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Population-based biobanks, now established in many countries, offer opportunities for large-scale studies investigating the incidence of various diseases. Biobank data is typically collected from a study cohort recruited over a defined calendar period, with subjects entering the study at various ages falling between $R_L$ and $R_U$. This work focuses on biobank data that includes individuals in whom onset of the disease of interest occurred before recruitment, termed prevalent cases, along with individuals initially recruited as disease-free in whom disease onset occurred during the follow-up period. We propose a novel cumulative incidence function (CIF) estimator that goes beyond existing methods in that it incorporates all disease cases, both prevalent and incident, irrespective of their subsequent life course. In particular, the new method can handle situations involving diseases that can occur at young ages with long survival after disease onset. Asymptotic properties of the new method are established and a simulation study is presented examining the performance of the method. We illustrate the use of the method and highlight its advantages over existing methods with an applica

Dementia affects over 55 million people worldwide, yet whether distinct domains of physical fitness independently protect against neurodegeneration through shared or divergent biological mechanisms remains unknown. Using the UK Biobank (n = 51,517; 12-year follow-up), we integrated epidemiological, proteomic, and neuroimaging analyses to systematically characterize the multidimensional fitness-dementia relationship. Higher handgrip strength, cardiorespiratory fitness, and pulmonary function were each independently associated with reduced dementia risk (HRs 0.50, 0.62, and 0.73, respectively, for highest vs. lowest tertiles), with stronger associations in women and younger individuals. Plasma proteomic profiling revealed domain-specific molecular signatures--neurofilament light chain predominating for muscular and cardiorespiratory fitness, and inflammatory mediators including GDF15 for pulmonary function--with 22-40 proteins per domain independently predicting dementia, converging on neuroinflammatory and neurovascular pathways. Brain MRI analyses identified hippocampal volume as a significant structural mediator (proportion mediated: 3.7-10.1%), indicating structural preservation

The human heart is a sophisticated system composed of four cardiac chambers with distinct shapes, which function in a coordinated manner. Existing shape models of the heart mainly focus on the ventricular chambers and they are derived from relatively small datasets. Here, we present a spatio-temporal (3D+t) statistical shape model of all four cardiac chambers, learnt from a large population of nearly 100,000 participants from the UK Biobank. A deep learning-based pipeline is developed to reconstruct 3D+t four-chamber meshes from the cardiac magnetic resonance images of the UK Biobank imaging population. Based on the reconstructed meshes, a 3D+t statistical shape model is learnt to characterise the shape variations and motion patterns of the four cardiac chambers. We reveal the associations of the four-chamber shape model with demographics, anthropometrics, cardiovascular risk factors, and cardiac diseases. Compared to conventional image-derived phenotypes, we validate that the four-chamber shape-derived phenotypes significantly enhance the performance in downstream tasks, including cardiovascular disease classification and heart age prediction. Furthermore, we demonstrate the effec

The systemic, metabolic, lifestyle factors have established associations with Alzheimer's Disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains retinal structural signatures corresponding to these AD-related risk domains remains unclear. To determine whether deep learning (DL) models can predict 12 AD-related risk factors from CFP and to characterize the retinal structures underlying these predictions, thereby assessing whether CFP reflects pathways to AD vulnerability. Using 62,876 CFPs from 44,501 unique participants from the UK Biobank, DL models were trained to predict 12 factors linked to AD incidence: 6 categorical (sex, smoking, sleeplessness, economic status, alcohol use, depression) and 6 continuous (age, age at completing education, BMI, systolic, diastolic blood pressure, HbA1c). Model performance, model saliency, and saliency-derived scores (CAM-Score) were evaluated and compared to retinal morphometry. The scores were also compared between incident-AD cases (average 8.55 years before onset) and matched controls. Performance of DL ranged from AUROC= 0.5654-0.9480 for categorical and R2=-0.0291-0.7620 for

Electronic health record (EHR)-linked biobank data hold tremendous promise for large-scale discoveries via genome-wide association study (GWAS) on diverse phenotypic traits and biomarkers routinely captured in the EHR. However, heterogeneous missingness in biomarkers compromises the validity and efficiency of statistical analyses. Prediction-based (PB) inference methods meet this challenge by using external machine learning (ML) predictions to impute missing biomarker outcomes, thereby improving statistical power and estimation accuracy in association analyses. Yet, their suitability remains unclear when outcomes are subject to clinically informative observation processes, that is, when laboratory tests are ordered based on both measured and unmeasured patient- and health system-level characteristics. In this paper, we review the statistical underpinnings of popular PB methods and then evaluate nine methods, including four PB methods and five traditional missing-data approaches, under an encompassing set of outcome observation processes for continuous and binary outcomes. PB methods can substantially improve statistical power and estimation efficiency when the missing-data mechanis

Myocardial infarction causes myocardium thinning, fibrosis, and progressive heart failure. Engineered human myocardium (EHM) is tested clinically as a first-in-class product for sustainable remuscularization in patients with advanced heart failure. Current EHM production procedure from iPSC-derived cardiomyocytes and stromal cells, is time consuming and involves thin constructs. Here, I introduce 4D-DLP-printed foldable scaffolds with potential to create modular cylindrical cardiac bricks. This enables self-assembly into thicker and aligned sarcomeres with synchronous contractility mimicking a native myocardium. When optimized and integrated with cryopreservation protocols, the biomanufacturing and biobanking of these cellular building blocks may overcome current EHM limitations and advance translational regenerative therapies for myocardial infarction. The structure-material properties investigations into these new class of life building blocks paves the way for future medical breakthroughs.

Dual-energy X-ray absorptiometry (DXA) is widely used for large-scale skeletal assessment, yet learning controllable and interpretable factor-specific anatomical variation remains challenging. We propose a metadata-conditioned causal hierarchical variational autoencoder (CHVAE) for causally consistent generation of anteroposterior (AP) spine DXA images from the UK Biobank (UKB). The model is trained on 3,743 raw AP spine scans from the first imaging visit and conditioned on basic participant attributes and lumbar morphometry. Causal consistency is evaluated in a baseline-to-follow-up setting using abduction--action--prediction (AAP): latent variables are abducted from baseline images, age is intervened to the repeat-imaging value, and the resulting counterfactual follow-up morphometry is compared with observed repeat-imaging measurements. Results show strong absolute-level agreement for key vertebral morphometry variables under age intervention, supporting intervention-aligned synthesis of anatomically plausible DXA images.

While national biobanks are essential for advancing medical research, their non-probability sampling designs limit their representativeness of the target population. This paper proposes a method that leverages high-quality national surveys to create synthetic sampling weights for non-probabilistic cohort studies, aiming to improve representativeness. Specifically, we focus on deriving more accurate base weights, which enhance calibration by meeting population constraints, and on automating data-supported selection of cross-tabulations for calibration. This approach combines a pseudo-design-based model with a novel Last-In-First-Out criterion, enhancing the accuracy and stability of the estimates. Extensive simulations demonstrate that our method, named RAILS, reduces bias, improves efficiency, and strengthens inference compared to existing approaches. We apply the proposed method to the All of Us Research Program, using data from the National Health Interview Survey 2020 and the American Community Survey 2022 and comparing prevalence estimates for common phenotypes against national benchmarks. The results underscore our method's ability to effectively reduce selection bias in non-p

Brain aging trajectories differ between males and females, yet the genetic factors underlying these differences remain underexplored. Using structural MRI and genotyping data from 40,940 UK Biobank participants (aged 45-83), we computed Brain Age Gap Estimates (BrainAGE) for total brain, hippocampal, and ventricular volumes. We conducted sex-stratified genome-wide association studies (GWAS) and Post-GWAS analyses to identify genetic variants associated with accelerated brain aging. Distinct gene sets emerged by sex: in females, neurotransmitter transport and mitochondrial stress response genes were implicated; in males, immune and inflammation-related genes dominated. Shared genes, including GMNC and OSTN, were consistently linked to brain volumes across sexes, suggesting core roles in neurostructural maintenance. Tissue expression analyses revealed sex-specific enrichment in pathways tied to neurodegeneration. These findings highlight the importance of sex-stratified approaches in aging research and suggest genetic targets for personalized interventions against age-related cognitive decline.

We present a scalable framework for computing polygenic risk scores (PRS) in high-dimensional genomic settings using the recently introduced Univariate-Guided Sparse Regression (uniLasso). UniLasso is a two-stage penalized regression procedure that leverages univariate coefficients and magnitudes to stabilize feature selection and enhance interpretability. Building on its theoretical and empirical advantages, we adapt uniLasso for application to the UK Biobank, a population-based repository comprising over one million genetic variants measured on hundreds of thousands of individuals from the United Kingdom. We further extend the framework to incorporate external summary statistics to increase predictive accuracy. Our results demonstrate that uniLasso attains predictive performance comparable to standard Lasso while selecting substantially fewer variants, yielding sparser and more interpretable models. Moreover, it exhibits superior performance in estimating PRS relative to its competitors, such as PRS-CS. Integrating external scores further improves prediction while maintaining sparsity.

Physical activity is a modifiable lifestyle factor with potential to support cognitive resilience. However, the association of moderate-to-vigorous physical activity (MVPA) intensity, and timing, with cognitive function and region-specific brain structure remain poorly understood. We analyzed data from 45,892 UK Biobank participants aged 60 years and older with valid wrist-worn accelerometer data, cognitive testing, and structural brain MRI. MVPA was measured both continuously (mins per week) and categorically (thresholded using >=150 min/week based on WHO guidelines). Associations with cognitive performance and regional brain volumes were evaluated using multivariable linear models adjusted for demographic, socioeconomic, and health-related covariates. We conducted secondary analyses on MVPA timing and subgroup effects. Higher MVPA was associated with better performance across cognitive domains, including reasoning, memory, executive function, and processing speed. These associations persisted in fully adjusted models and were higher among participants meeting WHO guidelines. Greater MVPA was also associated with subcortical brain regions (caudate, putamen, pallidum, thalamus),

A cardiac digital twin is a virtual replica of a patient's heart for screening, diagnosis, prognosis, risk assessment, and treatment planning of cardiovascular diseases. This requires an anatomically accurate patient-specific 3D structural representation of the heart, suitable for electro-mechanical simulations or study of disease mechanisms. However, generation of cardiac digital twins at scale is demanding and there are no public repositories of models across demographic groups. We describe an automatic open-source pipeline for creating patient-specific left and right ventricular meshes from cardiovascular magnetic resonance images, its application to a large cohort of ~55000 participants from UK Biobank, and the construction of the most comprehensive cohort of adult heart models to date, comprising 1423 representative meshes across sex (male, female), body mass index (range: 16 - 42 kg/m$^2$) and age (range: 49 - 80 years). Our code is available at https://github.com/cdttk/biv-volumetric-meshing/tree/plos2025 , and pre-trained networks, representative volumetric meshes with fibers and UVCs will be made available soon.

Multiple studies have shown that scalar summaries of objectively measured physical activity (PA) using accelerometers are the strongest predictors of mortality, outperforming all traditional risk factors, including age, sex, body mass index (BMI), and smoking. Here we show that diurnal patterns of PA and their day-to-day variability provide additional information about mortality. To do that, we introduce a class of extended functional Cox models and corresponding inferential tools designed to quantify the association between multiple functional and scalar predictors with time-to-event outcomes in large-scale (large $n$) high-dimensional (large $p$) datasets. Methods are applied to the UK Biobank study, which collected PA at every minute of the day for up to seven days, as well as time to mortality ($93{,}370$ participants with good quality accelerometry data and $931$ events). Simulation studies show that methods perform well in realistic scenarios and scale up to studies an order of magnitude larger than the UK Biobank accelerometry study. Establishing the feasibility and scalability of these methods for such complex and large data sets is a major milestone in applied Functional D

In linear regression models with non-Gaussian errors, transformations of the response variable are widely used in a broad range of applications. Motivated by various genetic association studies, transformation methods for hypothesis testing have received substantial interest. In recent years, the rise of biobank-scale genetic studies, which feature a vast number of participants that could be around half a million, spurred the need for new transformation methods that are both powerful for detecting weak genetic signals and computationally efficient for large-scale data. In this work, we propose a novel transformation method that leverages the information of the error density. This transformation leads to locally most powerful tests and therefore has strong power for detecting weak signals. To make the computation scalable to biobank-scale studies, we harnessed the nature of weak genetic signals and proposed a consistent and computationally efficient estimator of the transformation function. Through extensive simulations and a gene-based analysis of spirometry traits from the UK Biobank, we validate that our approach maintains stringent control over type I error rates and significant

Predictive modelling is vital to guide preventive efforts. Whilst large-scale prospective cohort studies and a diverse toolkit of available machine learning (ML) algorithms have facilitated such survival task efforts, choosing the best-performing algorithm remains challenging. Benchmarking studies to date focus on relatively small-scale datasets and it is unclear how well such findings translate to large datasets that combine omics and clinical features. We sought to benchmark eight distinct survival task implementations, ranging from linear to deep learning (DL) models, within the large-scale prospective cohort study UK Biobank (UKB). We compared discrimination and computational requirements across heterogenous predictor matrices and endpoints. Finally, we assessed how well different architectures scale with sample sizes ranging from n = 5,000 to n = 250,000 individuals. Our results show that discriminative performance across a multitude of metrices is dependent on endpoint frequency and predictor matrix properties, with very robust performance of (penalised) COX Proportional Hazards (COX-PH) models. Of note, there are certain scenarios which favour more complex frameworks, specif

Alterations in retinal layer thickness, measurable using Optical Coherence Tomography (OCT), have been associated with neurodegenerative diseases such as Alzheimer's disease (AD). While previous studies have mainly focused on segmented layer thickness measurements, this study explored the direct classification of OCT B-scan images for the early detection of AD. To our knowledge, this is the first application of deep learning to raw OCT B-scans for AD prediction in the literature. Unlike conventional medical image classification tasks, early detection is more challenging than diagnosis because imaging precedes clinical diagnosis by several years. We fine-tuned and evaluated multiple pretrained models, including ImageNet-based networks and the OCT-specific RETFound transformer, using subject-level cross-validation datasets matched for age, sex, and imaging instances from the UK Biobank cohort. To reduce overfitting in this small, high-dimensional dataset, both standard and OCT-specific augmentation techniques were applied, along with a year-weighted loss function that prioritized cases diagnosed within four years of imaging. ResNet-34 produced the most stable results, achieving an AU

The UK Biobank is a large-scale study collecting whole-body MR imaging and non-imaging health data. Robust and accurate inter-subject image registration of these whole-body MR images would enable their body-wide spatial standardization, and region-/voxel-wise correlation analysis of non-imaging data with image-derived parameters (e.g., tissue volume or fat content). We propose a sex-stratified inter-subject whole-body MR image registration approach that uses subcutaneous adipose tissue- and muscle-masks from the state-of-the-art VIBESegmentator method to augment intensity-based graph-cut registration. The proposed method was evaluated on a subset of 4000 subjects by comparing it to an intensity-only method as well as two previously published registration methods, uniGradICON and MIRTK. The evaluation comprised overlap measures applied to the 71 VIBESegmentator masks: 1) Dice scores, and 2) voxel-wise label error frequency. Additionally, voxel-wise correlation between age and each of fat content and tissue volume was studied to exemplify the usefulness for medical research. The proposed method exhibited a mean dice score of 0.773 / 0.744 across the cohort and the 69 masks for males/

Precision medicine aims to create biomedical solutions tailored to specific factors that affect disease risk and treatment responses within the population. The success of the genomics era and recent widespread availability of electronic health records (EHR) has ushered in a new wave of genomic biobanks connected to EHR databases (EHR-linked biobanks). This perspective aims to discuss how race, ethnicity, and genetic ancestry are currently utilized to study common disease variation through genetic association studies. Although genetic ancestry plays a significant role in shaping the genetic landscape underlying disease risk in humans, the overall risk of a disease is caused by a complex combination of environmental, sociocultural, and genetic factors. When using EHR-linked biobanks to interrogate underlying disease etiology, it is also important to be aware of how the biases associated with commonly used descent-associated concepts such as race and ethnicity can propagate to downstream analyses. We intend for this resource to support researchers who perform or analyze genetic association studies in the EHR-linked biobank setting such as those involved in consortium-wide biobanking e

Motivation: Modern biobanks, with unprecedented sample sizes and phenotypic diversity, have become foundational resources for genomic studies, enabling powerful cross-phenotype and population-scale analyses. As studies grow in complexity, Bayesian hierarchical models offer a principled framework for jointly modeling multiple units such as cells, traits, and experimental conditions, increasing statistical power through information sharing. However, adoption of Bayesian hierarchical models in biobank-scale studies remains limited due to computational inefficiencies, particularly in posterior inference over high-dimensional parameter spaces. Deterministic approximations such as variational inference provide scalable alternatives to Markov Chain Monte Carlo, yet current implementations do not fully exploit the structure of genome-wide multi-unit modeling, especially when biological effects of interest are concentrated in a few units. Results: We propose an adaptive focus (AF) strategy within a block coordinate ascent variational inference (CAVI) framework that selectively updates subsets of parameters at each iteration, corresponding to units deemed relevant based on current estimates.