Mingxia Liu

Hao Guan, Mingxia Liu

Domain adaptation (DA) is an important technique for modern machine learning-based medical data analysis, which aims at reducing distribution differences between different medical datasets. A proper domain adaptation method can significantly enhance the statistical power by pooling data acquired from multiple sites/centers. To this end, we have developed the Domain Adaptation Toolbox for Medical data analysis (DomainATM) - an open-source software package designed for fast facilitation and easy customization of domain adaptation methods for medical data analysis. The DomainATM is implemented in MATLAB with a user-friendly graphical interface, and it consists of a collection of popular data adaptation algorithms that have been extensively applied to medical image analysis and computer vision. With DomainATM, researchers are able to facilitate fast feature-level and image-level adaptation, visualization and performance evaluation of different adaptation methods for medical data analysis. More importantly, the DomainATM enables the users to develop and test their own adaptation methods through scripting, greatly enhancing its utility and extensibility. An overview characteristic and usage of DomainATM is presented and illustrated with three example experiments, demonstrating its effectiveness, simplicity, and flexibility. The software, source code, and manual are available online.

Yuqi Fang, Pew-Thian Yap, Weili Lin et al.

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.

Lintao Zhang, Lihong Wang, Minhui Yu et al.

Late-life depression (LLD) is a highly prevalent mood disorder occurring in older adults and is frequently accompanied by cognitive impairment (CI). Studies have shown that LLD may increase the risk of Alzheimer's disease (AD). However, the heterogeneity of presentation of geriatric depression suggests that multiple biological mechanisms may underlie it. Current biological research on LLD progression incorporates machine learning that combines neuroimaging data with clinical observations. There are few studies on incident cognitive diagnostic outcomes in LLD based on structural MRI (sMRI). In this paper, we describe the development of a hybrid representation learning (HRL) framework for predicting cognitive diagnosis over 5 years based on T1-weighted sMRI data. Specifically, we first extract prediction-oriented MRI features via a deep neural network, and then integrate them with handcrafted MRI features via a Transformer encoder for cognitive diagnosis prediction. Two tasks are investigated in this work, including (1) identifying cognitively normal subjects with LLD and never-depressed older healthy subjects, and (2) identifying LLD subjects who developed CI (or even AD) and those who stayed cognitively normal over five years. To the best of our knowledge, this is among the first attempts to study the complex heterogeneous progression of LLD based on task-oriented and handcrafted MRI features. We validate the proposed HRL on 294 subjects with T1-weighted MRIs from two clinically harmonized studies. Experimental results suggest that the HRL outperforms several classical machine learning and state-of-the-art deep learning methods in LLD identification and prediction tasks.

Qianqian Wang, Wei Wang, Yuqi Fang et al.

Resting-state functional magnetic resonance imaging (rs-fMRI) can reflect spontaneous neural activities in brain and is widely used for brain disorder analysis.Previous studies propose to extract fMRI representations through diverse machine/deep learning methods for subsequent analysis. But the learned features typically lack biological interpretability, which limits their clinical utility. From the view of graph theory, the brain exhibits a remarkable modular structure in spontaneous brain functional networks, with each module comprised of functionally interconnected brain regions-of-interest (ROIs). However, most existing learning-based methods for fMRI analysis fail to adequately utilize such brain modularity prior. In this paper, we propose a Brain Modularity-constrained dynamic Representation learning (BMR) framework for interpretable fMRI analysis, consisting of three major components: (1) dynamic graph construction, (2) dynamic graph learning via a novel modularity-constrained graph neural network(MGNN), (3) prediction and biomarker detection for interpretable fMRI analysis. Especially, three core neurocognitive modules (i.e., salience network, central executive network, and default mode network) are explicitly incorporated into the MGNN, encouraging the nodes/ROIs within the same module to share similar representations. To further enhance discriminative ability of learned features, we also encourage the MGNN to preserve the network topology of input graphs via a graph topology reconstruction constraint. Experimental results on 534 subjects with rs-fMRI scans from two datasets validate the effectiveness of the proposed method. The identified discriminative brain ROIs and functional connectivities can be regarded as potential fMRI biomarkers to aid in clinical diagnosis.

Lintao Zhang, Jinjian Wu, Lihong Wang et al.

Brain structural MRI has been widely used to assess the future progression of cognitive impairment (CI). Previous learning-based studies usually suffer from the issue of small-sized labeled training data, while there exist a huge amount of structural MRIs in large-scale public databases. Intuitively, brain anatomical structures derived from these public MRIs (even without task-specific label information) can be used to boost CI progression trajectory prediction. However, previous studies seldom take advantage of such brain anatomy prior. To this end, this paper proposes a brain anatomy prior modeling (BAPM) framework to forecast the clinical progression of cognitive impairment with small-sized target MRIs by exploring anatomical brain structures. Specifically, the BAPM consists of a pretext model and a downstream model, with a shared brain anatomy-guided encoder to model brain anatomy prior explicitly. Besides the encoder, the pretext model also contains two decoders for two auxiliary tasks (i.e., MRI reconstruction and brain tissue segmentation), while the downstream model relies on a predictor for classification. The brain anatomy-guided encoder is pre-trained with the pretext model on 9,344 auxiliary MRIs without diagnostic labels for anatomy prior modeling. With this encoder frozen, the downstream model is then fine-tuned on limited target MRIs for prediction. We validate the BAPM on two CI-related studies with T1-weighted MRIs from 448 subjects. Experimental results suggest the effectiveness of BAPM in (1) four CI progression prediction tasks, (2) MR image reconstruction, and (3) brain tissue segmentation, compared with several state-of-the-art methods.

Yuqi Fang, Jinjian Wu, Qianqian Wang et al.

Resting-state functional MRI (rs-fMRI) is increasingly employed in multi-site research to aid neurological disorder analysis. Existing studies usually suffer from significant cross-site/domain data heterogeneity caused by site effects such as differences in scanners/protocols. Many methods have been proposed to reduce fMRI heterogeneity between source and target domains, heavily relying on the availability of source data. But acquiring source data is challenging due to privacy concerns and/or data storage burdens in multi-site studies. To this end, we design a source-free collaborative domain adaptation (SCDA) framework for fMRI analysis, where only a pretrained source model and unlabeled target data are accessible. Specifically, a multi-perspective feature enrichment method (MFE) is developed for target fMRI analysis, consisting of multiple collaborative branches to dynamically capture fMRI features of unlabeled target data from multiple views. Each branch has a data-feeding module, a spatiotemporal feature encoder, and a class predictor. A mutual-consistency constraint is designed to encourage pair-wise consistency of latent features of the same input generated from these branches for robust representation learning. To facilitate efficient cross-domain knowledge transfer without source data, we initialize MFE using parameters of a pretrained source model. We also introduce an unsupervised pretraining strategy using 3,806 unlabeled fMRIs from three large-scale auxiliary databases, aiming to obtain a general feature encoder. Experimental results on three public datasets and one private dataset demonstrate the efficacy of our method in cross-scanner and cross-study prediction tasks. The model pretrained on large-scale rs-fMRI data has been released to the public.

Junhao Zhang, Qianqian Wang, Xiaochuan Wang et al.

Resting-state functional magnetic resonance imaging (rs-fMRI) offers a non-invasive approach to examining abnormal brain connectivity associated with brain disorders. Graph neural network (GNN) gains popularity in fMRI representation learning and brain disorder analysis with powerful graph representation capabilities. Training a general GNN often necessitates a large-scale dataset from multiple imaging centers/sites, but centralizing multi-site data generally faces inherent challenges related to data privacy, security, and storage burden. Federated Learning (FL) enables collaborative model training without centralized multi-site fMRI data. Unfortunately, previous FL approaches for fMRI analysis often ignore site-specificity, including demographic factors such as age, gender, and education level. To this end, we propose a specificity-aware federated graph learning (SFGL) framework for rs-fMRI analysis and automated brain disorder identification, with a server and multiple clients/sites for federated model aggregation and prediction. At each client, our model consists of a shared and a personalized branch, where parameters of the shared branch are sent to the server while those of the personalized branch remain local. This can facilitate knowledge sharing among sites and also helps preserve site specificity. In the shared branch, we employ a spatio-temporal attention graph isomorphism network to learn dynamic fMRI representations. In the personalized branch, we integrate vectorized demographic information (i.e., age, gender, and education years) and functional connectivity networks to preserve site-specific characteristics. Representations generated by the two branches are then fused for classification. Experimental results on two fMRI datasets with a total of 1,218 subjects suggest that SFGL outperforms several state-of-the-art approaches.

Mengqi Wu, Minhui Yu, Shuaiming Jing et al.

Multi-site structural MRI is increasingly used in neuroimaging studies to diversify subject cohorts. However, combining MR images acquired from various sites/centers may introduce site-related non-biological variations. Retrospective image harmonization helps address this issue, but current methods usually perform harmonization on pre-extracted hand-crafted radiomic features, limiting downstream applicability. Several image-level approaches focus on 2D slices, disregarding inherent volumetric information, leading to suboptimal outcomes. To this end, we propose a novel 3D MRI Harmonization framework through Conditional Latent Diffusion (HCLD) by explicitly considering image style and brain anatomy. It comprises a generalizable 3D autoencoder that encodes and decodes MRIs through a 4D latent space, and a conditional latent diffusion model that learns the latent distribution and generates harmonized MRIs with anatomical information from source MRIs while conditioned on target image style. This enables efficient volume-level MRI harmonization through latent style translation, without requiring paired images from target and source domains during training. The HCLD is trained and evaluated on 4,158 T1-weighted brain MRIs from three datasets in three tasks, assessing its ability to remove site-related variations while retaining essential biological features. Qualitative and quantitative experiments suggest the effectiveness of HCLD over several state-of-the-arts

Yuqi Fang, Junhao Zhang, Linmin Wang et al.

Functional magnetic resonance imaging (fMRI) has been increasingly employed to investigate functional brain activity. Many fMRI-related software/toolboxes have been developed, providing specialized algorithms for fMRI analysis. However, existing toolboxes seldom consider fMRI data augmentation, which is quite useful, especially in studies with limited or imbalanced data. Moreover, current studies usually focus on analyzing fMRI using conventional machine learning models that rely on human-engineered fMRI features, without investigating deep learning models that can automatically learn data-driven fMRI representations. In this work, we develop an open-source toolbox, called Augmentation and Computation Toolbox for braIn netwOrk aNalysis (ACTION), offering comprehensive functions to streamline fMRI analysis. The ACTION is a Python-based and cross-platform toolbox with graphical user-friendly interfaces. It enables automatic fMRI augmentation, covering blood-oxygen-level-dependent (BOLD) signal augmentation and brain network augmentation. Many popular methods for brain network construction and network feature extraction are included. In particular, it supports constructing deep learning models, which leverage large-scale auxiliary unlabeled data (3,800+ resting-state fMRI scans) for model pretraining to enhance model performance for downstream tasks. To facilitate multi-site fMRI studies, it is also equipped with several popular federated learning strategies. Furthermore, it enables users to design and test custom algorithms through scripting, greatly improving its utility and extensibility. We demonstrate the effectiveness and user-friendliness of ACTION on real fMRI data and present the experimental results. The software, along with its source code and manual, can be accessed online.

Yongheng Sun, Mingxia Liu, Chunfeng Lian

Brain tumor segmentation is crucial for accurate diagnosisand treatment planning, but the small size and irregular shapeof tumors pose significant challenges. Existing methods of-ten fail to effectively incorporate medical domain knowledgesuch as tumor grade, which correlates with tumor aggres-siveness and morphology, providing critical insights for moreaccurate detection of tumor subregions during segmentation.We propose an Automated and Editable Prompt Learning(AEPL) framework that integrates tumor grade into the seg-mentation process by combining multi-task learning andprompt learning with automatic and editable prompt gen-eration. Specifically, AEPL employs an encoder to extractimage features for both tumor-grade prediction and segmen-tation mask generation. The predicted tumor grades serveas auto-generated prompts, guiding the decoder to produceprecise segmentation masks. This eliminates the need formanual prompts while allowing clinicians to manually editthe auto-generated prompts to fine-tune the segmentation,enhancing both flexibility and precision. The proposed AEPLachieves state-of-the-art performance on the BraTS 2018dataset, demonstrating its effectiveness and clinical potential.The source code can be accessed online.

Mengqi Wu, Lintao Zhang, Pew-Thian Yap et al.

Brain magnetic resonance imaging (MRI) has been extensively employed across clinical and research fields, but often exhibits sensitivity to site effects arising from non-biological variations such as differences in field strength and scanner vendors. Numerous retrospective MRI harmonization techniques have demonstrated encouraging outcomes in reducing the site effects at the image level. However, existing methods generally suffer from high computational requirements and limited generalizability, restricting their applicability to unseen MRIs. In this paper, we design a novel disentangled latent energy-based style translation (DLEST) framework for unpaired image-level MRI harmonization, consisting of (a) site-invariant image generation (SIG), (b) site-specific style translation (SST), and (c) site-specific MRI synthesis (SMS). Specifically, the SIG employs a latent autoencoder to encode MRIs into a low-dimensional latent space and reconstruct MRIs from latent codes. The SST utilizes an energy-based model to comprehend the global latent distribution of a target domain and translate source latent codes toward the target domain, while SMS enables MRI synthesis with a target-specific style. By disentangling image generation and style translation in latent space, the DLEST can achieve efficient style translation. Our model was trained on T1-weighted MRIs from a public dataset (with 3,984 subjects across 58 acquisition sites/settings) and validated on an independent dataset (with 9 traveling subjects scanned in 11 sites/settings) in four tasks: histogram and feature visualization, site classification, brain tissue segmentation, and site-specific structural MRI synthesis. Qualitative and quantitative results demonstrate the superiority of our method over several state-of-the-arts.

Lintao Zhang, Mengqi Wu, Lihong Wang et al.

Image noise and motion artifacts greatly affect the quality of brain MRI and negatively influence downstream medical image analysis. Previous studies often focus on 2D methods that process each volumetric MR image slice-by-slice, thus losing important 3D anatomical information. Additionally, these studies generally treat image denoising and artifact correction as two standalone tasks, without considering their potential relationship, especially on low-quality images where severe noise and motion artifacts occur simultaneously. To address these issues, we propose a Joint image Denoising and motion Artifact Correction (JDAC) framework via iterative learning to handle noisy MRIs with motion artifacts, consisting of an adaptive denoising model and an anti-artifact model. In the adaptive denoising model, we first design a novel noise level estimation strategy, and then adaptively reduce the noise through a U-Net backbone with feature normalization conditioning on the estimated noise variance. The anti-artifact model employs another U-Net for eliminating motion artifacts, incorporating a novel gradient-based loss function designed to maintain the integrity of brain anatomy during the motion correction process. These two models are iteratively employed for joint image denoising and artifact correction through an iterative learning framework. An early stopping strategy depending on noise level estimation is applied to accelerate the iteration process. The denoising model is trained with 9,544 T1-weighted MRIs with manually added Gaussian noise as supervision. The anti-artifact model is trained on 552 T1-weighted MRIs with motion artifacts and paired motion-free images. Experimental results on a public dataset and a clinical study suggest the effectiveness of JDAC in both tasks of denoising and motion artifact correction, compared with several state-of-the-art methods.

Meimei Yang, Yongheng Sun, Qianqian Wang et al.

Multimodal neuroimages, such as diffusion tensor imaging (DTI) and resting-state functional MRI (fMRI), offer complementary perspectives on brain activities by capturing structural or functional interactions among brain regions. While existing studies suggest that fusing these multimodal data helps detect abnormal brain activity caused by neurocognitive decline, they are generally implemented in Euclidean space and can't effectively capture intrinsic hierarchical organization of structural/functional brain networks. This paper presents a hyperbolic kernel graph fusion (HKGF) framework for neurocognitive decline analysis with multimodal neuroimages. It consists of a multimodal graph construction module, a graph representation learning module that encodes brain graphs in hyperbolic space through a family of hyperbolic kernel graph neural networks (HKGNNs), a cross-modality coupling module that enables effective multimodal data fusion, and a hyperbolic neural network for downstream predictions. Notably, HKGNNs represent graphs in hyperbolic space to capture both local and global dependencies among brain regions while preserving the hierarchical structure of brain networks. Extensive experiments involving over 4,000 subjects with DTI and/or fMRI data suggest the superiority of HKGF over state-of-the-art methods in two neurocognitive decline prediction tasks. HKGF is a general framework for multimodal data analysis, facilitating objective quantification of structural/functional brain connectivity changes associated with neurocognitive decline.

Qianqian Wang, Wei Wang, Yuqi Fang et al.

Brain networks/graphs derived from resting-state functional MRI (fMRI) help study underlying pathophysiology of neurocognitive disorders by measuring neuronal activities in the brain. Some studies utilize learning-based methods for brain network analysis, but typically suffer from low model generalizability caused by scarce labeled fMRI data. As a notable self-supervised strategy, graph contrastive learning helps leverage auxiliary unlabeled data. But existing methods generally arbitrarily perturb graph nodes/edges to generate augmented graphs, without considering essential topology information of brain networks. To this end, we propose a topology-aware graph augmentation (TGA) framework, comprising a pretext model to train a generalizable encoder on large-scale unlabeled fMRI cohorts and a task-specific model to perform downstream tasks on a small target dataset. In the pretext model, we design two novel topology-aware graph augmentation strategies: (1) hub-preserving node dropping that prioritizes preserving brain hub regions according to node importance, and (2) weight-dependent edge removing that focuses on keeping important functional connectivities based on edge weights. Experiments on 1, 688 fMRI scans suggest that TGA outperforms several state-of-the-art methods.

Mengting Xu, Tao Zhang, Zhongnian Li et al.

Deep learning models (with neural networks) have been widely used in challenging tasks such as computer-aided disease diagnosis based on medical images. Recent studies have shown deep diagnostic models may not be robust in the inference process and may pose severe security concerns in clinical practice. Among all the factors that make the model not robust, the most serious one is adversarial examples. The so-called "adversarial example" is a well-designed perturbation that is not easily perceived by humans but results in a false output of deep diagnostic models with high confidence. In this paper, we evaluate the robustness of deep diagnostic models by adversarial attack. Specifically, we have performed two types of adversarial attacks to three deep diagnostic models in both single-label and multi-label classification tasks, and found that these models are not reliable when attacked by adversarial example. We have further explored how adversarial examples attack the models, by analyzing their quantitative classification results, intermediate features, discriminability of features and correlation of estimated labels for both original/clean images and those adversarial ones. We have also designed two new defense methods to handle adversarial examples in deep diagnostic models, i.e., Multi-Perturbations Adversarial Training (MPAdvT) and Misclassification-Aware Adversarial Training (MAAdvT). The experimental results have shown that the use of defense methods can significantly improve the robustness of deep diagnostic models against adversarial attacks.

Li Zhang, Mingliang Wang, Mingxia Liu et al.

Deep learning has been recently used for the analysis of neuroimages, such as structural magnetic resonance imaging (MRI), functional MRI, and positron emission tomography (PET), and has achieved significant performance improvements over traditional machine learning in computer-aided diagnosis of brain disorders. This paper reviews the applications of deep learning methods for neuroimaging-based brain disorder analysis. We first provide a comprehensive overview of deep learning techniques and popular network architectures, by introducing various types of deep neural networks and recent developments. We then review deep learning methods for computer-aided analysis of four typical brain disorders, including Alzheimer's disease, Parkinson's disease, Autism spectrum disorder, and Schizophrenia, where the first two diseases are neurodegenerative disorders and the last two are neurodevelopmental and psychiatric disorders, respectively. More importantly, we discuss the limitations of existing studies and present possible future directions.

Kelei He, Wei Zhao, Xingzhi Xie et al.

Understanding chest CT imaging of the coronavirus disease 2019 (COVID-19) will help detect infections early and assess the disease progression. Especially, automated severity assessment of COVID-19 in CT images plays an essential role in identifying cases that are in great need of intensive clinical care. However, it is often challenging to accurately assess the severity of this disease in CT images, due to variable infection regions in the lungs, similar imaging biomarkers, and large inter-case variations. To this end, we propose a synergistic learning framework for automated severity assessment of COVID-19 in 3D CT images, by jointly performing lung lobe segmentation and multi-instance classification. Considering that only a few infection regions in a CT image are related to the severity assessment, we first represent each input image by a bag that contains a set of 2D image patches (with each cropped from a specific slice). A multi-task multi-instance deep network (called M$^2$UNet) is then developed to assess the severity of COVID-19 patients and also segment the lung lobe simultaneously. Our M$^2$UNet consists of a patch-level encoder, a segmentation sub-network for lung lobe segmentation, and a classification sub-network for severity assessment (with a unique hierarchical multi-instance learning strategy). Here, the context information provided by segmentation can be implicitly employed to improve the performance of severity assessment. Extensive experiments were performed on a real COVID-19 CT image dataset consisting of 666 chest CT images, with results suggesting the effectiveness of our proposed method compared to several state-of-the-art methods.

Weida Li, Mingxia Liu, Daoqiang Zhang

Recently, Nyström method has proved its prominence empirically and theoretically in speeding up the training of kernel machines while retaining satisfactory performances and accuracy. So far, there are several different approaches proposed to exploit Nyström method in scaling up kernel machines. However, there is no comparative study over these approaches, and they were individually analyzed for specific types of kernel machines. Therefore, it remains a question that the philosophy of which approach is more promising when it extends to other kernel machines. In this work, motivated by the column inclusion property of Gram matrices, we develop a new approach with a clear geometric interpretation for running Nyström-based kernel machines. We show that the other two well-studied approaches can be equivalently transformed to be our proposed one. Consequently, analysis established for the proposed approach also works for these two. Particularly, our proposed approach makes it possible to develop approximation errors in a general setting. Besides, our analysis also manifests the relations among the aforementioned two approaches and another naive one. First, the analytical forms of the corresponding approximate solutions are only at odds with one term. Second, the naive approach can be implemented efficiently by sharing the same training procedure with others. These analytical results lead to the conjecture that the naive approach can provide more accurate approximate solutions than the other two sophisticated approaches. Since our analysis also offers ways for computing the accuracy of these approximate solutions, we run experiments with classification tasks to confirm our conjecture.

Weida Li, Mingxia Liu, Fang Chen et al.

Aggregating multi-subject functional magnetic resonance imaging (fMRI) data is indispensable for generating valid and general inferences from patterns distributed across human brains. The disparities in anatomical structures and functional topographies of human brains warrant aligning fMRI data across subjects. However, the existing functional alignment methods cannot handle well various kinds of fMRI datasets today, especially when they are not temporally-aligned, i.e., some of the subjects probably lack the responses to some stimuli, or different subjects might follow different sequences of stimuli. In this paper, a cross-subject graph that depicts the (dis)similarities between samples across subjects is used as a priori for developing a more flexible framework that suits an assortment of fMRI datasets. However, the high dimension of fMRI data and the use of multiple subjects makes the crude framework time-consuming or unpractical. To address this issue, we further regularize the framework, so that a novel feasible kernel-based optimization, which permits nonlinear feature extraction, could be theoretically developed. Specifically, a low-dimension assumption is imposed on each new feature space to avoid overfitting caused by the highspatial-low-temporal resolution of fMRI data. Experimental results on five datasets suggest that the proposed method is not only superior to several state-of-the-art methods on temporally-aligned fMRI data, but also suitable for dealing `with temporally-unaligned fMRI data.