When drug discovery fails: scientists share their frustrations with the process
In clinical trials, there are many times (and ways) a therapeutic can come up short. In clinical trials, there are many times (and ways) a therapeutic can come up short.
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In clinical trials, there are many times (and ways) a therapeutic can come up short. In clinical trials, there are many times (and ways) a therapeutic can come up short.
arXiv:2508.02721v2 Announce Type: replace-cross Abstract: While powerful, the inherent non-determinism of large language model (LLM) agents limits their application in structured operational environments where procedural fidelity and predictable execution are strict requirements. This limitation stems from current architectures that conflate probabilistic, high-level planning with low-level action execution within a single generative process. To address this, we introduce the \textsc{Source Code Agent} framework, a new paradigm built on the ``Blueprint First, Model Second'' philosophy that decouples workflow logic from the generative model. An expert-defined operational procedure is first codified into a source code-based Execution Blueprint, which is then executed by a deterministic engine. The LLM is strategically invoked as a specialized tool to handle bounded, complex sub-tasks within the workflow, but never to decide the workflow's path. We evaluate on the TravelPlanner benchmark for constraint-aware travel planning. The \textsc{Source Code Agent} achieves a 35.56\% final pass rate, a 97.6\% improvement over the state-of-the-art ATLAS baseline (18.00\%) on the same Claude-Sonnet-4 backbone. Critically, it reduces constraint violations by 96.0\% (11 vs 275) while improving execution efficiency by 27.1\% (10.2$\pm$0.7 steps vs 14.0). Two production incident-diagnosis deployments and additional results on ScienceWorld and ALFWorld confirm that the architecture transfers beyond travel planning to procedurally well-defined, constraint-intensive workflows. Our work enables the verifiable and reliable deployment of autonomous agents in applications governed by strict procedural logic.
arXiv:2605.26783v3 Announce Type: replace Abstract: Inhomogeneous ensembles of two-level systems are central to both fundamental light-matter physics and quantum-network applications. Understanding and optimizing ensemble-based quantum memories and entanglement protocols requires a unified framework that describes how to store quantum states of light as collective matter excitations and retrieve them on demand. Here we develop such a framework, the waveguide model, by mapping the dark collective modes of the ensemble onto an effective waveguide with well-defined input-output relations, valid in both the weak-excitation regime and near population inversion. This model reveals that inhomogeneous coupling – often regarded as a limitation – is instead the physical origin of noisy-echo suppression by adiabatic pulses, a key ingredient for realizing noiseless quantum memories. For entanglement generation, the same mechanism exposes a previously unexplored shortcoming of robust control pulses and leads to a new composite-pulse protocol that overcomes it. These results establish the waveguide model as a practical bridge between fundamental collective physics and quantum-network protocol design, recasting inhomogeneous coupling from an obstacle into a control knob for collective emission.
arXiv:2111.14631v2 Announce Type: replace-cross Abstract: Model risk in credit portfolio models is a serious issue for banks but has so far not been tackled comprehensively. We will demonstrate how to deal with uncertainty in all model parameters in an all-embracing, yet easy-to-implement way.
arXiv:2606.19793v1 Announce Type: cross Abstract: The challenge associated with recognizing dysarthric speech primarily arises from pronounced acoustic variability attributed to impaired articulatory precision. Past research has demonstrated improved recognition through the use of hybrid DNN/HMM sequence discriminative training. This paper presents a comprehensive investigation of various combinations of acoustic features tailored to different Acoustic Models, offering suitable feature selections for each. The incorporation of Pitch features notably improved recognition performance, especially for sentence recognition tasks involving dysarthric speech. Through a systematic examination of the TORGO database, we have demonstrated the potential to enhance the performance of the state-of-the-art Factorized Time Delay Neural Network (F-TDNN) model for recognizing dysarthric speech. Our methods, implemented with the F-TDNN model, resulted in a 4.65\% relative improvement in isolated word recognition and a 4.63\% relative improvement in sentence recognition for dysarthric speech, compared to previous research. This improvement effectively compensates for speech variability, attributable to our deliberate selection of the number of overlapping frames between consecutive training example chunks.
arXiv:2606.19909v1 Announce Type: cross Abstract: Despite the theoretical appeal of their non-reversibility, to date, no Piecewise Deterministic Markov Process (PDMP) samplers have been developed that scale better than $\mathcal{O}(\sqrt{d})$ in computational complexity with respect to the target dimension $d$. We prove that this is a fundamental limitation by establishing an $\Omega(\sqrt{d})$ lower bound on the algorithmic complexity of PDMP samplers in a standard setup. By relaxing the assumption that the target density must remain invariant at all continuous times, we then demonstrate how to bypass this barrier. Specifically, we introduce a novel PDMP sampling scheme and show that it achieves an empirical complexity of $\mathcal{O}(d^\alpha)$, where $\alpha \in [0.2, 0.3]$ for Gaussian-tailed targets. In addition, this PDMP scheme is locally adaptive in both trajectory length and distance between velocity updates.
Mixture-of-Experts (MoE) architectures efficiently scale Large Language Models (LLMs) by activating only a small fraction of their experts per token, yet the full parameter count - dominated by the expert parameters - must be held in training and inference memory. To address this, we introduce Expert Tying, an architectural modification that shares expert parameters across consecutive transformer layers while preserving independent, layer-wise routing and attention. We evaluate this approach across common, state-of-the-art architectures, including OLMoE, Qwen3, and DeepSeek-style MoEs. Our pretraining experiments demonstrate that tying experts can reduce memory footprint by almost 2x at virtually no degradation in perplexity or downstream quality. By exploiting the parameter redundancy inherent in MoE pathways, our method provides a highly favorable compute-to-memory trade-off, advancing efficient training and scaling of next-generation LLMs.
The rapid advancement of photorealistic Text-to-Video (T2V) generation brings in an urgent need for up-to-date evaluation methods. Existing benchmarks largely overlooked implausible scenarios and do not measure audio-visual alignment. We introduce BRITE, the first framework that unifies (1) implausible prompting, (2) fine-grained assessment of audio-visual consistency, and (3) QA-based interpretable evaluation into a comprehensive T2V benchmark. Unlike fully automated Multimodal LLM-based pipelines, which are prone to hallucination and prompt ambiguity, BRITE guarantees reliability through a rigorous human-in-the-loop protocol for benchmark creation. Evaluating five state-of-the-art models (Sora 2, Veo 3.1, Runway Gen4.5, Pixverse V5.5, and Qwen3Max), we reveal a critical performance gap: while models excel at static object composition, they exhibit significant degradation in object-action binding and audio-visual synchronization. Our framework offers the community a reliable, interpretable benchmark and evaluation framework that can detect and locate limitations in the next generation of T2V models, especially for off-manifold prompts
Existing benchmarks in e-commerce primarily focus on basic user intents, such as finding or purchasing products. However, real-world users often pursue more complex goals, such as applying vouchers, managing budgets, and finding multi-products seller. To bridge this gap, we propose ShoppingBench, a novel end-to-end shopping benchmark designed to encompass increasingly challenging levels of grounded intent. Specifically, we propose a scalable framework to simulate user instructions based on various intents derived from sampled real-world products. To facilitate consistent and reliable evaluations, we provide a large-scale shopping sandbox that serves as an interactive simulated environment, incorporating over 2.5 million real-world products. Experimental results demonstrate that even state-of-the-art language agents (such as GPT-4.1) achieve absolute success rates under 50% on our benchmark tasks, highlighting the significant challenges posed by our ShoppingBench. In addition, we propose a trajectory distillation strategy and leverage supervised fine-tuning, along with reinforcement learning on synthetic trajectories, to distill the capabilities of a large language agent into a smaller one. As a result, our trained agent achieves competitive performance compared to GPT-4.1.
arXiv:2606.14022v1 Announce Type: new Abstract: LayerNorm-based GNNs routinely erase the topology signals (degree, centrality, $k$-core) that node-selection policies should depend on, but the literature has not located where in the residual block the erasure happens. We answer that question: a positive per-node scalar inserted before LayerNorm is divided out up to a stabilizer term, while the same scalar inserted after LayerNorm reaches the score head as representation magnitude. The surviving slot is the post-LayerNorm position. We instantiate it with PostDeg, a parameter-free post-LayerNorm inverse-degree scale, and pre-register four falsifiers (graphwise scalars, extra LayerNorm, expressive same-slot capacity, backbone-agnostic source) that would reject the rule. PostDeg gains $+3.5\%/+2.5\%/+5.6\%$ over the LN backbone on influence maximization, network dismantling, and maximum independent set, with $10/10$ paired-seed wins per task; none of the four falsifiers fires. The takeaway is that placement, not parameterization, carries the gain – a small invariance check that generalizes to any positive topology scalar in any normalized residual stack.
arXiv:2606.17995v1 Announce Type: cross Abstract: We study the privacy of releasing posterior sample paths from a Gaussian process (GP) when the entire training set including covariates and responses is private. Unlike standard differential-privacy (DP) mechanisms that add external noise, posterior sampling is random by construction. We show that this intrinsic randomness yields DP guarantees by deriving explicit Rényi-DP bounds for GP posterior sample-path release. The bounds separate posterior-mean leakage from data-dependent posterior-covariance leakage showing that meaningful privacy depends sharply on effective ridge regularisation. We apply membership-inference attacks to show that empirical leakage follows the predicted dependence on regularisation, posterior variance and the number of released posterior sample-paths. Utility experiments on downstream posterior-sampling tasks identify noisy-observation regimes where privacy-compatible regularisation preserves useful decisions with modest utility loss. When stronger privacy is needed, the intrinsic guarantee can be sharpened by adding calibrated GP noise, providing an explicit additional privacy knob.
With the growing volume of CT examinations, there is an increasing demand for automated tools such as organ segmentation, abnormality detection, and report generation to support radiologists in managing their clinical workload. Multi-label classification of 3D Chest CT scans remains a critical yet challenging problem due to the complex spatial relationships inherent in volumetric data and the wide variability of abnormalities. Existing methods based on 3D convolutional neural networks struggle to capture long-range dependencies, while Vision Transformers often require extensive pre-training on large-scale, domain-specific datasets to perform competitively. In this work, we propose a 2.5D alternative by introducing a new graph-based framework that represents 3D CT volumes as structured graphs, where axial slice triplets serve as nodes processed through spectral graph convolution, enabling the model to reason over inter-slice dependencies while maintaining complexity compatible with clinical deployment. Our method, trained and evaluated on 3 datasets from independent institutions, achieves strong cross-dataset generalization, and shows competitive performance compared to state-of-the-art visual encoders. We further conduct comprehensive ablation studies to evaluate the impact of various aggregation strategies, edge-weighting schemes, and graph connectivity patterns. Additionally, we demonstrate the broader applicability of our approach through transfer experiments on automated radiology report generation and abdominal CT data.
Background Heart failure in hypertensive patients is heterogeneous and poorly captured by traditional left ventricular ejection fraction (LVEF) based classification. Multivariate echocardiographic data combined with unsupervised machine learning may provide a more precise phenotypic characterization. This pilot study evaluated the feasibility of unsupervised clustering of routine transthoracic echocardiographic data to identify phenotypic subgroups of hypertensive heart failure. Methods This retrospective pilot study analyzed transthoracic echocardiography reports from hypertensive patients with clinical heart failure. After data cleaning and exclusion of incomplete records, 102 patients with 11 echocardiographic variables were included. Variables describing left ventricular geometry, systolic function, and diastolic performance were standardized and subjected to K-means clustering. Optimal cluster number was determined using the elbow method and silhouette analysis. Cluster characteristics were assessed using descriptive statistics and Kruskal Wallis testing. Concordance with LVEF based heart failure categories was evaluated. Results Three distinct echocardiographic phenotypes were identified. Cluster 0 (n = 50) demonstrated preserved LVEF with concentric remodeling, consistent with heart failure with preserved ejection fraction (HFpEF) phenotype. Cluster 1 (n = 37) showed marked ventricular dilation and reduced systolic function, consistent with heart failure with reduced ejection fraction (HFrEF). Cluster 2 (n = 15) exhibited concentric hypertrophy with intermediate LVEF, consistent with heart failure with mildly reduced ejection fraction (HFmrEF) like phenotype. All echocardiographic variables differed significantly across clusters (p < 0.001). While Cluster 0 showed strong concordance with HFpEF (96%), Clusters 1 and 2 demonstrated substantial overlap across LVEF categories, indicating partial discordance between structural phenotypes and LVEF based classification. Conclusion Application of unsupervised machine learning to routine echocardiographic data identifies distinct heart failure phenotypes in hypertensive patients. These phenotypes demonstrate significant structural heterogeneity beyond LVEF based classification, supporting the utility of data-driven approaches for refined cardiac phenotyping. This pilot study provides a foundation for larger prospective studies.
Dementia and depression are the most prevalent neuropsychiatric disorders in geriatric populations, and their overlapping symptoms pose major challenges for differential diagnosis. In this study, we investigate open-weights Large Language Models (LLMs) for predicting dementia and depression severity from speech samples collected during standardized history taking interviews with 154 German-speaking subjects. We introduce an observer-based Global Depression Scale (GDS-D) aligned with the established Global Deterioration Scale (GDS), enabling parallel global staging of affective and cognitive symptoms. We compare three LLMs (Mistral 3.1, DeepHermes, Qwen3) in two settings: (1) zero-shot prediction and (2) LLM-based feature extraction for Support Vector Regression, using human and pause-enriched transcripts. Results show that LLMs effectively predict depression severity in zero-shot settings (best MAE of 0.60), while dementia assessment benefits substantially from structured feature extraction (best MAE of 0.78), reducing errors by up to 35% over zero-shot baselines. Pause-enriched transcripts achieve competitive performance with human transcriptions, demonstrating the viability of fully automatic screening pipelines for differential neuropsychiatric assessment.
arXiv:2606.15843v1 Announce Type: new Abstract: We study dynamical orthogonal (DO) approximations of stochastic differential equations and investigate their long-time behaviour. The DO formulation represents the solution by a low-rank decomposition and leads to a coupled system consisting of an evolution equation on the Stiefel manifold and a reduced stochastic process. We establish the well-posedness of the strong DO system and derive quantitative error estimates between the original stochastic differential equation and its low-rank approximation in the Wasserstein distance. Our main contribution is the analysis of invariant probability measures for the DO dynamics. Under suitable dissipativity, Lipschitz continuity, and non-degeneracy assumptions on the coefficients, we prove the existence of an invariant probability measure for the strong DO system. The proof combines uniform moment estimates, a Krylov–Bogoliubov argument for an associated frozen system, and a Kakutani-Fan-Glicksberg fixed-point theorem to recover the self-consistent dynamics. We further show that the induced low-rank process admits an invariant probability measure and discuss the structure of invariant measures through several illustrative examples. These results provide a rigorous foundation for the use of dynamical low-rank approximations in the approximation of long-time statistical properties of stochastic dynamical systems.
Sensitive personal information can appear in large-scale pre-training corpora for large language models (LLMs). Detecting and filtering such information is therefore essential to ensure compliance with privacy regulations and prevent unintended information leakage. However, in contrast to English and other languages, research into sensitive personal information has been limited in the Japanese language. In this study, we focus on sensitive personal data defined as special care-required personal information (SCPI) under Japan's Act on the Protection of Personal Information (APPI). We construct an SCPI dataset using LLM-based annotation and train machine learning models to rapidly detect SCPI in text. As a result, our SCPI classifier can effectively identify information related to SCPI. This study is the first to explore SCPI detection in Japanese text corpora, highlighting the challenges of accurate detection.
arXiv:2604.17805v2 Announce Type: replace-cross Abstract: Pairwise ranking systems based on Maximum Likelihood Estimation (MLE), such as the Bradley-Terry model, are widely used to aggregate preferences from pairwise comparisons. However, their robustness under strategic data manipulation remains insufficiently understood. In this paper, we study the vulnerability of MLE-based ranking systems to adversarial perturbations. We formulate the manipulation task as a constrained combinatorial optimization problem and propose an Adaptive Subset Selection Attack (ASSA) to efficiently identify high-impact perturbations. Experimental results on both synthetic data and real-world election datasets show that MLE-based rankings exhibit a sharp phase-transition behavior: beyond a small perturbation budget, a limited number of strategic voters can significantly alter the global ranking. In particular, our method consistently outperforms random and greedy baselines under constrained budgets. These findings reveal a fundamental sensitivity of MLE-based ranking mechanisms to structured perturbations and highlight the need for more robust aggregation methods in collective decision-making systems.
arXiv:2602.22962v2 Announce Type: replace Abstract: Data-driven models are revolutionizing weather forecasting. To optimize training efficiency and model performance, this paper analyzes empirical scaling laws within this domain. We investigate the relationship between model performance (validation loss) and three key factors: model size ($N$), dataset size ($D$), and compute budget ($C$). Across a range of models, we find that Aurora exhibits the strongest data-scaling behavior: increasing the training dataset by 10x reduces validation loss by up to 3.2x. GraphCast demonstrates the highest parameter efficiency, yet suffers from limited hardware utilization. Our compute-optimal analysis indicates that, under fixed compute budgets, allocating resources to more total training data yields greater performance gains than increasing model size. Furthermore, we analyze model shape and uncover scaling behaviors that differ fundamentally from those observed in language models: weather forecasting models consistently favor increased width over depth. These findings suggest that future weather models should prioritize wider architectures and larger effective training datasets to maximize predictive performance.
LLM-based agents have shown increasing potential in automating scientific discovery. Given an optimizable metric and an execution environment, they can propose, validate, and iterate scientific solutions, and have produced results that outperform human-designed approaches. As model capabilities continue to improve, we argue that the bottleneck for autonomous scientific discovery is shifting from prescribing agent workflows to designing agent environments: the resources, constraints, and interfaces that shape agent behavior. We frame this as environment engineering: building environments that amplify productive behaviors, such as open-ended exploration, systematic artifact management, and inter-agent collaboration, while suppressing harmful behaviors, such as reward hacking and high-friction human oversight. We present EurekAgent, an environment-engineered agent system for metric-driven autonomous scientific discovery. EurekAgent engineers the environment along four dimensions: permissions engineering for bounded agent execution and isolated evaluation; artifact engineering for filesystem and Git-based collaboration; budget engineering for budget-aware exploration; and human-in-the-loop engineering for easy human supervision and intervention. EurekAgent sets new state-of-the-art results on multiple mathematics, kernel engineering, and machine learning tasks, including new state-of-the-art 26-circle packing results discovered with less than $11 in total API cost. We open-source our code and results, and call for environment engineering as a core research direction for developing reliable autonomous research agents.
Evaluating generalist robot manipulation policies in the real world is expensive, slow, and difficult to scale. Action-conditioned video world models offer a scalable alternative by simulating policy rollouts. Autoregressive rollouts accumulate compounding errors, observations across multiple camera views must remain mutually consistent, and the evaluator must generalize to policies whose behaviors lie outside the training distribution. We address these challenges with SC3-Eval, a self-consistent video generation recipe that adapts a pre-trained video foundation model into an accurate policy evaluator by enforcing three complementary forms of consistency. First, forward-inverse dynamics consistency jointly trains the model to predict frames from actions and to recover actions from frames, anchoring generated rollouts to a physically plausible action manifold and counteracting the drift a forward-only model cannot penalize. Second, cross-view consistency trains the model to inpaint each camera view from the other, keeping the multi-camera observation coherent over long rollouts without any explicit memory mechanism. Third, test-time consistency reuses the inverse dynamics mode at inference as a per-action-chunk uncertainty signal that terminates rollouts whose generated frames drift away from the requested actions. We also demonstrate SC3-Eval rollouts reproduce the failure modes that policies exhibit in real-world rollouts, supporting fine-grained diagnostic comparison rather than aggregate ranking alone. Across seven real-world vision-language-action policies, SC3-Eval attains a closed-loop Pearson correlation of $0.929$ and MMRV of $0.119$, outperforming three strong prior video-model-based baselines, and generalizes to new tasks.
arXiv:2602.10635v3 Announce Type: replace Abstract: Socially intelligent AI systems must reason across diverse human behavioral tasks and generalize to new social contexts. However, behavioral data is inherently heterogeneous, comprising diverse modalities and prediction targets that produce uneven training signals across samples, creating imbalanced learning dynamics that challenge existing AI models. To address this, we develop Omnisapiens-7B 2.0, a foundation model for social behavior processing that explicitly addresses learning from heterogeneous behavioral data. This is enabled through Heterogeneity-Aware Relative Policy Optimization, a new RL method that rebalances learning signals across samples by approximating each sample's contribution to the policy update and using these estimates to drive geometrically centered, inertially smoothed advantage modulation for stable training. Omnisapiens-7B 2.0 achieves the best and most consistent performance across 10 behavioral tasks, while also attaining the best performance on all five held-out benchmarks, with gains of up to +12.02% and +9.37% respectively. Furthermore, it demonstrates more consistent and interpretable reasoning traces, supporting reliable real-world behavioral applications. Our model is available at https://github.com/MIT-MI/human_behavior_atlas.
The automated analysis of heterogeneous natural textures is frequently hindered by physical damage and data loss, presenting a significant challenge to computer vision. While deep learning has shown success in controlled environments, its application to complex geological materials under conditions of incomplete information remains underexplored. This study presents an integrated framework for the inpainting and classification of high-resolution core sample images. We propose an end-to-end pipeline that utilizes object detection for sample segmentation, followed by image inpainting using Generative Adversarial Networks (GANs) with Contextual Residual Aggregation (CRA) to reconstruct missing high-frequency details. Subsequently, we evaluate the performance of modern Transformer-based (Swin, ViT) and CNN architectures on the reconstructed data. Our experiments revealed a critical divergence between reconstruction quality and downstream utility: despite high structural fidelity (PSNR 28.7~dB, FID 74.01), classification accuracy plateaued at 53\%. To improve minority-class detection, we propose a confidence-based hybrid ensemble that raises MCA from 48\% to 58\%. These results highlight the limitations of current state-of-the-art generative models, which may produce visually plausible but semantically ambiguous features ("hallucinations") that confound classifiers. This work provides insights into the dependencies between image reconstruction quality and classification performance, offering a reproducible baseline for future research in non-destructive testing and material science. Given that cross-well accuracy remains in the 49–53\% range, we position the resulting system as a decision-support and screening tool for lithofacies interpretation rather than as a fully autonomous classifier. The code is available at https://github.com/GalymzhanAbdimanap/Lithology_recognition
Classification of textual data in terms of sentiment, or more nuanced sociopsychological markers (e.g., agency), is now a popular approach commonly applied at the sentence level. In this paper, we exploit the integrated gradient (IG) method to capture the classification output at the word level, revealing which words actually contribute to the classification process. This approach improves explainability and provides in-depth insights into the text. We focus on sociopsychological markers beyond sentiment and investigate how to effectively train IG in agency, one of the very few markers for which a verified deep learning classifier, BERTAgent, is currently available. Performance and system parameters are carefully tested, alternatives to the IG approach are evaluated, and the usefulness of the result is verified in a relevant application scenario. The method is also applied in a scenario where only a small labeled dataset is available, with the aim of exploiting IG to identify the salient words that contribute to building the different classes that relate to relevant sociopsychological markers. To achieve this, an uncommon training procedure that encourages overfitting is employed to enhance the distinctiveness of each class. The results are analyzed through the lens of social psychology, offering valuable insights.
arXiv:2606.20357v1 Announce Type: new Abstract: We analyze the variance of temporal difference (TD) learning using the phased setting with tabular representation, and show that one of the mechanisms behind its ability to reduce variance is by effectively aggregating over a larger number of independent trajectories. Based on this insight, we demonstrate that (1) the variance of TD is asymptotically bounded from above by Monte Carlo (MC) estimators, and (2) shorter horizon updates incurs less variance for a fixed number of samples. Beyond TD, we show that Direct Advantage Estimation (DAE), a method for estimating the advantage function, can be seen as a type of regression-adjusted control variate, which achieves a tighter bound on the variance compared to TD in the large-sample limit. Finally, we numerically illustrate the behaviors of these estimators with carefully designed environments.
arXiv:2602.08470v3 Announce Type: replace Abstract: Credal predictors are models that are aware of epistemic uncertainty and produce a convex set of probabilistic predictions. They offer a principled way to quantify predictive epistemic uncertainty (EU) and have been shown to improve model robustness in various settings. However, most state-of-the-art methods mainly define EU as disagreement caused by random training initializations, which mostly reflects sensitivity to optimization randomness rather than uncertainty from deeper sources. To address this, we define EU as disagreement among models trained with varying relaxations of the i.i.d. assumption between training and test data. Based on this idea, we propose CreDRO, which learns an ensemble of plausible models through distributionally robust optimization. As a result, CreDRO captures EU not only from training randomness but also from meaningful disagreement due to potential distribution shifts between training and test data. Empirical results show that CreDRO consistently outperforms existing credal methods on tasks such as out-of-distribution detection across multiple benchmarks and selective classification in medical applications.