CPAgents: Agentic Composite Phenotype Generation for Cardiac Disease Association
Authors: Zuoou Li, Wenlong Zhao, Kelly Yu, Weitong Zhang, Paul M. Matthews, Wenjia Bai, Bernhard Kainz, Mengyun Qiao
Organizations: Department of Mechanical Engineering, University College London, London, UK · CSIG Group, Tencent, Beijing, China · Department of Computing, Imperial College London, London, UK · Department of Brain Sciences, Imperial College London, London, UK · UK Dementia Research Institute, Imperial College London, London, UK · Rosalind Franklin Institute, Harwell Science and Innovation Campus, Didcot, UK · Data Science Institute, Imperial College London, London, UK · FAU Erlangen–Nürnberg, Erlangen, DE
Abstract
Identifying robust associations between cardiac imaging phenotypes and clinical diseases is fundamental to population-scale cardiovascular research and reliable risk stratification. However, current phenome-wide association studies rely on pre-defined, single-variable phenotypes or expert-crafted features, which limits their ability to capture clinically meaningful non-linear effects and cross-phenotype interactions. To address this, we propose CPAgents, an iterative phenotype-Composition framework for cardiovascular Phenome-wide association study (PheWAS) that automatically constructs and validates interpretable composite phenotypes (e.g., polynomial, ratio, and interaction forms) from base imaging features. Specifically, our system coordinates three agents: (i) an Analyst that identifies statistical pathologies and nominates candidate transformations; (ii) a Proposer that generates constrained, medically and statistically motivated expressions under numerical safety rules; and (iii) a Verifier that evaluates candidates using multi-stage criteria and produces transparent evidence trails for accepted phenotypes. Evaluated on a population-scale cardiac imaging cohort, the discovered composite phenotypes markedly improve disease discrimination: across 72 classifier-disease-metric combinations, our variants achieve the top rank in 56 cases versus 18 for baselines, with gains observed across all nine clinical disease categories. Our framework yields compact, clinically interpretable phenotype formulas with transparent evidence trails, enabling scalable discovery of stronger phenotype-disease associations beyond expert-driven feature selection.
Cardiac discharge phenotyping informs post-discharge treatment and follow-up, but real-world records are often incomplete and class-imbalanced, increasing the risk of missed high-risk phenotypes. We propose CW-B, a clinical risk-aligned class-weighted XGBoost pipeline for five-class cardiac discharge phenotyping under real-world class imbalance and missingness. CW-B combines fold-specific class-balanced instance weighting, missingness-indicator augmentation, and classwise error auditing to improve recognition of clinically prioritized phenotypes while preserving interpretable and auditable decision logic. In five-fold stratified cross-validation, CW-B achieves the best Accuracy, Macro-F1, Balanced Accuracy, and Prioritized F1 among tree-based, ensemble, and neural baselines. Overall, CW-B provides a practical and deployment-oriented approach for more reliable cardiac discharge phenotyping in real-world clinical settings.
Comprehensive quantification of cardiac structures from computed tomography (CT) remains limited not by data availability but by the scalability of measurements, which makes routine use impractical. Here we present a unified framework for comprehensive cardiac CT segmentation and phenotyping that combines a human-in-the-loop annotation pipeline, a cardiac CT augmentation technique, and a self-supervised foundation model pre-trained on 60,000 unlabeled cardiac CT scans. Using this approach, we assembled the largest and most comprehensive expert-annotated cardiac CT segmentation dataset to date, comprising 1598 cases and 14 distinct cardiac structures (1000 for training, 598 for the external test set). Across five external datasets, the framework segmented all structures more accurately and comprehensively than existing open-source tools. Self-supervised pre-training improved labeling efficiency, with the most significant gains observed during external evaluation in the low-data regime. Benchmarking across convolutional, transformer, and state-space architectures showed comparable performance, indicating that data quality and pre-training, rather than architecture, drove accuracy. The framework was scaled to population-level phenotyping, with segmented anatomy that carries functionally relevant information about ventricular function and disease severity beyond demographic variables. By openly releasing the largest dataset with human labels, code, model weights, a CT augmentation library, and software, this work provides a reproducible foundation for opportunistic cardiac phenotyping from routinely acquired CT scans.
Pooya Mohammadi Kazaj, Leo Fridolin Weber, Wen Xie +17
Cardiologists interpret electrocardiograms by localizing waveform components, measuring rhythm and interval patterns, and translating these structured observations into diagnostic evidence. Whether this expert reading process can serve as an effective prior for ECG agents remains unclear. To address this question, we introduce LuminaECG, a clinically structured ECG reasoning framework that reformulates ECG interpretation as measurement-grounded visual reading. ECG signals are rendered on standard electrocardiographic grid paper to preserve the spatial and scale cues used in clinical reading. P-wave, QRS-complex, and T-wave boundaries are explicitly delineated, and color-coded segmentation decomposes the waveform into discrete visual measurement primitives. A general 2B vision-language backbone is then trained with low-rank supervised fine-tuning to associate these primitives with diagnostic reasoning, without architectural modification. Across open, proprietary, and ECG-specialist zero-shot baselines, LuminaECG improves both waveform measurement and diagnostic recovery. It reaches a clinically meaningful reader tier on the CODE-test benchmark, transfers across geographically diverse ECG datasets without retraining, and generates reports whose structure contains an emergent prognostic signal. These findings suggest that effective ECG agents require not only larger models, but supervision that preserves the alignment between measurable waveform evidence and clinical knowledge.