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01.
arXiv (CS.LG) 2026-06-24

Constrained Variable Projection for Structured Problems

arXiv:2606.23939v1 Announce Type: cross Abstract: Variable projection is a classical technique for separable nonlinear least-squares problems, in which variables that enter linearly are eliminated exactly, yielding a reduced nonlinear problem. By expressing this framework as a particular instance of a broader class of bilevel optimization problems, we develop a constrained variable-projection framework for data-science models, where the remaining variables are subject to convex constraints and the eliminated variables arise from a lower-level least-squares problem. In particular, by interpreting variable projection as a collapsed bilevel optimization problem, we derive exact reduced-gradient formulas compatible with automatic differentiation and propose a conditional-gradient algorithm for the resulting constrained reduced problem. We establish convergence guarantees under standard smoothness and compactness assumptions, and discuss extensions to structured lower-level variables. Numerical experiments on sparse autoencoding, dictionary learning, blind deconvolution, and few-shot learning suggest that the method can improve wall-clock efficiency and data efficiency relative to natural joint-optimization baselines.

02.
medRxiv (Medicine) 2026-06-23

Shared Polygenic Architecture Across Arteriopathies: An Integrative Cross-Trait Analysis

Background: Non-monogenic arteriopathies are often classified as distinct entities according to the arterial territory involved, yet they share clinical features and may co-occur in the same individual. This pattern suggests shared susceptibility across anatomically distinct arteriopathies, potentially driven by common biological and genetic mechanisms. Methods: We investigated the shared genetic architecture of five arteriopathies (cervical artery dissection (CeAD), intracranial aneurysm (IA), spontaneous coronary artery dissection (SCAD), aortic aneurysm and dissection (AAD), and fibromuscular dysplasia (FMD)) using LD score regression, Association analysis based on SubSETs (ASSET), pairwise Multi-Trait Analysis of Genome-wide association summary statistics (MTAG), pleiotropy mapping and Mendelian randomization (MR) to identify shared loci and prioritise candidate causal genes. Results: LD score regression identified significant positive genetic correlations between CeAD-SCAD (rg = 0.64), IA-AAD (rg = 0.33), IA-SCAD (rg = 0.37), CeAD-AAD (rg = 0.56) and SCAD-AAD (rg = 0.20). ASSET identified 37 shared independent loci, and in MTAG analyses, one novel locus was identified for CeAD and SCAD (SLC39A8) and one for IA (FGF5). 13 loci showed strong cross-trait colocalization, including PHACTR1, LRP1, and CDKN2B-AS1. Using the Genotype-Phenotype Map, we found that arteriopathy-associated variants colocalized with blood pressure- and migraine-related traits, while many showed effect directions opposite to those observed for coronary artery disease. Proteome-wide MR identified 67 circulating proteins associated with at least one trait, including ECM1 and SHISA5 for CeAD and FGF5 for IA, with 17 supported by colocalization. Transcriptome-wide MR identified 204 colocalized tissue?specific signals, of which, 14 were shared across multiple traits. Enrichment analyses implicated pathways related to vascular development, smooth muscle cell function, extracellular matrix organization, and TGF-? signaling. Conclusions: These findings support shared genetic architecture across anatomically distinct arteriopathies, implicating pathways involved in vascular structure and prioritising therapeutic targets for future mechanistic investigation.

03.
PLOS Computational Biology 2026-06-22

pyhgf: A neural network library for predictive coding

by Nicolas Legrand, Lilian Weber, Peter Thestrup Waade, Anna Hedvig Møller Daugaard, Mojtaba Khodadadi, Nace Mikuš, Christoph Mathys Bayesian models of cognition have gained considerable traction in computational neuroscience and psychiatry. Their scopes are now expected to expand rapidly to artificial intelligence, providing general inference frameworks to support embodied, adaptable, and energy-efficient autonomous agents. A central theory in this domain is predictive coding, which posits that learning and behaviour are driven by hierarchical probabilistic inferences about the causes of sensory inputs. Biological realism constrains these networks to rely on simple local computations in the form of precision-weighted predictions and prediction errors. This can make this framework highly efficient, but its implementation comes with unique challenges on the software development side. Embedding such models in standard neural network libraries often becomes limiting, as these libraries’ compilation and differentiation backends can force a conceptual separation between optimization algorithms and the systems being optimized. This critically departs from other biological principles such as self-monitoring, self-organisation, cellular growth, and functional plasticity. In this paper, we introduce pyhgf: a Python package backed by JAX and Rust for creating, manipulating, and sampling dynamic networks for predictive coding. We improve over other frameworks by enclosing the network components as transparent, modular, and malleable variables in the message-passing steps. The resulting graphs can implement arbitrary algorithms as belief propagation. Moreover, the transparency of core variables can also translate into inference processes that leverage self-organisation principles and express structure learning, meta-learning, or causal discovery as the consequence of network structural adaptation to surprising inputs. The main functions of the library are differentiable and seamlessly integrate into sampling or optimization workflows. Additionally, we offer generalized Bayesian filtering and the hierarchical Gaussian filter as key examples of dynamic networks implemented in our library. The source code, tutorials, and documentation are hosted under the main repository at https://github.com/ComputationalPsychiatry/pyhgf.

04.
arXiv (CS.AI) 2026-06-18

Pareto Q-Learning with Reward Machines

arXiv:2606.19134v1 Announce Type: cross Abstract: We present Pareto Q-Learning with Reward Machines (PQLRM), a multi-objective reinforcement learning algorithm for tasks whose reward structure is specified by a set of reward machines (RMs). PQLRM combines Pareto Q-Learning (PQL), which maintains sets of vector-valued Q-estimates to approximate the Pareto front, with enhancements from Q-Learning with Reward Machines (QRM), which exploits the factored automaton structure of the reward signal. This yields a multi-policy algorithm that remains sample-efficient under non-Markovian, RM-encoded rewards. Experimental trials show that PQLRM converges faster than a naive PQL baseline applied to the cross-product MDP and can synthesize Pareto-optimal policies that QRM cannot.

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

Time-Varying Audio Effect Modeling by End-to-End Adversarial Training

arXiv:2512.15313v2 Announce Type: replace-cross Abstract: Deep learning has become a standard approach for the modeling of audio effects, yet strictly black-box modeling remains problematic for time-varying systems. Unlike time-invariant effects, training models on devices with internal modulation typically requires the recording or extraction of control signals to ensure the time-alignment required by standard loss functions. This paper introduces a Generative Adversarial Network (GAN) framework to model such effects using only input-output audio recordings, without requiring a modulation signal extraction. We propose a convolutional-recurrent architecture trained via a two-stage strategy: an initial adversarial phase allows the model to learn the distribution of the modulation behavior without strict phase constraints, followed by a supervised fine-tuning phase where a State Prediction Network (SPN) estimates the initial internal states required to synchronize the model with the target. Additionally, a new metric based on chirp-train signals is developed to quantify modulation accuracy. Experiments modeling a vintage hardware phaser demonstrate the method's ability to capture time-varying dynamics in a fully black-box context.

06.
bioRxiv (Bioinfo) 2026-06-11

Tumour evolution as ground truth for cancer whole-genome sequencing

Cancer genomes are shaped by evolutionary processes that couple mutagenesis, clonal selection, chromosomal instability, spatial growth and treatment response into structured genomic patterns, yet current benchmarking strategies largely ignore this evolutionary dependency. Here, we present SCOUT, a large-scale synthetic whole-genome sequencing resource of over 200 samples, designed for systematic benchmarking of tumour genomic analysis and evolutionary inference under controlled evolutionary ground truth. Unlike conventional task-specific simulations, SCOUT models tumour evolution as a latent generative process that simultaneously shapes mutations, copy-number alterations, variant allele frequencies, mutational signatures and clonal architectures. SCOUT recapitulates key features of solid and haematological malignancies, including driver mutations, chromosomal instability, intratumour heterogeneity, spatial sampling and treatment-associated evolutionary dynamics in tumour and matched-normal longitudinal and multi-region sequencing designs. Using SCOUT, we benchmarked widely used methods for somatic variant detection, copy-number analysis, mutational signature inference and tumour evolutionary reconstruction. Across analytical tasks, performance deteriorated in low-purity, highly subclonal and structurally complex tumours, while spatial sampling bias and hypermutation generated spurious evolutionary signals that confounded tumour interpretation across multiple inference layers. Evolutionary simulations further distinguished lineage-restricted genetic bottlenecks from multi-lineage resistance dynamics associated with tumour plasticity. Tumour purity consistently exerted a stronger effect on inference accuracy than sequencing depth. Together, our results establish evolutionary ground truth as a prerequisite for reproducible benchmarking and biologically interpretable analysis of cancer whole-genome sequencing data.