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Hongtu Zhu

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Published work

22 published item(s)

preprint2026arXiv

An Uncertainty-Aware Generalization Framework for Cardiovascular Image Segmentation

Deep learning models have achieved significant success in segmenting cardiovascular structures, but there is a growing need to improve their generalization and robustness. Current methods often face challenges such as overfitting and limited accuracy, largely due to their reliance on large annotated datasets and limited optimization techniques. This paper introduces the UU-Mamba model, an extension of the U-Mamba architecture, designed to address these challenges in both cardiac and vascular segmentation. By incorporating Sharpness-Aware Minimization (SAM), the model enhances generalization by seeking flatter minima in the loss landscape. Additionally, we propose an uncertainty-aware loss function that integrates region-based, distribution-based, and pixel-based components, improving segmentation accuracy by capturing both local and global features. We expand our evaluations on the ImageCAS (coronary artery) and Aorta (aortic branches and zones) datasets, which present more complex segmentation challenges than the ACDC dataset (left and right ventricles) used in prior work, showcasing the model's adaptability and resilience. Our results confirm UU-Mamba's superior performance compared to leading models such as TransUNet, Swin-Unet, nnUNet, and nnFormer. We also provide a more in-depth assessment of the model's robustness and segmentation accuracy through extensive experiments.

preprint2026arXiv

AutoResearchClaw: Self-Reinforcing Autonomous Research with Human-AI Collaboration

Automating scientific discovery requires more than generating papers from ideas. Real research is iterative: hypotheses are challenged from multiple perspectives, experiments fail and inform the next attempt, and lessons accumulate across cycles. Existing autonomous research systems often model this process as a linear pipeline: they rely on single-agent reasoning, stop when execution fails, and do not carry experience across runs. We present AutoResearchClaw, a multi-agent autonomous research pipeline built on five mechanisms: structured multi-agent debate for hypothesis generation and result analysis, a self-healing executor with a \textsc{Pivot}/\textsc{Refine} decision loop that transforms failures into information, verifiable result reporting that prevents fabricated numbers and hallucinated citations, human-in-the-loop collaboration with seven intervention modes spanning full autonomy to step-by-step oversight, and cross-run evolution that converts past mistakes into future safeguards. On ARC-Bench, a 25-topic experiment-stage benchmark, AutoResearchClaw outperforms AI Scientist v2 by 54.7%. A human-in-the-loop ablation across seven intervention modes reveals that precise, targeted collaboration at high-leverage decision points consistently outperforms both full autonomy and exhaustive step-by-step oversight. We position AutoResearchClaw as a research amplifier that augments rather than replaces human scientific judgment. Code is available at https://github.com/aiming-lab/AutoResearchClaw.

preprint2026arXiv

Robust Sequential Experimental Design for A/B Testing

Experimental design has emerged as a powerful approach for improving the sample efficiency of A/B testing, yet existing designs rely critically on correctly specified models. We study robust sequential experimental design under model misspecification and develop a unified framework that covers both contextual bandit and dynamic settings. Theoretically, we prove that our design bounds the worst-case mean squared error of the estimated treatment effect. Empirically, we demonstrate the effectiveness of the proposed approach using synthetic and real-world datasets from a leading technology company.

preprint2023arXiv

Source-Free Unsupervised Domain Adaptation: A Survey

Unsupervised domain adaptation (UDA) via deep learning has attracted appealing attention for tackling domain-shift problems caused by distribution discrepancy across different domains. Existing UDA approaches highly depend on the accessibility of source domain data, which is usually limited in practical scenarios due to privacy protection, data storage and transmission cost, and computation burden. To tackle this issue, many source-free unsupervised domain adaptation (SFUDA) methods have been proposed recently, which perform knowledge transfer from a pre-trained source model to unlabeled target domain with source data inaccessible. A comprehensive review of these works on SFUDA is of great significance. In this paper, we provide a timely and systematic literature review of existing SFUDA approaches from a technical perspective. Specifically, we categorize current SFUDA studies into two groups, i.e., white-box SFUDA and black-box SFUDA, and further divide them into finer subcategories based on different learning strategies they use. We also investigate the challenges of methods in each subcategory, discuss the advantages/disadvantages of white-box and black-box SFUDA methods, conclude the commonly used benchmark datasets, and summarize the popular techniques for improved generalizability of models learned without using source data. We finally discuss several promising future directions in this field.

preprint2022arXiv

Estimating trans-ancestry genetic correlation with unbalanced data resources

The aim of this paper is to propose a novel estimation method of using genetic-predicted observations to estimate trans-ancestry genetic correlations, which describes how genetic architecture of complex traits varies among populations, in genome-wide association studies (GWAS). Our new estimator corrects for prediction errors caused by high-dimensional weak GWAS signals, while addressing the heterogeneity of GWAS data across ethnicities, such as linkage disequilibrium (LD) differences, which can lead to biased findings in homogeneity-agnostic analyses. Moreover, our estimator only requires one population to have a large GWAS sample size, and the second population can only have a much smaller number of participants (for example, hundreds). It is designed to specifically address the unbalanced data resources such that the GWAS sample size for European populations is usually larger than that of non-European ancestry groups. Extensive simulations and real data analyses of 30 complex traits in the UK Biobank study show that our method is capable of providing reliable estimates of a wide range of complex traits. Our results provide deep insights into the transferability of population-specific genetic findings.

preprint2022arXiv

Mapping the Genetic-Imaging-Clinical Pathway with Applications to Alzheimer's Disease

Alzheimer's disease is a progressive form of dementia that results in problems with memory, thinking, and behavior. It often starts with abnormal aggregation and deposition of beta amyloid and tau, followed by neuronal damage such as atrophy of the hippocampi, leading to Alzheimer's Disease (AD). The aim of this paper is to map the genetic-imaging-clinical pathway for AD in order to delineate the genetically regulated brain changes that drive disease progression based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We develop a novel two-step approach to delineate the association between high-dimensional 2D hippocampal surface exposures and the Alzheimer's Disease Assessment Scale (ADAS) cognitive score, while taking into account the ultra-high dimensional clinical and genetic covariates at baseline. Analysis results suggest that the radial distance of each pixel of both hippocampi is negatively associated with the severity of behavioral deficits conditional on observed clinical and genetic covariates. These associations are stronger in Cornu Ammonis region 1 (CA1) and subiculum subregions compared to Cornu Ammonis region 2 (CA2) and Cornu Ammonis region 3 (CA3) subregions.

preprint2022arXiv

On block-wise and reference panel-based estimators for genetic data prediction in high dimensions

Genetic prediction of complex traits and diseases has attracted enormous attention in precision medicine, mainly because it has the potential to translate discoveries from genome-wide association studies (GWAS) into medical advances. As the high dimensional covariance matrix (or the linkage disequilibrium (LD) pattern) of genetic variants has a block-diagonal structure, many existing methods attempt to account for the dependence among variants in predetermined local LD blocks/regions. Moreover, due to privacy restrictions and data protection concerns, genetic variant dependence in each LD block is typically estimated from external reference panels rather than the original training dataset. This paper presents a unified analysis of block-wise and reference panel-based estimators in a high-dimensional prediction framework without sparsity restrictions. We find that, surprisingly, even when the covariance matrix has a block-diagonal structure with well-defined boundaries, block-wise estimation methods adjusting for local dependence can be substantially less accurate than methods controlling for the whole covariance matrix. Further, estimation methods built on the original training dataset and external reference panels are likely to have varying performance in high dimensions, which may reflect the cost of having only access to summary level data from the training dataset. This analysis is based on our novel results in random matrix theory for block-diagonal covariance matrix. We numerically evaluate our results using extensive simulations and the large-scale UK Biobank real data analysis of 36 complex traits.

preprint2022arXiv

Statistically Efficient Advantage Learning for Offline Reinforcement Learning in Infinite Horizons

We consider reinforcement learning (RL) methods in offline domains without additional online data collection, such as mobile health applications. Most of existing policy optimization algorithms in the computer science literature are developed in online settings where data are easy to collect or simulate. Their generalizations to mobile health applications with a pre-collected offline dataset remain unknown. The aim of this paper is to develop a novel advantage learning framework in order to efficiently use pre-collected data for policy optimization. The proposed method takes an optimal Q-estimator computed by any existing state-of-the-art RL algorithms as input, and outputs a new policy whose value is guaranteed to converge at a faster rate than the policy derived based on the initial Q-estimator. Extensive numerical experiments are conducted to back up our theoretical findings. A Python implementation of our proposed method is available at https://github.com/leyuanheart/SEAL.

preprint2020arXiv

Optimal Passenger-Seeking Policies on E-hailing Platforms Using Markov Decision Process and Imitation Learning

Vacant taxi drivers' passenger seeking process in a road network generates additional vehicle miles traveled, adding congestion and pollution into the road network and the environment. This paper aims to employ a Markov Decision Process (MDP) to model idle e-hailing drivers' optimal sequential decisions in passenger-seeking. Transportation network companies (TNC) or e-hailing (e.g., Didi, Uber) drivers exhibit different behaviors from traditional taxi drivers because e-hailing drivers do not need to actually search for passengers. Instead, they reposition themselves so that the matching platform can match a passenger. Accordingly, we incorporate e-hailing drivers' new features into our MDP model. The reward function used in the MDP model is uncovered by leveraging an inverse reinforcement learning technique. We then use 44,160 Didi drivers' 3-day trajectories to train the model. To validate the effectiveness of the model, a Monte Carlo simulation is conducted to simulate the performance of drivers under the guidance of the optimal policy, which is then compared with the performance of drivers following one baseline heuristic, namely, the local hotspot strategy. The results show that our model is able to achieve a 17.5% improvement over the local hotspot strategy in terms of the rate of return. The proposed MDP model captures the supply-demand ratio considering the fact that the number of drivers in this study is sufficiently large and thus the number of unmatched orders is assumed to be negligible. To better incorporate the competition among multiple drivers into the model, we have also devised and calibrated a dynamic adjustment strategy of the order matching probability.

preprint2019arXiv

ACE of Space: Estimating Genetic Components of High-Dimensional Imaging Data

It is of great interest to quantify the contributions of genetic variation to brain structure and function, which are usually measured by high-dimensional imaging data (e.g., magnetic resonance imaging). In addition to the variance, the covariance patterns in the genetic effects of a functional phenotype are of biological importance, and covariance patterns have been linked to psychiatric disorders. The aim of this paper is to develop a scalable method to estimate heritability and the non-stationary covariance components in high-dimensional imaging data from twin studies. Our motivating example is from the Human Connectome Project (HCP). Several major big-data challenges arise from estimating the genetic and environmental covariance functions of functional phenotypes extracted from imaging data, such as cortical thickness with 60,000 vertices. Notably, truncating to positive eigenvalues and their eigenfunctions from unconstrained estimators can result in large bias. This motivated our development of a novel estimator ensuring positive semidefiniteness. Simulation studies demonstrate large improvements over existing approaches, both with respect to heritability estimates and covariance estimation. We applied the proposed method to cortical thickness data from the HCP. Our analysis suggests fine-scale differences in covariance patterns, identifying locations in which genetic control is correlated with large areas of the brain and locations where it is highly localized.

preprint2016arXiv

Bayesian spatial transformation models with applications in neuroimaging data

The aim of this paper is to develop a class of spatial transformation models (STM) to spatially model the varying association between imaging measures in a three-dimensional (3D) volume (or 2D surface) and a set of covariates. Our STMs include a varying Box-Cox transformation model for dealing with the issue of non-Gaussian distributed imaging data and a Gaussian Markov Random Field model for incorporating spatial smoothness of the imaging data. Posterior computation proceeds via an efficient Markov chain Monte Carlo algorithm. Simulations and real data analysis demonstrate that the STM significantly outperforms the voxel-wise linear model with Gaussian noise in recovering meaningful geometric patterns. Our STM is able to reveal important brain regions with morphological changes in children with attention deficit hyperactivity disorder.

preprint2016arXiv

Local Region Sparse Learning for Image-on-Scalar Regression

Identification of regions of interest (ROI) associated with certain disease has a great impact on public health. Imposing sparsity of pixel values and extracting active regions simultaneously greatly complicate the image analysis. We address these challenges by introducing a novel region-selection penalty in the framework of image-on-scalar regression. Our penalty combines the Smoothly Clipped Absolute Deviation (SCAD) regularization, enforcing sparsity, and the SCAD of total variation (TV) regularization, enforcing spatial contiguity, into one group, which segments contiguous spatial regions against zero-valued background. Efficient algorithm is based on the alternative direction method of multipliers (ADMM) which decomposes the non-convex problem into two iterative optimization problems with explicit solutions. Another virtue of the proposed method is that a divide and conquer learning algorithm is developed, thereby allowing scaling to large images. Several examples are presented and the experimental results are compared with other state-of-the-art approaches.

preprint2015arXiv

Extrinsic local regression on manifold-valued data

We propose an extrinsic regression framework for modeling data with manifold valued responses and Euclidean predictors. Regression with manifold responses has wide applications in shape analysis, neuroscience, medical imaging and many other areas. Our approach embeds the manifold where the responses lie onto a higher dimensional Euclidean space, obtains a local regression estimate in that space, and then projects this estimate back onto the image of the manifold. Outside the regression setting both intrinsic and extrinsic approaches have been proposed for modeling i.i.d manifold-valued data. However, to our knowledge our work is the first to take an extrinsic approach to the regression problem. The proposed extrinsic regression framework is general, computationally efficient and theoretically appealing. Asymptotic distributions and convergence rates of the extrinsic regression estimates are derived and a large class of examples are considered indicating the wide applicability of our approach.

preprint2013arXiv

Multiscale adaptive smoothing models for the hemodynamic response function in fMRI

In the event-related functional magnetic resonance imaging (fMRI) data analysis, there is an extensive interest in accurately and robustly estimating the hemodynamic response function (HRF) and its associated statistics (e.g., the magnitude and duration of the activation). Most methods to date are developed in the time domain and they have utilized almost exclusively the temporal information of fMRI data without accounting for the spatial information. The aim of this paper is to develop a multiscale adaptive smoothing model (MASM) in the frequency domain by integrating the spatial and frequency information to adaptively and accurately estimate HRFs pertaining to each stimulus sequence across all voxels in a three-dimensional (3D) volume. We use two sets of simulation studies and a real data set to examine the finite sample performance of MASM in estimating HRFs. Our real and simulated data analyses confirm that MASM outperforms several other state-of-the-art methods, such as the smooth finite impulse response (sFIR) model.

preprint2013arXiv

Multivariate varying coefficient model for functional responses

Motivated by recent work studying massive imaging data in the neuroimaging literature, we propose multivariate varying coefficient models (MVCM) for modeling the relation between multiple functional responses and a set of covariates. We develop several statistical inference procedures for MVCM and systematically study their theoretical properties. We first establish the weak convergence of the local linear estimate of coefficient functions, as well as its asymptotic bias and variance, and then we derive asymptotic bias and mean integrated squared error of smoothed individual functions and their uniform convergence rate. We establish the uniform convergence rate of the estimated covariance function of the individual functions and its associated eigenvalue and eigenfunctions. We propose a global test for linear hypotheses of varying coefficient functions, and derive its asymptotic distribution under the null hypothesis. We also propose a simultaneous confidence band for each individual effect curve. We conduct Monte Carlo simulation to examine the finite-sample performance of the proposed procedures. We apply MVCM to investigate the development of white matter diffusivities along the genu tract of the corpus callosum in a clinical study of neurodevelopment.

preprint2013arXiv

Spatially Varying Coefficient Model for Neuroimaging Data with Jump Discontinuities

Motivated by recent work on studying massive imaging data in various neuroimaging studies, we propose a novel spatially varying coefficient model (SVCM) to spatially model the varying association between imaging measures in a three-dimensional (3D) volume (or 2D surface) with a set of covariates. Two key features of most neuorimaging data are the presence of multiple piecewise smooth regions with unknown edges and jumps and substantial spatial correlations. To specifically account for these two features, SVCM includes a measurement model with multiple varying coefficient functions, a jumping surface model for each varying coefficient function, and a functional principal component model. We develop a three-stage estimation procedure to simultaneously estimate the varying coefficient functions and the spatial correlations. The estimation procedure includes a fast multiscale adaptive estimation and testing procedure to independently estimate each varying coefficient function, while preserving its edges among different piecewise-smooth regions. We systematically investigate the asymptotic properties (e.g., consistency and asymptotic normality) of the multiscale adaptive parameter estimates. We also establish the uniform convergence rate of the estimated spatial covariance function and its associated eigenvalue and eigenfunctions. Our Monte Carlo simulation and real data analysis have confirmed the excellent performance of SVCM.

preprint2013arXiv

Surprising Asymptotic Conical Structure in Critical Sample Eigen-Directions

The aim of this paper is to establish several deep theoretical properties of principal component analysis for multiple-component spike covariance models. Our new results reveal a surprising asymptotic conical structure in critical sample eigendirections under the spike models with distinguishable (or indistinguishable) eigenvalues, when the sample size and/or the number of variables (or dimension) tend to infinity. The consistency of the sample eigenvectors relative to their population counterparts is determined by the ratio between the dimension and the product of the sample size with the spike size. When this ratio converges to a nonzero constant, the sample eigenvector converges to a cone, with a certain angle to its corresponding population eigenvector.In the High Dimension, Low Sample Size case, the angle between the sample eigenvector and its population counterpart converges to a limiting distribution.Several generalizations of the multi-spike covariance models are also explored, and additional theoretical results are presented.

preprint2013arXiv

Varying coefficient model for modeling diffusion tensors along white matter tracts

Diffusion tensor imaging provides important information on tissue structure and orientation of fiber tracts in brain white matter in vivo. It results in diffusion tensors, which are $3\times3$ symmetric positive definite (SPD) matrices, along fiber bundles. This paper develops a functional data analysis framework to model diffusion tensors along fiber tracts as functional data in a Riemannian manifold with a set of covariates of interest, such as age and gender. We propose a statistical model with varying coefficient functions to characterize the dynamic association between functional SPD matrix-valued responses and covariates. We calculate weighted least squares estimators of the varying coefficient functions for the log-Euclidean metric in the space of SPD matrices. We also develop a global test statistic to test specific hypotheses about these coefficient functions and construct their simultaneous confidence bands. Simulated data are further used to examine the finite sample performance of the estimated varying coefficient functions. We apply our model to study potential gender differences and find a statistically significant aspect of the development of diffusion tensors along the right internal capsule tract in a clinical study of neurodevelopment.

preprint2012arXiv

High Dimensional Principal Component Scores and Data Visualization

Principal component analysis is a useful dimension reduction and data visualization method. However, in high dimension, low sample size asymptotic contexts, where the sample size is fixed and the dimension goes to infinity,a paradox has arisen. In particular, despite the useful real data insights commonly obtained from principal component score visualization, these scores are not consistent even when the sample eigen-vectors are consistent. This paradox is resolved by asymptotic study of the ratio between the sample and population principal component scores. In particular, it is seen that this proportion converges to a non-degenerate random variable. The realization is the same for each data point, i.e. there is a common random rescaling, which appears for each eigen-direction. This then gives inconsistent axis labels for the standard scores plot, yet the relative positions of the points (typically the main visual content) are consistent. This paradox disappears when the sample size goes to infinity.

preprint2012arXiv

Perturbation and scaled Cook's distance

Cook's distance [Technometrics 19 (1977) 15-18] is one of the most important diagnostic tools for detecting influential individual or subsets of observations in linear regression for cross-sectional data. However, for many complex data structures (e.g., longitudinal data), no rigorous approach has been developed to address a fundamental issue: deleting subsets with different numbers of observations introduces different degrees of perturbation to the current model fitted to the data, and the magnitude of Cook's distance is associated with the degree of the perturbation. The aim of this paper is to address this issue in general parametric models with complex data structures. We propose a new quantity for measuring the degree of the perturbation introduced by deleting a subset. We use stochastic ordering to quantify the stochastic relationship between the degree of the perturbation and the magnitude of Cook's distance. We develop several scaled Cook's distances to resolve the comparison of Cook's distance for different subset deletions. Theoretical and numerical examples are examined to highlight the broad spectrum of applications of these scaled Cook's distances in a formal influence analysis.

preprint2012arXiv

Tensor Regression with Applications in Neuroimaging Data Analysis

Classical regression methods treat covariates as a vector and estimate a corresponding vector of regression coefficients. Modern applications in medical imaging generate covariates of more complex form such as multidimensional arrays (tensors). Traditional statistical and computational methods are proving insufficient for analysis of these high-throughput data due to their ultrahigh dimensionality as well as complex structure. In this article, we propose a new family of tensor regression models that efficiently exploit the special structure of tensor covariates. Under this framework, ultrahigh dimensionality is reduced to a manageable level, resulting in efficient estimation and prediction. A fast and highly scalable estimation algorithm is proposed for maximum likelihood estimation and its associated asymptotic properties are studied. Effectiveness of the new methods is demonstrated on both synthetic and real MRI imaging data.

preprint2011arXiv

Two-stage empirical likelihood for longitudinal neuroimaging data

Longitudinal imaging studies are essential to understanding the neural development of neuropsychiatric disorders, substance use disorders, and the normal brain. The main objective of this paper is to develop a two-stage adjusted exponentially tilted empirical likelihood (TETEL) for the spatial analysis of neuroimaging data from longitudinal studies. The TETEL method as a frequentist approach allows us to efficiently analyze longitudinal data without modeling temporal correlation and to classify different time-dependent covariate types. To account for spatial dependence, the TETEL method developed here specifically combines all the data in the closest neighborhood of each voxel (or pixel) on a 3-dimensional (3D) volume (or 2D surface) with appropriate weights to calculate adaptive parameter estimates and adaptive test statistics. Simulation studies are used to examine the finite sample performance of the adjusted exponential tilted likelihood ratio statistic and TETEL. We demonstrate the application of our statistical methods to the detection of the difference in the morphological changes of the hippocampus across time between schizophrenia patients and healthy subjects in a longitudinal schizophrenia study.