Shichuan Zhang

Ran Gu, Guotai Wang, Jiangshan Lu et al.

Generalization to previously unseen images with potential domain shifts and different styles is essential for clinically applicable medical image segmentation, and the ability to disentangle domain-specific and domain-invariant features is key for achieving Domain Generalization (DG). However, existing DG methods can hardly achieve effective disentanglement to get high generalizability. To deal with this problem, we propose an efficient Contrastive Domain Disentanglement and Style Augmentation (CDDSA) framework for generalizable medical image segmentation. First, a disentangle network is proposed to decompose an image into a domain-invariant anatomical representation and a domain-specific style code, where the former is sent to a segmentation model that is not affected by the domain shift, and the disentangle network is regularized by a decoder that combines the anatomical and style codes to reconstruct the input image. Second, to achieve better disentanglement, a contrastive loss is proposed to encourage the style codes from the same domain and different domains to be compact and divergent, respectively. Thirdly, to further improve generalizability, we propose a style augmentation method based on the disentanglement representation to synthesize images in various unseen styles with shared anatomical structures. Our method was validated on a public multi-site fundus image dataset for optic cup and disc segmentation and an in-house multi-site Nasopharyngeal Carcinoma Magnetic Resonance Image (NPC-MRI) dataset for nasopharynx Gross Tumor Volume (GTVnx) segmentation. Experimental results showed that the proposed CDDSA achieved remarkable generalizability across different domains, and it outperformed several state-of-the-art methods in domain-generalizable segmentation.

Zhongyi Shui, Sunyi Zheng, Chenglu Zhu et al.

Point-based cell detection (PCD), which pursues high-performance cell sensing under low-cost data annotation, has garnered increased attention in computational pathology community. Unlike mainstream PCD methods that rely on intermediate density map representations, the Point-to-Point network (P2PNet) has recently emerged as an end-to-end solution for PCD, demonstrating impressive cell detection accuracy and efficiency. Nevertheless, P2PNet is limited to decoding from a single-level feature map due to the scale-agnostic property of point proposals, which is insufficient to leverage multi-scale information. Moreover, the spatial distribution of pre-set point proposals is biased from that of cells, leading to inaccurate cell localization. To lift these limitations, we present DPA-P2PNet in this work. The proposed method directly extracts multi-scale features for decoding according to the coordinates of point proposals on hierarchical feature maps. On this basis, we further devise deformable point proposals to mitigate the positional bias between proposals and potential cells to promote cell localization. Inspired by practical pathological diagnosis that usually combines high-level tissue structure and low-level cell morphology for accurate cell classification, we propose a multi-field-of-view (mFoV) variant of DPA-P2PNet to accommodate additional large FoV images with tissue information as model input. Finally, we execute the first self-supervised pre-training on immunohistochemistry histopathology image data and evaluate the suitability of four representative self-supervised methods on the PCD task. Experimental results on three benchmarks and a large-scale and real-world interval dataset demonstrate the superiority of our proposed models over the state-of-the-art counterparts. Codes and pre-trained weights will be available.

Pingyi Chen, Chenglu Zhu, Zhongyi Shui et al.

The success of supervised deep learning models in medical image segmentation relies on detailed annotations. However, labor-intensive manual labeling is costly and inefficient, especially in dense object segmentation. To this end, we propose a self-supervised learning based approach with a Prior Self-activation Module (PSM) that generates self-activation maps from the input images to avoid labeling costs and further produce pseudo masks for the downstream task. To be specific, we firstly train a neural network using self-supervised learning and utilize the gradient information in the shallow layers of the network to generate self-activation maps. Afterwards, a semantic-guided generator is then introduced as a pipeline to transform visual representations from PSM to pixel-level semantic pseudo masks for downstream tasks. Furthermore, a two-stage training module, consisting of a nuclei detection network and a nuclei segmentation network, is adopted to achieve the final segmentation. Experimental results show the effectiveness on two public pathological datasets. Compared with other fully-supervised and weakly-supervised methods, our method can achieve competitive performance without any manual annotations.

Zhongyi Shui, Yizhi Zhao, Sunyi Zheng et al.

Cell recognition is a fundamental task in digital histopathology image analysis. Point-based cell recognition (PCR) methods normally require a vast number of annotations, which is extremely costly, time-consuming and labor-intensive. Semi-supervised learning (SSL) can provide a shortcut to make full use of cell information in gigapixel whole slide images without exhaustive labeling. However, research into semi-supervised point-based cell recognition (SSPCR) remains largely overlooked. Previous SSPCR works are all built on density map-based PCR models, which suffer from unsatisfactory accuracy, slow inference speed and high sensitivity to hyper-parameters. To address these issues, end-to-end PCR models are proposed recently. In this paper, we develop a SSPCR framework suitable for the end-to-end PCR models for the first time. Overall, we use the current models to generate pseudo labels for unlabeled images, which are in turn utilized to supervise the models training. Besides, we introduce a co-teaching strategy to overcome the confirmation bias problem that generally exists in self-training. A distribution alignment technique is also incorporated to produce high-quality, unbiased pseudo labels for unlabeled data. Experimental results on four histopathology datasets concerning different types of staining styles show the effectiveness and versatility of the proposed framework. Code is available at \textcolor{magenta}{\url{https://github.com/windygooo/SSPCR}

Hao Fu, Guotai Wang, Wenhui Lei et al.

Accurate segmentation of Anatomical brain Barriers to Cancer spread (ABCs) plays an important role for automatic delineation of Clinical Target Volume (CTV) of brain tumors in radiotherapy. Despite that variants of U-Net are state-of-the-art segmentation models, they have limited performance when dealing with ABCs structures with various shapes and sizes, especially thin structures (e.g., the falx cerebri) that span only few slices. To deal with this problem, we propose a High and Multi-Resolution Network (HMRNet) that consists of a multi-scale feature learning branch and a high-resolution branch, which can maintain the high-resolution contextual information and extract more robust representations of anatomical structures with various scales. We further design a Bidirectional Feature Calibration (BFC) block to enable the two branches to generate spatial attention maps for mutual feature calibration. Considering the different sizes and positions of ABCs structures, our network was applied after a rough localization of each structure to obtain fine segmentation results. Experiments on the MICCAI 2020 ABCs challenge dataset showed that: 1) Our proposed two-stage segmentation strategy largely outperformed methods segmenting all the structures in just one stage; 2) The proposed HMRNet with two branches can maintain high-resolution representations and is effective to improve the performance on thin structures; 3) The proposed BFC block outperformed existing attention methods using monodirectional feature calibration. Our method won the second place of ABCs 2020 challenge and has a potential for more accurate and reasonable delineation of CTV of brain tumors.

Jingxiong Li, Sunyi Zheng, Zhongyi Shui et al.

Karyotyping is of importance for detecting chromosomal aberrations in human disease. However, chromosomes easily appear curved in microscopic images, which prevents cytogeneticists from analyzing chromosome types. To address this issue, we propose a framework for chromosome straightening, which comprises a preliminary processing algorithm and a generative model called masked conditional variational autoencoders (MC-VAE). The processing method utilizes patch rearrangement to address the difficulty in erasing low degrees of curvature, providing reasonable preliminary results for the MC-VAE. The MC-VAE further straightens the results by leveraging chromosome patches conditioned on their curvatures to learn the mapping between banding patterns and conditions. During model training, we apply a masking strategy with a high masking ratio to train the MC-VAE with eliminated redundancy. This yields a non-trivial reconstruction task, allowing the model to effectively preserve chromosome banding patterns and structure details in the reconstructed results. Extensive experiments on three public datasets with two stain styles show that our framework surpasses the performance of state-of-the-art methods in retaining banding patterns and structure details. Compared to using real-world bent chromosomes, the use of high-quality straightened chromosomes generated by our proposed method can improve the performance of various deep learning models for chromosome classification by a large margin. Such a straightening approach has the potential to be combined with other karyotyping systems to assist cytogeneticists in chromosome analysis.

Zhongyi Shui, Shichuan Zhang, Chenglu Zhu et al.

Reliable quantitative analysis of immunohistochemical staining images requires accurate and robust cell detection and classification. Recent weakly-supervised methods usually estimate probability density maps for cell recognition. However, in dense cell scenarios, their performance can be limited by pre- and post-processing as it is impossible to find a universal parameter setting. In this paper, we introduce an end-to-end framework that applies direct regression and classification for preset anchor points. Specifically, we propose a pyramidal feature aggregation strategy to combine low-level features and high-level semantics simultaneously, which provides accurate cell recognition for our purely point-based model. In addition, an optimized cost function is designed to adapt our multi-task learning framework by matching ground truth and predicted points. The experimental results demonstrate the superior accuracy and efficiency of the proposed method, which reveals the high potentiality in assisting pathologist assessments.

Pingyi Chen, Chenglu Zhu, Zhongyi Shui et al.

The success of supervised deep learning models on cell recognition tasks relies on detailed annotations. Many previous works have managed to reduce the dependency on labels. However, considering the large number of cells contained in a patch, costly and inefficient labeling is still inevitable. To this end, we explored label-free methods for cell recognition. Prior self-activation maps (PSM) are proposed to generate pseudo masks as training targets. To be specific, an activation network is trained with self-supervised learning. The gradient information in the shallow layers of the network is aggregated to generate prior self-activation maps. Afterward, a semantic clustering module is then introduced as a pipeline to transform PSMs to pixel-level semantic pseudo masks for downstream tasks. We evaluated our method on two histological datasets: MoNuSeg (cell segmentation) and BCData (multi-class cell detection). Compared with other fully-supervised and weakly-supervised methods, our method can achieve competitive performance without any manual annotations. Our simple but effective framework can also achieve multi-class cell detection which can not be done by existing unsupervised methods. The results show the potential of PSMs that might inspire other research to deal with the hunger for labels in medical area.

Honglin Li, Yusuan Sun, Chenglu Zhu et al.

Cervical Cancer continues to be the leading gynecological malignancy, posing a persistent threat to women's health on a global scale. Early screening via cytology Whole Slide Image (WSI) diagnosis is critical to prevent this Cancer progression and improve survival rate, but pathologist's single test suffers inevitable false negative due to the immense number of cells that need to be reviewed within a WSI. Though computer-aided automated diagnostic models can serve as strong complement for pathologists, their effectiveness is hampered by the paucity of extensive and detailed annotations, coupled with the limited interpretability and robustness. These factors significantly hinder their practical applicability and reliability in clinical settings. To tackle these challenges, we develop an AI approach, which is a Scalable Technology for Robust and Interpretable Diagnosis built on Extensive data (STRIDE) of cervical cytology. STRIDE addresses the bottleneck of limited annotations by integrating patient-level labels with a small portion of cell-level labels through an end-to-end training strategy, facilitating scalable learning across extensive datasets. To further improve the robustness to real-world domain shifts of cytology slide-making and imaging, STRIDE employs color adversarial samples training that mimic staining and imaging variations. Lastly, to achieve pathologist-level interpretability for the trustworthiness in clinical settings, STRIDE can generate explanatory textual descriptions that simulates pathologists' diagnostic processes by cell image feature and textual description alignment. Conducting extensive experiments and evaluations in 183 medical centers with a dataset of 341,889 WSIs and 0.1 billion cells from cervical cytology patients, STRIDE has demonstrated a remarkable superiority over previous state-of-the-art techniques.

Zihao Luo, Zijun Gao, Wenjun Liao et al.

Accurate lymph node (LN) segmentation is critical in radiotherapy treatment and prognosis analysis, but is limited by the need for large annotated datasets. While deep learning-based segmentation foundation models show potential in developing high-performing models with fewer samples, their medical adaptation faces LN domain-specific prior deficiencies and inefficient few-shot fine-tuning for complex clinical practices, highlighting the necessity of an LN segmentation foundation model. In this work, we annotated 36,106 visible LNs from 3,346 publicly available head-and-neck CT scans to establish a robust LN segmentation model (nnUNetv2). Building on this, we propose Dynamic Gradient Sparsification Training (DGST), a few-shot fine-tuning approach that preserves foundational knowledge while dynamically updating the most critical parameters of the LN segmentation model with few annotations. We validate it on two publicly available LN segmentation datasets: SegRap2023 and LNQ2023. The results show that DGST outperforms existing few-shot fine-tuning methods, achieving satisfactory performance with limited labeled data. We release the dataset, models and all implementations to facilitate relevant research: https://github.com/Zihaoluoh/LN-Seg-FM.

Shichuan Zhang, Sunyi Zheng, Zhongyi Shui et al.

Multi-modal Learning has attracted widespread attention in medical image analysis. Using multi-modal data, whole slide images (WSIs) and clinical information, can improve the performance of deep learning models in the diagnosis of axillary lymph node metastasis. However, clinical information is not easy to collect in clinical practice due to privacy concerns, limited resources, lack of interoperability, etc. Although patient selection can ensure the training set to have multi-modal data for model development, missing modality of clinical information can appear during test. This normally leads to performance degradation, which limits the use of multi-modal models in the clinic. To alleviate this problem, we propose a bidirectional distillation framework consisting of a multi-modal branch and a single-modal branch. The single-modal branch acquires the complete multi-modal knowledge from the multi-modal branch, while the multi-modal learns the robust features of WSI from the single-modal. We conduct experiments on a public dataset of Lymph Node Metastasis in Early Breast Cancer to validate the method. Our approach not only achieves state-of-the-art performance with an AUC of 0.861 on the test set without missing data, but also yields an AUC of 0.842 when the rate of missing modality is 80\%. This shows the effectiveness of the approach in dealing with multi-modal data and missing modality. Such a model has the potential to improve treatment decision-making for early breast cancer patients who have axillary lymph node metastatic status.

Xiaochuan Ma, Jia Fu, Wenjun Liao et al.

Brain tumor segmentation is important for diagnosis of the tumor, and current deep-learning methods rely on a large set of annotated images for training, with high annotation costs. Unsupervised segmentation is promising to avoid human annotations while the performance is often limited. In this study, we present a novel unsupervised segmentation approach that leverages the capabilities of foundation models, and it consists of three main steps: (1) A vision-language model (i.e., CLIP) is employed to obtain image-level pseudo-labels for training a classification network. Class Activation Mapping (CAM) is then employed to extract Regions of Interest (ROIs), where an adaptive masking-based data augmentation is used to enhance ROI identification.(2) The ROIs are used to generate bounding box and point prompts for the Segment Anything Model (SAM) to obtain segmentation pseudo-labels. (3) A 3D segmentation network is trained with the SAM-derived pseudo-labels, where low-quality pseudo-labels are filtered out in a self-learning process based on the similarity between the SAM's output and the network's prediction. Evaluation on the BraTS2020 dataset demonstrates that our approach obtained an average Dice Similarity Score (DSC) of 85.60%, outperforming five state-of-the-art unsupervised segmentation methods by more than 10 percentage points. Besides, our approach outperforms directly using SAM for zero-shot inference, and its performance is close to fully supervised learning.

Zixia Jia, Junpeng Li, Shichuan Zhang et al.

Traditional supervised learning heavily relies on human-annotated datasets, especially in data-hungry neural approaches. However, various tasks, especially multi-label tasks like document-level relation extraction, pose challenges in fully manual annotation due to the specific domain knowledge and large class sets. Therefore, we address the multi-label positive-unlabelled learning (MLPUL) problem, where only a subset of positive classes is annotated. We propose Mixture Learner for Partially Annotated Classification (MLPAC), an RL-based framework combining the exploration ability of reinforcement learning and the exploitation ability of supervised learning. Experimental results across various tasks, including document-level relation extraction, multi-label image classification, and binary PU learning, demonstrate the generalization and effectiveness of our framework.

Shichuan Zhang, Chenglu Zhu, Honglin Li et al.

Cell classification and counting in immunohistochemical cytoplasm staining images play a pivotal role in cancer diagnosis. Weakly supervised learning is a potential method to deal with labor-intensive labeling. However, the inconstant cell morphology and subtle differences between classes also bring challenges. To this end, we present a novel cell recognition framework based on multi-task learning, which utilizes two additional auxiliary tasks to guide robust representation learning of the main task. To deal with misclassification, the tissue prior learning branch is introduced to capture the spatial representation of tumor cells without additional tissue annotation. Moreover, dynamic masks and consistency learning are adopted to learn the invariance of cell scale and shape. We have evaluated our framework on immunohistochemical cytoplasm staining images, and the results demonstrate that our method outperforms recent cell recognition approaches. Besides, we have also done some ablation studies to show significant improvements after adding the auxiliary branches.

Jiatong Cai, Chenglu Zhu, Can Cui et al.

Ki67 is a significant biomarker in the diagnosis and prognosis of cancer, whose index can be evaluated by quantifying its expression in Ki67 immunohistochemistry (IHC) stained images. However, quantitative analysis on multi-source Ki67 images is yet a challenging task in practice due to cross-domain distribution differences, which result from imaging variation, staining styles, and lesion types. Many recent studies have made some efforts on domain generalization (DG), whereas there are still some noteworthy limitations. Specifically in the case of Ki67 images, learning invariant representation is at the mercy of the insufficient number of domains and the cell categories mismatching in different domains. In this paper, we propose a novel method to improve DG by searching the domain-agnostic subnetwork in a domain merging scenario. Partial model parameters are iteratively pruned according to the domain gap, which is caused by the data converting from a single domain into merged domains during training. In addition, the model is optimized by fine-tuning on merged domains to eliminate the interference of class mismatching among various domains. Furthermore, an appropriate implementation is attained by applying the pruning method to different parts of the framework. Compared with known DG methods, our method yields excellent performance in multiclass nucleus recognition of Ki67 IHC images, especially in the lost category cases. Moreover, our competitive results are also evaluated on the public dataset over the state-of-the-art DG methods.