL) 2026-06-12

ArogyaSutra: A Multi-Agent Framework for Multimodal Medical Reasoning in Indic Languages

Multimodal Large Language Models (MLLMs) have shown promising reasoning capabilities in general domains, yet their performance remains limited in specialized settings such as healthcare, especially in multilingual and low-resource scenarios. This gap is critical in regions like rural India, where patients often express complex medical queries in native Indic languages and rely on multimodal inputs such as medical images. Existing English-centric MLLMs struggle to support such use cases, limiting equitable access to AI-driven healthcare assistance. To address this challenge, we introduce ArogyaBodha, a large-scale multilingual multimodal medical question-answer dataset constructed from eight heterogeneous sources, covering 31 body systems, six imaging modalities, and 21 clinical domains across English and seven major Indian languages. We further propose ArogyaSutra, an actor-critic-based multi-agent framework that integrates tool grounding with dual-memory mechanisms for step-wise, reasoning-aware decision making, and uses stored actor-critic simulation trajectories for distillation. Experiments show that our dataset and framework improve multilingual medical reasoning accuracy across all Indic languages, with ablations validating the contribution of each component. The source code and dataset are available at: https://iitp-cse.github.io/ ArogyaSutra/

18.
arXiv (math.PR) 2026-06-16

Excursion Fluctuations and Spectral Universality in Gaussian Fields

arXiv:2606.15630v1 Announce Type: new Abstract: We study the large-scale spatial fluctuations of excursion volumes for a class of smooth stationary Gaussian fields. In the case of Berry's random wave model in dimension $d \geq 2$, we show that the spatial fluctuations for fixed $u>0$ converge to the fractional Gaussian field $(-\Delta)^{-1/4}W$ in the space of tempered distributions $\mathcal S'(\mathbb{R}^d)$, where $W$ is the $d$-dimensional Gaussian white noise. This explains the long-range correlations in the apparent filament structure of the Random Plane Wave model. For a class of smooth planar Gaussian fields whose spectral density has a power-law singularity at the origin, we prove convergence to fractional Gaussian fields with an index determined by the singularity exponent. More generally, the results illustrate that, for stationary random measures, large-scale spatial fluctuations are determined by the behaviour of the spectral measure density exponent near zero.

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

Predictability as a Fine-Grained Measure for Privacy

arXiv:2606.20546v1 Announce Type: new Abstract: Differential privacy (DP) ensures rigorous individual-level privacy guarantees against even the most knowledgeable attackers, but its worst-case nature can impose a costly privacy-accuracy tradeoff. We introduce privacy via predictability, a fine-grained framework that explicitly incorporates the attacker's core knowledge, a compromised portion of the dataset generated by a stochastic process, and a specified family of queries. Predictability measures privacy leakage as the incremental gain in an attacker's ability to predict sensitive information about unknown individuals after observing the algorithm's output, beyond what can already be inferred from the compromised data. We show that predictability and DP are generally incomparable: each can be small while the other is large. However, in the worst-case regime where all but one individual is compromised, and all binary queries are considered sensitive, predictability implies mutual-information DP. More generally, predictability provides a finer-grained privacy metric tailored to specific sensitive information and specific attacker models. We introduce a general framework, using the generalized method of moments (GMM), to analyze asymptotic predictability when the compromised data is generated by a stationary, ergodic, mixing process. Using this analysis, we derive a predictability-calibrated output perturbation scheme for ERM. Our approach is complementary to DP and can be used alongside DP to provide fine-grained privacy control.

20.
medRxiv (Medicine) 2026-06-15

An epidemiological scenario for Mass Events During the World Cup

This brief work discusses potential superspreading events that may occur during the World Cup in Mexico. The study is particularly focused on the city of Guadalajara due to a large recent outbreak in January and February and insufficient vaccine coverage prior to 2026. Keywords: Superspreading; measles outbreak; branching process; individual reproduction number; World Cup

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

Clay-CNN Hybrids: Leveraging Geo-Foundational Models as Auxiliary Context for Landslide Detection

Rapid post-event landslide mapping is essential for disaster response but remains difficult to automate due to extreme class imbalance. This study evaluates whether Clay v1.5, a Geo-Foundational Model (GFM), can improve pixel-level landslide segmentation on the Landslide4Sense (L4S) benchmark, which contains 3,799 training chips with 14 Sentinel-2 and terrain bands and approximately 2% positive pixels. We compare three strategies: Clay as the primary encoder with multi-scale residual terrain fusion, a U-Net backbone augmented with Clay semantic context at the bottleneck, and a standard U-Net baseline. The hybrid U-Net + Clay model with two-stage Low-Rank Adaptation (LoRA) achieved the best test F1 of 64.5 +/- 1.8% over three seeds, surpassing the Clay-only backbone (55.2 +/- 3.6%) and the U-Net baseline (59.9%). Clay as a standalone encoder underperformed the U-Net due to the absence of multi-scale skip connections, but its pretrained representations consistently improved performance when injected as auxiliary context. These findings suggest that GFMs are most effective for landslide detection when they complement spatially detailed convolutional architectures rather than replace them.

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

Seed-Guided Semi-Supervised Clustering by A-Contrario Anomaly Detection

arXiv:2606.18833v1 Announce Type: new Abstract: This paper introduces a semi-supervised clustering framework grounded in the statistical duality between grouping principles and anomaly detection. We address the challenge of robust cluster definition in noisy environments – a task where partitioning algorithms often over-assign outliers and density-based methods remain sensitive to heuristic global parameters. Drawing on a-contrario statistical reasoning and Gestalt proximity principles, we define a cluster as a maximal subset of data points containing no anomalies relative to a null hypothesis of uniform randomness. Central to this approach is the Perception algorithm, which utilises a principled expectation-based threshold ($\mathbb{E} < 1$) to identify outliers without manual parameter tuning. By treating clustering as the dual of anomaly detection, we employ an iterative ``clustering-by-exclusion'' mechanism. The algorithm is seed-guided, leveraging minimal user-provided labels to initialise robust cluster medians and form initial groups, which are subsequently expanded by admitting non-anomalous points. This approach naturally isolates fringe points, isolated noise, and emerging unknown clusters. We evaluate the method on synthetic and real-world benchmarks, including image and text datasets represented through raw, linear-reduced, and neighbourhood-preserving embeddings. Results demonstrate that with as few as 10–30 seeds per cluster, the proposed method achieves competitive and often very strong performance under a practical low-tuning benchmarking protocol, while maintaining linear scalability with respect to both observations and dimensionality for a fixed number of seeded clusters and iterations.

23.
medRxiv (Medicine) 2026-06-11

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

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

24.
PLOS Computational Biology 2026-06-10

Interpreting higher-order dependence in multimorbidity using cohort data: A partial information decomposition approach

by Cillian Hourican, Geeske Peeters, René J. F. Melis, Almar Kok, Natasja M. van Schoor, Sandra Wezeman, Mike Lees, Marcel G. M. Olde Rikkert, Rick Quax In the context of multimorbidity, clinical features seldom act in isolation: symptoms, signs and behaviours form interdependent systems in which joint effects on function can be demonstrated only when features are considered together. We introduce an open, reusable workflow that detects and interprets these “together-only” interactions using bivariate Partial Information Decomposition (PID; two sources to one target), linking synergy-based dependence to the broader network of clinical variables rather than to a single target. The workflow estimates synergy with small-sample bias correction and summarises each pair in a Breadth–Uniformity–Synergy–Total (BUST) map: breadth of synergy across target variables (broad “generalist” vs narrow “specialist” patterns), cross-stratum uniformity across age, sex and multimorbidity (uniform vs subgroup-specific), synergy strength, and total shared information. Simple diagnostics contrast observed targets with additive expectations, revealing the specific joint configurations through which non-additive effects arise. Applied to data from the Longitudinal Ageing Study Amsterdam, we treated all health-related variables—covering symptoms, clinical signs, behaviours, lifestyle factors, and self-rated health indicators—as both sources and targets in the PID framework. This symmetric design permits synergy to be quantified for every pair of variables with respect to every other variable. The workflow identifies synergistic constellations that additive models miss. Multidomain cliques involving subjective health, pain, cognition and grip strength showed multiple non-additive configurations, whereas pairs such as alcohol use with grip strength exhibited focused, narrow but uniform synergy. Notably, the pairs with the strongest synergistic contributions were largely distinct from those with the highest total mutual information, indicating that synergy captures dependency structure overlooked by conventional association measures. Rather than a new measure, this work provides a bias-aware workflow that makes higher-order dependence visible and transferable. Our results support synergy-aware mapping as a practical complement to conventional multimorbidity analyses: it highlights specific combinations of routinely assessed features whose joint states may be especially informative across multiple health targets and therefore candidates for prioritised joint assessment and future multi-domain intervention studies.

25.
medRxiv (Medicine) 2026-06-22

The impact of changes in age-based eligibility criteria on seasonal influenza vaccine uptake in England between 2019 and 2024: A retrospective cohort study

Objectives: To examine changes in seasonal influenza vaccine uptake among clinical risk groups over periods of differing age-based eligibility. Design: Retrospective cohort study. Setting: Individuals in England registered in the Clinical Practice Research Datalink Aurum. Participants: Between 1,239,802 (2019/20) and 1,289,330 (2023/24) individuals aged 40-69 years in clinical risk groups. Interventions: Natural experiment involving temporary expansion of age-based eligibility for influenza vaccination to include 50-64-year-olds from 2020/21 to 2022/23. Main outcome measures: Influenza vaccine uptake from 1st September to 28th February, incidence rate ratio (IRR) of vaccine uptake across consecutive seasons within age groups, and the ratio of IRRs between age groups. Results: Influenza vaccine uptake increased in all age groups in 2020/21 relative to 2019/20. The increase was larger in individuals aged 50-64 years (13.3%; IRR 1.50, 95% CI 1.50-1.51) compared with those aged 40-49 years (8.3%; IRR 1.35, 95% CI 1.34-1.35) and 65-69 years (6.8%; IRR 1.34, 95% CI 1.33-1.35). From 2020/21 to 2022/23, vaccine uptake decreased, with a more pronounced decline among those aged 40-49 years (-5.4%) compared with age-eligible groups (50-64 years: -3.0%; 65-69 years: -3.1%). The reversion of age eligibility in 2023/24 was associated with a larger decrease in uptake among those aged 50-64 years (-9.6% vs 2022/23; IRR 0.79, 95% CI: 0.79-0.79) compared with those aged 40-49 years (-4.9%; IRR 0.87, 95% CI: 0.87-0.88) and 65-69 years (-3.3%; IRR 0.97, 95% CI: 0.96-0.97). Patterns were broadly consistent across clinical risk groups. Conclusions: The COVID-19 pandemic saw a general increase in seasonal influenza vaccine uptake in clinical risk groups. This increase was larger and more sustained in 50-64 year-olds who had also become eligible based on age. Our findings highlight the potential gains in vaccine coverage among clinical risk groups based on expanded age-based eligibility.