This work introduces Ui2i, a novel model for unpaired image-to-image translation, trained on content-wise unpaired datasets to enable style transfer across domains while preserving content. Building on CycleGAN, Ui2i incorporates key modifications to better disentangle content and style features, and preserve content integrity. Specifically, Ui2i employs U-Net-based generators with skip connections to propagate localized shallow features deep into the generator. Ui2i removes feature-based normalization layers from all modules and replaces them with approximate bidirectional spectral normalization -- a parameter-based alternative that enhances training stability. To further support content preservation, channel and spatial attention mechanisms are integrated into the generators. Training is facilitated through image scale augmentation. Evaluation on two biomedical tasks -- domain adaptation for nuclear segmentation in immunohistochemistry (IHC) images and unmixing of biological structures superimposed in single-channel immunofluorescence (IF) images -- demonstrates Ui2i's ability to preserve content fidelity in settings that demand more accurate structural preservation than typical translation tasks. To the best of our knowledge, Ui2i is the first approach capable of separating superimposed signals in IF images using real, unpaired training data.
Nuclear instance segmentation and classification provide critical quantitative foundations for digital pathology diagnosis. With the advent of the foundational Segment Anything Model (SAM), the accuracy and efficiency of nuclear segmentation have improved significantly. However, SAM imposes a strong reliance on precise prompts, and its class-agnostic design renders its classification results entirely dependent on the provided prompts. Therefore, we focus on generating prompts with more accurate localization and classification and propose \textbf{APSeg}, \textbf{A}uto-\textbf{P}rompt model with acquired and injected knowledge for nuclear instance \textbf{Seg}mentation and classification. APSeg incorporates two knowledge-aware modules: (1) Distribution-Guided Proposal Offset Module (\textbf{DG-POM}), which learns distribution knowledge through density map guided, and (2) Category Knowledge Semantic Injection Module (\textbf{CK-SIM}), which injects morphological knowledge derived from category descriptions. We conducted extensive experiments on the PanNuke and CoNSeP datasets, demonstrating the effectiveness of our approach. The code will be released upon acceptance.
Nuclear instance segmentation has played a critical role in pathology image analysis. The main challenges arise from the difficulty in accurately segmenting instances and the high cost of precise mask-level annotations for fully-supervised training.In this work, we propose a fourier guidance framework for solving the weakly-supervised nuclear instance segmentation problem. In this framework, we construct a fourier guidance module to fuse the priori information into the training process of the model, which facilitates the model to capture the relevant features of the nuclear. Meanwhile, in order to further improve the model's ability to represent the features of nuclear, we propose the guide-based instance level contrastive module. This module makes full use of the framework's own properties and guide information to effectively enhance the representation features of nuclear. We show on two public datasets that our model can outperform current SOTA methods under fully-supervised design, and in weakly-supervised experiments, with only a small amount of labeling our model still maintains close to the performance under full supervision.In addition, we also perform generalization experiments on a private dataset, and without any labeling, our model is able to segment nuclear images that have not been seen during training quite effectively. As open science, all codes and pre-trained models are available at https://github.com/LQY404/FrGNet.
Domain generalisation in computational histopathology is challenging because the images are substantially affected by differences among hospitals due to factors like fixation and staining of tissue and imaging equipment. We hypothesise that focusing on nuclei can improve the out-of-domain (OOD) generalisation in cancer detection. We propose a simple approach to improve OOD generalisation for cancer detection by focusing on nuclear morphology and organisation, as these are domain-invariant features critical in cancer detection. Our approach integrates original images with nuclear segmentation masks during training, encouraging the model to prioritise nuclei and their spatial arrangement. Going beyond mere data augmentation, we introduce a regularisation technique that aligns the representations of masks and original images. We show, using multiple datasets, that our method improves OOD generalisation and also leads to increased robustness to image corruptions and adversarial attacks. The source code is available at https://github.com/undercutspiky/SFL/
Driven by the recent advances in deep learning methods and, in particular, by the development of modern self-supervised learning algorithms, increased interest and efforts have been devoted to build foundation models (FMs) for medical images. In this work, we present our scalable training pipeline for large pathology imaging data, and a comprehensive analysis of various hyperparameter choices and training techniques for building pathology FMs. We release and make publicly available the first batch of our pathology FMs (https://github.com/kaiko-ai/towards_large_pathology_fms) trained on open-access TCGA whole slide images, a commonly used collection of pathology images. The experimental evaluation shows that our models reach state-of-the-art performance on various patch-level downstream tasks, ranging from breast cancer subtyping to colorectal nuclear segmentation. Finally, to unify the evaluation approaches used in the field and to simplify future comparisons of different FMs, we present an open-source framework (https://github.com/kaiko-ai/eva) designed for the consistent evaluation of pathology FMs across various downstream tasks.
In computational digital pathology, accurate nuclear segmentation of Hematoxylin and Eosin (H&E) stained whole slide images (WSIs) is a critical step for many analyses and tissue characterizations. One popular deep learning-based nuclear segmentation approach, HoverNet, offers remarkably accurate results but lacks the high-throughput performance needed for clinical deployment in resource-constrained settings. Our approach, HoverFast, aims to provide fast and accurate nuclear segmentation in H&E images using knowledge distillation from HoverNet. By redesigning the tool with software engineering best practices, HoverFast introduces advanced parallel processing capabilities, efficient data handling, and optimized postprocessing. These improvements facilitate scalable high-throughput performance, making HoverFast more suitable for real-time analysis and application in resource-limited environments. Using a consumer grade Nvidia A5000 GPU, HoverFast showed a 21x speed improvement as compared to HoverNet; reducing mean analysis time for 40x WSIs from ~2 hours to 6 minutes while retaining a concordant mean Dice score of 0.91 against the original HoverNet output. Peak memory usage was also reduced 71% from 44.4GB, to 12.8GB, without requiring SSD-based caching. To ease adoption in research and clinical contexts, HoverFast aligns with best-practices in terms of (a) installation, and (b) containerization, while (c) providing outputs compatible with existing popular open-source image viewing tools such as QuPath. HoverFast has been made open-source and is available at andrewjanowczyk.com/open-source-tools/hoverfast.
Nuclear detection, segmentation and morphometric profiling are essential in helping us further understand the relationship between histology and patient outcome. To drive innovation in this area, we setup a community-wide challenge using the largest available dataset of its kind to assess nuclear segmentation and cellular composition. Our challenge, named CoNIC, stimulated the development of reproducible algorithms for cellular recognition with real-time result inspection on public leaderboards. We conducted an extensive post-challenge analysis based on the top-performing models using 1,658 whole-slide images of colon tissue. With around 700 million detected nuclei per model, associated features were used for dysplasia grading and survival analysis, where we demonstrated that the challenge's improvement over the previous state-of-the-art led to significant boosts in downstream performance. Our findings also suggest that eosinophils and neutrophils play an important role in the tumour microevironment. We release challenge models and WSI-level results to foster the development of further methods for biomarker discovery.
Automated nuclei segmentation and classification are the keys to analyze and understand the cellular characteristics and functionality, supporting computer-aided digital pathology in disease diagnosis. However, the task still remains challenging due to the intrinsic variations in size, intensity, and morphology of different types of nuclei. Herein, we propose a self-guided ordinal regression neural network for simultaneous nuclear segmentation and classification that can exploit the intrinsic characteristics of nuclei and focus on highly uncertain areas during training. The proposed network formulates nuclei segmentation as an ordinal regression learning by introducing a distance decreasing discretization strategy, which stratifies nuclei in a way that inner regions forming a regular shape of nuclei are separated from outer regions forming an irregular shape. It also adopts a self-guided training strategy to adaptively adjust the weights associated with nuclear pixels, depending on the difficulty of the pixels that is assessed by the network itself. To evaluate the performance of the proposed network, we employ large-scale multi-tissue datasets with 276349 exhaustively annotated nuclei. We show that the proposed network achieves the state-of-the-art performance in both nuclei segmentation and classification in comparison to several methods that are recently developed for segmentation and/or classification.
Since the introduction of digital and computational pathology as a field, one of the major problems in the clinical application of algorithms has been the struggle to generalize well to examples outside the distribution of the training data. Existing work to address this in both pathology and natural images has focused almost exclusively on classification tasks. We explore and evaluate the robustness of the 7 best performing nuclear segmentation and classification models from the largest computational pathology challenge for this problem to date, the CoNIC challenge. We demonstrate that existing state-of-the-art (SoTA) models are robust towards compression artifacts but suffer substantial performance reduction when subjected to shifts in the color domain. We find that using stain normalization to address the domain shift problem can be detrimental to the model performance. On the other hand, neural style transfer is more consistent in improving test performance when presented with large color variations in the wild.
Automated synthesis of histology images has several potential applications in computational pathology. However, no existing method can generate realistic tissue images with a bespoke cellular layout or user-defined histology parameters. In this work, we propose a novel framework called SynCLay (Synthesis from Cellular Layouts) that can construct realistic and high-quality histology images from user-defined cellular layouts along with annotated cellular boundaries. Tissue image generation based on bespoke cellular layouts through the proposed framework allows users to generate different histological patterns from arbitrary topological arrangement of different types of cells. SynCLay generated synthetic images can be helpful in studying the role of different types of cells present in the tumor microenvironmet. Additionally, they can assist in balancing the distribution of cellular counts in tissue images for designing accurate cellular composition predictors by minimizing the effects of data imbalance. We train SynCLay in an adversarial manner and integrate a nuclear segmentation and classification model in its training to refine nuclear structures and generate nuclear masks in conjunction with synthetic images. During inference, we combine the model with another parametric model for generating colon images and associated cellular counts as annotations given the grade of differentiation and cell densities of different cells. We assess the generated images quantitatively and report on feedback from trained pathologists who assigned realism scores to a set of images generated by the framework. The average realism score across all pathologists for synthetic images was as high as that for the real images. We also show that augmenting limited real data with the synthetic data generated by our framework can significantly boost prediction performance of the cellular composition prediction task.
Nucleus segmentation and classification are the prerequisites in the workflow of digital pathology processing. However, it is very challenging due to its high-level heterogeneity and wide variations. This work proposes a deep neural network to simultaneously achieve nuclear classification and segmentation, which is designed using a unified framework with three different branches, including segmentation, HoVer mapping, and classification. The segmentation branch aims to generate the boundaries of each nucleus. The HoVer branch calculates the horizontal and vertical distances of nuclear pixels to their centres of mass. The nuclear classification branch is used to distinguish the class of pixels inside the nucleus obtained from segmentation.
Identification and quantification of nuclei in colorectal cancer haematoxylin \& eosin (H\&E) stained histology images is crucial to prognosis and patient management. In computational pathology these tasks are referred to as nuclear segmentation, classification and composition and are used to extract meaningful interpretable cytological and architectural features for downstream analysis. The CoNIC challenge poses the task of automated nuclei segmentation, classification and composition into six different types of nuclei from the largest publicly known nuclei dataset - Lizard. In this regard, we have developed pipelines for the prediction of nuclei segmentation using HoVer-Net and ALBRT for cellular composition. On testing on the preliminary test set, HoVer-Net achieved a PQ of 0.58, a PQ+ of 0.58 and finally a mPQ+ of 0.35. For the prediction of cellular composition with ALBRT on the preliminary test set, we achieved an overall $R^2$ score of 0.53, consisting of 0.84 for lymphocytes, 0.70 for epithelial cells, 0.70 for plasma and .060 for eosinophils.
Nuclear segmentation, classification and quantification within Haematoxylin & Eosin stained histology images enables the extraction of interpretable cell-based features that can be used in downstream explainable models in computational pathology (CPath). However, automatic recognition of different nuclei is faced with a major challenge in that there are several different types of nuclei, some of them exhibiting large intraclass variability. In this work, we propose an approach that combine Separable-HoverNet and Instance-YOLOv5 to indentify colon nuclei small and unbalanced. Our approach can achieve mPQ+ 0.389 on the Segmentation and Classification-Preliminary Test Dataset and r2 0.599 on the Cellular Composition-Preliminary Test Dataset on ISBI 2022 CoNIC Challenge.
Nuclear segmentation and classification is an essential step for computational pathology. TIA lab from Warwick University organized a nuclear segmentation and classification challenge (CoNIC) for H&E stained histopathology images in colorectal cancer with two highly correlated tasks, nuclei segmentation and classification task and cellular composition task. There are a few obstacles we have to address in this challenge, 1) limited training samples, 2) color variation, 3) imbalanced annotations, 4) similar morphological appearance among classes. To deal with these challenges, we proposed a standardized pipeline for nuclear segmentation and classification by integrating several pluggable components. First, we built a GAN-based model to automatically generate pseudo images for data augmentation. Then we trained a self-supervised stain normalization model to solve the color variation problem. Next we constructed a baseline model HoVer-Net with cost-sensitive loss to encourage the model pay more attention on the minority classes. According to the results of the leaderboard, our proposed pipeline achieves 0.40665 mPQ+ (Rank 49th) and 0.62199 r2 (Rank 10th) in the preliminary test phase.
We address the problem of automated nuclear segmentation, classification, and quantification from Haematoxylin and Eosin stained histology images, which is of great relevance for several downstream computational pathology applications. In this work, we present a solution framed as a simultaneous semantic and instance segmentation framework. Our solution is part of the Colon Nuclei Identification and Counting (CoNIC) Challenge. We first train a semantic and instance segmentation model separately. Our framework uses as backbone HoverNet and Cascade Mask-RCNN models. We then ensemble the results with a custom Non-Maximum Suppression embedding (NMS). In our framework, the semantic model computes a class prediction for the cells whilst the instance model provides a refined segmentation. We demonstrate, through our experimental results, that our model outperforms the provided baselines by a large margin.
Nuclear segmentation, classification and quantification within Haematoxylin & Eosin stained histology images enables the extraction of interpretable cell-based features that can be used in downstream explainable models in computational pathology. The Colon Nuclei Identification and Counting (CoNIC) Challenge is held to help drive forward research and innovation for automatic nuclei recognition in computational pathology. This report describes our proposed method submitted to the CoNIC challenge. Our method employs a multi-task learning framework, which performs a panoptic segmentation task and a regression task. For the panoptic segmentation task, we use encoder-decoder type deep neural networks predicting a direction map in addition to a segmentation map in order to separate neighboring nuclei into different instances
Nuclear segmentation, classification and quantification within Haematoxylin & Eosin stained histology images enables the extraction of interpretable cell-based features that can be used in downstream explainable models in computational pathology (CPath). However, automatic recognition of different nuclei is faced with a major challenge in that there are several different types of nuclei, some of them exhibiting large intra-class variability. To help drive forward research and innovation for automatic nuclei recognition in CPath, we organise the Colon Nuclei Identification and Counting (CoNIC) Challenge. The challenge encourages researchers to develop algorithms that perform segmentation, classification and counting of nuclei within the current largest known publicly available nuclei-level dataset in CPath, containing around half a million labelled nuclei. Therefore, the CoNIC challenge utilises over 10 times the number of nuclei as the previous largest challenge dataset for nuclei recognition. It is important for algorithms to be robust to input variation if we wish to deploy them in a clinical setting. Therefore, as part of this challenge we will also test the sensitivity of each submitted algorithm to certain input variations.
Nuclei segmentation is a fundamental task in digital pathology analysis and can be automated by deep learning-based methods. However, the development of such an automated method requires a large amount of data with precisely annotated masks which is hard to obtain. Training with weakly labeled data is a popular solution for reducing the workload of annotation. In this paper, we propose a novel meta-learning-based nuclei segmentation method which follows the label correction paradigm to leverage data with noisy masks. Specifically, we design a fully conventional meta-model that can correct noisy masks using a small amount of clean meta-data. Then the corrected masks can be used to supervise the training of the segmentation model. Meanwhile, a bi-level optimization method is adopted to alternately update the parameters of the main segmentation model and the meta-model in an end-to-end way. Extensive experimental results on two nuclear segmentation datasets show that our method achieves the state-of-the-art result. It even achieves comparable performance with the model training on supervised data in some noisy settings.
Instance segmentation is a key step for quantitative microscopy. While several machine learning based methods have been proposed for this problem, most of them rely on computationally complex models that are trained on surrogate tasks. Building on recent developments towards end-to-end trainable instance segmentation, we propose a minimalist recurrent network called recurrent dilated convolutional network (RDCNet), consisting of a shared stacked dilated convolution (sSDC) layer that iteratively refines its output and thereby generates interpretable intermediate predictions. It is light-weight and has few critical hyperparameters, which can be related to physical aspects such as object size or density.We perform a sensitivity analysis of its main parameters and we demonstrate its versatility on 3 tasks with different imaging modalities: nuclear segmentation of H&E slides, of 3D anisotropic stacks from light-sheet fluorescence microscopy and leaf segmentation of top-view images of plants. It achieves state-of-the-art on 2 of the 3 datasets.
In this paper, we propose an easily trained yet powerful representation learning approach with performance highly competitive to deep neural networks in a digital pathology image segmentation task. The method, called sparse coding driven deep decision tree ensembles that we abbreviate as ScD2TE, provides a new perspective on representation learning. We explore the possibility of stacking several layers based on non-differentiable pairwise modules and generate a densely concatenated architecture holding the characteristics of feature map reuse and end-to-end dense learning. Under this architecture, fast convolutional sparse coding is used to extract multi-level features from the output of each layer. In this way, rich image appearance models together with more contextual information are integrated by learning a series of decision tree ensembles. The appearance and the high-level context features of all the previous layers are seamlessly combined by concatenating them to feed-forward as input, which in turn makes the outputs of subsequent layers more accurate and the whole model efficient to train. Compared with deep neural networks, our proposed ScD2TE does not require back-propagation computation and depends on less hyper-parameters. ScD2TE is able to achieve a fast end-to-end pixel-wise training in a layer-wise manner. We demonstrated the superiority of our segmentation technique by evaluating it on the multi-disease state and multi-organ dataset where consistently higher performances were obtained for comparison against several state-of-the-art deep learning methods such as convolutional neural networks (CNN), fully convolutional networks (FCN), etc.