Rongguang Wang

Rongguang Wang, Pratik Chaudhari, Christos Davatzikos

Despite the great promise that machine learning has offered in many fields of medicine, it has also raised concerns about potential biases and poor generalization across genders, age distributions, races and ethnicities, hospitals, and data acquisition equipment and protocols. In the current study, and in the context of three brain diseases, we provide evidence which suggests that when properly trained, machine learning models can generalize well across diverse conditions and do not necessarily suffer from bias. Specifically, by using multi-study magnetic resonance imaging consortia for diagnosing Alzheimer's disease, schizophrenia, and autism spectrum disorder, we find that well-trained models have a high area-under-the-curve (AUC) on subjects across different subgroups pertaining to attributes such as gender, age, racial groups, and different clinical studies and are unbiased under multiple fairness metrics such as demographic parity difference, equalized odds difference, equal opportunity difference etc. We find that models that incorporate multi-source data from demographic, clinical, genetic factors and cognitive scores are also unbiased. These models have better predictive AUC across subgroups than those trained only with imaging features but there are also situations when these additional features do not help.

Rongguang Wang, Vishnu Bashyam, Zhijian Yang et al.

Generative adversarial networks (GANs) are one powerful type of deep learning models that have been successfully utilized in numerous fields. They belong to a broader family called generative methods, which generate new data with a probabilistic model by learning sample distribution from real examples. In the clinical context, GANs have shown enhanced capabilities in capturing spatially complex, nonlinear, and potentially subtle disease effects compared to traditional generative methods. This review appraises the existing literature on the applications of GANs in imaging studies of various neurological conditions, including Alzheimer's disease, brain tumors, brain aging, and multiple sclerosis. We provide an intuitive explanation of various GAN methods for each application and further discuss the main challenges, open questions, and promising future directions of leveraging GANs in neuroimaging. We aim to bridge the gap between advanced deep learning methods and neurology research by highlighting how GANs can be leveraged to support clinical decision making and contribute to a better understanding of the structural and functional patterns of brain diseases.

Rongguang Wang, Guray Erus, Pratik Chaudhari et al.

Machine learning (ML) has shown great promise for revolutionizing a number of areas, including healthcare. However, it is also facing a reproducibility crisis, especially in medicine. ML models that are carefully constructed from and evaluated on a training set might not generalize well on data from different patient populations or acquisition instrument settings and protocols. We tackle this problem in the context of neuroimaging of Alzheimer's disease (AD), schizophrenia (SZ) and brain aging. We develop a weighted empirical risk minimization approach that optimally combines data from a source group, e.g., subjects are stratified by attributes such as sex, age group, race and clinical cohort to make predictions on a target group, e.g., other sex, age group, etc. using a small fraction (10%) of data from the target group. We apply this method to multi-source data of 15,363 individuals from 20 neuroimaging studies to build ML models for diagnosis of AD and SZ, and estimation of brain age. We found that this approach achieves substantially better accuracy than existing domain adaptation techniques: it obtains area under curve greater than 0.95 for AD classification, area under curve greater than 0.7 for SZ classification and mean absolute error less than 5 years for brain age prediction on all target groups, achieving robustness to variations of scanners, protocols, and demographic or clinical characteristics. In some cases, it is even better than training on all data from the target group, because it leverages the diversity and size of a larger training set. We also demonstrate the utility of our models for prognostic tasks such as predicting disease progression in individuals with mild cognitive impairment. Critically, our brain age prediction models lead to new clinical insights regarding correlations with neurophysiological tests.

Hang Zhang, Rongguang Wang, Renjiu Hu et al.

Chronic active multiple sclerosis lesions, also termed as rim+ lesions, can be characterized by a hyperintense rim at the edge of the lesion on quantitative susceptibility maps. These rim+ lesions exhibit a geometrically simple structure, where gradients at the lesion edge are radially oriented and a greater magnitude of gradients is observed in contrast to rim- (non rim+) lesions. However, recent studies have shown that the identification performance of such lesions remains unsatisfied due to the limited amount of data and high class imbalance. In this paper, we propose a simple yet effective image processing operation, deep directed accumulator (DeDA), that provides a new perspective for injecting domain-specific inductive biases (priors) into neural networks for rim+ lesion identification. Given a feature map and a set of sampling grids, DeDA creates and quantizes an accumulator space into finite intervals, and accumulates feature values accordingly. This DeDA operation is a generalized discrete Radon transform and can also be regarded as a symmetric operation to the grid sampling within the forward-backward neural network framework, the process of which is order-agnostic, and can be efficiently implemented with the native CUDA programming. Experimental results on a dataset with 177 rim+ and 3986 rim- lesions show that 10.1% of improvement in a partial (false positive rate<0.1) area under the receiver operating characteristic curve (pROC AUC) and 10.2% of improvement in an area under the precision recall curve (PR AUC) can be achieved respectively comparing to other state-of-the-art methods. The source code is available online at https://github.com/tinymilky/DeDA

Hang Zhang, Renjiu Hu, Xiang Chen et al.

Recent research highlights that the Directed Accumulator (DA), through its parametrization of geometric priors into neural networks, has notably improved the performance of medical image recognition, particularly with small and imbalanced datasets. However, DA's potential in pixel-wise dense predictions is unexplored. To bridge this gap, we present the Directed Accumulator Grid (DAGrid), which allows geometric-preserving filtering in neural networks, thus broadening the scope of DA's applications to include pixel-level dense prediction tasks. DAGrid utilizes homogeneous data types in conjunction with designed sampling grids to construct geometrically transformed representations, retaining intricate geometric information and promoting long-range information propagation within the neural networks. Contrary to its symmetric counterpart, grid sampling, which might lose information in the sampling process, DAGrid aggregates all pixels, ensuring a comprehensive representation in the transformed space. The parallelization of DAGrid on modern GPUs is facilitated using CUDA programming, and also back propagation is enabled for deep neural network training. Empirical results show DAGrid-enhanced neural networks excel in supervised skin lesion segmentation and unsupervised cardiac image registration. Specifically, the network incorporating DAGrid has realized a 70.8% reduction in network parameter size and a 96.8% decrease in FLOPs, while concurrently improving the Dice score for skin lesion segmentation by 1.0% compared to state-of-the-art transformers. Furthermore, it has achieved improvements of 4.4% and 8.2% in the average Dice score and Dice score of the left ventricular mass, respectively, indicating an increase in registration accuracy for cardiac images. The source code is available at https://github.com/tinymilky/DeDA.

Hang Zhang, Xiang Chen, Renjiu Hu et al.

Many existing learning-based deformable image registration methods impose constraints on deformation fields to ensure they are globally smooth and continuous. However, this assumption does not hold in cardiac image registration, where different anatomical regions exhibit asymmetric motions during respiration and movements due to sliding organs within the chest. Consequently, such global constraints fail to accommodate local discontinuities across organ boundaries, potentially resulting in erroneous and unrealistic displacement fields. In this paper, we address this issue with MemWarp, a learning framework that leverages a memory network to store prototypical information tailored to different anatomical regions. MemWarp is different from earlier approaches in two main aspects: firstly, by decoupling feature extraction from similarity matching in moving and fixed images, it facilitates more effective utilization of feature maps; secondly, despite its capability to preserve discontinuities, it eliminates the need for segmentation masks during model inference. In experiments on a publicly available cardiac dataset, our method achieves considerable improvements in registration accuracy and producing realistic deformations, outperforming state-of-the-art methods with a remarkable 7.1\% Dice score improvement over the runner-up semi-supervised method. Source code will be available at https://github.com/tinymilky/Mem-Warp.

Xiang Chen, Min Liu, Rongguang Wang et al.

Medical images are often characterized by their structured anatomical representations and spatially inhomogeneous contrasts. Leveraging anatomical priors in neural networks can greatly enhance their utility in resource-constrained clinical settings. Prior research has harnessed such information for image segmentation, yet progress in deformable image registration has been modest. Our work introduces textSCF, a novel method that integrates spatially covariant filters and textual anatomical prompts encoded by visual-language models, to fill this gap. This approach optimizes an implicit function that correlates text embeddings of anatomical regions to filter weights, relaxing the typical translation-invariance constraint of convolutional operations. TextSCF not only boosts computational efficiency but can also retain or improve registration accuracy. By capturing the contextual interplay between anatomical regions, it offers impressive inter-regional transferability and the ability to preserve structural discontinuities during registration. TextSCF's performance has been rigorously tested on inter-subject brain MRI and abdominal CT registration tasks, outperforming existing state-of-the-art models in the MICCAI Learn2Reg 2021 challenge and leading the leaderboard. In abdominal registrations, textSCF's larger model variant improved the Dice score by 11.3% over the second-best model, while its smaller variant maintained similar accuracy but with an 89.13% reduction in network parameters and a 98.34\% decrease in computational operations.

Hang Zhang, Rongguang Wang, Jinwei Zhang et al.

Compared to natural images, medical images usually show stronger visual patterns and therefore this adds flexibility and elasticity to resource-limited clinical applications by injecting proper priors into neural networks. In this paper, we propose spatially covariant pixel-aligned classifier (SCP) to improve the computational efficiency and meantime maintain or increase accuracy for lesion segmentation. SCP relaxes the spatial invariance constraint imposed by convolutional operations and optimizes an underlying implicit function that maps image coordinates to network weights, the parameters of which are obtained along with the backbone network training and later used for generating network weights to capture spatially covariant contextual information. We demonstrate the effectiveness and efficiency of the proposed SCP using two lesion segmentation tasks from different imaging modalities: white matter hyperintensity segmentation in magnetic resonance imaging and liver tumor segmentation in contrast-enhanced abdominal computerized tomography. The network using SCP has achieved 23.8%, 64.9% and 74.7% reduction in GPU memory usage, FLOPs, and network size with similar or better accuracy for lesion segmentation.

Lifu Tu, Rongguang Wang, Tao Sheng et al.

Robustness evaluation for Natural Language to SQL (NL2SQL) systems is essential because real-world database environments are dynamic, noisy, and continuously evolving, whereas conventional benchmark evaluations typically assume static schemas and well-formed user inputs. In this work, we introduce a robustness evaluation benchmark containing approximately ten types of perturbations and conduct evaluations under both traditional and agentic settings. We assess multiple state-of-the-art large language models (LLMs), including Grok-4.1, Gemini-3-Pro, Claude-Opus-4.6, and GPT-5.2. Our results show that these models generally maintain strong performance under several perturbations; however, notable performance degradation is observed for surface-level noise (e.g., character-level corruption) and linguistic variation that preserves semantics while altering lexical or syntactic forms. Furthermore, we observe that surface-level noise causes larger performance drops in traditional pipelines, whereas linguistic variation presents greater challenges in agentic settings. These findings highlight the remaining challenges in achieving robust NL2SQL systems, particularly in handling linguistic variability.

Hang Zhang, Xiang Chen, Renjiu Hu et al.

Learning-based deformable image registration (DIR) accelerates alignment by amortizing traditional optimization via neural networks. Label supervision further enhances accuracy, enabling efficient and precise nonlinear alignment of unseen scans. However, images with sparse features amid large smooth regions, such as retinal vessels, introduce aperture and large-displacement challenges that unsupervised DIR methods struggle to address. This limitation occurs because neural networks predict deformation fields in a single forward pass, leaving fields unconstrained post-training and shifting the regularization burden entirely to network weights. To address these issues, we introduce SmoothProper, a plug-and-play neural module enforcing smoothness and promoting message passing within the network's forward pass. By integrating a duality-based optimization layer with tailored interaction terms, SmoothProper efficiently propagates flow signals across spatial locations, enforces smoothness, and preserves structural consistency. It is model-agnostic, seamlessly integrates into existing registration frameworks with minimal parameter overhead, and eliminates regularizer hyperparameter tuning. Preliminary results on a retinal vessel dataset exhibiting aperture and large-displacement challenges demonstrate our method reduces registration error to 1.88 pixels on 2912x2912 images, marking the first unsupervised DIR approach to effectively address both challenges. The source code will be available at https://github.com/tinymilky/SmoothProper.

Xingyu Li, Rongguang Wang, Yuying Wang et al.

Large language models (LLMs) remain brittle on multi-hop question answering (MHQA), where answering requires combining evidence across documents through retrieval and reasoning. Iterative retrieval systems can fail by locking onto an early low-recall trajectory and amplifying downstream errors, while planning-only approaches may produce static query sets that cannot adapt when intermediate evidence changes. We propose \textbf{Planned Active Retrieval and Reasoning RAG (PAR$^2$-RAG)}, a two-stage framework that separates \emph{coverage} from \emph{commitment}. PAR$^2$-RAG first performs breadth-first anchoring to build a high-recall evidence frontier, then applies depth-first refinement with evidence sufficiency control in an iterative loop. Across four MHQA benchmarks, PAR$^2$-RAG consistently outperforms existing state-of-the-art baselines, compared with IRCoT, PAR$^2$-RAG achieves up to \textbf{23.5\%} higher accuracy, with retrieval gains of up to \textbf{10.5\%} in NDCG.

Hang Zhang, Rongguang Wang, Jinwei Zhang et al.

We introduce Neural Representation of Distribution (NeRD) technique, a module for convolutional neural networks (CNNs) that can estimate the feature distribution by optimizing an underlying function mapping image coordinates to the feature distribution. Using NeRD, we propose an end-to-end deep learning model for medical image segmentation that can compensate the negative impact of feature distribution shifting issue caused by commonly used network operations such as padding and pooling. An implicit function is used to represent the parameter space of the feature distribution by querying the image coordinate. With NeRD, the impact of issues such as over-segmenting and missing have been reduced, and experimental results on the challenging white matter lesion segmentation and left atrial segmentation verify the effectiveness of the proposed method. The code is available via https://github.com/tinymilky/NeRD.

Ruizhong Miao, Yuying Wang, Rongguang Wang et al.

Semantic search in retrieval-augmented generation (RAG) systems is often insufficient for complex information needs, particularly when relevant evidence is scattered across multiple sources. Prior approaches to this problem include agentic retrieval strategies, which expand the semantic search space by generating additional queries. However, these methods do not fully leverage the organizational structure of the data and instead rely on iterative exploration, which can lead to inefficient retrieval. Another class of approaches employs knowledge graphs to model non-semantic relationships through graph edges. Although effective in capturing richer proximities, such methods incur significant maintenance costs and are often incompatible with the vector stores used in most production systems. To address these limitations, we propose GraphER, a graph-based enrichment and reranking method that captures multiple forms of proximity beyond semantic similarity. GraphER independently enriches data objects during offline indexing and performs graph-based reranking over candidate objects at query time. This design does not require a knowledge graph, allowing GraphER to integrate seamlessly with standard vector stores. In addition, GraphER is retriever-agnostic and introduces negligible latency overhead. Experiments on multiple retrieval benchmarks demonstrate the effectiveness of the proposed approach.

Junhao Wen, Mathilde Antoniades, Zhijian Yang et al.

Machine learning has been increasingly used to obtain individualized neuroimaging signatures for disease diagnosis, prognosis, and response to treatment in neuropsychiatric and neurodegenerative disorders. Therefore, it has contributed to a better understanding of disease heterogeneity by identifying disease subtypes that present significant differences in various brain phenotypic measures. In this review, we first present a systematic literature overview of studies using machine learning and multimodal MRI to unravel disease heterogeneity in various neuropsychiatric and neurodegenerative disorders, including Alzheimer disease, schizophrenia, major depressive disorder, autism spectrum disorder, multiple sclerosis, as well as their potential in transdiagnostic settings. Subsequently, we summarize relevant machine learning methodologies and discuss an emerging paradigm which we call dimensional neuroimaging endophenotype (DNE). DNE dissects the neurobiological heterogeneity of neuropsychiatric and neurodegenerative disorders into a low dimensional yet informative, quantitative brain phenotypic representation, serving as a robust intermediate phenotype (i.e., endophenotype) largely reflecting underlying genetics and etiology. Finally, we discuss the potential clinical implications of the current findings and envision future research avenues.

Xin Zhang, Xingyu Li, Rongguang Wang et al.

Accurate chart comprehension represents a critical challenge in advancing multimodal learning systems, as extensive information is compressed into structured visual representations. However, existing vision-language models (VLMs) frequently struggle to generalize on unseen charts because it requires abstract, symbolic, and quantitative reasoning over structured visual representations. In this work, we introduce Chart-RL, an effective reinforcement learning (RL) method that employs mathematically verifiable rewards to enhance chart question answering in VLMs. Our experiments demonstrate that Chart-RL consistently outperforms supervised fine-tuning (SFT) across different chart understanding benchmarks, achieving relative improvements of 16.7% on MutlChartQA, and 11.5% on ChartInsights. We conduct robustness analysis, where Chart-RL achieves enhanced performance in 18 of 25 perturbed chart categories, demonstrating strong consistency and reasoning capability across visual variations. Furthermore, we demonstrate that task difficulty and inherent complexity are more critical than data quantity in RL training. For instance, Chart-RL trained on merely 10 complex chart-query examples significantly outperforms models trained on over 6,000 simple examples. Additionally, training on challenging reasoning tasks not only improves in-domain generalization relative to simpler tasks, but also facilitate strong transfer to out-of-domain visual mathematical problems.

Jiacheng Wang, Xiang Chen, Renjiu Hu et al.

Co-examination of second-harmonic generation (SHG) and bright-field (BF) microscopy enables the differentiation of tissue components and collagen fibers, aiding the analysis of human breast and pancreatic cancer tissues. However, large discrepancies between SHG and BF images pose challenges for current learning-based registration models in aligning SHG to BF. In this paper, we propose a novel multi-modal registration framework that employs fidelity-imposed displacement editing to address these challenges. The framework integrates batch-wise contrastive learning, feature-based pre-alignment, and instance-level optimization. Experimental results from the Learn2Reg COMULISglobe SHG-BF Challenge validate the effectiveness of our method, securing the 1st place on the online leaderboard.

Hang Zhang, Xiang Chen, Rongguang Wang et al.

In medical imaging, scans often reveal objects with varied contrasts but consistent internal intensities or textures. This characteristic enables the use of low-frequency approximations for tasks such as segmentation and deformation field estimation. Yet, integrating this concept into neural network architectures for medical image analysis remains underexplored. In this paper, we propose the Slicer Network, a novel architecture designed to leverage these traits. Comprising an encoder utilizing models like vision transformers for feature extraction and a slicer employing a learnable bilateral grid, the Slicer Network strategically refines and upsamples feature maps via a splatting-blurring-slicing process. This introduces an edge-preserving low-frequency approximation for the network outcome, effectively enlarging the effective receptive field. The enhancement not only reduces computational complexity but also boosts overall performance. Experiments across different medical imaging applications, including unsupervised and keypoints-based image registration and lesion segmentation, have verified the Slicer Network's improved accuracy and efficiency.

Rongguang Wang, Pratik Chaudhari, Christos Davatzikos

Heterogeneity in medical data, e.g., from data collected at different sites and with different protocols in a clinical study, is a fundamental hurdle for accurate prediction using machine learning models, as such models often fail to generalize well. This paper leverages a recently proposed normalizing-flow-based method to perform counterfactual inference upon a structural causal model (SCM), in order to achieve harmonization of such data. A causal model is used to model observed effects (brain magnetic resonance imaging data) that result from known confounders (site, gender and age) and exogenous noise variables. Our formulation exploits the bijection induced by flow for the purpose of harmonization. We infer the posterior of exogenous variables, intervene on observations, and draw samples from the resultant SCM to obtain counterfactuals. This approach is evaluated extensively on multiple, large, real-world medical datasets and displayed better cross-domain generalization compared to state-of-the-art algorithms. Further experiments that evaluate the quality of confounder-independent data generated by our model using regression and classification tasks are provided.

Rongguang Wang, Pratik Chaudhari, Christos Davatzikos

Domain shift, the mismatch between training and testing data characteristics, causes significant degradation in the predictive performance in multi-source imaging scenarios. In medical imaging, the heterogeneity of population, scanners and acquisition protocols at different sites presents a significant domain shift challenge and has limited the widespread clinical adoption of machine learning models. Harmonization methods which aim to learn a representation of data invariant to these differences are the prevalent tools to address domain shift, but they typically result in degradation of predictive accuracy. This paper takes a different perspective of the problem: we embrace this disharmony in data and design a simple but effective framework for tackling domain shift. The key idea, based on our theoretical arguments, is to build a pretrained classifier on the source data and adapt this model to new data. The classifier can be fine-tuned for intra-site domain adaptation. We can also tackle situations where we do not have access to ground-truth labels on target data; we show how one can use auxiliary tasks for adaptation; these tasks employ covariates such as age, gender and race which are easy to obtain but nevertheless correlated to the main task. We demonstrate substantial improvements in both intra-site domain adaptation and inter-site domain generalization on large-scale real-world 3D brain MRI datasets for classifying Alzheimer's disease and schizophrenia.

Hang Zhang, Jinwei Zhang, Rongguang Wang et al.

Multiple sclerosis (MS) lesions occupy a small fraction of the brain volume, and are heterogeneous with regards to shape, size and locations, which poses a great challenge for training deep learning based segmentation models. We proposed a new geometric loss formula to address the data imbalance and exploit the geometric property of MS lesions. We showed that traditional region-based and boundary-aware loss functions can be associated with the formula. We further develop and instantiate two loss functions containing first- and second-order geometric information of lesion regions to enforce regularization on optimizing deep segmentation models. Experimental results on two MS lesion datasets with different scales, acquisition protocols and resolutions demonstrated the superiority of our proposed methods compared to other state-of-the-art methods.

Hang Zhang, Jinwei Zhang, Rongguang Wang et al.

Recently, 3D medical image reconstruction (MIR) and segmentation (MIS) based on deep neural networks have been developed with promising results, and attention mechanism has been further designed to capture global contextual information for performance enhancement. However, the large size of 3D volume images poses a great computational challenge to traditional attention methods. In this paper, we propose a folded attention (FA) approach to improve the computational efficiency of traditional attention methods on 3D medical images. The main idea is that we apply tensor folding and unfolding operations with four permutations to build four small sub-affinity matrices to approximate the original affinity matrix. Through four consecutive sub-attention modules of FA, each element in the feature tensor can aggregate spatial-channel information from all other elements. Compared to traditional attention methods, with moderate improvement of accuracy, FA can substantially reduce the computational complexity and GPU memory consumption. We demonstrate the superiority of our method on two challenging tasks for 3D MIR and MIS, which are quantitative susceptibility mapping and multiple sclerosis lesion segmentation.