Association of Progressive PPFE and Mortality in Lung Cancer Screening Cohorts

Background: Pleuroparenchymal fibroelastosis (PPFE) is an upper lobe predominant fibrotic lung abnormality associated with increased mortality in established interstitial lung disease. However, the clinical significance of radiologic PPFE progression in lung cancer screening (LCS) populations remains unclear. Methods: We analysed longitudinal low-dose CT scans and clinical data from two LCS studies: National Lung Screening Trial (NLST; n=7,980); SUMMIT study (n=8,561). An automated algorithm quantified PPFE volume on baseline and follow-up scans. Annualised change in PPFE was derived and dichotomised using a distribution-based threshold to define progressive PPFE. Associations between progressive PPFE and mortality were evaluated using Cox proportional hazards models adjusted for demographic and clinical variables. In SUMMIT cohort, associations between progressive PPFE and clinical outcomes were assessed using incidence rate ratios (IRR) and odds ratios (OR). Findings: Progressive PPFE independently associated with mortality in both LCS cohorts (NLST: Hazard Ratio (HR)=1.25, 95% Confidence Interval (CI): 1.01--1.56, p=0.042; SUMMIT: HR=3.14, 95% CI: 1.66--5.97, p<0.001). Within SUMMIT, progressive PPFE was strongly associated with higher respiratory admissions (IRR=2.79, p<0.001), increased antibiotic and steroid use (IRR=1.55, p=0.010), and showed a trend towards higher modified medical research council scores (OR=1.40, p=0.055). Interpretation: Radiologic PPFE progression independently associates with mortality across two large LCS cohorts, and associates with adverse clinical outcomes. Quantitative assessment of PPFE progression may provide a clinically relevant imaging biomarker to identify individuals at increased risk of respiratory morbidity within LCS programmes.

Association of Radiologic PPFE Change with Mortality in Lung Cancer Screening Cohorts

Background: Pleuroparenchymal fibroelastosis (PPFE) is an upper lobe predominant fibrotic lung abnormality associated with increased mortality in established interstitial lung disease. However, the clinical significance of radiologic PPFE progression in lung cancer screening populations remains unclear. We investigated whether longitudinal change in PPFE quantified on low dose CT independently associates with mortality and respiratory morbidity. Methods: We analysed longitudinal low-dose CT scans and clinical data from two lung cancer screening studies: the National Lung Screening Trial (NLST; n=7980) and the SUMMIT study (n=8561). An automated algorithm quantified PPFE volume on baseline and follow up scans. Annualised change in PPFE (dPPFE) was derived and dichotomised using a distribution based threshold to define progressive PPFE. Associations between dPPFE and mortality were evaluated using Cox proportional hazards models adjusted for demographic and clinical variables. In the SUMMIT cohort, dPPFE was also examined in relation to clinical outcomes. Findings: dPPFE independently associated with mortality in both cohorts (NLST: HR 1.25, 95% CI 1.01-1.56, p=0.042; SUMMIT: HR 3.14, 95% CI 1.66-5.97, p<0.001). Kaplan-Meier curves showed reduced survival among participants with progressive PPFE in both cohorts. In SUMMIT, dPPFE was associated with higher respiratory admissions (IRR 2.79, p<0.001), increased antibiotic and steroid use (IRR 1.55, p=0.010), and a trend towards higher mMRC scores (OR 1.40, p=0.055). Interpretation: Radiologic PPFE progression independently associates with mortality across two large lung cancer screening cohorts and with adverse clinical outcomes. Quantitative assessment of PPFE progression may provide a clinically relevant imaging biomarker for identifying individuals at increased respiratory risk within screening programmes.

Composing Linear Layers from Irreducibles

Contemporary large models often exhibit behaviors suggesting the presence of low-level primitives that compose into modules with richer functionality, but these fundamental building blocks remain poorly understood. We investigate this compositional structure in linear layers by asking: can we identify/synthesize linear transformations from a minimal set of geometric primitives? Using Clifford algebra, we show that linear layers can be expressed as compositions of bivectors -- geometric objects encoding oriented planes -- and introduce a differentiable algorithm that decomposes them into products of rotors. This construction uses only O(log^2 d) parameters, versus O(d^2) required by dense matrices. Applied to the key, query, and value projections in LLM attention layers, our rotor-based layers match the performance of strong baselines such as block-Hadamard and low-rank approximations. Our findings provide an algebraic perspective on how these geometric primitives can compose into higher-level functions within deep models.

A computationally frugal open-source foundation model for thoracic disease detection in lung cancer screening programs

Low-dose computed tomography (LDCT) imaging employed in lung cancer screening (LCS) programs is increasing in uptake worldwide. LCS programs herald a generational opportunity to simultaneously detect cancer and non-cancer-related early-stage lung disease. Yet these efforts are hampered by a shortage of radiologists to interpret scans at scale. Here, we present TANGERINE, a computationally frugal, open-source vision foundation model for volumetric LDCT analysis. Designed for broad accessibility and rapid adaptation, TANGERINE can be fine-tuned off the shelf for a wide range of disease-specific tasks with limited computational resources and training data. Relative to models trained from scratch, TANGERINE demonstrates fast convergence during fine-tuning, thereby requiring significantly fewer GPU hours, and displays strong label efficiency, achieving comparable or superior performance with a fraction of fine-tuning data. Pretrained using self-supervised learning on over 98,000 thoracic LDCTs, including the UK's largest LCS initiative to date and 27 public datasets, TANGERINE achieves state-of-the-art performance across 14 disease classification tasks, including lung cancer and multiple respiratory diseases, while generalising robustly across diverse clinical centres. By extending a masked autoencoder framework to 3D imaging, TANGERINE offers a scalable solution for LDCT analysis, departing from recent closed, resource-intensive models by combining architectural simplicity, public availability, and modest computational requirements. Its accessible, open-source lightweight design lays the foundation for rapid integration into next-generation medical imaging tools that could transform LCS initiatives, allowing them to pivot from a singular focus on lung cancer detection to comprehensive respiratory disease management in high-risk populations.

Adaptive Scoring and Thresholding with Human Feedback for Robust Out-of-Distribution Detection

Machine Learning (ML) models are trained on in-distribution (ID) data but often encounter out-of-distribution (OOD) inputs during deployment -- posing serious risks in safety-critical domains. Recent works have focused on designing scoring functions to quantify OOD uncertainty, with score thresholds typically set based solely on ID data to achieve a target true positive rate (TPR), since OOD data is limited before deployment. However, these TPR-based thresholds leave false positive rates (FPR) uncontrolled, often resulting in high FPRs where OOD points are misclassified as ID. Moreover, fixed scoring functions and thresholds lack the adaptivity needed to handle newly observed, evolving OOD inputs, leading to sub-optimal performance. To address these challenges, we propose a human-in-the-loop framework that \emph{safely updates both scoring functions and thresholds on the fly} based on real-world OOD inputs. Our method maximizes TPR while strictly controlling FPR at all times, even as the system adapts over time. We provide theoretical guarantees for FPR control under stationary conditions and present extensive empirical evaluations on OpenOOD benchmarks to demonstrate that our approach outperforms existing methods by achieving higher TPRs while maintaining FPR control.