Predictive modeling in biology and medicine: Digital twins and multi-scale modeling
by Mark Alber, Amber Smith, Reinhard Laubenbacher, Roeland M. H. Merks
Academic Intelligence · Curated Daily
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by Mark Alber, Amber Smith, Reinhard Laubenbacher, Roeland M. H. Merks
Genome sequencing of the heterogeneous primary mitochondrial disorders (PMD) frequently reveals variants of uncertain significance that require functional tests for diagnosis, and does not identify variants in all patients. We analyzed mitochondrial enzyme assays, blue native polyacrylamide gel electrophoresis (BN-PAGE) with in-gel activity staining, complex I assembly blot, and select protein abundances in fibroblasts of a case series of 204 PMD patients divided into functional classes, in comparison to 51 controls and 53 differential diagnostic conditions. Overall, sensitivity and specificity for respiratory chain enzyme assays were 46% and 93% respectively, for BN-PAGE 40% and 98%, for complex I assembly assay 49% and 99%. The overall sensitivity of all tests was 76%, specificity 93%, with positive predictive value 96% and negative predictive value 67%. Categories with high sensitivity were isolated complex deficiencies, nuclear DNA-encoded mitochondrial protein synthesis defects, co-factor defects, and mitochondrial amino-acyl-tRNA synthetase conditions when aided by protein abundance. Mitochondrial DNA mutations and maintenance disorders showed poor sensitivities. Secondary dysfunctions were rare. A complete battery of functional tests showed strong diagnostic clinical utility in fibroblasts.
arXiv:2605.14738v3 Announce Type: replace-cross Abstract: Recent work has promoted task-aware layer pruning as a way to improve model performance on particular tasks, as shown by TALE. In this paper, we investigate when such improvements occur and why. We show first that, across controlled polynomial regression tasks and large language models, such pruning yields no benefit on in-distribution (ID) data but consistently improves out-of-distribution (OOD) accuracy. We further show empirically that OOD inputs induce layerwise norm and pairwise-distance profiles that deviate from the corresponding ID profiles. This leads to a geometric explanation of task-aware pruning: each task induces a task-adapted geometry, characterized empirically by the representation profiles observed on ID inputs. OOD inputs can introduce a distorted version of the task-adapted geometry. Task-aware pruning identifies layers that create or amplify this distortion; by removing them, it shifts OOD representational norms and pairwise distances toward those observed on the adapted distribution. This realigns OOD inputs with the model's task-adapted geometry and improves performance. We provide causal evidence through controlled distribution shifts and residual-scaling interventions, and demonstrate consistent behavior across model scales.
As deforestation in the Amazon falls, fresh evidence shows that the rainforest can withstand global warming, but only if there is a worldwide effort to stop cutting it down. As deforestation in the Amazon falls, fresh evidence shows that the rainforest can withstand global warming, but only if there is a worldwide effort to stop cutting it down.
arXiv:2606.15805v1 Announce Type: new Abstract: Discrete diffusion language models enable parallel token generation, offering a pathway to low-latency decoding. However, selecting tokens independently by marginal confidence limits effective parallelism: tokens that appear reliable in isolation can form incompatible configurations when several positions are updated at once. We introduce a training-free decoding framework that coordinates these parallel updates. At each forward pass, the method assigns a commit score to each masked position and refines these scores using pairwise interactions derived from the model's predictive distributions. A variational relaxation yields a simple fixed-point update that suppresses conflicting simultaneous commitments within a single forward pass. This mechanism allows the decoder to commit more tokens in parallel while maintaining competitive generation quality. The method is lightweight, requires no auxiliary model or retraining, and drops into existing diffusion decoding pipelines without modification. Experiments on reasoning and code-generation benchmarks show consistent improvements in the quality-latency trade-off.
Background Accurate assessment of the QT interval is challenging in the presence of QRS prolongation, such as during ventricular pacing or bundle branch block. Current correction methods are heterogeneous and lack consensus. To evaluate the relationship between QRS duration and QT interval during ventricular pacing and to develop a practical correction method for QT assessment. Methods In this prospective single-centre study, 94 patients undergoing electrophysiology study for supraventricular tachycardia were included. Standardised pacing was performed at the same cycle length from the right ventricular (RV) apex, high output and low output pacing from His catheter, and coronary sinus (reference). QRS and QT intervals were measured from 12-lead ECGs. Changes in QT (QT) and QRS duration (QRS) were analysed using linear regression and mixed-effects modelling. QT correction formulas of the form QT corrected = QT N x QRS were evaluated using Bland-Altman analysis across multiple coefficients. Results A significant positive correlation between QRS and QT was observed across all pacing sites (r = 0.52-0.74, p < 0.001). In mixed-effects modelling, QRS was a strong independent predictor of QT (0.59, p < 0.001), with no significant interaction between pacing site and QRS, supporting a consistent relationship across pacing locations. Bland-Altman analysis demonstrated that correction coefficients of 0.65-0.70 minimised systematic bias compared with lower coefficients, with similar precision across models (SD 16 ms) and no evidence of proportional bias. A coefficient of 0.65 provided the most balanced performance between bias and variability. Conclusion QT prolongation during ventricular pacing is primarily driven by QRS widening and follows a consistent linear relationship across pacing sites. A simple correction using QT corrected = QT 0.65 x (QRS 100 ms) provides a practical and accurate method for QT assessment, with potential clinical applicability in patients with conduction abnormalities or ventricular pacing.
The growth of agent skills has transformed how agentic systems are built, evaluated, and deployed. As skill libraries continue to scale, rigorous evaluation becomes critical to ensuring their utility, quality, and safety in real-world applications. Consequently, the field is undergoing an emerging paradigm shift from isolated skill creation to automated, evaluation-driven skill evolution. In this survey, we systematically examine the landscape of skill evolution and evaluation beyond foundational skill creation. We categorize evolution into four distinct paradigms, spanning execution feedback, trajectory distillation, compression, and reinforcement learning, showing how each element contributes to improving skill utility and reliability. We also provide an analysis of six skill-centric benchmark categories, identifying structural gaps in benchmark coverage, trade-offs, and metric richness to advance skill research. Finally, we identify open directions for building skill ecosystems that are generalizable, efficient, and verifiably safe. The project URL is https://github.com/Cassie07/AgentSkill_Survey
Prompting has become the primary interface between humans and generative AI, yet many natural language prompts remain fragile: roles, goals, constraints, and expected outputs are often buried in prose or left implicit. In agentic and software development workflows, a misread at the first handoff can propagate through every step, since a significant portion of agent failures stem from context ambiguities rather than model limitations. This paper introduces PromptMN, a pseudo-prompting domain-specific language that annotates natural language with compact, %-prefixed typed directives covering roles, goals, requirements, priorities, constraints, plans, inputs, and outputs. Semantic resolution lets authors write in any order while the model interprets directives by function. PromptMN sits between informal prompting and programming-style pseudocode: structured enough to be inspectable and reusable, yet lightweight enough for analysts, managers, developers, and stakeholders across the software development lifecycle (SDLC). PromptMN also pairs with reverse prompt engineering. Asking a model to restate a desired outcome as PromptMN lets users inspect the inferred roles, goals, constraints, and missing assumptions before acting, reducing repair cycles and yielding a reusable artifact for aligning people and AI tools. PromptMN's feasibility is evaluated across several frontier models, including Claude Fable 5, Claude Opus 4.8, Gemini 3.1 Pro, and GPT-5.5. The models correctly resolved PromptMN instructions, including complex structures such as repetition, conditionals, methods, and a prime-checking task, without fine-tuning. The same vocabulary applies across new codebases, maintenance, and redesign in the SDLC scenarios presented. While large-scale validation remains future work, these early results suggest PromptMN is a practical step toward clearer, more reviewable human-to-AI interaction.
arXiv:2506.14126v2 Announce Type: replace-cross Abstract: Modern deep learning is increasingly characterized by the use of open-weight foundation models that can be fine-tuned on specialized datasets. This has led to a proliferation of expert models and adapters, often shared via platforms like HuggingFace and AdapterHub. Model merging has recently emerged as an effective way to leverage these existing resources, enabling the composition of capabilities from different model checkpoints. A natural pipeline has thus formed to harness the benefits of transfer learning and amortize sunk training costs: models are pre-trained on general data, fine-tuned on specific tasks, and then multiple checkpoints are merged to obtain a more capable model. A prevailing assumption is that improvements at one stage of this pipeline propagate downstream, leading to gains at subsequent steps. In this work, we challenge that assumption by examining how expert fine-tuning affects model merging. We show that long fine-tuning of experts that optimizes for their individual performance leads to degraded merging performance across vision and language modalities, multiple model scales, and both fully fine-tuned and LoRA-adapted models. We trace this degradation to the memorization of a small set of difficult examples that dominate late fine-tuning steps. This causes negative parameter interference and encodes knowledge that is forgotten during merging. Finally, we demonstrate that task-dependent aggressive early stopping strategies can significantly improve model merging performance.
arXiv:2606.12503v1 Announce Type: new Abstract: Self-supervised learning (SSL) has opened new opportunities in bioacoustics by enabling scalable modeling of animal vocalizations without the need for expensive manual annotation. However, current SSL models in this domain prioritize broad generalization across species and are not optimized for uncovering the fine-grained structure of individual communication systems. In this work, we collect and release a novel dataset of over five years of longitudinal recordings, from five known dolphins in a semi-naturalistic marine environment, an unprecedented resource for studying dolphin communication. We adapt the Wav2Vec2.0 Baevski et al. (2020) architecture to this domain and introduce Dolph2Vec, the first large-scale, species-specific SSL model trained exclusively on this data. We benchmark our model on two biologically relevant tasks: signature whistle classification and whistle detection. Dolph2Vec significantly outperforms general-purpose baselines in both tasks. Beyond performance, we show that learned embeddings and codebook structure capture interpretable acoustic units aligned with dolphin whistle categories and possibly sub-whistle structure, enabling fine-grained analysis of communication patterns. Our findings demonstrate how SSL can serve as both a model and a scientific tool to explore hypotheses in animal communication research.
arXiv:2606.09022v2 Announce Type: replace Abstract: This paper studies heterogeneous mean-field models in which agent parameters are sampled from a population distribution. We establish an $O(1/M)$ bound on the steady-state mean-square error between the occupancy measure of the $M$-agent system and the corresponding annealed mean-field equilibrium. The analysis extends Stein's method for homogeneous mean-field models and reveals a fundamental difference between homogeneous and heterogeneous systems. While stability of the mean-field dynamics is sufficient in the homogeneous setting, heterogeneous systems further require uniform robustness of the occupancy dynamics with respect to perturbations of the initial condition. The results are illustrated through a heterogeneous SIS epidemic model.
arXiv:2606.11679v1 Announce Type: cross Abstract: The position operator plays a central role in condensed-matter observables such as velocity, orbital moment, and electric polarization. In solid-state physics, the evaluation of operators incorporating the position operator has not reached a consensus, as observed in the operator-level discrepancy between the local circulation of Wannier functions and the self-rotation of wave packets. Here, to achieve a consistent evaluation of such operators, we propose three rules for evaluating operators involving the position operator in the Bloch representation. The rules are devised to satisfy physical conditions: independence from the choice of unit cell, preservation of Hermitian conjugacy for the product of operators, and recovery of the correct intraband velocity. We further address the gauge dependence of the position operator and introduce a scheme termed gauge filtration, which systematically removes gauge-dependent contributions from the operators containing the position operator. This methodology ensures that the quantities obtained from the operator evaluation correspond to observable physical phenomena. By applying our framework, we reconcile the results concerning the self-rotation of the wave packet and the local circulation of the Wannier function. We expect our proposal to establish a consistent framework for evaluating operators involving the position operator.
arXiv:2606.15514v1 Announce Type: cross Abstract: Robotic systems perceive the world through multiple input modalities – including visual camera streams and natural language instructions – and must select appropriate actions based on these signals. However, assuming the permanent availability of all input devices is unrealistic, as sensors may fail, become occluded, or drop out entirely during deployment. Robust handling of such missing-modality scenarios is therefore essential for real-world robot operation. This paper introduces RL4IL, a reinforcement learning guided method for imitation learning that selects the most suitable action for a given observation by identifying the most relevant expert demonstrations from a training library. A reinforcement learning policy, trained via Proximal Policy Optimisation over Breadth-First Search candidate sets, ranks candidate demonstrations and a soft cross-attention fusion head aggregates their action signals to produce the final prediction. When a modality is missing at inference time, a dedicated per-modality RL retrieval policy identifies donor demonstrations from the training library, and a soft imputation head reconstructs the missing embedding via cross-attention over the top-ranked donors – without requiring any retraining of the system. Experiments on three LIBERO benchmark suites demonstrate that RL4IL substantially outperforms state-of-the-art imitation learning methods under sensor dropout conditions, while requiring no policy network training. The code can be found at https://github.com/h-ismkhan/Reinforcement-Learning-via-kNN-for-Robotic-Learning-with-Missing-Camera
How can we scalably generate data for robotic manipulation, especially on human-like platforms such as dexterous multi-fingered hands? Learning from human videos has recently emerged as a likely answer to this question. However, difficulties in estimating hand-object interaction and crossing the human-to-robot embodiment gap have hindered the adoption of abundant monocular RGB-only human videos as the primary source of robot manipulation data. In this work, we present DO AS I DO, an algorithm to reconstruct and retarget monocular RGB human videos to multi-fingered dexterous robotic hands. DO AS I DO reconstructs hand-object interactions from various egocentric and exocentric in-the-wild video sources. The algorithm then retargets these hand-object interaction estimates into a sequence of actions executable in the real world, yielding robot-complete manipulation data from disparate human videos. Overall, DO AS I DO outperforms previous state of the art in estimating hand-object interactions and extracting dexterous manipulation trajectories from RGB videos, as we show in experiments on datasets with ground truths and on a dataset of video clips collected online. Our experiments enable us to propose an efficacy playbook for practitioners collecting human data for manipulation.
Vision foundation models (VFMs) have demonstrated strong robustness and transferability across a wide range of visual tasks. However, each model typically encodes strong inductive biases shaped by its pre-training objective and data domain, resulting in fragmented yet complementary visual knowledge. As a result, a single model often struggles to capture the diverse visual representations required across multiple dense prediction tasks. To address this limitation, we propose TIGER (Task-Instruction-Guided Expert Routing), a framework that coordinates multiple heterogeneous VFMs for multi-task dense prediction. Instead of naively aggregating expert features, TIGER leverages natural-language task instructions to guide a routing network that assigns token-level expert weights conditioned on task semantics, enabling adaptive integration of complementary expert features. TIGER further introduces a counterfactual loss that aligns routing decisions with each expert's causal contribution by measuring prediction changes when experts are excluded, encouraging more reliable and interpretable routing. We evaluate TIGER on two multi-task dense prediction benchmarks, NYUD-v2 and Pascal Context, where it consistently outperforms recent multi-task learning baselines while keeping all VFMs frozen. These results demonstrate that combining instruction-guided expert routing with counterfactual causal alignment enables effective coordination of heterogeneous vision foundation models.
NAT2 is an important pharmacogene which encodes the N-acetyltransferase 2 enzyme that is involved in the metabolism of multiple medications, and variants in this gene can affect patient response to these medications. CPIC has published a clinical guideline for prescribing hydralazine using NAT2 genotypes. Just prior to the guideline, updated NAT2 star allele numbering and definitions were released, differing somewhat from the historical nomenclature. Clinical pharmacogenomic testing panels often test for the most common star alleles, so knowledge of the most common updated NAT2 star alleles is critical for the implementation of the CPIC NAT2/hydralazine guideline. We first determine NAT2 diplotype frequencies from UK Biobank (UKBB) 200k phased genomes, then analyzed allele, diplotype, and phenotype population frequencies from the All of Us Research program, PennMedicine BioBank (PMBB) and UKBB 500k datasets. We found that analyzing NAT2 diplotypes from phased data provides critical information for algorithms designed to predict diplotypes from unphased data. We observed that NAT2*5, *6, and *4 were the most common star alleles in that order, and the top 11 most frequent NAT2 star alleles were the same across all biobanks. However, differences in star allele frequencies across biogeographical populations were observed. The largest difference led to a higher frequency of NAT2 poor metabolizer phenotypes as compared to rapid and intermediate metabolizer phenotypes in all global populations except in the EAS population, where NAT2 poor metabolizers were in the minority.
arXiv:2606.14900v1 Announce Type: new Abstract: Multi-source transfer learning faces a fundamental scalability bottleneck: existing approaches require either loading all K source models into memory simultaneously during parameter fusion, requiring O(K) memory, or deploying all models at inference time, making production deployment infeasible. We propose GRASP (Gradient-Aligned Sequential Parameter Transfer), which achieves superior knowledge integration while maintaining O(1) memory consumption through three key innovations: (1) sequential processing that merges one source at a time into an evolving target model, (2) parameter-wise gradient alignment that selectively transfers only parameters whose optimization directions align with the target domain, avoiding negative transfer, and (3) iterative fine-tuning that adapts transferred knowledge before integrating the next source. Extensive experiments across three continual learning benchmarks (Yearbook, CLEAR-10, CLEAR-100) spanning 10 to 108-year temporal distribution shifts and four architectures (1.3M to 25.6M parameters) demonstrate that GRASP achieves 93.5% mean accuracy over all datasets and architectures compared to ensemble method's 71.7% accuracy while requiring only constant memory versus K models for standard multi-source fusion. Critically, GRASP's sequential previously merged models and scales to arbitrarily many sources without memory growth, making it uniquely suitable for resource-constrained deployment and continually evolving source domains.
Reward models guide text-to-image (T2I) systems toward outputs aligned with human preferences. However, typical reward models such as HPSv3 are trained on pre-annotated data from earlier T2I models, without accounting for quality discriminative shifts arising from evolving model capabilities and reinforcement learning (RL) iterations, limiting their broader applicability. In this work, we propose HPSv3++, a reward model framework that elevates the HPSv3 model for varying T2I model capabilities and their RL iteration changes across the full capability-iteration spectrum. Specifically, we first introduce HPDv3++, a 212K dual-dimension preference dataset annotated for text fidelity and aesthetic quality using a recent high-capability (Qwen-Image) model with human supervision. We then propose a two-stage training framework. Stage 1 employs data-aware orthogonal gradient projection to incorporate diverse aesthetic perception from HPDv3++ while preserving the original effective human preference knowledge in HPSv3. Stage 2 further leverages unlabeled data from T2I models spanning different capability levels and RL iterations, and introduces a joint capability-iterations conditioned signal for the reward model together with a standard deviation-driven unsupervised guidance mechanism, strengthening reward model across the capability-iteration spectrum. HPSv3++ achieves state-of-the-art preference prediction, outperforming HPSv3 9.8% on HPDv3, 5.5% on GenAI-Bench, while achieving 79.1%/88.1% on our proposed HPDv3++. When used for T2I RL training, it consistently improves GenEval scores across diverse T2I models, demonstrating its wide-range capabilities. The code is available at https://github.com/PlantPotatoOnMoon/HPSv3-PlusPlus.
arXiv:2606.16301v1 Announce Type: new Abstract: Domain Generalization (DG) aims to train models that generalize to unseen target domains but often overfit to domain-specific features, known as undesired correlations. Gradient-based DG methods typically guide gradients in a dominant direction but often inadvertently reinforce spurious correlations. Recent work has employed dropout to regularize overconfident parameters, but has not explicitly adjusted gradient alignment or ensured balanced parameter updates. We propose GENIE (Generalization-ENhancing Iterative Equalizer), a novel optimizer that leverages the One-Step Generalization Ratio (OSGR) to quantify each parameter's contribution to loss reduction and assess gradient alignment. By dynamically equalizing OSGR via a preconditioning factor, GENIE prevents a small subset of parameters from dominating optimization, thereby promoting domain-invariant feature learning. Theoretically, GENIE balances convergence contribution and gradient alignment among parameters, achieving higher OSGR while retaining SGD's convergence rate. Empirically, it outperforms existing optimizers and enhances performance when integrated with various DG and single-DG methods.
arXiv:2606.20513v1 Announce Type: new Abstract: We introduce the Frontier decoder, a pruned dynamic-programming decoder for sparse quantum decoding problems. Frontier processes error variables in a chosen order, merges prefixes with the same residual syndrome and logical label, and approximates logical-coset posterior masses by retaining only a narrow scored frontier. Without pruning, the recursion is exact ordered inference with exponential complexity. In the code-capacity setting, the decoder reaches thresholds close to optimal for the surface code and the color code. In the circuit-level noise model, it achieves state-of-the-art performance with a very small average retained list size: less than 100 for the gross code $[[144,12,12]]$ at a physical error rate of $0.001$. When the list size is constant, the decoder has linear complexity, suggesting the possibility of low-latency implementations.
arXiv:2405.19881v3 Announce Type: replace Abstract: We ask whether a stationary lattice in dimension $d$ whose points are shifted by identically distributed but possibly dependent perturbations remains hyperuniform. When $d = 1$ or $2$, we show that it is the case when the perturbations have a finite $d$-moment, and that this condition is sharp. When $d \geq 3$, we construct arbitrarily small perturbations such that the resulting point process is not hyperuniform. As a side remark of independent interest, we exhibit hyperuniform processes with arbitrarily slow decay of their number variance.
arXiv:2606.17952v1 Announce Type: cross Abstract: Sparse Mixture-of-Experts (MoE) architectures enable scaling LLM parameters under a fixed inference budget by activating only a small subset of experts via top-$k$ routing. While this preserves causality and suits autoregressive language models, the discrete top-$k$ operator is not differentiable, forcing a fixed number of active experts per input and resulting in inefficient use of computation. We propose SoftMoE, which replaces discrete routing with a truncated soft top-$k$ LapSum relaxation, allowing gradient-based optimization of expert routing. We further parameterize the mean number of active experts per layer and impose a global budget constraint, enabling the model to learn how to allocate expert capacity across layers. SoftMoE remains fully compatible with autoregressive modeling and achieves performance comparable to or better than sparse MoE on language modeling and downstream tasks, while activating significantly fewer experts. Notably, the learned allocation is highly non-uniform, with later layers activating more experts. The source code is publicly available$^\dagger$.
arXiv:2505.22829v2 Announce Type: replace-cross Abstract: This paper bridges distribution shift and AI safety through a comprehensive analysis of their conceptual and methodological synergies. While prior discussions often focus on narrow cases or informal analogies, we establish two types connections between specific causes of distribution shift and fine-grained AI safety issues: (1) methods addressing a specific shift type can help achieve corresponding safety goals, or (2) certain shifts and safety issues can be formally reduced to each other, enabling mutual adaptation of their methods. Our findings provide a unified perspective that encourages deeper integration between distribution shift and AI safety research.
Byte-level tokenization enables language models to handle any Unicode input, but models can generate invalid UTF-8 sequences when encountering rare or unseen characters. We investigate the relationship between training scale and UTF-8 generation reliability with a 355M parameter model trained on 80B tokens from a balanced multilingual corpus of English, Japanese, Korean, and Chinese. We introduce multiple evaluation protocols that isolate UTF-8 structural validity from language modeling. UTF-8 validity convergence lags perplexity by a roughly a factor of two: perplexity stabilizes after 2.1B tokens, but UTF-8 validity requires 4.2B tokens. In context-free generation, rare characters achieve higher structural validity than common characters, suggesting over-specialization of frequent character representations. Through experiments, we observed that reliable UTF-8 generation is a distinct capability requiring evaluation beyond perplexity.
Novelty is a crucial metric for assessing the quality of academic papers. Scholars strive to highlight the novel aspects of their work, particularly in the title, abstract, and introduction. Peer review, serving as the gatekeeper of scientific rigor, rigorously evaluates the novelty of papers, yet a cognitive gap may exist between author self-promotion and reviewer evaluation. To investigate this, we analyzed 15,328 academic papers published in Nature Communications from 2016 to 2021, along with their peer-review comments. We found that both reviewers and authors emphasize result-oriented innovation, with reviewers adopting a more comprehensive evaluation perspective. Furthermore, by examining promotional intensity against inherent paper novelty, we found that its effect depends on the paper's actual innovation level. Highly innovative papers benefit from stronger promotional language, receiving more positive evaluations. We also found that promotional language significantly correlates with reviewer disagreement on novelty specifically for papers of moderate innovativeness, whereas it has negligible impact for papers with either very high or very low novelty. This reveals how promotional language operates most prominently in the gray area of academic evaluation.