Kuan-Jui Su

Lei Huang, Hui Shen, Kuan-Jui Su et al.

Genotype-based cis-expression prediction depends on accurately modeling local regulatory architecture. We present block-sparse Bayesian sparse linear mixed model (bsBSLMM), an extension of Bayesian sparse linear mixed model (BSLMM) that incorporates linkage disequilibrium (LD)-block spike-and-slab sparsity and a transcription start site (TSS)-informed SNP inclusion prior. Across 23,098 genes from GEUVADIS European-ancestry lymphoblastoid cell lines, bsBSLMM retained more predictable genes than BSLMM, LASSO, BLUP, TIGAR elastic net, and TIGAR Dirichlet-process regression under matched evaluation criteria. Compared with BSLMM, bsBSLMM improved held-out prediction performance for most shared genes, with gains driven primarily by LD-block sparsity and further enhanced by the TSS-informed prior. Variants selected by bsBSLMM showed stronger enrichment in GM12878 DNase and H3K27ac regulatory regions than variants selected by BSLMM. In transcriptome-wide association study (TWAS) analysis, bsBSLMM recovered established inflammatory bowel disease signals, including IL23R, and identified additional genome-wide significant genes not detected by BSLMM. Independent validation in the Louisiana Osteoporosis Study reproduced the increased prediction yield across ancestries and recovered biologically relevant bone mineral density pathways in downstream TWAS and gene set enrichment analyses. These results demonstrate that incorporating LD-block structure and biologically informed SNP priors improves cis-expression prediction and enhances downstream TWAS discovery.

Zixin Shi, Chen Zhao, Meiling Zhou et al.

Purpose: To compare dual-energy X-ray absorptiometry (DXA)-derived hip skeletal phenotypes in relation to hip fracture risk using prespecified confounder adjustment and to assess whether phenotypes ranked by their backdoor-adjusted average treatment effects (ATEs) improve risk stratification. Methods: We analyzed 21,098 UK Biobank participants with linked health records, hip DXA-derived skeletal measures, and prespecified covariates. Sixteen phenotypes spanning bone mineral content (BMC), bone mineral density (BMD), and T-score across hip-related regions were evaluated. Confounder selection was guided by a prespecified directed acyclic graph (DAG). Backdoor-adjusted ATEs were estimated on the absolute risk-difference scale per standard deviation (SD) increase. Effect heterogeneity was evaluated for total femur BMD, and downstream prediction was assessed using clinical variables combined with phenotypes ranked by ATE magnitude. Results: Among 21,098 participants, 115 had hip fractures. All 16 phenotypes showed negative backdoor-adjusted ATEs per SD increase. The largest ATEs were observed for total femur BMC and total femur BMD, each with a risk difference of -0.0047, corresponding to approximately 4.7 fewer hip fractures per 1,000 participants per SD higher phenotype value. Conditional effects of total femur BMD were stronger among older participants and those with lower BMI. In prediction, clinical variables plus the top 11 ATE-ranked phenotypes achieved higher AUC than FRAX with femoral neck BMD (0.842 vs. 0.709), with higher sensitivity (0.748 vs. 0.443) and similar specificity (0.793 vs. 0.777). Conclusion: DXA-derived hip skeletal phenotypes differed in their backdoor-adjusted ATEs. Phenotype-level causal evaluation may help identify informative DXA measures for risk stratification.

Chen Zhao, Kuan-Jui Su, Chong Wu et al.

Background: Missing data is a common challenge in mass spectrometry-based metabolomics, which can lead to biased and incomplete analyses. The integration of whole-genome sequencing (WGS) data with metabolomics data has emerged as a promising approach to enhance the accuracy of data imputation in metabolomics studies. Method: In this study, we propose a novel method that leverages the information from WGS data and reference metabolites to impute unknown metabolites. Our approach utilizes a multi-view variational autoencoder to jointly model the burden score, polygenetic risk score (PGS), and linkage disequilibrium (LD) pruned single nucleotide polymorphisms (SNPs) for feature extraction and missing metabolomics data imputation. By learning the latent representations of both omics data, our method can effectively impute missing metabolomics values based on genomic information. Results: We evaluate the performance of our method on empirical metabolomics datasets with missing values and demonstrate its superiority compared to conventional imputation techniques. Using 35 template metabolites derived burden scores, PGS and LD-pruned SNPs, the proposed methods achieved R^2-scores > 0.01 for 71.55% of metabolites. Conclusion: The integration of WGS data in metabolomics imputation not only improves data completeness but also enhances downstream analyses, paving the way for more comprehensive and accurate investigations of metabolic pathways and disease associations. Our findings offer valuable insights into the potential benefits of utilizing WGS data for metabolomics data imputation and underscore the importance of leveraging multi-modal data integration in precision medicine research.

Rochak Dhakal, Chen Zhao, Zixin Shi et al.

Quantitative computed tomography (QCT) plays a crucial role in assessing bone strength and fracture risk by enabling volumetric analysis of bone density distribution in the proximal femur. However, deploying automated segmentation models in practice remains difficult because deep networks trained on one dataset often fail when applied to another. This failure stems from domain shift, where scanners, reconstruction settings, and patient demographics vary across institutions, leading to unstable predictions and unreliable quantitative metrics. Overcoming this barrier is essential for multi-center osteoporosis research and for ensuring that radiomics and structural finite element analysis results remain reproducible across sites. In this work, we developed a domain-adaptive transformer segmentation framework tailored for multi-institutional QCT. Our model is trained and validated on one of the largest hip fracture related research cohorts to date, comprising 1,024 QCT images scans from Tulane University and 384 scans from Rochester, Minnesota for proximal femur segmentation. To address domain shift, we integrate two complementary strategies within a 3D TransUNet backbone: adversarial alignment via Gradient Reversal Layer (GRL), which discourages the network from encoding site-specific cues, and statistical alignment via Maximum Mean Discrepancy (MMD), which explicitly reduces distributional mismatches between institutions. This dual mechanism balances invariance and fine-grained alignment, enabling scanner-agnostic feature learning while preserving anatomical detail.

Chen Zhao, Anjum Shaik, Joyce H. Keyak et al.

Hip fractures represent a major health concern, particularly among the elderly, often leading decreased mobility and increased mortality. Early and accurate detection of at risk individuals is crucial for effective intervention. In this study, we propose Iterative Cross Graph Matching for Hip Fracture Risk Assessment (ICGM-FRAX), a novel approach for predicting hip fractures using Dual-energy X-ray Absorptiometry (DXA) images. ICGM-FRAX involves iteratively comparing a test (subject) graph with multiple template graphs representing the characteristics of hip fracture subjects to assess the similarity and accurately to predict hip fracture risk. These graphs are obtained as follows. The DXA images are separated into multiple regions of interest (RoIs), such as the femoral head, shaft, and lesser trochanter. Radiomic features are then calculated for each RoI, with the central coordinates used as nodes in a graph. The connectivity between nodes is established according to the Euclidean distance between these coordinates. This process transforms each DXA image into a graph, where each node represents a RoI, and edges derived by the centroids of RoIs capture the spatial relationships between them. If the test graph closely matches a set of template graphs representing subjects with incident hip fractures, it is classified as indicating high hip fracture risk. We evaluated our method using 547 subjects from the UK Biobank dataset, and experimental results show that ICGM-FRAX achieved a sensitivity of 0.9869, demonstrating high accuracy in predicting hip fractures.

Yipu Zhang, Likai Wang, Kuan-Jui Su et al.

Resting-state functional magnetic resonance imaging (rs-fMRI) and its derived functional connectivity networks (FCNs) have become critical for understanding neurological disorders. However, collaborative analyses and the generalizability of models still face significant challenges due to privacy regulations and the non-IID (non-independent and identically distributed) property of multiple data sources. To mitigate these difficulties, we propose Domain Adversarial Federated Learning (DAFed), a novel federated deep learning framework specifically designed for non-IID fMRI data analysis in multi-site settings. DAFed addresses these challenges through feature disentanglement, decomposing the latent feature space into domain-invariant and domain-specific components, to ensure robust global learning while preserving local data specificity. Furthermore, adversarial training facilitates effective knowledge transfer between labeled and unlabeled datasets, while a contrastive learning module enhances the global representation of domain-invariant features. We evaluated DAFed on the diagnosis of ASD and further validated its generalizability in the classification of AD, demonstrating its superior classification accuracy compared to state-of-the-art methods. Additionally, an enhanced Score-CAM module identifies key brain regions and functional connectivity significantly associated with ASD and MCI, respectively, uncovering shared neurobiological patterns across sites. These findings highlight the potential of DAFed to advance multi-site collaborative research in neuroimaging while protecting data confidentiality.

Lei Huang, Chuan Qiu, Kuan-Jui Su et al.

Genotype imputation enables dense variant coverage for genome-wide association and risk-prediction studies, yet conventional reference-panel methods remain limited by ancestry bias and reduced rare-variant accuracy. We present Genotype Bidirectional Encoder Representations from Transformers (GenoBERT), a transformer-based, reference-free framework that tokenizes phased genotypes and uses a self-attention mechanism to capture both short- and long-range linkage disequilibrium (LD) dependencies. Benchmarking on two independent datasets including the Louisiana Osteoporosis Study (LOS) and the 1000 Genomes Project (1KGP) across ancestry groups and multiple genotype missingness levels (5-50%) shows that GenoBERT achieves the highest overall accuracy compared to four baseline methods (Beagle5.4, SCDA, BiU-Net, and STICI). At practical sparsity levels (up to 25% missing), GenoBERT attains high overall imputation accuracy ($r^2 approx 0.98$) across datasets, and maintains robust performance ($r^2 > 0.90$) even at 50% missingness. Experimental results across different ancestries confirm consistent gains across datasets, with resilience to small sample sizes and weak LD. A 128-SNP (single-nucleotide polymorphism) context window (approximately 100 Kb) is validated through LD-decay analyses as sufficient to capture local correlation structures. By eliminating reference-panel dependence while preserving high accuracy, GenoBERT provides a scalable and robust solution for genotype imputation and a foundation for downstream genomic modeling.

Shuo Sun, Meiling Zhou, Chen Zhao et al.

Clinical risk prediction models often fail to be generalized across cohorts because underlying data distributions differ by clinical site, region, demographics, and measurement protocols. This limitation is particularly pronounced in hip fracture risk prediction, where the performance of models trained on one cohort (the source cohort) can degrade substantially when deployed in other cohorts (target cohorts). We used a shared set of clinical and DXA-derived features across three large cohorts - the Study of Osteoporotic Fractures (SOF), the Osteoporotic Fractures in Men Study (MrOS), and the UK Biobank (UKB), to systematically evaluate the performance of three domain adaptation methods - Maximum Mean Discrepancy (MMD), Correlation Alignment (CORAL), and Domain - Adversarial Neural Networks (DANN) and their combinations. For a source cohort with males only and a source cohort with females only, domain-adaptation methods consistently showed improved performance than the no-adaptation baseline (source-only training), and the use of combinations of multiple domain adaptation methods delivered the largest and most stable gains. The method that combines MMD, CORAL, and DANN achieved the highest discrimination with the area under curve (AUC) of 0.88 for a source cohort with males only and 0.95 for a source cohort with females only), demonstrating that integrating multiple domain adaptation methods could produce feature representations that are less sensitive to dataset differences. Unlike existing methods that rely heavily on supervised tuning or assume known outcomes of samples in target cohorts, our outcome-free approaches enable the model selection under realistic deployment conditions and improve generalization of models in hip fracture risk prediction.

Shuo Sun, Meiling Zhou, Chen Zhao et al.

Hip fractures are a major cause of disability, mortality, and healthcare burden in older adults, underscoring the need for early risk assessment. However, commonly used tools such as the DXA T-score and FRAX often lack sensitivity and miss individuals at high risk, particularly those without prior fractures or with osteopenia. To address this limitation, we propose a sequential two-stage model that integrates clinical and imaging information to improve prediction accuracy. Using data from the Osteoporotic Fractures in Men Study (MrOS), the Study of Osteoporotic Fractures (SOF), and the UK Biobank, Stage 1 (Screening) employs clinical, demographic, and functional variables to estimate baseline risk, while Stage 2 (Imaging) incorporates DXA-derived features for refinement. The model was rigorously validated through internal and external testing, showing consistent performance and adaptability across cohorts. Compared to T-score and FRAX, the two-stage framework achieved higher sensitivity and reduced missed cases, offering a cost-effective and personalized approach for early hip fracture risk assessment. Keywords: Hip Fracture, Two-Stage Model, Risk Prediction, Sensitivity, DXA, FRAX