#01Nov 10, 2026
cs.LG
Pyrite: Building and Benchmarking Protein-Ligand Pose Ranking Agents
Megha Srivastava, Michael H. Lim, Allison M. Keys and 2 more
Predicting how a ligand binds to its target is central to small-molecule drug discovery. Modern cofolding models can generate diverse candidate poses, but reliably ranking these candidates remains challenging. We introduce Pyrite, a pairwise pose-ranking benchmark comprising 1,500 pose pairs across diverse protein-ligand complexes. Expert chemists equipped with 3D visualization tools and physics-based scores perform near chance, highlighting the difficulty of interpreting available chemical signals. To investigate automated ranking, we introduce PyriteRep, a structured representation of molecular geometry, protein-ligand interactions, and physicochemical scores, and develop two LLM-based agents: PyriteReasoner, which directly compares poses through text-based reasoning, and PyriteFeaturizer, which generates executable code to construct features for logistic regression, optionally incorporating features derived from LLM subcalls. These agents achieve up to 67% and 74% accuracy, respectively, exceeding observed expert performance. LLM-guided feature discovery generally outperforms direct reasoning, while Group Relative Policy Optimization (GRPO) improves open-weight models, enabling them to match or surpass closed-source frontier models in our evaluations. These results establish Pyrite as a challenging test of pose-ranking ability and highlight LLM-guided feature discovery as a promising approach to interpret and combine the outputs of computational chemistry tools.
#02Nov 10, 2026
cs.LG
Causal Concept Explanations for Deep Neural Models
Josh Rountree, Pulkit Verma, Oswin So and 2 more
Concept-based explanations in neural models are important for the development, certification, and adoption of autonomous systems. Yet, interpretability remains correlational. Without methods to guide and quantify causal relationships between explanations, a concept explanation can be provided without being necessary or sufficient for the observed output thereby appearing correct while misleading. We introduce Causal Concept Wrapper Network (CCW-Net), the first use of interventional mediation analysis from fields such as economics, medicine, and epidemiology as a training objective to align causal effects of concept-based explanations with a model's output. We further apply mediation analysis as an evaluation tool to quantify, per concept label combination, how much of any model's output is causally attributable to each concept explanation. As a training objective, CCW-Net shapes a model's concept representations such that they are both necessary and sufficient for the outputs they are credited with and independent of other concepts' contributions. Counterfactual concept representations anchor a set of causal alignment criteria: necessity, sufficiency, and independence. Necessity drives irrelevant concept effects toward zero, sufficiency ensures relevant concept representations fully reconstruct a model's output, and independence enforces the total effect decomposes linearly across concepts. We evaluate CCW-Net across aircraft control, driving, and image classification. CCW-Net provides a step toward concept-based explanations that are not merely interpretable, but quantifiably causal, supporting safer evaluation, certification, and deployment of transparent and trustworthy neural models.
#03Nov 10, 2026
cs.LG
Forward-Value Discretization: Faster Stochastic Diffusion Sampling Without High-Order Approximation
Yuchen Jiao, Na Li, Changxiao Cai and 2 more
Stochastic diffusion samplers often require substantially more neural function evaluations (NFEs) than deterministic samplers to achieve comparable sample quality. Although higher-order discretization accelerates deterministic sampling, its benefits for stochastic sampling remains unclear. We establish matching upper and worst-case lower bounds showing that stochastic samplers with higher-order approximations remain first-order convergent, even with exact score functions. Thus, increasing the approximation order does not generally improve the convergence order. Motivated by this limitation, we introduce forward-value discretization, a training-free framework that evaluates the data/noise prediction model at a lookahead estimate constructed from previous predictions. For deterministic sampling, the resulting Forward DPMSolver (F-DPMSolver), improves sample quality at low NFE budgets through its DDIM-based variant, despite remaining first-order convergent. For stochastic sampling, we develop Forward DDPM (F-DDPM), which evaluates the model at a cleaner lookahead point adjusted for subsequent noise injection. This estimate reuses both the previous model prediction and the previously injected noise. Both variants admit first-order convergence guarantees with one model evaluation per iteration. Across CIFAR-10, ImageNet, FFHQ, and LSUN, F-DDPM consistently achieves lower FID than the evaluated stochastic baselines at matched NFE budgets. With 1.5 times as many NFEs as deterministic baselines, it achieves competitive sample quality, narrowing the practical efficiency gap between stochastic and deterministic sampling. Code is available at https://github.com/Na-Li66/F-DDPM.
#04Nov 10, 2026
stat.ML
A Theory of Cross-Validation Variance
Nathaniel S. O'Connell, Jaime L. Speiser
Cross-validation estimates predictive performance by repeatedly splitting the data into training and validation sets, fitting the model on the first and evaluating it on the second. Every observation influences the estimate in two roles, through its own evaluation when it is held out and through the models it helps fit when it trains. The random splits determine its weight in each role. From this representation, we prove an exact finite-sample identity for the variance of the cross-validated estimate. For a given splitting scheme with a common training set size, the variance is a function of these weights, with constants of the model, the metric, and the population. It covers metrics averaged over observations, such as mean squared error, and over case--control pairs, such as the AUC. The identity shows which schemes to use. The variance decomposes into sampling variance, which depends only on the training size, and variance due to the random fold splitting, which arises when the weights change from one draw of the splits to the next. K-fold cross-validation, whose weights are equal across observations by design, is therefore variance optimal at first order; Monte Carlo and bootstrap cross-validation are not. The first-order variance of K-fold does not depend on K, and under reasonable conditions on the model leave-one-out has the smallest variance of any K-fold scheme. For the AUC the same holds for leave-pair-out, which evaluates every case--control pair. Finally, we show the cross-validated estimate is asymptotically normal with the identity's full variance. Together, these results provide a general theoretical foundation for inference on cross-validated performance and establish principles for selecting variance-optimal cross-validation designs.
#05Nov 10, 2026
stat.ME
One Curve, Different Weights: AUC, the Brier Score, Decision-Weighted AUC, and the Policy Youden Index
Yegor Baranovski
AUC and the Brier score are standard summaries of a binary risk score, yet they can rank models differently. We introduce a weighted AUC, AUC$_π$, which weights each pair of observations by how differently a decision maker with probability of acting $π$ treats them. We show that all three are built on weighted averages of one curve, the Youden index $J(t) = \mathrm{TPR}(t) - \mathrm{FPR}(t)$ across cutoffs $t$, and that the averages differ in the weights they put on the cutoffs. Each weights a cutoff by how much something rises across it: for AUC, the distribution of all scores; for the Brier score, the true probability $\mathbb{E}[Y \mid S]$; for AUC$_π$, the decision maker's probability of acting. Up to normalization, AUC$_π$ is the Brier skill score of the ideal forecast with its weight moved to the cutoffs the decision maker cares about. We also show that weighting pairs by $|π(s) - π(s')|$ is, up to scale, the only pair weight fixed in advance that makes a pair-weighted AUC an average of the Youden curve for every score distribution. As a ranking measure, AUC weights every model the same way. Hand (2009) shows that it can also be read as an average over cost thresholds, and in that reading each model weights the thresholds differently. The numerator of AUC$_π$, which we call the policy Youden index, is the expected share of class 1 a fixed policy acts on minus the expected share of class 0. It judges every model by the same policy and so avoids this; the full ratio AUC$_π$ does not.