Hsin-Hsiung Huang

Bulent Soykan, Gulsah Hancerliogullari Koksalmis, Hsin-Hsiung Huang et al.

Predicting individual cognitive decline in Alzheimer's disease (AD) is difficult due to the heterogeneity of disease progression. Reliable clinical tools require not only high accuracy but also fairness across demographics and robustness to missing data. We present CognitiveTwin, a digital twin framework that predicts patient-specific cognitive trajectories. The model integrates multi-modal longitudinal data (cognitive scores, magnetic resonance imaging, positron emission tomography, cerebrospinal fluid biomarkers, and genetics). We use a Transformer-based architecture to fuse these modalities and a Deep Markov Model to capture temporal dynamics. We trained and evaluated the framework using data from 1,666 patients in the TADPOLE (Alzheimer's Disease Neuroimaging Initiative) dataset. We assessed the model for prediction error, demographic fairness, and robustness to missing-not-at-random (MNAR) data patterns. ognitiveTwin provides accurate and personalized predictions of cognitive decline. Its demonstrated fairness across patient demographics and resilience to clinical dropout make it a reliable tool for clinical trial enrichment and personalized care planning.

Hsin-Hsiung Huang, Feng Yu, Xing Fan et al.

While matrix variate regression models have been studied in many existing works, classical statistical and computational methods for the analysis of the regression coefficient estimation are highly affected by high dimensional and noisy matrix-valued predictors. To address these issues, this paper proposes a framework of matrix variate regression models based on a rank constraint, vector regularization (e.g., sparsity), and a general loss function with three special cases considered: ordinary matrix regression, robust matrix regression, and matrix logistic regression. We also propose an alternating projected gradient descent algorithm. Based on analyzing our objective functions on manifolds with bounded curvature, we show that the algorithm is guaranteed to converge, all accumulation points of the iterates have estimation errors in the order of $O(1/\sqrt{n})$ asymptotically and substantially attaining the minimax rate. Our theoretical analysis can be applied to general optimization problems on manifolds with bounded curvature and can be considered an important technical contribution to this work. We validate the proposed method through simulation studies and real image data examples.

Hsin-Hsiung Huang, Bulent Soykan

Digital twins for radiation-based imaging and therapy are most useful when they assimilate patient data, quantify predictive uncertainty, and support clinically constrained decisions. This paper presents a modular framework for actionable digital twins in radiation-based imaging and therapy and instantiates its reproducible open-data component using the \openkbpfull{} benchmark. The framework couples PatientData, Model, Solver, Calibration, and Decision modules and formalizes latent-state updating, uncertainty propagation, and chance-constrained action selection. As an initial implementation, we build a GPU-ready PyTorch/MONAI reimplementation of the \openkbp{} starter pipeline: an 11-channel, 19.2M-parameter 3D U-Net trained with a masked loss over the feasible region and equipped with Monte Carlo dropout for voxel-wise epistemic uncertainty. To emulate the update loop on a static benchmark, we introduce decoder-only proxy recalibration and illustrate uncertainty-aware virtual-therapy evaluation using DVH-based and biological utilities. A complete three-fraction loop including recalibration, Monte Carlo inference, and spatial optimization executes in 10.3~s. On the 100-patient test set, the model achieved mean dose and DVH scores of 2.65 and 1.82~Gy, respectively, with 0.58~s mean inference time per patient. The \openkbp{} case study thus serves as a reproducible test bed for dose prediction, uncertainty propagation, and proxy closed-loop adaptation, while future institutional studies will address longitudinal calibration with delivered-dose logs and repeat imaging.

Brad Ye, Bulent Soykan, Gulsah Hancerliogullari Koksalmis et al.

Accurate prediction of conversion from Mild Cognitive Impairment (MCI) to Alzheimers Diseases (AD) is essential for early intervention, however, developing reliable conversion predictive models is difficult to develop due to limited longitudinal data availability We evaluate TabPFN (Tabular Pre-Trained Foundation Network) against traditional machine learning methods for predicting 3 year MCI to AD conversion using the TADPOLE dataset derived from ADNI. Using multimodal biomarker features extracted from demographics, APOE4, MRI volumes, CSF markers, and PET imaging, we conducted an experimental comparison across varying training set sizes (N=50 to 1000) and models including XGBoost, Random Forest, LightGBM, and Logistic Regression. TabPFN achieved one the highest performance (AUC=0.892), outperforming LightGBM (AUC=0.860) and demonstrating advantages in low data settings. At N=50 training samples, TabPFN maintained strong AUC while the traditional machine learning models struggles at small training samples. These findings demonstrate that foundation models are promising for disease prediction in data limited scenarios, such as Alzheimers diseases.

Bulent Soykan, Gulsah Hancerliogullari Koksalmis, Hsin-Hsiung Huang et al.

Cognitive decline is highly heterogeneous across individuals, which complicates prognosis, trial design, and treatment planning. We present the Personalized Cognitive Decline Assessment Digital Twin (PCD-DT), a multimodal and uncertainty-aware framework for modeling patient-specific disease trajectories from sparse, noisy, and irregular longitudinal data. The framework combines three methodological components: (1) latent state-space models for individualized temporal dynamics, (2) multimodal fusion for clinical, biomarker, and imaging features, and (3) uncertainty-aware validation and adaptive updating for robust digital twin operation. We also outline how conditional generative models can support data augmentation and stress testing for underrepresented progression patterns. As a preliminary feasibility study, we analyze longitudinal TADPOLE trajectories and show clear separation between cognitively normal and Alzheimer's disease cohorts in ADAS13, ventricle volume, and hippocampal volume over five years. We further conduct a multimodal next-visit prediction ablation using an LSTM sequence model on 3{,}003 visit-pair sequences derived from TADPOLE, where the combined cognitive plus MRI configuration achieves the lowest standardized RMSE for both ADAS13 (0.4419) and ventricle volume (0.5842), outperforming a Last Observation Carried Forward baseline. A Bayesian tensor modeling component for high-dimensional imaging fusion is also discussed. These results support the feasibility of the proposed architecture while also highlighting the need for stronger uncertainty calibration and longer-horizon predictive evaluation. The PCD-DT framework provides a principled starting point for personalized in silico modeling in neurodegenerative disease. This work positions PCD-DT as a foundational step toward clinically deployable, uncertainty-aware digital twin systems.

Hsin-Hsiung Huang, Hayden Hampton

Forecasting geopolitical conflict from data sources like the Global Database of Events, Language, and Tone (GDELT) is a critical challenge for national security. The inherent sparsity, burstiness, and overdispersion of such data cause standard deep learning models, including the Temporal Fusion Transformer (TFT), to produce unreliable long-horizon predictions. We introduce STFT-VNNGP, a hybrid architecture that won the 2023 Algorithms for Threat Detection (ATD) competition by overcoming these limitations. Designed to bridge this gap, our model employs a two-stage process: first, a TFT captures complex temporal dynamics to generate multi-quantile forecasts. These quantiles then serve as informed inputs for a Variational Nearest Neighbor Gaussian Process (VNNGP), which performs principled spatiotemporal smoothing and uncertainty quantification. In a case study forecasting conflict dynamics in the Middle East and the U.S., STFT-VNNGP consistently outperforms a standalone TFT, showing a superior ability to predict the timing and magnitude of bursty event periods, particularly at long-range horizons. This work offers a robust framework for generating more reliable and actionable intelligence from challenging event data, with all code and workflows made publicly available to ensure reproducibility.

Gulsah Hancerliogullari Koksalmis, Bulent Soykan, Laura J. Brattain et al.

Alzheimer's Disease (AD) is marked by significant inter-individual variability in its progression, complicating accurate prognosis and personalized care planning. This heterogeneity underscores the critical need for predictive models capable of forecasting patient-specific disease trajectories. Artificial Intelligence (AI) offers powerful tools to address this challenge by analyzing complex, multi-modal, and longitudinal patient data. This paper provides a comprehensive survey of AI methodologies applied to personalized AD progression prediction. We review key approaches including state-space models for capturing temporal dynamics, deep learning techniques like Recurrent Neural Networks for sequence modeling, Graph Neural Networks (GNNs) for leveraging network structures, and the emerging concept of AI-driven digital twins for individualized simulation. Recognizing that data limitations often impede progress, we examine common challenges such as high dimensionality, missing data, and dataset imbalance. We further discuss AI-driven mitigation strategies, with a specific focus on synthetic data generation using Variational Autoencoders (VAEs) and Generative Adversarial Networks (GANs) to augment and balance datasets. The survey synthesizes the strengths and limitations of current approaches, emphasizing the trend towards multimodal integration and the persistent need for model interpretability and generalizability. Finally, we identify critical open challenges, including robust external validation, clinical integration, and ethical considerations, and outline promising future research directions such as hybrid models, causal inference, and federated learning. This review aims to consolidate current knowledge and guide future efforts in developing clinically relevant AI tools for personalized AD prognostication.

Chih-Wei Chen, Charles Harrison, Hsin-Hsiung Huang

In real-world application scenarios, it is crucial for marine navigators and security analysts to predict vessel movement trajectories at sea based on the Automated Identification System (AIS) data in a given time span. This article presents an unsupervised method of ship movement trajectory prediction which represents the data in a three-dimensional space which consists of time difference between points, the scaled error distance between the tested and its predicted forward and backward locations, and the space-time angle. The representation feature space reduces the search scope for the next point to a collection of candidates which fit the local path prediction well, and therefore improve the accuracy. Unlike most statistical learning or deep learning methods, the proposed clustering-based trajectory reconstruction method does not require computationally expensive model training. This makes real-time reliable and accurate prediction feasible without using a training set. Our results show that the most prediction trajectories accurately consist of the true vessel paths.