#01Aug 21, 2026
q-bio.QM
PerturbRx: Learning Treatment-Conditioned Latent Transitions for Patient Drug Response Prediction
Yoshitaka Inoue, Minoh Jeong, Alfred Hero and 2 more
Scarce data and tumor heterogeneity limit patient-level cancer treatment-response prediction. Existing approaches predict response from pretreatment molecular profiles and drug representations, without explicitly modeling the molecular changes expected under treatment. We propose PerturbRx, a treatment-conditioned representation learning framework that learns intervention-induced latent transitions and uses them as patient-drug response features. PerturbRx trains a drug- and dose-conditioned transition predictor from context-matched but cell-unpaired control and treated single-cell populations, then freezes and transfers the predictor to pretreatment patient profiles without requiring post-treatment measurements. The transition is combined with patient and drug representations to predict response. Across TCGA and patient-derived xenograft benchmarks, PerturbRx achieves the strongest aggregate predictive performance among the evaluated methods. These results support perturbation-pretrained latent transitions as useful representations for patient-level drug-response prediction.
#02Aug 21, 2026
math.OC
Primal Acceleration of Newton's Method
Nikita Doikov
We develop a new direct accelerated Newton method for minimizing convex functions with Lipschitz continuous Hessian. The algorithm uses only primal variables and performs just one linear solve per iteration. With a simple predetermined choice of parameters, it achieves the global convergence rate of $O(1/k^3)$ in terms of the functional residual. To the best of our knowledge, this is the first second-order method for this problem class attaining this rate while relying solely on one linear system solve per iteration (without solving auxiliary nonlinear regularized subproblems, such as cubic regularization, performing nonlinear parameter searches, or using dual extragradient corrections). Our method can be implemented in a Hessian-free way, using an inexact linear system solver, while preserving the fast global rate. We further extend our construction to arbitrary geometry through Bregman divergence, and to composite optimization problems.
#03Aug 21, 2026
stat.ML
The Exceedance Design Effect: Effective Sample Size for Thresholds under Clustering
Adam Noonan
Many machine-learning systems set a threshold at a quantile of a calibration set: conformal predictors that promise 90% coverage by drawing their cutoff at the calibration set's 90th percentile, abstention gates that decline to answer when a model's score falls below the calibration set's tenth percentile, safety filters that block any output scoring above the 99th percentile of a reference set. All of them promise that the threshold will hold at the stated rate on new data. The promise assumes the calibration examples are independent, and in modern pipelines they usually are not: they share a prompt, a document, a reasoning trace. Survey statistics has known how to discount correlated data since 1965, by counting how many independent observations a sample is worth, but only for averages. We show that a threshold needs a different count. The count depends on how often clustered scores land on the same side of the threshold, and that changes with where the threshold is set. How similar the scores are as numbers does not enter. We prove a closed-form law for the resulting effective sample size and for the spread of the coverage a deployed system actually sees. Three consequences follow. The correction now used in the conformal literature is the wrong quantity, and can miss in either direction. A dataset has no single effective sample size. It has one for each level the threshold is set at. And the damage is invisible in coverage averaged over many runs, and fully felt by whoever deploys once. On a released calibration set of 25,028 examples, we measure the reliability of about 1,300.
#04Aug 21, 2026
cs.AI
Anatomy-Informed Neural Networks: Encoding Anatomic Priors in Loss and Architecture, with an SE(3) Formulation of Guidewire-Induced Aortoiliac Deformation
David P. Stonko
Deep-learning models of anatomy can be numerically plausible yet anatomically impossible, and they generalize poorly when data are scarce. We introduce Anatomy-Informed Neural Networks (AINN), in which soft anatomic priors enter as penalty terms in the loss (e.g., a branching penalty that treats a renal transplant artery off the iliac instead of the aorta as unexpected rather than impossible), in direct analogy to a physics-informed neural network, and hard anatomic priors (e.g., continuity of the vessel) are built into the architecture and state representation, making such invalid predictions impossible by construction wherever the prior admits architectural enforcement. We develop it on a clinical test case with limited data: how the aortoiliac tree deforms when a stiff wire is introduced endoluminally. This is important to contemporary aortic surgery and will matter to autonomous endovascular navigation. We lift the vessel centerline and the wire path from R^3 to curves of frames in the Lie group SE(3), and couple a Cosserat-rod wire to a tortuosity-modulated, anatomically anchored vessel through a unilateral lumen-contact inequality. The prediction is a constrained minimizer of the coupled elastic energy, with contact forces as its Lagrange multipliers. Supervision is a Wasserstein-2 optimal-transport loss between the predicted projection through the C-arm geometry and the observed angiogram, so a 2D angiogram can train a 3D prediction. The kinematics, loss and projection are verified against known ground truth; the mechanics solver only against its own optimality conditions, and predicted displacement is not yet mesh-converged. Here, no network is trained. Future work will transfer this in silico model to real CT scans and test whether it improves predictive accuracy and reduces the training data required.
#05Aug 21, 2026
cs.AI
CLEAR: Continuous Latent Adapter Routing for Utility-Preserving LLM Safety Alignment
Chengxiao Wang, Enyi Jiang, Xiaojing Liao and 1 more
Improving the safety of large language models (LLMs) often comes at the expense of utility, as globally applied safety tuning may affect model responses to both harmful and benign inputs. We propose \textbf{C}ontinuous \textbf{L}at\textbf{E}nt \textbf{A}dapter \textbf{R}outing (CLEAR), a conditional safety adaptation framework that uses a lightweight hidden-state gate to continuously control the activation strength of a safety low-rank adapter. CLEAR aims to reduce harmful completions while avoiding unnecessary changes to the frozen backbone that could degrade performance on benign prompts. Experiments on widely used safety and utility benchmarks show that CLEAR improves robustness on HarmBench while reducing the utility degradation observed with globally applied safety tuning such as SFT or standard low-rank adaptation (LoRA). On Llama-3-8B-Instruct, CLEAR reduces HarmBench ASR from 32.3\% to 0.5\%, while retaining most of the base model's utility and achieving up to 7.1 percentage points higher GSM8K accuracy than globally applied SFT or LoRA. These results suggest that CLEAR is a promising mechanism for improving the safety--utility trade-off in LLM alignment.