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Early detection of cancer can help improve patient prognosis by early intervention. Head and neck cancer is diagnosed in specialist centres after a surgical biopsy, however, there is a potential for these to be missed leading to delayed diagnosis. To overcome these challenges, we present an attention based pipeline that identifies suspected lesions, segments, and classifies them as non-dysplastic, dysplastic and cancerous lesions. We propose (a) a vision transformer based Mask R-CNN network for lesion detection and segmentation of clinical images, and (b) Multiple Instance Learning (MIL) based scheme for classification. Current results show that the segmentation model produces segmentation masks and bounding boxes with up to 82% overlap accuracy score on unseen external test data and surpassing reviewed segmentation benchmarks. Next, a classification F1-score of 85% on the internal cohort test set. An app has been developed to perform lesion segmentation taken via a smart device. Future work involves employing endoscopic video data for precise early detection and prognosis., Comment: 5 pages, 3 figures, accepted in ISBI 2024, update: corrected typos

Whole Slide Images (WSIs) provide exceptional detail for studying tissue architecture at the cell level. To study tumour microenvironment (TME) with the context of various protein biomarkers and cell sub-types, analysis and registration of features using multi-stained WSIs is often required. Multi-stained WSI pairs normally suffer from rigid and non-rigid deformities in addition to slide artefacts and control tissue which present challenges at precise registration. Traditional registration methods mainly focus on global rigid/non-rigid registration but struggle with aligning slides with complex tissue deformations at the nuclei level. However, nuclei level non-rigid registration is essential for downstream tasks such as cell sub-type analysis in the context of protein biomarker signatures. This paper focuses on local level non-rigid registration using a nuclei-location based point set registration approach for aligning multi-stained WSIs. We exploit the spatial distribution of nuclei that is prominent and consistent (to a large level) across different stains to establish a spatial correspondence. We evaluate our approach using the HYRECO dataset consisting of 54 re-stained images of H\&E and PHH3 image pairs. The approach can be extended to other IHC and IF stained WSIs considering a good nuclei detection algorithm is accessible. The performance of the model is tested against established registration algorithms and is shown to outperform the model for nuclei level registration., Comment: 15 pages, 5 figures, Submitted to Medical Image Understanding and Analysis Conference 2024

Gastric and oesophageal (OG) cancers are the leading causes of cancer mortality worldwide. In OG cancers, recent studies have showed that PDL1 immune checkpoint inhibitors (ICI) in combination with chemotherapy improves patient survival. However, our understanding of the tumour immune microenvironment in OG cancers remains limited. In this study, we interrogate multiplex immunofluorescence (mIF) images taken from patients with advanced Oesophagogastric Adenocarcinoma (OGA) who received first-line fluoropyrimidine and platinum-based chemotherapy in the PLATFORM trial (NCT02678182) to predict the efficacy of the treatment and to explore the biological basis of patients responding to maintenance durvalumab (PDL1 inhibitor). Our proposed Artificial Intelligence (AI) based marker successfully identified responder from non-responder (p < 0.05) as well as those who could potentially benefit from ICI with statistical significance (p < 0.05) for both progression free and overall survival. Our findings suggest that T cells that express FOXP3 seem to heavily influence the patient treatment response and survival outcome. We also observed that higher levels of CD8+PD1+ cells are consistently linked to poor prognosis for both OS and PFS, regardless of ICI.

Lung adenocarcinoma is a morphologically heterogeneous disease, characterized by five primary histologic growth patterns. The quantity of these patterns can be related to tumor behavior and has a significant impact on patient prognosis. In this work, we propose a novel machine learning pipeline capable of classifying tissue tiles into one of the five patterns or as non-tumor, with an Area Under the Receiver Operating Characteristic Curve (AUCROC) score of 0.97. Our model's strength lies in its comprehensive consideration of cellular spatial patterns, where it first generates cell maps from Hematoxylin and Eosin (H&E) whole slide images (WSIs), which are then fed into a convolutional neural network classification model. Exploiting these cell maps provides the model with robust generalizability to new data, achieving approximately 30% higher accuracy on unseen test-sets compared to current state of the art approaches. The insights derived from our model can be used to predict prognosis, enhancing patient outcomes.

Tumour-infiltrating lymphocytes (TILs) are considered as a valuable prognostic markers in both triple-negative and human epidermal growth factor receptor 2 (HER2) positive breast cancer. In this study, we introduce an innovative deep learning pipeline based on the Efficient-UNet architecture to predict the TILs score for breast cancer whole-slide images (WSIs). We first segment tumour and stromal regions in order to compute a tumour bulk mask. We then detect TILs within the tumour-associated stroma, generating a TILs score by closely mirroring the pathologist's workflow. Our method exhibits state-of-the-art performance in segmenting tumour/stroma areas and TILs detection, as demonstrated by internal cross-validation on the TiGER Challenge training dataset and evaluation on the final leaderboards. Additionally, our TILs score proves competitive in predicting survival outcomes within the same challenge, underscoring the clinical relevance and potential of our automated TILs scoring pipeline as a breast cancer prognostic tool., Comment: 5 pages, 1 figure, 2 tables

Oral epithelial dysplasia (OED) is a premalignant histopathological diagnosis given to lesions of the oral cavity. OED grading is subject to large inter/intra-rater variability, resulting in the under/over-treatment of patients. We developed a new Transformer-based pipeline to improve detection and segmentation of OED in haematoxylin and eosin (H&E) stained whole slide images (WSIs). Our model was trained on OED cases (n = 260) and controls (n = 105) collected using three different scanners, and validated on test data from three external centres in the United Kingdom and Brazil (n = 78). Our internal experiments yield a mean F1-score of 0.81 for OED segmentation, which reduced slightly to 0.71 on external testing, showing good generalisability, and gaining state-of-the-art results. This is the first externally validated study to use Transformers for segmentation in precancerous histology images. Our publicly available model shows great promise to be the first step of a fully-integrated pipeline, allowing earlier and more efficient OED diagnosis, ultimately benefiting patient outcomes., Comment: 5 pages, 2 figures, 4 tables

Deep learning models have exhibited exceptional effectiveness in Computational Pathology (CPath) by tackling intricate tasks across an array of histology image analysis applications. Nevertheless, the presence of out-of-distribution data (stemming from a multitude of sources such as disparate imaging devices and diverse tissue preparation methods) can cause \emph{domain shift} (DS). DS decreases the generalization of trained models to unseen datasets with slightly different data distributions, prompting the need for innovative \emph{domain generalization} (DG) solutions. Recognizing the potential of DG methods to significantly influence diagnostic and prognostic models in cancer studies and clinical practice, we present this survey along with guidelines on achieving DG in CPath. We rigorously define various DS types, systematically review and categorize existing DG approaches and resources in CPath, and provide insights into their advantages, limitations, and applicability. We also conduct thorough benchmarking experiments with 28 cutting-edge DG algorithms to address a complex DG problem. Our findings suggest that careful experiment design and CPath-specific Stain Augmentation technique can be very effective. However, there is no one-size-fits-all solution for DG in CPath. Therefore, we establish clear guidelines for detecting and managing DS depending on different scenarios. While most of the concepts, guidelines, and recommendations are given for applications in CPath, we believe that they are applicable to most medical image analysis tasks as well., Comment: Extended Version

Oral epithelial dysplasia (OED) is a premalignant histopathological diagnosis given to lesions of the oral cavity. Its grading suffers from significant inter-/intra- observer variability, and does not reliably predict malignancy progression, potentially leading to suboptimal treatment decisions. To address this, we developed a novel artificial intelligence algorithm that can assign an Oral Malignant Transformation (OMT) risk score, based on histological patterns in the in Haematoxylin and Eosin stained whole slide images, to quantify the risk of OED progression. The algorithm is based on the detection and segmentation of nuclei within (and around) the epithelium using an in-house segmentation model. We then employed a shallow neural network fed with interpretable morphological/spatial features, emulating histological markers. We conducted internal cross-validation on our development cohort (Sheffield; n = 193 cases) followed by independent validation on two external cohorts (Birmingham and Belfast; n = 92 cases). The proposed OMTscore yields an AUROC = 0.74 in predicting whether an OED progresses to malignancy or not. Survival analyses showed the prognostic value of our OMTscore for predicting malignancy transformation, when compared to the manually-assigned WHO and binary grades. Analysis of the correctly predicted cases elucidated the presence of peri-epithelial and epithelium-infiltrating lymphocytes in the most predictive patches of cases that transformed (p < 0.0001). This is the first study to propose a completely automated algorithm for predicting OED transformation based on interpretable nuclear features, whilst being validated on external datasets. The algorithm shows better-than-human-level performance for prediction of OED malignant transformation and offers a promising solution to the challenges of grading OED in routine clinical practice.

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.

Semantic segmentation of various tissue and nuclei types in histology images is fundamental to many downstream tasks in the area of computational pathology (CPath). In recent years, Deep Learning (DL) methods have been shown to perform well on segmentation tasks but DL methods generally require a large amount of pixel-wise annotated data. Pixel-wise annotation sometimes requires expert's knowledge and time which is laborious and costly to obtain. In this paper, we present a consistency based semi-supervised learning (SSL) approach that can help mitigate this challenge by exploiting a large amount of unlabelled data for model training thus alleviating the need for a large annotated dataset. However, SSL models might also be susceptible to changing context and features perturbations exhibiting poor generalisation due to the limited training data. We propose an SSL method that learns robust features from both labelled and unlabelled images by enforcing consistency against varying contexts and feature perturbations. The proposed method incorporates context-aware consistency by contrasting pairs of overlapping images in a pixel-wise manner from changing contexts resulting in robust and context invariant features. We show that cross-consistency training makes the encoder features invariant to different perturbations and improves the prediction confidence. Finally, entropy minimisation is employed to further boost the confidence of the final prediction maps from unlabelled data. We conduct an extensive set of experiments on two publicly available large datasets (BCSS and MoNuSeg) and show superior performance compared to the state-of-the-art methods.

We introduce LYSTO, the Lymphocyte Assessment Hackathon, which was held in conjunction with the MICCAI 2019 Conference in Shenzen (China). The competition required participants to automatically assess the number of lymphocytes, in particular T-cells, in histopathological images of colon, breast, and prostate cancer stained with CD3 and CD8 immunohistochemistry. Differently from other challenges setup in medical image analysis, LYSTO participants were solely given a few hours to address this problem. In this paper, we describe the goal and the multi-phase organization of the hackathon; we describe the proposed methods and the on-site results. Additionally, we present post-competition results where we show how the presented methods perform on an independent set of lung cancer slides, which was not part of the initial competition, as well as a comparison on lymphocyte assessment between presented methods and a panel of pathologists. We show that some of the participants were capable to achieve pathologist-level performance at lymphocyte assessment. After the hackathon, LYSTO was left as a lightweight plug-and-play benchmark dataset on grand-challenge website, together with an automatic evaluation platform. LYSTO has supported a number of research in lymphocyte assessment in oncology. LYSTO will be a long-lasting educational challenge for deep learning and digital pathology, it is available at https://lysto.grand-challenge.org/., Comment: will be sumitted to IEEE-JBHI

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., Comment: Oral presentation at MICCAI MLMI 2022, 7 pages, 6 figures

Counting of mitotic figures is a fundamental step in grading and prognostication of several cancers. However, manual mitosis counting is tedious and time-consuming. In addition, variation in the appearance of mitotic figures causes a high degree of discordance among pathologists. With advances in deep learning models, several automatic mitosis detection algorithms have been proposed but they are sensitive to {\em domain shift} often seen in histology images. We propose a robust and efficient two-stage mitosis detection framework, which comprises mitosis candidate segmentation ({\em Detecting Fast}) and candidate refinement ({\em Detecting Slow}) stages. The proposed candidate segmentation model, termed \textit{EUNet}, is fast and accurate due to its architectural design. EUNet can precisely segment candidates at a lower resolution to considerably speed up candidate detection. Candidates are then refined using a deeper classifier network, EfficientNet-B7, in the second stage. We make sure both stages are robust against domain shift by incorporating domain generalization methods. We demonstrate state-of-the-art performance and generalizability of the proposed model on the three largest publicly available mitosis datasets, winning the two mitosis domain generalization challenge contests (MIDOG21 and MIDOG22). Finally, we showcase the utility of the proposed algorithm by processing the TCGA breast cancer cohort (1,125 whole-slide images) to generate and release a repository of more than 620K mitotic figures., Comment: Extended version of the work done for MIDOG challenge submission

The quantification of tumor-infiltrating lymphocytes (TILs) has been shown to be an independent predictor for prognosis of breast cancer patients. Typically, pathologists give an estimate of the proportion of the stromal region that contains TILs to obtain a TILs score. The Tumor InfiltratinG lymphocytes in breast cancER (TiGER) challenge, aims to assess the prognostic significance of computer-generated TILs scores for predicting survival as part of a Cox proportional hazards model. For this challenge, as the TIAger team, we have developed an algorithm to first segment tumor vs. stroma, before localising the tumor bulk region for TILs detection. Finally, we use these outputs to generate a TILs score for each case. On preliminary testing, our approach achieved a tumor-stroma weighted Dice score of 0.791 and a FROC score of 0.572 for lymphocytic detection. For predicting survival, our model achieved a C-index of 0.719. These results achieved first place across the preliminary testing leaderboards of the TiGER challenge., Comment: TiGER Challenge entry

The recent surge in performance for image analysis of digitised pathology slides can largely be attributed to the advances in deep learning. Deep models can be used to initially localise various structures in the tissue and hence facilitate the extraction of interpretable features for biomarker discovery. However, these models are typically trained for a single task and therefore scale poorly as we wish to adapt the model for an increasing number of different tasks. Also, supervised deep learning models are very data hungry and therefore rely on large amounts of training data to perform well. In this paper, we present a multi-task learning approach for segmentation and classification of nuclei, glands, lumina and different tissue regions that leverages data from multiple independent data sources. While ensuring that our tasks are aligned by the same tissue type and resolution, we enable meaningful simultaneous prediction with a single network. As a result of feature sharing, we also show that the learned representation can be used to improve the performance of additional tasks via transfer learning, including nuclear classification and signet ring cell detection. As part of this work, we train our developed Cerberus model on a huge amount of data, consisting of over 600K objects for segmentation and 440K patches for classification. We use our approach to process 599 colorectal whole-slide images from TCGA, where we localise 377 million, 900K and 2.1 million nuclei, glands and lumina, respectively and make the results available to the community for downstream analysis.

The accurate diagnosis and molecular profiling of colorectal cancers are critical for planning the best treatment options for patients. Microsatellite instability (MSI) or mismatch repair (MMR) status plays a vital role in appropriate treatment selection, has prognostic implications and is used to investigate the possibility of patients having underlying genetic disorders (Lynch syndrome). NICE recommends that all CRC patients should be offered MMR/MSI testing. Immunohistochemistry is commonly used to assess MMR status with subsequent molecular testing performed as required. This incurs significant extra costs and requires additional resources. The introduction of automated methods that can predict MSI or MMR status from a target image could substantially reduce the cost associated with MMR testing. Unlike previous studies on MSI prediction involving training a CNN using coarse labels (MSI vs Microsatellite Stable (MSS)), we have utilised fine-grain MMR labels for training purposes. In this paper, we present our work on predicting MSI status in a two-stage process using a single target slide either stained with CK8/18 or H&E. First, we trained a multi-headed convolutional neural network model where each head was responsible for predicting one of the MMR protein expressions. To this end, we performed the registration of MMR stained slides to the target slide as a pre-processing step. In the second stage, statistical features computed from the MMR prediction maps were used for the final MSI prediction. Our results demonstrated that MSI classification can be improved by incorporating fine-grained MMR labels in comparison to the previous approaches in which only coarse labels were utilised.

Cross-slide image analysis provides additional information by analysing the expression of different biomarkers as compared to a single slide analysis. These biomarker stained slides are analysed side by side, revealing unknown relations between them. During the slide preparation, a tissue section may be placed at an arbitrary orientation as compared to other sections of the same tissue block. The problem is compounded by the fact that tissue contents are likely to change from one section to the next and there may be unique artefacts on some of the slides. This makes registration of each section to a reference section of the same tissue block an important pre-requisite task before any cross-slide analysis. We propose a deep feature based registration (DFBR) method which utilises data-driven features to estimate the rigid transformation. We adopted a multi-stage strategy for improving the quality of registration. We also developed a visualisation tool to view registered pairs of WSIs at different magnifications. With the help of this tool, one can apply a transformation on the fly without the need to generate transformed source WSI in a pyramidal form. We compared the performance of data-driven features with that of hand-crafted features on the COMET dataset. Our approach can align the images with low registration errors. Generally, the success of non-rigid registration is dependent on the quality of rigid registration. To evaluate the efficacy of the DFBR method, the first two steps of the ANHIR winner's framework are replaced with our DFBR to register challenge provided image pairs. The modified framework produces comparable results to that of challenge winning team.

Diagnostic, prognostic and therapeutic decision-making of cancer in pathology clinics can now be carried out based on analysis of multi-gigapixel tissue images, also known as whole-slide images (WSIs). Recently, deep convolutional neural networks (CNNs) have been proposed to derive unsupervised WSI representations; these are attractive as they rely less on expert annotation which is cumbersome. However, a major trade-off is that higher predictive power generally comes at the cost of interpretability, posing a challenge to their clinical use where transparency in decision-making is generally expected. To address this challenge, we present a handcrafted framework based on deep CNN for constructing holistic WSI-level representations. Building on recent findings about the internal working of the Transformer in the domain of natural language processing, we break down its processes and handcraft them into a more transparent framework that we term as the Handcrafted Histological Transformer or H2T. Based on our experiments involving various datasets consisting of a total of 5,306 WSIs, the results demonstrate that H2T based holistic WSI-level representations offer competitive performance compared to recent state-of-the-art methods and can be readily utilized for various downstream analysis tasks. Finally, our results demonstrate that the H2T framework can be up to 14 times faster than the Transformer models.

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.

Federated learning (FL) enables collaborative learning of a deep learning model without sharing the data of participating sites. FL in medical image analysis tasks is relatively new and open for enhancements. In this study, we propose FedDropoutAvg, a new federated learning approach for training a generalizable model. The proposed method takes advantage of randomness, both in client selection and also in federated averaging process. We compare FedDropoutAvg to several algorithms in an FL scenario for real-world multi-site histopathology image classification task. We show that with FedDropoutAvg, the final model can achieve performance better than other FL approaches and closer to a classical deep learning model that requires all data to be shared for centralized training. We test the trained models on a large dataset consisting of 1.2 million image tiles from 21 different centers. To evaluate the generalization ability of the proposed approach, we use held-out test sets from centers whose data was used in the FL and for unseen data from other independent centers whose data was not used in the federated training. We show that the proposed approach is more generalizable than other state-of-the-art federated training approaches. To the best of our knowledge, ours is the first study to use a randomized client and local model parameter selection procedure in a federated setting for a medical image analysis task., Comment: This work has been submitted to the IEEE for possible publication

The development of deep segmentation models for computational pathology (CPath) can help foster the investigation of interpretable morphological biomarkers. Yet, there is a major bottleneck in the success of such approaches because supervised deep learning models require an abundance of accurately labelled data. This issue is exacerbated in the field of CPath because the generation of detailed annotations usually demands the input of a pathologist to be able to distinguish between different tissue constructs and nuclei. Manually labelling nuclei may not be a feasible approach for collecting large-scale annotated datasets, especially when a single image region can contain thousands of different cells. However, solely relying on automatic generation of annotations will limit the accuracy and reliability of ground truth. Therefore, to help overcome the above challenges, we propose a multi-stage annotation pipeline to enable the collection of large-scale datasets for histology image analysis, with pathologist-in-the-loop refinement steps. Using this pipeline, we generate the largest known nuclear instance segmentation and classification dataset, containing nearly half a million labelled nuclei in H&E stained colon tissue. We have released the dataset and encourage the research community to utilise it to drive forward the development of downstream cell-based models in CPath.

Recent advances in whole slide imaging (WSI) technology have led to the development of a myriad of computer vision and artificial intelligence (AI) based diagnostic, prognostic, and predictive algorithms. Computational Pathology (CPath) offers an integrated solution to utilize information embedded in pathology WSIs beyond what we obtain through visual assessment. For automated analysis of WSIs and validation of machine learning (ML) models, annotations at the slide, tissue and cellular levels are required. The annotation of important visual constructs in pathology images is an important component of CPath projects. Improper annotations can result in algorithms which are hard to interpret and can potentially produce inaccurate and inconsistent results. Despite the crucial role of annotations in CPath projects, there are no well-defined guidelines or best practices on how annotations should be carried out. In this paper, we address this shortcoming by presenting the experience and best practices acquired during the execution of a large-scale annotation exercise involving a multidisciplinary team of pathologists, ML experts and researchers as part of the Pathology image data Lake for Analytics, Knowledge and Education (PathLAKE) consortium. We present a real-world case study along with examples of different types of annotations, diagnostic algorithm, annotation data dictionary and annotation constructs. The analyses reported in this work highlight best practice recommendations that can be used as annotation guidelines over the lifecycle of a CPath project.

The infiltration of T-lymphocytes in the stroma and tumour is an indication of an effective immune response against the tumour, resulting in better survival. In this study, our aim is to explore the prognostic significance of tumour-associated stroma infiltrating lymphocytes (TASILs) in head and neck squamous cell carcinoma (HNSCC) through an AI based automated method. A deep learning based automated method was employed to segment tumour, stroma and lymphocytes in digitally scanned whole slide images of HNSCC tissue slides. The spatial patterns of lymphocytes and tumour-associated stroma were digitally quantified to compute the TASIL-score. Finally, prognostic significance of the TASIL-score for disease-specific and disease-free survival was investigated with the Cox proportional hazard analysis. Three different cohorts of Haematoxylin & Eosin (H&E) stained tissue slides of HNSCC cases (n=537 in total) were studied, including publicly available TCGA head and neck cancer cases. The TASIL-score carries prognostic significance (p=0.002) for disease-specific survival of HNSCC patients. The TASIL-score also shows a better separation between low- and high-risk patients as compared to the manual TIL scoring by pathologists for both disease-specific and disease-free survival. A positive correlation of TASIL-score with molecular estimates of CD8+ T cells was also found, which is in line with existing findings. To the best of our knowledge, this is the first study to automate the quantification of TASIL from routine H&E slides of head and neck cancer. Our TASIL-score based findings are aligned with the clinical knowledge with the added advantages of objectivity, reproducibility and strong prognostic value. A comprehensive evaluation on large multicentric cohorts is required before the proposed digital score can be adopted in clinical practice.