Representation learning for Whole Slide Images (WSIs) is pivotal in developing image-based systems to achieve higher precision in diagnostic pathology. We propose a two-stage framework for WSI representation learning. We sample relevant patches using a color-based method and use graph neural networks to learn relations among sampled patches to aggregate the image information into a single vector representation. We introduce attention via graph pooling to automatically infer patches with higher relevance. We demonstrate the performance of our approach for discriminating two sub-types of lung cancers, Lung Adenocarcinoma (LUAD) & Lung Squamous Cell Carcinoma (LUSC). We collected 1,026 lung cancer WSIs with the 40$\times$ magnification from The Cancer Genome Atlas (TCGA) dataset, the largest public repository of histopathology images and achieved state-of-the-art accuracy of 88.8% and AUC of 0.89 on lung cancer sub-type classification by extracting features from a pre-trained DenseNet
Dartmouth College（达特茅斯学院）；Dartmouth-Hitchcock Medical Center（达特茅斯-希区柯克医疗中心）；Minnesota Gastroenterology PA（明尼苏达胃肠病学协会）；Fairview Southdale Hospital（费尔维尤索斯代尔医院）；University of North Carolina（北卡罗来纳大学）
Histological classification of colorectal polyps plays a critical role in both screening for colorectal cancer and care of affected patients. An accurate and automated algorithm for the classification of colorectal polyps on digitized histopathology slides could benefit clinicians and patients. Evaluate the performance and assess the generalizability of a deep neural network for colorectal polyp classification on histopathology slide images using a multi-institutional dataset. In this study, we developed a deep neural network for classification of four major colorectal polyp types, tubular ade…
Indian Institute of Technology Bombay（印度理工学院孟买分校）；University of Illinois（伊利诺伊大学）
Spatial arrangement of cells of various types, such as tumor infiltrating lymphocytes and the advancing edge of a tumor, are important features for detecting and characterizing cancers. However, convolutional neural networks (CNNs) do not explicitly extract intricate features of the spatial arrangements of the cells from histopathology images. In this work, we propose to classify cancers using graph convolutional networks (GCNs) by modeling a tissue section as a multi-attributed spatial graph of its constituent cells. Cells are detected using their nuclei in H&E stained tissue image, and each …
Sunnybrook Research Institute（森尼布鲁克研究所）；University of Toronto（多伦多大学）
Histopathological images contain rich phenotypic information that can be used to monitor underlying mechanisms contributing to diseases progression and patient survival outcomes. Recently, deep learning has become the mainstream methodological choice for analyzing and interpreting cancer histology images. In this paper, we present a comprehensive review of state-of-the-art deep learning approaches that have been used in the context of histopathological image analysis. From the survey of over 130 papers, we review the fields progress based on the methodological aspect of different machine learn…
Isfahan University of Technology（伊斯法罕工业大学）；University of Michigan（密歇根大学）；University of Queensland（昆士兰大学）
Histopathology images contain essential information for medical diagnosis and prognosis of cancerous disease. Segmentation of glands in histopathology images is a primary step for analysis and diagnosis of an unhealthy patient. Due to the widespread application and the great success of deep neural networks in intelligent medical diagnosis and histopathology, we propose a modified version of LinkNet for gland segmentation and recognition of malignant cases. We show that using specific handcrafted features such as invariant local binary pattern drastically improves the system performance. The ex…
Jalpaiguri Government Engineering College（贾尔派古里政府工程学院）
Invasive ductal carcinoma (IDC), which is also sometimes known as the infiltrating ductal carcinoma, is the most regular form of breast cancer. It accounts for about 80% of all breast cancers. According to the American Cancer Society, more than 180,000 women in the United States are diagnosed with invasive breast cancer each year. The survival rate associated with this form of cancer is about 77% to 93% depending on the stage at which they are being diagnosed. The invasiveness and the frequency of the occurrence of these disease makes it one of the difficult cancers to be diagnosed. Our propos…
Burdur Mehmet Akif Ersoy University（布尔杜尔穆罕默德·阿基夫·埃尔索伊大学）；Süleyman Demirel University（苏莱曼·德米雷尔大学）
The aim of this study is to propose an alternative and hybrid solution method for diagnosing the disease from histopathology images taken from animals with paratuberculosis and intact intestine. In detail, the hybrid method is based on using both image processing and deep learning for better results. Reliable disease detection from histo-pathology images is known as an open problem in medical image processing and alternative solutions need to be developed. In this context, 520 histopathology images were collected in a joint study with Burdur Mehmet Akif Ersoy University, Faculty of Veterinary …
Preparing and scanning histopathology slides consists of several steps, each with a multitude of parameters. The parameters can vary between pathology labs and within the same lab over time, resulting in significant variability of the tissue appearance that hampers the generalization of automatic image analysis methods. Typically, this is addressed with ad-hoc approaches such as staining normalization that aim to reduce the appearance variability. In this paper, we propose a systematic solution based on domain-adversarial neural networks. We hypothesize that removing the domain information fro…
Shiraz University of Technology（设拉子理工大学）；National Brain Mapping Laboratory（国家脑图谱实验室）
We propose a two-step domain shift-invariant mitosis cell detection method based on Faster RCNN and a convolutional neural network (CNN). We generate various domain-shifted versions of existing histopathology images using a stain augmentation technique, enabling our method to effectively learn various stain domains and achieve better generalization. The performance of our method is evaluated on the preliminary test data set of the MIDOG-2021 challenge. The experimental results demonstrate that the proposed mitosis detection method can achieve promising performance for domain-shifted histopatho…
Top Data Science Ltd.（顶级数据科学有限公司）；University of Helsinki（赫尔辛基大学）；Skåne University Hospital（斯科讷大学医院）；Helsinki University Hospital（赫尔辛基大学医院）
Deep neural networks have introduced significant advancements in the field of machine learning-based analysis of digital pathology images including prostate tissue images. With the help of transfer learning, classification and segmentation performance of neural network models have been further increased. However, due to the absence of large, extensively annotated, publicly available prostate histopathology datasets, several previous studies employ datasets from well-studied computer vision tasks such as ImageNet dataset. In this work, we propose a transfer learning scheme from breast histopath…
Northeastern University（东北大学）；Stevens Institute of Technology（史蒂文斯理工学院）；Cancer Hospital of China Medical University（中国医科大学附属肿瘤医院）；Chengdu University of Information Technology（成都信息工程大学）
Breast cancer is one of the most common and deadliest cancers among women. Since histopathological images contain sufficient phenotypic information, they play an indispensable role in the diagnosis and treatment of breast cancers. To improve the accuracy and objectivity of Breast Histopathological Image Analysis (BHIA), Artificial Neural Network (ANN) approaches are widely used in the segmentation and classification tasks of breast histopathological images. In this review, we present a comprehensive overview of the BHIA techniques based on ANNs. First of all, we categorize the BHIA systems int…
Center for Wireless Networks & Applications (WNA), Amrita Vishwa Vidyapeetham（阿姆里塔·维什瓦·维迪亚皮塔姆大学无线网络与应用中心）；Valeo（法雷奥）；Department of Computer Science and Engineering, Amrita Vishwa Vidyapeetham（阿姆里塔·维什瓦·维迪亚皮塔姆大学计算机科学与工程系）；School of Computing and Electrical Engineering, IIT Mandi（印度理工学院曼迪分校计算与电气工程学院）
Computer assisted diagnosis in digital pathology is becoming ubiquitous as it can provide more efficient and objective healthcare diagnostics. Recent advances have shown that the convolutional Neural Network (CNN) architectures, a well-established deep learning paradigm, can be used to design a Computer Aided Diagnostic (CAD) System for breast cancer detection. However, the challenges due to stain variability and the effect of stain normalization with such deep learning frameworks are yet to be well explored. Moreover, performance analysis with arguably more efficient network models, which may…
Cancer is the uncontrollable cell division of abnormal cells inside the human body, which can spread to other body organs. It is one of the non-communicable diseases (NCDs) and NCDs accounts for 71% of total deaths worldwide whereas lung cancer is the second most diagnosed cancer after female breast cancer. Cancer survival rate of lung cancer is only 19%. There are various methods for the diagnosis of lung cancer, such as X-ray, CT scan, PET-CT scan, bronchoscopy and biopsy. However, to know the subtype of lung cancer based on the tissue type H and E staining is widely used, where the staining…
GRAPHITE: Graph-Based Interpretable Tissue Examination for Enhanced Explainability in Breast Cancer Histopathology
School of Computer Science and Engineering（计算机科学与工程学院）；University of New South Wales（新南威尔士大学）；St. George and Sutherland Clinical School（圣乔治与萨瑟兰临床学院）；Department of Anatomical Pathology（解剖病理学部）；NSW Health Pathology（新南威尔士州卫生病理学）；Cancer Care Centre（癌症护理中心）
National University of Sciences and Technology (NUST)（巴基斯坦国立科技大学（NUST））；Riphah International University（里法国际大学）
Unavailability of large training datasets is a bottleneck that needs to be overcome to realize the true potential of deep learning in histopathology applications. Although slide digitization via whole slide imaging scanners has increased the speed of data acquisition, labeling of virtual slides requires a substantial time investment from pathologists. Eye gaze annotations have the potential to speed up the slide labeling process. This work explores the viability and timing comparisons of eye gaze labeling compared to conventional manual labeling for training object detectors. Challenges associ…
University of Waterloo（滑铁卢大学）；University of Toronto（多伦多大学）；Vector Institute（矢量研究院）
Recent advances in digital pathology have led to the need for Histopathology Image Retrieval (HIR) systems that search through databases of biopsy images to find similar cases to a given query image. These HIR systems allow pathologists to effortlessly and efficiently access thousands of previously diagnosed cases in order to exploit the knowledge in the corresponding pathology reports. Since HIR systems may have to deal with millions of gigapixel images, the extraction of compact and expressive image features must be available to allow for efficient and accurate retrieval. In this paper, we p…
University of Waterloo（滑铁卢大学）；Amirkabir University of Technology（阿米尔卡比尔理工大学）
We explore the problem of classification within a medical image data-set based on a feature vector extracted from the deepest layer of pre-trained Convolution Neural Networks. We have used feature vectors from several pre-trained structures, including networks with/without transfer learning to evaluate the performance of pre-trained deep features versus CNNs which have been trained by that specific dataset as well as the impact of transfer learning with a small number of samples. All experiments are done on Kimia Path24 dataset which consists of 27,055 histopathology training patches in 24 tis…
We propose a virtual staining methodology based on Generative Adversarial Networks to map histopathology images of breast cancer tissue from H&E stain to PHH3 and vice versa. We use the resulting synthetic images to build Convolutional Neural Networks (CNN) for automatic detection of mitotic figures, a strong prognostic biomarker used in routine breast cancer diagnosis and grading. We propose several scenarios, in which CNN trained with synthetically generated histopathology images perform on par with or even better than the same baseline model trained with real images. We discuss the potentia…
Feature-interactive Siamese graph encoder-based image analysis to predict STAS from histopathology images in lung cancer
Hunan University（湖南大学）；The Second Xiangya Hospital, Central South University（中南大学湘雅二医院）；Central South University（中南大学）；Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis（湖南省肿瘤致病基因检测与诊断临床医学研究中心）；Shanghai Cancer Institute（上海市肿瘤研究所）；Renji Hospital, School of Medicine, Shanghai Jiaotong University（上海交通大学医学院附属仁济医院）；Shanghai Jiaotong University（上海交通大学）
Despite the promise of Convolutional neural network (CNN) based classification models for histopathological images, it is infeasible to quantify its uncertainties. Moreover, CNNs may suffer from overfitting when the data is biased. We show that Bayesian-CNN can overcome these limitations by regularizing automatically and by quantifying the uncertainty. We have developed a novel technique to utilize the uncertainties provided by the Bayesian-CNN that significantly improves the performance on a large fraction of the test data (about 6% improvement in accuracy on 77% of test data). Further, we pr…
University of Michigan（密歇根大学）；Imbio LLC（Imbio有限责任公司）
Early detection of lung cancer is critical for improvement of patient survival. To address the clinical need for efficacious treatments, genetically engineered mouse models (GEMM) have become integral in identifying and evaluating the molecular underpinnings of this complex disease that may be exploited as therapeutic targets. Assessment of GEMM tumor burden on histopathological sections performed by manual inspection is both time consuming and prone to subjective bias. Therefore, an interplay of needs and challenges exists for computer-aided diagnostic tools, for accurate and efficient analys…
Modern histopathological image analysis relies on the segmentation of cell structures to derive quantitative metrics required in biomedical research and clinical diagnostics. State-of-the-art deep learning approaches predominantly apply convolutional layers in segmentation and are typically highly customized for a specific experimental configuration; often unable to generalize to unknown data. As the model capacity of classical convolutional layers is limited by a finite set of learned kernels, our approach uses a graph representation of the image and focuses on the node transitions in multipl…
Friedrich-Alexander-Universität Erlangen-Nürnberg（埃尔朗根-纽伦堡弗里德里希-亚历山大大学）；Freie Universität Berlin（柏林自由大学）；University of Veterinary Medicine, Vienna（维也纳兽医大学）；University Medical Centre Utrecht（乌得勒支大学医学中心）；Technische Hochschule Ingolstadt（因戈尔施塔特应用技术大学）
In histopathology, scanner-induced domain shifts are known to impede the performance of trained neural networks when tested on unseen data. Multi-domain pre-training or dedicated domain-generalization techniques can help to develop domain-agnostic algorithms. For this, multi-scanner datasets with a high variety of slide scanning systems are highly desirable. We present a publicly available multi-scanner dataset of canine cutaneous squamous cell carcinoma histopathology images, composed of 44 samples digitized with five slide scanners. This dataset provides local correspondences between images …
University of Connecticut（康涅狄格大学）；University of Connecticut Health Center（康涅狄格大学健康中心）
Prostate cancer is the most common cancer in men worldwide and the second leading cause of cancer death in the United States. One of the prognostic features in prostate cancer is the Gleason grading of histopathology images. The Gleason grade is assigned based on tumor architecture on Hematoxylin and Eosin (H&E) stained whole slide images (WSI) by the pathologists. This process is time-consuming and has known interobserver variability. In the past few years, deep learning algorithms have been used to analyze histopathology images, delivering promising results for grading prostate cancer. Howev…
Automated classification of histopathological whole-slide images (WSI) of breast tissue requires analysis at very high resolutions with a large contextual area. In this paper, we present context-aware stacked convolutional neural networks (CNN) for classification of breast WSIs into normal/benign, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC). We first train a CNN using high pixel resolution patches to capture cellular level information. The feature responses generated by this model are then fed as input to a second CNN, stacked on top of the first. Training of this stac…
Studies estimate that there will be 266,120 new cases of invasive breast cancer and 40,920 breast cancer induced deaths in the year of 2018 alone. Despite the pervasiveness of this affliction, the current process to obtain an accurate breast cancer prognosis is tedious and time consuming, requiring a trained pathologist to manually examine histopathological images in order to identify the features that characterize various cancer severity levels. We propose MITOS-RCNN: a novel region based convolutional neural network (RCNN) geared for small object detection to accurately grade one of the thre…
SIGMMA: Hierarchical Graph-Based Multi-Scale Multi-modal Contrastive Alignment of Histopathology Image and Spatial Transcriptome
Wellcome Sanger Institute（沃森桑格研究所）；Cambridge Centre for AI in Medicine（剑桥人工智能医学中心）；Institute of AI for Health（人工智能与健康研究所）；Cambridge Stem Cell Institute（剑桥干细胞研究所）
Dartmouth College（达特茅斯学院）；Dartmouth-Hitchcock Medical Center（达特茅斯-希区柯克医疗中心）
We present an image translation approach to generate augmented data for mitigating data imbalances in a dataset of histopathology images of colorectal polyps, adenomatous tumors that can lead to colorectal cancer if left untreated. By applying cycle-consistent generative adversarial networks (CycleGANs) to a source domain of normal colonic mucosa images, we generate synthetic colorectal polyp images that belong to diagnostically less common polyp classes. Generated images maintain the general structure of their source image but exhibit adenomatous features that can be enhanced with our propose…
As many algorithms depend on a suitable representation of data, learning unique features is considered a crucial task. Although supervised techniques using deep neural networks have boosted the performance of representation learning, the need for a large set of labeled data limits the application of such methods. As an example, high-quality delineations of regions of interest in the field of pathology is a tedious and time-consuming task due to the large image dimensions. In this work, we explored the performance of a deep neural network and triplet loss in the area of representation learning.…
ProBAG: Prototype-Guided Boundary-Aware Graph Diffusion for Weakly Supervised Histopathology Segmentation
AI VIETNAM Lab（AI越南实验室）；Washington University School of Medicine（华盛顿大学医学院）；Jeonbuk National University（全北国立大学）；Perelman School of Medicine, University of Pennsylvania（宾夕法尼亚大学佩雷尔曼医学院）
University of Toronto（多伦多大学）；National Cancer Research Centre（国家癌症研究中心）；Institute for Oncology and Radiology（肿瘤与放射学研究所）
Accurate diagnosis of breast cancer in histopathology images is challenging due to the heterogeneity of cancer cell growth as well as of a variety of benign breast tissue proliferative lesions. In this paper, we propose a practical and self-interpretable invasive cancer diagnosis solution. With minimum annotation information, the proposed method mines contrast patterns between normal and malignant images in unsupervised manner and generates a probability map of abnormalities to verify its reasoning. Particularly, a fully convolutional autoencoder is used to learn the dominant structural patter…
Dartmouth College（达特茅斯学院）；Dartmouth-Hitchcock Medical Center（达特茅斯-希区柯克医学中心）
With the rise of deep learning, there has been increased interest in using neural networks for histopathology image analysis, a field that investigates the properties of biopsy or resected specimens traditionally manually examined under a microscope by pathologists. However, challenges such as limited data, costly annotation, and processing high-resolution and variable-size images make it difficult to quickly iterate over model designs. Throughout scientific history, many significant research directions have leveraged small-scale experimental setups as petri dishes to efficiently evaluate expl…
Rose-Hulman Institute of Technology（罗斯-霍曼理工学院）；Honeywell FM&T（霍尼韦尔FM&T）
Classification of cancer cellularity within tissue samples is currently a manual process performed by pathologists. This process of correctly determining cancer cellularity can be time intensive. Deep Learning (DL) techniques in particular have become increasingly more popular for this purpose, due to the accuracy and performance they exhibit, which can be comparable to the pathologists. This work investigates the capabilities of two DL approaches to assess cancer cellularity in whole slide images (WSI) in the SPIE-AAPM-NCI BreastPathQ challenge dataset. The effects of training on augmented da…
Shenzhen Research Institute of Big Data（深圳大数据研究院）；The Chinese University of Hong Kong at Shenzhen（香港中文大学（深圳））；Pazhou Lab（琶洲实验室）；School of Computer Science and Engineering, Sun Yat-sen University（中山大学计算机科学与工程学院）；Artificial Intelligence Thrust, The Hong Kong University of Science and Technology at Guangzhou（香港科技大学广州人工智能部）；Shanghai Artificial Intelligence Laboratory（上海人工智能实验室）；Guangdong Provincial Key Laboratory of Big Data Computing（广东省大数据计算重点实验室）；Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases（广东省结直肠和盆底疾病重点实验室）
Nuclei classification provides valuable information for histopathology image analysis. However, the large variations in the appearance of different nuclei types cause difficulties in identifying nuclei. Most neural network based methods are affected by the local receptive field of convolutions, and pay less attention to the spatial distribution of nuclei or the irregular contour shape of a nucleus. In this paper, we first propose a novel polygon-structure feature learning mechanism that transforms a nucleus contour into a sequence of points sampled in order, and employ a recurrent neural netwo…
IBM Research（IBM研究院）；EPFL（洛桑联邦理工学院）；ETH（苏黎世联邦理工学院）
Advances in entity-graph based analysis of histopathology images have brought in a new paradigm to describe tissue composition, and learn the tissue structure-to-function relationship. Entity-graphs offer flexible and scalable representations to characterize tissue organization, while allowing the incorporation of prior pathological knowledge to further support model interpretability and explainability. However, entity-graph analysis requires prerequisites for image-to-graph translation and knowledge of state-of-the-art machine learning algorithms applied to graph-structured data, which can po…
Breast cancer has the highest mortality among cancers in women. Computer-aided pathology to analyze microscopic histopathology images for diagnosis with an increasing number of breast cancer patients can bring the cost and delays of diagnosis down. Deep learning in histopathology has attracted attention over the last decade of achieving state-of-the-art performance in classification and localization tasks. The convolutional neural network, a deep learning framework, provides remarkable results in tissue images analysis, but lacks in providing interpretation and reasoning behind the decisions. …
University of Geneva (UNIGE)（日内瓦大学）；University of Applied Sciences Western Switzerland (HES-SO)（瑞士西部应用科学大学）
Explanations for deep neural network predictions in terms of domain-related concepts can be valuable in medical applications, where justifications are important for confidence in the decision-making. In this work, we propose a methodology to exploit continuous concept measures as Regression Concept Vectors (RCVs) in the activation space of a layer. The directional derivative of the decision function along the RCVs represents the network sensitivity to increasing values of a given concept measure. When applied to breast cancer grading, nuclei texture emerges as a relevant concept in the detecti…
University Medical Center Hamburg-Eppendorf（汉堡埃彭多夫大学医学中心）；Center for Biomedical Artificial Intelligence (bAIome)（生物医学人工智能中心（bAIome））；Department of Computational Neuroscience（计算神经科学系）；I. Department of Internal Medicine（第一内科）；Department of Pathology（病理学系）；Department for Interdisciplinary Endoscopy（跨学科内镜检查科）
Histopathologic diagnosis relies on simultaneous integration of information from a broad range of scales, ranging from nuclear aberrations ($\approx \mathcal{O}(0.1{μm})$) through cellular structures ($\approx \mathcal{O}(10{μm})$) to the global tissue architecture ($\gtrapprox \mathcal{O}(1{mm})$). To explicitly mimic how human pathologists combine multi-scale information, we introduce a family of multi-encoder FCNs with deep fusion. We present a simple block for merging model paths with differing spatial scales in a spatial relationship-preserving fashion, which can readily be included in st…
Microsoft Research（微软研究院）；Beihang University（北京航空航天大学）；Tsinghua University（清华大学）
In this paper, we develop a new weakly-supervised learning algorithm to learn to segment cancerous regions in histopathology images. Our work is under a multiple instance learning framework (MIL) with a new formulation, deep weak supervision (DWS); we also propose an effective way to introduce constraints to our neural networks to assist the learning process. The contributions of our algorithm are threefold: (1) We build an end-to-end learning system that segments cancerous regions with fully convolutional networks (FCN) in which image-to-image weakly-supervised learning is performed. (2) We d…
While microscopic analysis of histopathological slides is generally considered as the gold standard method for performing cancer diagnosis and grading, the current method for analysis is extremely time consuming and labour intensive as it requires pathologists to visually inspect tissue samples in a detailed fashion for the presence of cancer. As such, there has been significant recent interest in computer aided diagnosis systems for analysing histopathological slides for cancer grading to aid pathologists to perform cancer diagnosis and grading in a more efficient, accurate, and consistent ma…
Advancement in digital pathology and artificial intelligence has enabled deep learning-based computer vision techniques for automated disease diagnosis and prognosis. However, WSIs present unique computational and algorithmic challenges. WSIs are gigapixel-sized, making them infeasible to be used directly for training deep neural networks. Hence, for modeling, a two-stage approach is adopted: Patch representations are extracted first, followed by the aggregation for WSI prediction. These approaches require detailed pixel-level annotations for training the patch encoder. However, obtaining thes…
Leveraging Medical Foundation Model Features in Graph Neural Network-Based Retrieval of Breast Histopathology Images
Artificial Intelligence Department, Faculty of Computer Engineering, University of Isfahan, Isfahan, Iran；Department of Computer Engineering Techniques, Mazaya University College, Nasiriyah, Iraq；Department of Medicine, Danube Private University, Krems an der Donau, Austria；Austrian Center for Medical Innovation；Research Center for Medical Image Analysis；Artificial Intelligence, Department of Medicine, Danube Private University, Krems an der Donau, Austria
University of Rochester（罗切斯特大学）；HistoWiz Inc.（HistoWiz公司）
Automated whole slide image (WSI) tagging has become a growing demand due to the increasing volume and diversity of WSIs collected nowadays in histopathology. Various methods have been studied to classify WSIs with single tags but none of them focuses on labeling WSIs with multiple tags. To this end, we propose a novel end-to-end trainable deep neural network named Patch Transformer which can effectively predict multiple slide-level tags from WSI patches based on both the correlations and the uniqueness between the tags. Specifically, the proposed method learns patch characteristics considerin…
