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01.
arXiv (CS.LG) 2026-06-18

Exponentially many initializations to avoid barren plateaus

arXiv:2606.18515v1 Announce Type: cross Abstract: Barren plateaus are stated as an average-case phenomenon: pick an ansatz, initialize it naively, and concentration follows. This has led to the common view that a potential cure for barren plateaus is simply to initialize the parameters more carefully. Here we show that the situation is subtler. We introduce a first-moment framework that gives a simple operator-level diagnostic for when an initialization may escape the fully concentrated barren-plateau fixed point, and for comparing the biases induced by different initialization strategies. Our framework recovers several known initialization schemes such as identity and Gaussian initialization, but also shows that barren-plateau avoidance is highly non-unique. Indeed, many shifted, biased, and non-symmetric parameter distributions can avoid concentration, and these choices need not be equivalent. In fact, our results show that one can generate exponentially many families of inequivalent initialization strategies. Then, our numerics indicate that different first-moment-distinct initializations can lead to different attained minima, suggesting that avoiding barren plateaus via smart initializations can trade the exponential concentration problem for the challenge of selecting the right trainable pocket amongst many options.

02.
arXiv (CS.CL) 2026-06-11

Cross-modal Consistency Guidance for Robust Emotion Control in Auto-Regressive TTS Models

While Text-to-Speech (TTS) systems enable emotional control via natural-language instructions, expressiveness, naturalness, and speech quality degrade when the target emotion conflicts with the textual semantics. We propose a Cross-modal Consistency Guided Classifier-Free Guidance (CCG-CFG) method with dynamic scales based on the degree of inconsistency between the text emotion and the explicit speech emotion, replacing the dropout condition with the text emotion. We also distill the CCG-CFG guidance signal using a hard-sample mining strategy, improving the TTS model's emotional alignment capability. Evaluations on five emotional corpora and two TTS benchmarks show that our approaches applied to CosyVoice2 achieve up to a 12% absolute improvement in emotion-recognition accuracy and a 10% relative improvement in subjective scores, outperforming baselines including HierSpeech++, Qwen3-TTS, and original CosyVoice2, while preserving intelligibility, naturalness, and high speech quality.

03.
arXiv (CS.CL) 2026-06-12

How reliable are LLMs when it comes to playing dice?

We investigate the probabilistic reasoning capabilities of large language models through a controlled benchmarking study on discrete probability problems. We constructed two datasets, respectively a set of standard exercises and a set of counterintuitive exercises, designed to trigger heuristic reasoning, and evaluated 8 state-of-the-art models, each tested with and without Chain-of-Thought prompting. Models achieve an average accuracy of 0.96 on standard problems but only 0.59 on counterintuitive ones. We further provide empirical evidence of token bias: performance drops by over 20% when canonical formulations are replaced by disguised variants. Embedding misleading suggestions in the prompt reduces performance by up to 34%, with no model proving immune. Taken together, the reported findings suggest that current LLMs are not yet genuine probabilistic reasoners, despite their success in advanced mathematical problems.

04.
arXiv (math.PR) 2026-06-15

On a stochastic phase-field model of cell motility with singular diffusion

arXiv:2601.05881v2 Announce Type: replace Abstract: We study existence of solutions in the variational sense for a class of stochastic phase-field models describing moving boundary problems. The models consist of stochastic reaction-diffusion equations with singular diffusion forced by a phase-field. We investigate both the case of an independently evolving phase-field and of coupled phase-field evolution driven by a viscous Hamilton-Jacobi equation. Such systems are used in the modelling of single-cell chemotaxis, where the contour of the cell shape corresponds to a level set of the phase-field. The technical challenge lies in the singularities at zero level sets of the phase-field. For large classes of initial data, we establish global existence of probabilistically weak solutions in $L^2$-spaces with weights which compensate for the singularities.

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

Bridging data-driven priors via the score function for posterior sampling – Comparative review and experimental study

arXiv:2606.14800v1 Announce Type: cross Abstract: This paper reviews how a diverse set of popular data-driven priors commonly used in Bayesian inverse problems can be unified through their respective score functions. By framing these priors under this common perspective, we show that they can benefit from their straightfoward and effective integration into a recently proposed sampling algorithm. The applicability of this common framework is illustrated by considering several data-driven priors, namely regularization-by-denoising, normalizing flow-based priors, score-based generative models, and convex-ridge regularizers. For these four particular priors, the performance of the method is evaluated when conducting image inpainting and single image super-resolution. These results, as well as those obtained when restoring real images acquired in a geological context, demonstrate the efficiency of the method. This unified framework proves versatile enough to handle any posterior distribution defined by a broad class of score function-based priors, beyond the specific cases considered in this paper.

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

Functional Gradient Descent with Adaptive Representations

arXiv:2606.16926v1 Announce Type: cross Abstract: Functional optimization problems are typically solved by optimizing the parameters of a fixed representation, such as a neural network, resulting in highly nonconvex losses that complicate both training and theoretical analysis. An interesting alternative is functional gradient descent (FGD), that is, gradient descent directly in function space, which benefits from strong convergence results and admits a clean theory. However, FGD is difficult to implement in practice because functional gradients are infinite-dimensional, and thus cannot be fully computed nor stored in memory. Existing implementations therefore rely on fixed approximations, which introduce approximation error. We propose a new, theoretically-grounded FGD algorithm that adapts the representation of the functional gradients over the course of optimization. By explicitly incorporating this approximation into the analysis, we establish convergence to a stationary point (for smooth losses) and to a global minimizer (under smoothness + a Polyak-Lojasiewicz-type condition) regardless of our approximations. To the best of our knowledge, this is the first implementable FGD method with such guarantees in a general setting. We demonstrate the effectiveness of our method on regression, numerical solution of PDEs, and modern computer vision. Across settings, our method consistently outperforms both FGD with fixed approximations and neural network baselines in efficiency and accuracy.

07.
PLOS Computational Biology 2026-06-17

Deciphering cell type-specific causal genetic effects on brain imaging-derived phenotypes and disorders with single-cell Mendelian randomization

作者:

by Anyi Yang, Xingzhong Zhao, Xing-Ming Zhao, Yucheng T. Yang Reconstructing causality routes from genetic effects to complex phenotypes in particular cell types is crucial for understanding biological mechanisms underlying the brain-associated phenotypes including imaging-derived phenotypes (IDPs), and brain disorders and behaviors (DBs). Here, we develop a single-cell Mendelian randomization framework to infer cell type-specific causal relationships between gene expression and diverse brain-associated complex phenotypes by integrating single-cell expression quantitative trait loci (cis-eQTLs) and genome-wide association study findings. We identifiy a set of 254 and 217 cis-eQTL target genes (eGenes) that may have causal effects on 112 IDPs and 26 DBs in eight cell types, respectively. These causal eGenes exhibit strong cell type specificity and varied pleiotropy among different types of brain-associated phenotypes. Further integrative analysis reveals putative causality routes among cell type-specific causal eGenes and brain-associated complex phenotypes. Finally, we characterize the spatiotemporal expression patterns of these causal eGenes, and highlight the coordinated associations of the brain-associated phenotypes based on the expression of their causal eGenes. Overall, our study presents a large-scale analysis of the genetic effects of brain structures, disorders and behaviors, providing a catalog of cell type-specific causal eGenes.

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

Zero-shot generalization of transformer neural operators to larger domains

arXiv:2606.14597v1 Announce Type: new Abstract: Transformer-based neural operators have shown remarkable performance for approximating solution operators of partial differential equations on complex geometries. However, existing approaches implicitly assume a fixed domain size, which limits their ability to generalize at inference. In this work, we investigate domain extension, namely zero-shot inference on spatial domains that are significantly larger than those encountered during training. We argue that this setting fundamentally requires spatial locality and translation equivariance. We propose to implement this locality via a decomposable bias in the attention logits computation, enabling finely controllable locality while remaining fully decomposable into query-key inner products and directly compatible with optimized attention kernels. Combined with rotary positional embeddings, it enables expressive embeddings with controllable spatial support without altering the transformer architecture. We empirically show that our approach substantially improves zero-shot generalization to larger domains across two PDE benchmarks and a 3D industrial atmospheric flow application. Our code and datasets are available at https://github.com/cerea-daml/domain-extension.

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

CausalT5k: Diagnosing Refusal and Failure Modes in Trustworthy Causal Reasoning Across Causal Rungs

arXiv:2602.08939v2 Announce Type: replace Abstract: Large language models increasingly produce fluent causal explanations, yet they often fail in ways aggregate accuracy cannot diagnose: confusing association with intervention, abandoning correct judgments under pressure, over-refusing valid claims, or answering when evidence is underdetermined. We introduce CTK, a diagnostic benchmark of 5,147 cases and growing, across 10 domains and all three levels of Pearl's Ladder of Causation. Unlike benchmarks that only score correctness, CTK reveals why a model failed by annotating causal rung, trap type, pressure sensitivity, refusal quality, and Utility-Safety tradeoffs. Its Sheep/Wolf taxonomy separates valid causal designs from inferential traps; paired neutral/pressure variants measure sycophantic drift through Bad Flip Rate; and Wise Refusal fields test whether a model identifies the missing information needed before endorsing a claim. CTK exposes failure modes hidden by aggregate accuracy: the Skepticism Trap, Rung Collapse under scaling, pressure-induced drift, Detection-Correction gaps, and counterfactual error modes. Rather than prescribing a correction method, it provides the diagnostic substrate for studying causal-reasoning failure profiles.

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

Landmark-free Assessment of Lower-limb Alignment with Implicit Neural Shape Functions from Knee Radiographs

Radiographic assessment of lower-limb alignment (LLA) is important for predicting joint health and surgical outcomes in total knee arthroplasty. Traditional measurement methods are manual and time-consuming, while recent machine learning approaches typically rely on locating a fixed set of anatomical landmarks. This dependence limits flexibility and may require re-annotation when clinical definitions change. To address this, we propose an automated workflow using Implicit Neural Shape Functions (INSF). Rather than relying on explicit landmark coordinates, we encode the anatomy into a compact latent space and regress clinical alignment measurements directly from these latent codes. This architecture allows for rapid extendability to new tasks without altering the backbone representation. We trained our method on an internal dataset of 566 knee radiographs, each annotated with the outline of the femur and tibia. We evaluated it on both an internal test dataset of 50 patients and a separate external set of 402 preoperative cases from the MRKR dataset. Manual clinical measurements are available for these data, and the MRKR measurements will be made publicly accessible. Performance was comparable to state-of-the-art landmark-based methods and manual agreement, while offering a flexible shape representation that can be extended to additional measurement tasks.

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

SkillRevise: Improving LLM-Authored Agent Skills via Trace-Conditioned Skill Revision

arXiv:2606.01139v3 Announce Type: replace Abstract: Agent skills are procedural artifacts that enable LLM agents to execute workflows, verify constraints, and recover from failures. Existing self-evolving methods refine skills using accumulated trajectories. However, they struggle in cold-start settings, where only an initial, imperfect skill is available. Consequently, skill construction defaults to expert authoring or one-shot LLM generation. Expert-authored skills are costly and may not align with how LLM agents actually execute tasks, while one-shot generated skills can be syntactically well formed yet behaviorally weak. To bridge this gap, we propose SkillRevise, an execution-grounded framework designed to iteratively refine these initial skills. SkillRevise diagnoses skill defects from execution evidence, retrieves relevant repair principles from a general memory, and applies execution-anchored edits. By re-executing candidates, it retains the first verifier-passing skill within the revision budget and falls back to empirical utility only when no candidate succeeds. Evaluated across three benchmarks and five LLMs, SkillRevise substantially outperforms one-shot baselines, improving the base agent's success rate on SkillsBench from 36.05% to 61.63%. Furthermore, the revised skills transfer across both executors and task environments, suggesting that SkillRevise captures reusable procedural knowledge beyond any single executor.

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

On McDiarmid's Inequality under Dependence via Approximate Tensorization of Entropy

arXiv:2606.12720v1 Announce Type: new Abstract: We argue that dependent versions of McDiarmid's inequality are a useful but underutilized tool in mathematical statistics, learning theory and theoretical computer science. To make this point, we first highlight that approximate tensorization of entropy (ATE) implies McDiarmid's via the Entropy Method. Second, we derive McDiarmid's inequality for non-isotropic Gaussian random vectors $X \sim \mathcal N(\mu, \Sigma)$ through ATE with a constant of the order of the condition number of $\Sigma$. We both independently obtain this ATE through a simple application of stochastic localization and also discuss how a more general ATE for the Gibbs sampler due to Ascolani et al., 2026 generalizes McDiarmid's-like concentration to strongly log-concave and log-smooth probability measures. We then apply the resulting concentration inequalities to resolve a question on the concentration of $\operatorname{sign}(X)$ posed by Simone Bombari, investigate Erdős-Rényi graphs under dependence and prove a Dvoretzky-Kiefer-Wolfowitz-type inequality for observations from a joint measure fulfilling ATE and continuous marginal CDFs. For the class of strongly log-concave and log-smooth measures, this result improves upon a prior Dvoretzky-Kiefer-Wolfowitz-type inequality for non-i.i.d. observations due to Bobkov and Götze, 2010, by establishing the expected $1/\sqrt{n}$-rate of convergence under weak dependence instead of $n^{-1/3}$.

13.
arXiv (quant-ph) 2026-06-11

Towards the implementation of a quantum classifier

arXiv:2606.10150v2 Announce Type: replace Abstract: In this work, we investigate the use of a quantum circuit as a binary classification model in the context of quantum machine learning. We call this model, binary quantum classifier. First, we describe fundamental concepts of quantum computing and introduce the computational tool used: Qibo, an open-source framework for efficient quantum simulations and quantum hardware control. Then, we describe how to design a binary quantum classifier for the classification of images and small arrays of variables by showing how to input data in the circuit, defining a quantum circuit model Ansatz with trainable parameters and a loss function, and implementing multiple minimizers. We test our quantum classifier with two data sets. The first one is the MNIST data set which is composed of handwritten digits (reduced to only handwritten zeros and handwritten ones for binary classification). We study the behavior of different minimizers by increasing the number of layers of the Ansatz. The second data set represents two different high energy collisions that can occur at colliders such as LHC (CERN). Due to in-time proton-proton interactions known as pile-up, we distinguish two different data sets: "without pile-up" and "with pile-up". These collisions can be represented by images of size 32x32 or by six high-level variables that we call features. By increasing the size of the training data set and the number of layers of the Ansatz, we search for the best minimizer. Splitting the data set in training set and test set, we compute: ROC curve, AUC score, confusion matrices and test set accuracy. For "with pile-up" images, we compare the results obtained with the quantum classifier with a small convolutional neural network. We conclude that is possible to build a binary quantum classifier with a quantum circuit and we highlight its performances and limitations in comparison with classical technologies.

14.
arXiv (CS.CL) 2026-06-15

Right or Wrong, Models Comply: Directional Blindness in LLM Moral Judgment

As language models take integrated roles across many domains, the response of LLMs to user pushback becomes a critical alignment property. Yet many existing evaluations treat compliance as unidirectional, measuring whether models resist pressure but not whether they resist it selectively. We introduce Compliance Asymmetry (A = BCR/HCR), a bidirectional diagnostic that compares beneficial output change under helpful nudges with harmful change under misleading nudges. Across 9 models and 972,000 nudge-condition responses, we find that this selectivity differs in factual and moral judgments: models follow helpful nudges more than harmful ones on factual questions (A = 1.58), but follow both directions at nearly identical rates on moral questions (A = 1.04). This phenomenon persists across model families, capability levels, and nudging types. Interestingly, we also find that chain-of-thought prompting amplifies helpful and harmful compliance together, while identity-based prompting suppresses both by nearly identical margins. These results identify direction-blind moral compliance as a distinct failure mode in current LLMs and suggest that alignment should target directionally calibrated updating rather than lower compliance alone.

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

On the Influence of the Feature Computation Budget on Per-Instance Algorithm Selection for Black-Box Optimization

arXiv:2605.04954v2 Announce Type: replace-cross Abstract: Per-instance algorithm selection (PIAS) takes advantage of complementarity between a set of algorithms by deciding which algorithm to run on a given instance. This decision is based on features of the instances, which, in the context of black-box optimization (BBO), require a part of the optimization budget to be computed. This raises two questions: (a) from which fraction of the budget spent on feature computation does PIAS become worth it for BBO, and (b) which fraction of the budget optimizes the tradeoff between feature accuracy and PIAS performance. To this end, we perform a broad study where PIAS with varying sampling budgets for feature computation is compared to the single best algorithm on a broad range of algorithm selection scenarios. These scenarios consist of two portfolio sizes, three problem sets, 4 dimensionalities, and 10 target budgets. We find that PIAS is viable for the majority of tested scenarios, even when as much as a quarter of the total budget is spent on feature computation. The tradeoff for the fraction of the budget spent on feature computation to maximize the benefit of PIAS is highly dependent on the specific AS scenario. Further, on average 20 percent of PIAS loss to the virtual best solver is explained by the budget spent on feature computation, highlighting the importance of properly accounting for the feature budget.

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

I'm Sorry Driver, I'm Afraid I Can't Do That: Appraising the Safety of LLMs within Automotive Contexts

arXiv:2606.14327v1 Announce Type: cross Abstract: This paper appraises recent frameworks within AI development to integrate LLMs into control tasks in automotive contexts from the perspective of safety assurance. This work has built upon the rapid integration of LLMs across automotive settings. However, we find that at present, these frameworks face significant challenges, limiting their efficacy in real-time safety-critical contexts. Firstly, we consider conceptual challenges, including the fact that deployers are faced with a dual challenge, wherein they must assure a model which has been developed upstream, i.e. as general-purpose tools by the large AI labs, in a downstream context, i.e. into specific vehicle architectures. Secondly, we consider concrete challenges from across existing standards. We show that there are currently both fundamental engineering constraints covered in ISO21448, such as latency, and novel LLM-specific issues, such as alignment-related issues covered in ISO/PAS8800. We ground both examples in a concrete introductory, experimental case study exploring an existing open-source repository, Talk2Drive. We present a safety argument in order to make explicit the limitations of existing solutions. Nonetheless, given that the use of LLMs in automotive contexts is being explored at a technical level and operationalised, we propose potential assurance mechanisms for LLM-related hazardous events going forward.

17.
arXiv (CS.AI) 2026-06-16

Epileptic Seizure Detection in Separate Frequency Bands Using Feature Analysis and Graph Convolutional Neural Network (GCN) from Electroencephalogram (EEG) Signals

arXiv:2604.00163v2 Announce Type: replace-cross Abstract: Epileptic seizures are neurological disorders characterized by abnormal and excessive electrical activity in the brain, resulting in recurrent seizure events. Electroencephalogram (EEG) signals are widely used for seizure diagnosis due to their ability to capture temporal and spatial neural dynamics. While recent deep learning methods have achieved high detection accuracy, they often lack interpretability and neurophysiological relevance. This study presents a frequency-aware framework for epileptic seizure detection based on ictal-phase EEG analysis. The raw EEG signals are decomposed into five frequency bands (delta, theta, alpha, lower beta, and higher beta), and eleven discriminative features are extracted from each band. A graph convolutional neural network (GCN) is then employed to model spatial dependencies among EEG electrodes, represented as graph nodes. Experiments on the CHB-MIT scalp EEG dataset demonstrate high detection performance, achieving accuracies of 97.1%, 97.13%, 99.5%, 99.7%, and 51.4% across the respective frequency bands, with an overall broadband accuracy of 99.01%. The results highlight the strong discriminative capability of mid-frequency bands and reveal frequency-specific seizure patterns. The proposed approach improves interpretability and diagnostic precision compared to conventional broadband EEG-based methods.

18.
arXiv (CS.AI) 2026-06-16

Let Them Steal: Trapping Large Language Model Extraction Attacks with Knowledge Honeypot

arXiv:2606.15810v1 Announce Type: cross Abstract: Large language models deployed as commercial APIs are vulnerable to model extraction attacks, while existing defenses either act too late or degrade utility for legitimate users. We propose Knowledge Trap, a defense that redirects extraction attacks toward low-transferability knowledge through a Honeypot Knowledge Graph (HKG) and breadcrumb-guided exploration. Instead of blocking queries or perturbing outputs, Knowledge Trap consumes the attacker's limited query budget on knowledge with negligible downstream utility while preserving benign-user performance. Experiments in medical and financial domains show that Knowledge Trap reduces surrogate Agreement by 6.2\% on average without degrading legitimate-user accuracy, outperforming existing defenses that impose measurable user impact. These results suggest that defending knowledge-space traversal is a practical direction for mitigating LLM extraction attacks.

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

Spectral Analysis of Molecular Features: When Richer Features Do Not Guarantee Better Generalization

arXiv:2510.14217v2 Announce Type: replace Abstract: The spectral properties of feature embeddings offer critical insights into model generalization and representation quality. While deep learning models are widely used for molecular property prediction, kernel methods remain competitive in low-data regimes, yet their spectral behavior is largely unexplored. We present the first comprehensive spectral analysis of kernel ridge regression across diverse representations-including molecular fingerprints (ECFP), pretrained transformers, graph neural networks, and 3D descriptors-evaluated on QM9 and 3 MoleculeNet benchmarks. Surprisingly, richer spectral features do not consistently yield better generalization performance, contradicting common representation heuristics used in self-supervised learning (SSL). Across 4 spectral metrics, only ECFP-based kernels show a strictly positive correlation with performance. Transformer and global 3D representations exhibit mixed behavior, whereas local 3D representations show consistently negative correlations. Truncation analysis further emphasizes this disparity: for local 3D representations on thermodynamic targets, fewer than 2\% of eigenvalues (and occasionally as few as 0.02\%) are needed to recover 95\% of performance, whereas ECFP and transformer kernels require significantly more. By demonstrating a strong dependence on both task and representation, our results challenge the heuristic that richer spectra inherently improve generalization, providing new guidance for evaluating representations in SSL and in label-limited scientific tasks.

20.
arXiv (quant-ph) 2026-06-19

Mapping molecular polariton transport via pump-probe microscopy

arXiv:2504.15501v4 Announce Type: replace Abstract: We demonstrate how the transport properties of molecular polaritons in optical cavities can be extracted from a microscopic modeling of pump-probe spectroscopy. Our approach combines a mean-field treatment of the light-matter Hamiltonian with a perturbative expansion of both light and matter components, along with spatial coarse-graining. This approach extends semiclassical cavity spectroscopy to multimode light-matter interactions, providing full access to spatially resolved transient spectra. By simulating a microscopy experiment with counter-propagating pump and probe pulses, we compute the differential transmission and show how molecular dephasing and persistent dark exciton populations drive sub-group-velocity transport of the root-mean-square displacement. We analyze transport across the polariton dispersion, showing how velocity renormalization correlates with excitonic weight, consistent with experimental observations, and further its dependence on the rate of molecular dephasing. Our results highlight the need to consider measured spectroscopic observables when characterizing transport in polaritonic systems.

21.
arXiv (CS.CL) 2026-06-18

ScholarSum: Student-Teacher Abstractive Summarization via Knowledge Graph Reasoning and Reflective Refinement

Abstractive summarization plays a crucial role in enabling efficient understanding of scientific literature, yet it inherently demands both linguistic fluency and factual faithfulness. Existing approaches often fail to reconcile these two requirements. Extractive methods rely on rigid sentence splicing that disrupts macro-level logical coherence, while large language model (LLM)-based generative approaches, despite mastering linguistic fluency, exhibit limited factual consistency. In this work, we propose ScholarSum, a hierarchical reflective graph-based framework that emulates a student-teacher writing process for fluent and faithful scientific summarization. ScholarSum first organizes the document into a hierarchical knowledge graph by segmenting it into semantically coherent units, whose multi-layered community structure captures global logic and macro-level themes. Guided by this global structure, the student generates an initial draft, which is subsequently refined through fine-grained evidence retrieval. To ensure factual consistency, a teacher-like reviewer then iteratively examines the draft, identifies unsupported content, and prompts targeted re-retrieval and rewriting until the summary meets rigorous quality standards. Extensive experiments demonstrate that ScholarSum significantly outperforms previous baselines in terms of both completeness and faithfulness. Our code is available at https://github.com/Xiaoyu-Tao/ScholarSum.

22.
medRxiv (Medicine) 2026-06-19

Hyperleukocytosis and outcomes in pediatric B-cell acute lymphoblastic leukemia: A report from the REDIAL Consortium

Hyperleukocytosis (white blood cell [WBC] count >100 000/uL) at diagnosis is an important prognostic risk factor in pediatric acute lymphoblastic leukemia (ALL), though its significance with contemporary therapy is unclear. We analyzed 1 826 pediatric ALL patients from a multi-institution cohort to determine whether hyperleukocytosis independently predicts outcomes using multivariable Cox proportional hazard modeling. Hyperleukocytosis occurred in 211 patients (12%), with 121 having B-ALL, and showed no prognostic significance in T-ALL patients. In B-ALL, 5-year event-free survival (EFS) was 65% versus 89% for non-hyperleukocytosis patients, and overall survival (OS) was 78% versus 93%. After adjustment for age, cytogenetic risk, central nervous system disease status, and treatment site, hyperleukocytosis remained an independent predictor of end-of-induction minimal residual disease (MRD) positivity (odds ratio 2.53 [95% confidence interval [CI]: 1.71-3.94; p

23.
arXiv (CS.AI) 2026-06-17

Treatment Response Optimized Clinical Decision Support AI System via Digital Twin Simulation

arXiv:2606.17405v1 Announce Type: new Abstract: Clinical decision support AI systems (CDSASs) must adapt to evolving patient conditions in real-time while adhering to strict safety constraints. We present an online adaptive framework that integrates Treatment Effect (TE) estimation to quantify clinical benefits, a patient Digital Twin (DT) to simulate treatment trajectories, and Reinforcement Learning (RL) for sequential decision-making. The AI system is initially trained on historical medical records and operates in a continuous learning loop. To ensure safety, a rule-based module monitors vital signs and blocks contraindicated treatments. Cases with strong internal model disagreement are flagged for clinician review, simulated in our experiments via a pre-trained outcome model. We validate our framework using both a synthetic clinical simulator and a real-world ovarian cancer dataset from The Cancer Genome Atlas (TCGA). In both simulated and clinical settings, our method demonstrated superior effectiveness and stability in recommending treatments compared to standard computational baselines. Furthermore, the AI system maintains low latency and requires expert consultation for only a minority of cases in our experimental validation, demonstrating its potential as a safe, clinician-supervised tool for personalized medicine that continuously improves through practical use.

24.
PLOS Computational Biology 2026-06-01

On real-time calibrated prediction for complex model-based decision support in pandemics: Part 2

by Trevelyan J. McKinley, Daniel B. Williamson, Xiaoyu Xiong, James M. Salter, Robert Challen, Leon Danon, Ben Youngman, Doug McNeall Calibration of complex stochastic infectious disease models is challenging. These often have high-dimensional input and output spaces, with the models exhibiting complex, non-linear dynamics. Coupled with a paucity of necessary data, this results in a large number of non-ignorable hidden states that must be handled by the inference routine. Likelihood-based approaches to this missing data problem are very flexible, but challenging to scale, due to having to monitor and update these hidden states. Methods based on simulating the hidden states directly from the model-of-interest have an advantage that they are often more straightforward to code, and thus are easier to implement and adapt in real-time. However, these often require evaluating very large numbers of simulations, rendering them infeasible for many large-scale problems. We present a framework for using emulation-based methods to calibrate a large-scale, stochastic, age-structured, spatial meta-population model of COVID-19 transmission in England and Wales. By embedding a model discrepancy process into the simulation model, and combining this with particle filtering, we show that it is possible to calibrate complex models to high-dimensional data by emulating the log-likelihood surface instead of individual data points. The use of embedded model discrepancy also helps to alleviate other key challenges, such as the introduction of infection across space and time. We conclude with a discussion of major challenges remaining and key areas for future work.