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Whole slide image (WSI) registration is an essential task for analysing the tumour microenvironment (TME) in histopathology. It involves the alignment of spatial information between WSIs of the same section or serial sections of a tissue sample. The tissue sections are usually stained with single or multiple biomarkers before imaging, and the goal is to identify neighbouring nuclei along the Z-axis for creating a 3D image or identifying subclasses of cells in the TME. This task is considerably more challenging compared to radiology image registration, such as magnetic resonance imaging or computed tomography, due to various factors. These include gigapixel size of images, variations in appearance between differently stained tissues, changes in structure and morphology between non-consecutive sections, and the presence of artefacts, tears, and deformations. Currently, there is a noticeable gap in the literature regarding a review of the current approaches and their limitations, as well as the challenges and opportunities they present. We aim to provide a comprehensive understanding of the available approaches and their application for various purposes. Furthermore, we investigate current deep learning methods used for WSI registration, emphasising their diverse methodologies. We examine the available datasets and explore tools and software employed in the field. Finally, we identify open challenges and potential future trends in this area of research.

Background: Phage therapy shows promise for treating antibiotic-resistant Klebsiella infections. Identifying phage depolymerases that target Klebsiella capsular polysaccharides is crucial, as these capsules contribute to biofilm formation and virulence. However, homology-based searches have limitations in novel depolymerase discovery. Objective: To develop a machine learning model for identifying and ranking potential phage depolymerases targeting Klebsiella. Methods: We developed DepoRanker, a machine learning algorithm to rank proteins by their likelihood of being depolymerases. The model was experimentally validated on 5 newly characterized proteins and compared to BLAST. Results: DepoRanker demonstrated superior performance to BLAST in identifying potential depolymerases. Experimental validation confirmed its predictive ability on novel proteins. Conclusions: DepoRanker provides an accurate and functional tool to expedite depolymerase discovery for phage therapy against Klebsiella. It is available as a webserver and open-source software. Availability: Webserver: https://deporanker.dcs.warwick.ac.uk/ Source code: https://github.com/wgrgwrght/deporanker

Machine learning in computational pathology (CPath) often aggregates patch-level predictions from multi-gigapixel Whole Slide Images (WSIs) to generate WSI-level prediction scores for crucial tasks such as survival prediction and drug effect prediction. However, current methods do not explicitly characterize distributional differences between patch sets within WSIs. We introduce HistoKernel, a novel Maximum Mean Discrepancy (MMD) kernel that measures distributional similarity between WSIs for enhanced prediction performance on downstream prediction tasks. Our comprehensive analysis demonstrates HistoKernel's effectiveness across various machine learning tasks, including retrieval (n = 9,362), drug sensitivity regression (n = 551), point mutation classification (n = 3,419), and survival analysis (n = 2,291), outperforming existing deep learning methods. Additionally, HistoKernel seamlessly integrates multi-modal data and offers a novel perturbation-based method for patch-level explainability. This work pioneers the use of kernel-based methods for WSI-level predictive modeling, opening new avenues for research. Code is available at https://github.com/pkeller00/HistoKernel., Comment: 28 pages, 5 figures, 1 Table. Preprint for article in review at Nature Machine Intelligence

Pathology reports are rich in clinical and pathological details but are often presented in free-text format. The unstructured nature of these reports presents a significant challenge limiting the accessibility of their content. In this work, we present a practical approach based on the use of large multimodal models (LMMs) for automatically extracting information from scanned images of pathology reports with the goal of generating a standardised report specifying the value of different fields along with estimated confidence about the accuracy of the extracted fields. The proposed approach overcomes limitations of existing methods which do not assign confidence scores to extracted fields limiting their practical use. The proposed framework uses two stages of prompting a Large Multimodal Model (LMM) for information extraction and validation. The framework generalises to textual reports from multiple medical centres as well as scanned images of legacy pathology reports. We show that the estimated confidence is an effective indicator of the accuracy of the extracted information that can be used to select only accurately extracted fields. We also show the prognostic significance of structured and unstructured data from pathology reports and show that the automatically extracted field values significant prognostic value for patient stratification. The framework is available for evaluation via the URL: https://labieb.dcs.warwick.ac.uk/., Comment: 19 pages, 6 figures

Digital pathology has gained significant traction in modern healthcare systems. This shift from optical microscopes to digital imagery brings with it the potential for improved diagnosis, efficiency, and the integration of AI tools into the pathologists workflow. A critical aspect of this is visualization. Throughout the development of a machine learning (ML) model in digital pathology, it is crucial to have flexible, openly available tools to visualize models, from their outputs and predictions to the underlying annotations and images used to train or test a model. We introduce TIAViz, a Python-based visualization tool built into TIAToolbox which allows flexible, interactive, fully zoomable overlay of a wide variety of information onto whole slide images, including graphs, heatmaps, segmentations, annotations and other WSIs. The UI is browser-based, allowing use either locally, on a remote machine, or on a server to provide publicly available demos. This tool is open source and is made available at: https://github.com/TissueImageAnalytics/tiatoolbox and via pip installation (pip install tiatoolbox) and conda as part of TIAToolbox., Comment: Application note to be submitted to bioinformatics

Quantum machine learning with quantum kernels for classification problems is a growing area of research. Recently, quantum kernel alignment techniques that parameterise the kernel have been developed, allowing the kernel to be trained and therefore aligned with a specific dataset. While quantum kernel alignment is a promising technique, it has been hampered by considerable training costs because the full kernel matrix must be constructed at every training iteration. Addressing this challenge, we introduce a novel method that seeks to balance efficiency and performance. We present a sub-sampling training approach that uses a subset of the kernel matrix at each training step, thereby reducing the overall computational cost of the training. In this work, we apply the sub-sampling method to synthetic datasets and a real-world breast cancer dataset and demonstrate considerable reductions in the number of circuits required to train the quantum kernel while maintaining classification accuracy., Comment: Paper as accepted on Quantum on 2024-09-18. The method showcased in this work is also available as a Jupyter notebook at https://github.com/qiskit-community/qiskit-machine-learning/tree/IEEE2024

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.

Generating realistic tissue images with annotations is a challenging task that is important in many computational histopathology applications. Synthetically generated images and annotations are valuable for training and evaluating algorithms in this domain. To address this, we propose an interactive framework generating pairs of realistic colorectal cancer histology images with corresponding glandular masks from glandular structure layouts. The framework accurately captures vital features like stroma, goblet cells, and glandular lumen. Users can control gland appearance by adjusting parameters such as the number of glands, their locations, and sizes. The generated images exhibit good Frechet Inception Distance (FID) scores compared to the state-of-the-art image-to-image translation model. Additionally, we demonstrate the utility of our synthetic annotations for evaluating gland segmentation algorithms. Furthermore, we present a methodology for constructing glandular masks using advanced deep generative models, such as latent diffusion models. These masks enable tissue image generation through a residual encoder-decoder network.

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.

Malignant mesothelioma is classified into three histological subtypes, Epithelioid, Sarcomatoid, and Biphasic according to the relative proportions of epithelioid and sarcomatoid tumor cells present. Biphasic tumors display significant populations of both cell types. This subtyping is subjective and limited by current diagnostic guidelines and can differ even between expert thoracic pathologists when characterising the continuum of relative proportions of epithelioid and sarcomatoid components using a three class system. In this work, we develop a novel dual-task Graph Neural Network (GNN) architecture with ranking loss to learn a model capable of scoring regions of tissue down to cellular resolution. This allows quantitative profiling of a tumor sample according to the aggregate sarcomatoid association score of all the cells in the sample. The proposed approach uses only core-level labels and frames the prediction task as a dual multiple instance learning (MIL) problem. Tissue is represented by a cell graph with both cell-level morphological and regional features. We use an external multi-centric test set from Mesobank, on which we demonstrate the predictive performance of our model. We validate our model predictions through an analysis of the typical morphological features of cells according to their predicted score, finding that some of the morphological differences identified by our model match known differences used by pathologists. We further show that the model score is predictive of patient survival with a hazard ratio of 2.30. The code for the proposed approach, along with the dataset, is available at: https://github.com/measty/MesoGraph.

How similar are two images? In computational pathology, where Whole Slide Images (WSIs) of digitally scanned tissue samples from patients can be multi-gigapixels in size, determination of degree of similarity between two WSIs is a challenging task with a number of practical applications. In this work, we explore a novel strategy based on kernelized Maximum Mean Discrepancy (MMD) analysis for determination of pairwise similarity between WSIs. The proposed approach works by calculating MMD between two WSIs using kernels over deep features of image patches. This allows representation of an entire dataset of WSIs as a kernel matrix for WSI level clustering, weakly-supervised prediction of TP-53 mutation status in breast cancer patients from their routine WSIs as well as survival analysis with state of the art prediction performance. We believe that this work will open up further avenues for application of WSI-level kernels for predictive and prognostic tasks in computational pathology., Comment: * Joint first authorship Accepted: IEEE - ISBI 2023 International Symposium on Biomedical Imaging

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

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.

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 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.

Motivation: Machine learning based prediction of compound-protein interactions (CPIs) is important for drug design, screening and repurposing studies and can improve the efficiency and cost-effectiveness of wet lab assays. Despite the publication of many research papers reporting CPI predictors in the recent years, we have observed a number of fundamental issues in experiment design that lead to over optimistic estimates of model performance. Results: In this paper, we analyze the impact of several important factors affecting generalization perfor-mance of CPI predictors that are overlooked in existing work: 1. Similarity between training and test examples in cross-validation 2. The strategy for generating negative examples, in the absence of experimentally verified negative examples. 3. Choice of evaluation protocols and performance metrics and their alignment with real-world use of CPI predictors in screening large compound libraries. Using both an existing state-of-the-art method (CPI-NN) and a proposed kernel based approach, we have found that assessment of predictive performance of CPI predictors requires careful con-trol over similarity between training and test examples. We also show that random pairing for gen-erating synthetic negative examples for training and performance evaluation results in models with better generalization performance in comparison to more sophisticated strategies used in existing studies. Furthermore, we have found that our kernel based approach, despite its simple design, exceeds the prediction performance of CPI-NN. We have used the proposed model for compound screening of several proteins including SARS-CoV-2 Spike and Human ACE2 proteins and found strong evidence in support of its top hits. Availability: Code and raw experimental results available at https://github.com/adibayaseen/HKRCPI Contact: Fayyaz.minhas@warwick.ac.uk, Comment: Supplementary information: Supplementary data files are available as part of the GitHub repository

Motivation: Digitization of pathology laboratories through digital slide scanners and advances in deep learning approaches for objective histological assessment have resulted in rapid progress in the field of computational pathology (CPath) with wide-ranging applications in medical and pharmaceutical research as well as clinical workflows. However, the estimation of robustness of CPath models to variations in input images is an open problem with a significant impact on the down-stream practical applicability, deployment and acceptability of these approaches. Furthermore, development of domain-specific strategies for enhancement of robustness of such models is of prime importance as well. Implementation and Availability: In this work, we propose the first domain-specific Robustness Evaluation and Enhancement Toolbox (REET) for computational pathology applications. It provides a suite of algorithmic strategies for enabling robustness assessment of predictive models with respect to specialized image transformations such as staining, compression, focusing, blurring, changes in spatial resolution, brightness variations, geometric changes as well as pixel-level adversarial perturbations. Furthermore, REET also enables efficient and robust training of deep learning pipelines in computational pathology. REET is implemented in Python and is available at the following URL: https://github.com/alexjfoote/reetoolbox. Contact: Fayyaz.minhas@warwick.ac.uk

Computational Pathology (CPath) is an emerging field concerned with the study of tissue pathology via computational algorithms for the processing and analysis of digitized high-resolution images of tissue slides. Recent deep learning based developments in CPath have successfully leveraged sheer volume of raw pixel data in histology images for predicting target parameters in the domains of diagnostics, prognostics, treatment sensitivity and patient stratification -- heralding the promise of a new data-driven AI era for both histopathology and oncology. With data serving as the fuel and AI as the engine, CPath algorithms are poised to be ready for takeoff and eventual launch into clinical and pharmaceutical orbits. In this paper, we discuss CPath limitations and associated challenges to enable the readers distinguish hope from hype and provide directions for future research to overcome some of the major challenges faced by this budding field to enable its launch into the two orbits.

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.

Human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive factor which is overexpressed in 15-20% of breast cancer (BCa). The determination of its status is a key clinical decision making step for selection of treatment regimen and prognostication. HER2 status is evaluated using transcroptomics or immunohistochemistry (IHC) through situ hybridisation (ISH) which require additional costs and tissue burden in addition to analytical variabilities in terms of manual observational biases in scoring. In this study, we propose a novel graph neural network (GNN) based model (termed SlideGraph+) to predict HER2 status directly from whole-slide images of routine Haematoxylin and Eosin (H&E) slides. The network was trained and tested on slides from The Cancer Genome Atlas (TCGA) in addition to two independent test datasets. We demonstrate that the proposed model outperforms the state-of-the-art methods with area under the ROC curve (AUC) values > 0.75 on TCGA and 0.8 on independent test sets. Our experiments show that the proposed approach can be utilised for case triaging as well as pre-ordering diagnostic tests in a diagnostic setting. It can also be used for other weakly supervised prediction problems in computational pathology. The SlideGraph+ code is available at https://github.com/wenqi006/SlideGraph., Comment: 20 pages, 11 figures, 3 tables

The detection of mitotic figures from different scanners/sites remains an important topic of research, owing to its potential in assisting clinicians with tumour grading. The MItosis DOmain Generalization (MIDOG) challenge aims to test the robustness of detection models on unseen data from multiple scanners for this task. We present a short summary of the approach employed by the TIA Centre team to address this challenge. Our approach is based on a hybrid detection model, where mitotic candidates are segmented on stain normalised images, before being refined by a deep learning classifier. Cross-validation on the training images achieved the F1-score of 0.786 and 0.765 on the preliminary test set, demonstrating the generalizability of our model to unseen data from new scanners., Comment: MIDOG challenge at MICCAI 2021

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.

"Is it possible to predict expression levels of different genes at a given spatial location in the routine histology image of a tumor section by modeling its stain absorption characteristics?" In this work, we propose a "stain-aware" machine learning approach for prediction of spatial transcriptomic gene expression profiles using digital pathology image of a routine Hematoxylin & Eosin (H&E) histology section. Unlike recent deep learning methods which are used for gene expression prediction, our proposed approach termed Neural Stain Learning (NSL) explicitly models the association of stain absorption characteristics of the tissue with gene expression patterns in spatial transcriptomics by learning a problem-specific stain deconvolution matrix in an end-to-end manner. The proposed method with only 11 trainable weight parameters outperforms both classical regression models with cellular composition and morphological features as well as deep learning methods. We have found that the gene expression predictions from the proposed approach show higher correlations with true expression values obtained through sequencing for a larger set of genes in comparison to other approaches., Comment: 14 pages, 4 figures, 1 table

Can we predict if an early stage cancer patient is at high risk of developing distant metastasis and what clinicopathological factors are associated with such a risk? In this paper, we propose a ranking based censoring-aware machine learning model for answering such questions. The proposed model is able to generate an interpretable formula for risk stratifi-cation using a minimal number of clinicopathological covariates through L1-regulrization. Using this approach, we analyze the association of time to distant metastasis (TTDM) with various clinical parameters for early stage, luminal (ER+ or HER2-) breast cancer patients who received endocrine therapy but no chemotherapy (n = 728). The TTDM risk stratification formula obtained using the proposed approach is primarily based on mitotic score, histolog-ical tumor type and lymphovascular invasion. These findings corroborate with the known role of these covariates in increased risk for distant metastasis. Our analysis shows that the proposed risk stratification formula can discriminate between cases with high and low risk of distant metastasis (p-value < 0.005) and can also rank cases based on their time to distant metastasis with a concordance-index of 0.73., Comment: Accepted in proc. (Machine Learning for Pharma and Healthcare Applications PharML 2021) European Conference on Machine Learning and Principles and Practice of Knowledge Discovery in Databases, Sep 13-17, 2021

Cellular composition prediction, i.e., predicting the presence and counts of different types of cells in the tumor microenvironment from a digitized image of a Hematoxylin and Eosin (H&E) stained tissue section can be used for various tasks in computational pathology such as the analysis of cellular topology and interactions, subtype prediction, survival analysis, etc. In this work, we propose an image-based cellular composition predictor (ALBRT) which can accurately predict the presence and counts of different types of cells in a given image patch. ALBRT, by its contrastive-learning inspired design, learns a compact and rotation-invariant feature representation that is then used for cellular composition prediction of different cell types. It offers significant improvement over existing state-of-the-art approaches for cell classification and counting. The patch-level feature representation learned by ALBRT is transferrable for cellular composition analysis over novel datasets and can also be utilized for downstream prediction tasks in CPath as well. The code and the inference webserver for the proposed method are available at the URL: https://github.com/engrodawood/ALBRT., Comment: 11 pages, 5 figures

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.

Deep learning models are routinely employed in computational pathology (CPath) for solving problems of diagnostic and prognostic significance. Typically, the generalization performance of CPath models is analyzed using evaluation protocols such as cross-validation and testing on multi-centric cohorts. However, to ensure that such CPath solutions are robust and safe for use in a clinical setting, a critical analysis of their predictive performance and vulnerability to adversarial attacks is required, which is the focus of this paper. Specifically, we show that a highly accurate model for classification of tumour patches in pathology images (AUC > 0.95) can easily be attacked with minimal perturbations which are imperceptible to lay humans and trained pathologists alike. Our analytical results show that it is possible to generate single-instance white-box attacks on specific input images with high success rate and low perturbation energy. Furthermore, we have also generated a single universal perturbation matrix using the training dataset only which, when added to unseen test images, results in forcing the trained neural network to flip its prediction labels with high confidence at a success rate of > 84%. We systematically analyze the relationship between perturbation energy of an adversarial attack, its impact on morphological constructs of clinical significance, their perceptibility by a trained pathologist and saliency maps obtained using deep learning models. Based on our analysis, we strongly recommend that computational pathology models be critically analyzed using the proposed adversarial validation strategy prior to clinical adoption., Comment: 10 pages

COVID-19 was declared a pandemic by the World Health Organization (WHO) on March 11th, 2020. With half of the world's countries in lockdown as of April due to this pandemic, monitoring and understanding the spread of the virus and infection rates and how these factors relate to behavioural and societal parameters is crucial for effective policy making. This paper aims to investigate the effectiveness of masks, social distancing, lockdown and self-isolation for reducing the spread of SARS-CoV-2 infections. Our findings based on agent-based simulation modelling show that whilst requiring a lockdown is widely believed to be the most efficient method to quickly reduce infection numbers, the practice of social distancing and the usage of surgical masks can potentially be more effective than requiring a lockdown. Our multivariate analysis of simulation results using the Morris Elementary Effects Method suggests that if a sufficient proportion of the population wore surgical masks and followed social distancing regulations, then SARS-CoV-2 infections can be controlled without requiring a lockdown., Comment: 14 pages, 10 figures

Synthetic images can be used for the development and evaluation of deep learning algorithms in the context of limited availability of data. In the field of computational pathology, where histology images are large in size and visual context is crucial, synthesis of large high resolution images via generative modeling is a challenging task. This is due to memory and computational constraints hindering the generation of large images. To address this challenge, we propose a novel SAFRON (Stitching Across the FRONtiers) framework to construct realistic, large high resolution tissue image tiles from ground truth annotations while preserving morphological features and with minimal boundary artifacts. We show that the proposed method can generate realistic image tiles of arbitrarily large size after training it on relatively small image patches. We demonstrate that our model can generate high quality images, both visually and in terms of the Frechet Inception Distance. Compared to other existing approaches, our framework is efficient in terms of the memory requirements for training and also in terms of the number of computations to construct a large high-resolution image. We also show that training on synthetic data generated by SAFRON can significantly boost the performance of a state-of-the-art algorithm for gland segmentation in colorectal cancer histology images. Sample high resolution images generated using SAFRON are available at the URL: https://warwick.ac.uk/TIALab/SAFRON

An artificial neuron is modelled as a weighted summation followed by an activation function which determines its output. A wide variety of activation functions such as rectified linear units (ReLU), leaky-ReLU, Swish, MISH, etc. have been explored in the literature. In this short paper, we explore what happens when the activation function of each neuron in an artificial neural network is learned natively from data alone. This is achieved by modelling the activation function of each neuron as a small neural network whose weights are shared by all neurons in the original network. We list our primary findings in the conclusions section. The code for our analysis is available at: https://github.com/amina01/Learning-Neural-Activations., Comment: 10 pages

Learning with rejection (LWR) allows development of machine learning systems with the ability to discard low confidence decisions generated by a prediction model. That is, just like human experts, LWR allows machine models to abstain from generating a prediction when reliability of the prediction is expected to be low. Several frameworks for this learning with rejection have been proposed in the literature. However, most of them work for classification problems only and regression with rejection has not been studied in much detail. In this work, we present a neural framework for LWR based on a generalized meta-loss function that involves simultaneous training of two neural network models: a predictor model for generating predictions and a rejecter model for deciding whether the prediction should be accepted or rejected. The proposed framework can be used for classification as well as regression and other related machine learning tasks. We have demonstrated the applicability and effectiveness of the method on synthetically generated data as well as benchmark datasets from UCI machine learning repository for both classification and regression problems. Despite being simpler in implementation, the proposed scheme for learning with rejection has shown to perform at par or better than previously proposed methods. Furthermore, we have applied the method to the problem of hurricane intensity prediction from satellite imagery. Significant improvement in performance as compared to conventional supervised methods shows the effectiveness of the proposed scheme in real-world regression problems.

The evolution of drug-resistant microbial species is one of the major challenges to global health. The development of new antimicrobial treatments such as antimicrobial peptides needs to be accelerated to combat this threat. However, the discovery of novel antimicrobial peptides is hampered by low-throughput biochemical assays. Computational techniques can be used for rapid screening of promising antimicrobial peptide candidates prior to testing in the wet lab. The vast majority of existing antimicrobial peptide predictors are non-targeted in nature, i.e., they can predict whether a given peptide sequence is antimicrobial, but they are unable to predict whether the sequence can target a particular microbial species. In this work, we have developed a targeted antimicrobial peptide activity predictor that can predict whether a peptide is effective against a given microbial species or not. This has been made possible through zero-shot and few-shot machine learning. The proposed predictor called AMP0 takes in the peptide amino acid sequence and any N/C-termini modifications together with the genomic sequence of a target microbial species to generate targeted predictions. It is important to note that the proposed method can generate predictions for species that are not part of its training set. The accuracy of predictions for novel test species can be further improved by providing a few example peptides for that species. Our computational cross-validation results show that the pro-posed scheme is particularly effective for targeted antimicrobial prediction in comparison to existing approaches and can be used for screening potential antimicrobial peptides in a targeted manner especially for cases in which the number of training examples is small. The webserver of the method is available at http://ampzero.pythonanywhere.com., Comment: Under journal submission, 2019

Multiple Instance Learning (MIL) is a weak supervision learning paradigm that allows modeling of machine learning problems in which labels are available only for groups of examples called bags. A positive bag may contain one or more positive examples but it is not known which examples in the bag are positive. All examples in a negative bag belong to the negative class. Such problems arise frequently in fields of computer vision, medical image processing and bioinformatics. Many neural network based solutions have been proposed in the literature for MIL, however, almost all of them rely on introducing specialized blocks and connectivity in the architectures. In this paper, we present a novel and effective approach to Multiple Instance Learning in neural networks. Instead of making changes to the architectures, we propose a simple bag-level ranking loss function that allows Multiple Instance Classification in any neural architecture. We have demonstrated the effectiveness of our proposed method for popular MIL benchmark datasets. In addition, we have tested the performance of our method in convolutional neural networks used to model an MIL problem derived from the well-known MNIST dataset. Results have shown that despite being simpler, our proposed scheme is comparable or better than existing methods in the literature in practical scenarios. Python code files for all the experiments can be found at https://github.com/amina01/ESMIL., Comment: 7 pages

If you want to tell people the truth, make them laugh, otherwise they'll kill you. (source unclear) Machine learning and deep learning are the technologies of the day for developing intelligent automatic systems. However, a key hurdle for progress in the field is the literature itself: we often encounter papers that report results that are difficult to reconstruct or reproduce, results that mis-represent the performance of the system, or contain other biases that limit their validity. In this semi-humorous article, we discuss issues that arise in running and reporting results of machine learning experiments. The purpose of the article is to provide a list of watch out points for researchers to be aware of when developing machine learning models or writing and reviewing machine learning papers., Comment: 11 pages, 8 figures