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

Beyond the Training Distribution: Evaluating Predictions Under Distribution Shift and Selection Bias

arXiv:2606.14506v1 Announce Type: cross Abstract: Understanding how a prediction model will perform in a new environment before deployment is essential to preventing harm when algorithms inform decision-making. Two common sources of model performance degradation are (i) covariate shift, where the target covariate distribution differs from the source, and (ii) selective labels, where the observability of outcomes depends on historical decisions. We study pre-deployment model evaluation under the joint presence of covariate shift and labeling of outcomes selectively based on observed features. In particular, we present a double machine learning procedure for estimating the target risk of an arbitrary black-box prediction model under a general loss function. We show identification of this estimand under standard assumptions and derive a bias-corrected estimator based on the influence function of the target risk. Finally, we evaluate our estimator through experiments using the eICU electronic health records database, showing that it tracks the true target risk more accurately than methods that address either selective labels or covariate shift alone, as well as baselines that combine standard plug-in approaches.

02.
medRxiv (Medicine) 2026-06-17

Accounting for Human Movement to Improve Exposure-Health Models

Background. Current exposure-health models rely on averaged, residential-based environmental exposures, failing to account for human movement. This aggregation can lead to exposure misclassification and biased exposure-response estimates, potentially distorting our understanding of the true health effects of environmental conditions. We developed exposure disaggregation regression models that explicitly account for human movement when linking environmental exposures to health outcomes. Methods. By weighting pixel-level exposures according to distance from home as a simple proxy for human movement, our model linked disaggregated environmental exposures to individual-level health outcomes. Weights were either fixed a priori or derived from a latent distance-decay power parameter learned from the data. We additionally evaluated model performance under a nonlinear exposure-response relationship. Model performance was assessed across multiple sample sizes (N = 1,114; 50,000; and 100,000). A simulation study examined parameter recovery using bias, empirical standard error (EmpSE), and credible interval coverage. As a case study, Demographic and Health Surveys (DHS) data from Albania were used to link acute respiratory infection (ARI) outcomes among children under five to pixel-level NDVI within a 3 km buffer around DHS cluster centroids, and the proposed models were applied to these data. Results. Across all models (fixed-weight, learned-weight, and restricted cubic spline models), parameter recovery improved with increasing sample size. At N = 1,114, estimates were biased and imprecise, with incorrect effect direction for exposure-response parameters (e.g., learned-weight {beta}1 bias = - 0.79; EmpSE = 2.61; coverage = 0.88). In contrast, the models accurately recovered parameters at larger sample sizes, including the latent distance-decay parameter (bias = - 0.02; EmpSE = 0.15; coverage = 0.95 at N = 100,000), demonstrating their ability to reliably learn movement-based exposure weights when sufficient data were available. Conclusion. Instead of relying on arbitrarily-sized buffers, this statistical framework provides a novel method for studying environmental exposure-health relationships whilst accounting for human movement. With sufficiently large sample sizes, it can accurately estimate the influence of disaggregated environmental exposures on individual-level health and help address exposure misclassification arising from residential-only metrics. This methodological framework remains scalable, interpretable, and adaptable to other exposures and outcomes, offering a foundation for future work that integrates richer mobility-informed exposure-health research.

03.
bioRxiv (Bioinfo) 2026-06-22

Drug-Prot: A query system for statistical inference of drug effects and interactions in dynamic proteomic networks

Understanding drug effects and drug-drug interactions is essential for developing combination therapies. We present Drug-Prot, a computational framework that leverages large-scale perturbation proteomics to quantify causal drug effects, drug-drug interactions, and dynamic protein relationships. Using data from 63 single drugs and 59 drug combinations applied to 18 breast cancer cell lines at 6, 24, and 48 hours, Drug-Prot estimates drug effects on protein expression and reconstructs directed temporal protein dependency networks. The publicly available software enables targeted analyses of user-defined protein sets, substantially reducing the multiple-testing burden. Through an interactive web application, users obtain corrected p-values for single-drug and combination effects, directed temporal dependency networks, and downloadable results without requiring access to the underlying proteomic dataset. As a use case, we apply invariance-regularized Random Forests to triple-negative breast cancer cell lines to identify proteins associated with drug response. Querying these proteins in Drug-Prot reveals drug-specific and interaction effects at the protein-network level, illustrating how the framework links candidate causal protein features to actionable drug combinations.

04.
medRxiv (Medicine) 2026-06-11

Electrical signatures of divergent connectivity in the human subgenual cingulate cortex

Background: Major depressive disorder remains a leading cause of disability. While subgenual cingulate cortex (sgCC) deep brain stimulation (DBS) shows promise for medically refractory depression, clinical outcomes have been heterogeneous, suggesting that individual differences in neural circuitry engagement may critically influence therapeutic efficacy. We aimed to define the electrophysiological signatures of sgCC efferent connectivity using single-pulse electrical stimulation (SPES) with intracranial stereo-EEG (sEEG) to inform rational targeting and physiological biomarkers for sgCC-DBS. Methods: In four patients undergoing clinically indicated sEEG for seizure mapping, SPES was delivered through sgCC pairs, while distributed brain stimulation-evoked potentials (BSEPs) were recorded across cortical and subcortical sites. Responses were characterized using Canonical Response Parameterization to extract reproducible waveforms and per-trial reliability. Results: sgCC stimulation elicited reproducible, spatially organized BSEPs across frontal, limbic, and paralimbic networks, aligning with known anatomical pathways. Frontal recruitment featured robust, lateralized orbitofrontal activation favoring the ipsilateral central, medial OFC and bilateral ventromedial prefrontal responses. Limbic effects demonstrated bilateral cingulate activation with stronger ipsilateral recruitment and lateralized amygdala and hippocampal responses. Paralimbic engagement included insular responses with subject-specific anterior predominance and bi-hemispheric temporal-polar slow-wave deflections. Conclusion: These findings provide direct electrophysiological evidence of distributed, lateralized sgCC divergent network connectivity in the human brain, offering physiologic confirmation of its role in affective circuitry. The observed topography and laterality have direct applications for sgCC-DBS targeting and implicate BSEP signatures as candidate biomarkers to guide patient-specific therapy.

05.
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.

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

Closed-Loop Triplet Synergistic Generation for Long-Form Video

Multi-shot long-form video generation remains challenging due to identity drift and compounding inconsistencies across shots. While storyboard-driven pipelines improve controllability, they are often executed in a feed-forward manner, with limited mechanisms to incorporate generated visual evidence back into subsequent conditioning. We propose CoTriSyGen, an agentic framework that formulates multi-shot long video generation as a closed-loop visual-text-memory synergy process, where planned intent, persistent memory, and generated visuals are jointly leveraged for iterative correction and long-range coherence. A vision-language-model-based analyzer reasons over this triplet and produces updates to both prompts and memory along two pathways: (i) intra-shot refinement, which triggers targeted regeneration when semantic or compositional violations are detected and refines image-to-video prompt for coherent motions; and (ii) inter-shot refinement, which rewrites subsequent-shot prompts to propagate newly manifested entities or attributes and improve prompt quality (e.g., compositional grounding and cinematic fluency) based on generated evidence. The loop is grounded in an entity-centric memory modeled as a mutable visual state that evolves as the story progresses, which is continuously updated by both the generator and the analyzer by adding new and evolved entities to reflect appearance changes, accumulated multi-view evidence, and multi-entity compositions. Experiments on our curated StoryBench benchmark demonstrate substantial improvements in cross-shot consistency, prompt adherence, and cinematic continuity over representative methods.

07.
arXiv (CS.LG) 2026-06-17

Perron–Frobenius Operator Matching for Generative Modeling

arXiv:2606.17465v1 Announce Type: new Abstract: We introduce Perron–Frobenius Operator Matching (PFOM), a generative framework that matches density evolution via the integral PF operator, subsuming flow, diffusion, and jump models. We prove that among Bregman divergences, only Kullback–Leibler divergence preserves equality between density-level and sample-conditioned objectives, yielding a practical loss equivalent to Koopman path matching. We further develop Nesterov-accelerated training and sampling that stabilize discretization and accelerate convergence. %On Gaussian mixtures and two-moons, PFOM achieves faster KL/$W_2$/MMD decrease and improved wall-clock efficiency with empirical validation. PFOM unifies operator-theoretic identification with modern generative modeling and opens paths to adaptive dictionaries and high-dimensional applications.

08.
arXiv (CS.AI) 2026-06-15

The Journal of Prompt-Engineered (Moral) Philosophy Or: Why AI-Assisted Ethics Research Requires Process Transparency

作者:

arXiv:2511.08639v4 Announce Type: replace-cross Abstract: Existing AI disclosure mandates in scholarship require that AI assistance be reported but leave transparency philosophically unspecified: they fix the duty without explaining what the duty serves. We argue that ethical inquiry is essentially contested at two independent levels – about what it is, and about what it demands of the inquirer – defeating output-only evaluation and welfare-economic dismissal of the transparency question, and, by extension, reproducibility framings imported from the empirical sciences. The transparency duty is grounded instead in agent-integrity: the legibility, before a community of inquiry, of the identity-constituting commitments that the author's mode of philosophising expresses. Because the standards for evaluating such work are not communally settled, the achievable goal for transparency is not evaluation against agreed criteria but tracking – accumulating the evidentiary record that lets each tradition assess the work on its own terms and makes future normative judgments possible. We develop a documentation-adequacy framework that operationalises Meaningful Human Control through five transparency elements – declaration, navigation, documentation account, process documentation, and development records – demonstrated by the paper itself, whose full documentation record is archived at a persistent identifier. The framework is a first iteration subject to revision, not a settled standard.

09.
arXiv (quant-ph) 2026-06-12

Certifying Nonclassical Proper-Time Histories with a Quantum Clock

作者:

arXiv:2606.12755v1 Announce Type: new Abstract: Quantum clocks can acquire relativistic phases from motional or gravitational proper-time differences, but reduced clock dephasing alone does not certify nonclassical proper-time histories. We formulate this distinction as a channel-certification problem. First, we show that any two-level single-time dephasing signal, including one generated by an effective quantum proper-time label, admits a classical random proper-time representation. We then define the convex set of classical mixtures of experimentally specified proper-time histories and prove a Choi-rank separation criterion for conditioned coherent history recombination. A two-branch Ramsey protocol gives explicit bright- and dark-port population witnesses outside this classical set. The certification is operational and relative to the specified history set: it rules out classical mixtures of the same implemented proper-time histories, not arbitrary classical protocols with different histories or controls.

10.
arXiv (CS.AI) 2026-06-24

Breaking the Filter Bubble: A Semantic Pareto-DQN Framework for Multi-Objective Recommendation

arXiv:2606.24042v1 Announce Type: new Abstract: Recommender systems often induce filter bubbles and semantic homogenization by monolithically optimizing for immediate user engagement. Standard single-objective models, including traditional Deep Q-Networks, are ill-equipped to navigate the trade-offs between platform retention and critical societal values like information diversity and provider fairness. To address these limitations, we introduce a multi-objective reinforcement learning framework that formalizes recommendation as a semantic multi-objective Markov decision process. By integrating high-fidelity semantic embeddings with a Pareto-DQN agent, our architecture treats engagement, diversity, and fairness as distinct, non-aggregable reward signals, avoiding the pitfalls of static reward scalarization. Empirical evaluations on the MovieLens small dataset shows that our hypervolume based action selection disrupts the feedback loops responsible for semantic collapse. By sustaining high state-trajectory variance, the Pareto-DQN effectively maps the Pareto frontier, achieving gains in auxiliary societal objectives with only marginal impacts on engagement. This work provides a path toward intrinsically aligned, responsible recommender systems.

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

From inverse problems to neural operators: prediction, mechanism, and generalization of data-driven models

作者:

arXiv:2606.08956v2 Announce Type: replace Abstract: Scientists have historically relied on mathematical models based on differential equations to relate system inputs – forces, fluxes, or heat sources – to outputs, such as displacement, velocity, concentration, and temperature. These models rely on deep domain knowledge to determine the form of the governing differential equation, which is then calibrated with data by solving an inverse problem. In recent years, the field of Scientific Machine Learning has introduced a variety of alternative modeling strategies for physical systems. A method called Sparse Identification of Nonlinear Dynamics learns the governing equation as a sparse linear combination of terms in a user-defined library. Neural Ordinary Differential Equations construct the governing equation by taking in the state and its derivatives at the input layer of a neural network. Entirely foregoing the modeling framework of differential equations, neural operators directly learn a non-linear mapping between the system inputs and outputs. From inverse problems to neural operators, all of these modeling strategies can be conceptualized as data-driven machinery to predict a system's response over a range of inputs. It is then natural to wonder how exactly these various strategies relate to each other, and whether they can be neatly taxonomized. Drawing from the philosophical literature on scientific models, we argue that many model types have a common structure, differing only in the assumed model class of the input-output relation they define. Connecting to philosophical ideas on mechanism, and arguing that data from physical systems arises from solutions to parsimonious differential equations, we propose that only certain models are capable of mechanism discovery, and thus generalization. Our analysis is intended to unite apparently disparate modeling strategies and provide insight into their appropriate use cases.

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

A Stationarity-and-Coupling Criterion for Training-Free Time-Lagged Spectral Embeddings of Multivariate Time Series

arXiv:2606.13823v1 Announce Type: new Abstract: We study training-free fixed-length descriptors for multivariate time series and ask not merely whether such a descriptor performs well, but when it can be expected to work at all. Our object of study is $D(\tau)$, built from a time-lagged correlation matrix truncated at the Marchenko-Pastur edge so that only signal-bearing eigenvalues survive and classified by cosine similarity to class centroids with zero learned parameters. The central contribution is not the descriptor but a falsifiable applicability criterion for it. Working from a stationary Gaussian VAR(1) model, we argue that $D(\tau)$ separates two classes when the signals are approximately stationary and the class information lives in their cross-channel temporal coupling rather than in marginal per-channel power. We derive, semi-formally, three consequences: a distinguishability condition, why the static ($\tau=0$) covariance collapses to chance, and why a stationary but power-discriminated paradigm defeats the descriptor. The criterion is operational: a two-part pre-flight test – an augmented Dickey-Fuller stationarity check and a power-baseline saturation check – predicts applicability before any training. We validate both halves on a mixed assortment. On four paradigms that satisfy the criterion (Sleep-EDF, BCI-IV-2a, MIT-BIH, ESC-50) the descriptor is competitive with strong baselines at a fraction of their cost, reaching $88.5\pm4.5\%$ under 20-subject leave-one-subject-out on Sleep-EDF on a single CPU thread. On three that violate it – non-stationary ERPs, and financial-volatility and wearable-stress regimes that are power-discriminated – it fails exactly as the pre-flight predicts, and these negatives are the more informative half. We are explicit that $D(\tau)$ is not the most accurate representation; its value is a compact, training-free embedding whose domain of validity is known in advance.

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

Energy Use of AI Inference, Efficiency Pathways, and Test-Time Scaling

arXiv:2509.20241v2 Announce Type: replace Abstract: As AI inference scales to billions of queries, estimates of per-query energy use are increasingly important for capacity planning, efficiency interventions, and policy. Yet many public estimates assume non-production settings, leading to systematic overestimation. We introduce a bottom-up framework estimating inference energy from token throughput, node power, and overhead under large-scale deployment assumptions. For frontier-scale models (>200B parameters) on H100 nodes, we estimate a median energy of 0.31 Wh/query (IQR 0.16-0.60), indicating widely cited estimates are overstated by 4-20x. In test-time scaling scenarios 15x longer than typical queries, the median energy rises 13x to 3.91 Wh (IQR 2.15-7.05). Across models, serving systems, and hardware, we estimate 8-20x line-of-sight energy reductions. At datacenter scale, serving 1 billion queries/day requires 0.7 GWh; if 10% are long queries, demand rises to 1.7 GWh/day. With efficiency interventions, it falls to 0.8 GWh/day, mitigating the energy impact of test-time scaling.

14.
arXiv (CS.CL) 2026-06-18

RECOM: A Validity Discrimination Tradeoff in Automatic Metrics for Open Ended Reddit Question Answering

Automatic metrics are the default for evaluating LLM-generated text, yet a metric is quietly asked to do two jobs: tell genuine content alignment from surface coincidence (validity), and tell a better system from a worse one (discriminative power). On open-ended, opinion-driven question answering, the two are in tension. We introduce RECOM (Reddit Evaluation for Correspondence of Models), a contamination-free evaluation dataset of 15,000 r/AskReddit questions (September 2025), each paired with its authentic community replies, which postdate every evaluated model's training cutoff. Scoring five open-source LLMs (7–10B) against every reply each metric paired with a random-derangement noise floor we find that no metric does both jobs well. Cosine similarity separates real from random answers (Cohen's $d \approx 2$) but cannot rank the five models ($|d| < 0.1$); BERTScore precision appears to rank the models (raw $|d|$ up to 0.63), but once response length is controlled this collapses to $|d| = 0.09$ and its validity is weak ($d \approx 0.8$, versus cosine's $\approx 2$). Because every metric scores the same outputs, this validity–discrimination tradeoff is a property of the metrics, not the models, and we argue it stems from representation design. Three independent LLM judges reproduce the validity gap and likewise separate the five models only weakly. We recommend reporting metrics on both axes, with an explicit random-baseline floor. RECOM is publicly available at https://anonymous.4open.science/r/recom-D4B0

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

The Mathematics of AI Winters: The mathematical Taxonomy of Paradigm Fragility in AI Winter

arXiv:2606.12610v1 Announce Type: new Abstract: Two major periods of reduced funding and confidence in artificial intelligence research, commonly called the first and second AI winters, are usually explained through engineering failure, commercial disappointment, and inflated expectations. This article develops a complementary thesis: that the dominant paradigms of those periods also met genuine formal barriers, including limitations of representation, optimisation, computational complexity, statistical learnability, and high-dimensional approximation. The contribution is synthetic rather than archival. We do not claim that particular theorems mechanically caused the winters; rather, we show that several central disappointments of early AI were aligned with mathematically precise bottlenecks. We analyse these bottlenecks through the perceptron impossibility results of Minsky and Papert, the complexity-theoretic hardness of exact neural-network training established by Blum and Rivest, minimax rates for nonparametric estimation in high dimension due to Stone, vanishing-gradient analyses by Hochreiter and by Bengio and collaborators, and classical statistical learning theory in the tradition of Vapnik and Chervonenkis, Valiant, and Blumer and collaborators. We then relate these barriers to the later breakthroughs that mitigated, rather than eliminated, them.

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

Trust but Verify: Mitigating Medical Hallucinations via Post-Hoc Adversarial Auditing and Multi-Agent Feedback Loops

arXiv:2606.14149v1 Announce Type: new Abstract: Large Language Models (LLMs) are increasingly deployed in healthcare settings, yet their tendency to hallucinate poses risks when clinical decisions are involved. This study examine whether LLMs recommend recently banned or withdrawn pharmaceuticals when answering clinical questions and tests an agent-based method for reducing such errors. We developed a five-agent "Trust but Verify" system using a single LLM backbone. To measure regulatory knowledge obsolescence, we created an adversarial dataset of 103 clinical MCQs where historically correct answers now refer to banned substances. This scale ensures statistical significance across various therapeutic classes. We evaluated three open-access model families (GPT-OSS, Llama-3, Falcon-3) under vanilla and agentic conditions. Performance was measured via pointwise score, label accuracy, Hallucination Error Rate (HER), and Component Fidelity (CF) score. We also observed clinical safety regression in proprietary models. In default configurations, all models showed high hallucination rates, consistently selecting banned drugs that matched training data patterns. Our proposed agentic architecture reduced HER by approximately 53% across models. Pointwise scores shifted from -0.25 (unsafe recommendation) toward 0.0 (appropriate refusal). The safety audit intercepted dangerous outputs even when models' parametric knowledge favored the banned substance. The proposed multi-agent framework offers a model-agnostic method for enforcing regulatory compliance that prioritizes patient safety over fluent text generation. Our work demonstrates a practical approach for deploying autonomous AI systems in safety-critical healthcare settings. It shows how real-time regulatory data can be integrated into LLM pipelines to support clinical decision-making.

18.
arXiv (CS.AI) 2026-06-24

RIFT-Bench: Dynamic Red-teaming For Agentic AI Systems

arXiv:2606.23927v1 Announce Type: new Abstract: Agentic AI systems powered by large language models (LLMs) are rapidly evolving into autonomous decision-making systems, exposing attack vectors beyond those of traditional LLM vulnerabilities. Existing security evaluations are often tied to specific implementations or domains, limiting unified comparison across heterogeneous systems. To address this gap, we introduce RIFT-Bench, a graph representation-driven methodology for dynamic red-teaming that enables unified evaluations across diverse agentic architectures. Building on a novel hierarchical representation, RIFT-Bench operates in two automated phases: Discovery, which extracts system structure, and Scanning, which deploys adaptive adversarial attacks and produces a comprehensive evaluation report. It evaluates the examined system itself, leveraging a broad set of dynamically adaptable adversarial probes across diverse attack vectors and objectives. We demonstrate the effectiveness of the proposed evaluation pipeline across 45 agentic systems spanning a diverse range of implementations, showing that the approach generalizes effectively to heterogeneous agentic architectures. Beyond systems and attacks, RIFT-Bench also supports direct evaluation of mitigation strategies. These key capabilities make RIFT-Bench a scalable foundation for security evaluation of agentic AI systems.

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

Extending Item Response Theory for Efficient and Meaningful Multilingual Evaluation

Multilingual benchmarks are central to evaluating large language models (LLMs) across languages, but they suffer from three issues: exhaustive evaluation scales linearly with the number of languages, automatic translation introduces errors that are easily missed at scale, and some items conflate general and culture-specific knowledge. We address all three with a unified statistical framework, Multilingual-IRT, which extends Item Response Theory with per-language difficulty deviations, split discriminability separating content from language effects, and per-language ability residuals. Fitting Multilingual-IRT on 25 LLMs across 29 languages of MMLU-Pro-X, we show that its fitted parameters support three practical applications: predicting unobserved (item, LLM, language) instances with 11-16% lower binary cross-entropy than the strongest accuracy-based baseline, surfacing candidate translation errors distributed across all 28 non-English languages, whereas accuracy-based baselines concentrate detections in a few languages, and recovering culture-specific items that accuracy-based baselines miss.

21.
medRxiv (Medicine) 2026-06-11

Polygenic risk scores associate with asthma phenotypes and proteomic analyses implicate IL1R1 in two family-based studies

Despite its high prevalence and the discovery of hundreds of genetic associations, the genetic determinants and heterogeneous manifestations of asthma remain incompletely understood. Incorporating polygenic risk scores (PRS) into asthma research offers a powerful approach to quantify inherited susceptibility, refine risk profiles, and advance mechanistic understanding of disease development. For this study, we leveraged whole-genome sequencing (WGS) data from two family-based cohorts of childhood asthma - the Genetics of Asthma in Costa Rica Study (GACRS) and the Childhood Asthma Management Program (CAMP) - to examine the transmission profiles of externally derived asthma PRS and their associations with clinical phenotypes in children with asthma. To further elucidate molecular mechanisms, we integrated large-scale external genome-wide association study (GWAS) summary statistics and genetic prediction models of protein abundance in a two-step proteome-wide association study (PWAS) of asthma. Our findings provide robust evidence supporting the validity of externally derived asthma PRS (asthma PRS association p-value p={10}^{-24} [GACRS and CAMP trios combined] for the Global Biobank Meta-analysis Initiative [GBMI]) and reveal consistent associations with spirometry measures and atopy markers across both studies, as 13 of 21 traits (62%) were significantly associated with the GBMI-PRS in the meta-analysis after multiple-testing correction. Moreover, the results of the integrative proteomic analysis implicate IL-1 signaling in the etiology of asthma, reinforcing the candidacy of IL1R1 antagonists for drug repurposing.

23.
arXiv (CS.CL) 2026-06-19

Beyond Uniform Forgetting: A Study of Sequential Direct Preference Optimization Across Preference Settings

Aligning language models with human preferences often requires optimising multiple behavioural objectives. A practical approach is to apply these objectives sequentially using preference optimisation methods such as Direct Preference Optimisation (DPO), but it remains unclear whether later training uniformly degrades preferences learned earlier or whether the effect depends on the relationship between objectives. We study sequential DPO across four preference settings covering distributional conflict, multi-attribute interaction, strong safety signal, and compatible response-quality objectives. Using Llama-3.1-8B-Instruct with LoRA adapters, we evaluate all objectives after every stage with a fixed base-model reference. We find that sequential DPO does not produce a single forgetting pattern; preference change ranges from partial degradation to stability, pair-level redistribution, or positive transfer depending on objective relationship, signal strength, and training order. Pair-level analysis using length-normalised policy margins shows that aggregate metrics can mask heterogeneous changes across preference pairs, whereas quartile decomposition reveals that high-confidence pairs can either degrade or improve depending on the setting. Mechanistic diagnostics show that Stage~2 gradients and adapter updates are near-orthogonal to the previous objective across all settings, providing little evidence that direct gradient opposition is the primary driver. These findings suggest that future sequential alignment pipelines should account for objective compatibility and signal strength, rather than assuming that later objectives affect earlier preferences uniformly.

24.
medRxiv (Medicine) 2026-06-24

Multifactorial tuberculosis severity score for people living with HIV based on the Rand Appropriateness Method

Background In people living with Human Immunodeficiency Virus (PLWH), tuberculosis (TB) is the leading cause of death and is often associated with substantial morbidity. Better identifying PLWH with severe forms of TB could help target early interventions to reduce mortality and severe morbidity. Existing TB severity assessment tools may be sub-optimal for assessing disease severity in PLWH, since they incompletely integrate key determinants of disease severity. We aimed to develop a consensus-based TB severity score tailored to PLWH. Methods We developed a multifactorial TB severity score (TBSS) for PLWH using a modified Delphi process with a multidisciplinary group of international TB experts as the second part of a RAND/UCLA Appropriateness Method, following a previously published systematic review. Results Eight of 15 invited experts (53%) participated in both Delphi rounds. Of 62 candidate factors, 15 reflecting TB-related characteristics, host-related characteristics as well as characteristics related to both TB and host were rated as having high appropriateness for inclusion in the final TBSS. The total score ranges from 0 (no severity) to 61 (highest severity). Conclusion This study represents a first step towards the development of a multidimensional TB severity assessment tool for PLWH. However, its clinical usefulness, feasibility, and added value compared with existing severity scores remain to be demonstrated through validation studies before routine implementation can be considered. Key words: tuberculosis, HIV, severity.

25.
arXiv (CS.LG) 2026-06-11

Spatially Masked Regression Reveals Local and Distributed Predictability in Electrophysiological Recordings

arXiv:2606.11415v1 Announce Type: cross Abstract: Neural recordings are often interpreted as local measurements, yet the signal at any one sensor can also reflect structured activity distributed across the broader network. This raises a basic question: to what extent does an electrode's signal reflect local versus distributed information in the underlying system? More specifically, how much of an electrode's activity is carried by its immediate neighborhood, and how much is embedded more broadly across the array? We address this with a Spatially Masked Regression (SMR) framework that reconstructs each electrode's timeseries from the remaining electrodes while excluding a configurable neighborhood around the target. By progressively increasing this mask, spatial locality becomes an experimental control for quantifying how much predictive information survives after nearby channels are withheld. We apply SMR to intracranial EEG with heterogeneous electrode coverage and to scalp EEG with standardized montages over sensorimotor cortex. Using distance correlation between original and reconstructed signals, we find strong within-subject reconstruction in both modalities, substantial residual predictability even when local neighbors are excluded, and markedly stronger cross-subject transfer in EEG than in iEEG. Masking shows that nearby electrodes contribute strongly to reconstruction but do not account for all of it, indicating that individual channels reflect both local redundancy and broader distributed structure. Surrogates that preserve selected marginal or spectral properties while disrupting phase structure or temporal ordering substantially reduce performance, supporting the conclusion that SMR depends on structured temporal and cross-channel organization rather than on marginal statistics alone. These results position SMR as an interpretable framework for quantifying the balance between local and distributed information in recordings.