Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer.

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.

Sparse Autoencoder for Unsupervised Nucleus Detection and Representation in Histopathology Images.

We propose a sparse Convolutional Autoencoder (CAE) for simultaneous nucleus detection and feature extraction in histopathology tissue images. Our CAE detects and encodes nuclei in image patches in tissue images into sparse feature maps that encode both the location and appearance of nuclei. A primary contribution of our work is the development of an unsupervised detection network by using the characteristics of histopathology image patches. The pretrained nucleus detection and feature extraction modules in our CAE can be fine-tuned for supervised learning in an end-to-end fashion. We evaluate our method on four datasets and achieve state-of-the-art results. In addition, we are able to achieve comparable performance with only 5% of the fully- supervised annotation cost.

Attention De-sparsification Matters: Inducing diversity in digital pathology representation learning.

We propose DiRL, a Diversity-inducing Representation Learning technique for histopathology imaging. Self-supervised learning (SSL) techniques, such as contrastive and non-contrastive approaches, have been shown to learn rich and effective representations of digitized tissue samples with limited pathologist supervision. Our analysis of vanilla SSL-pretrained models' attention distribution reveals an insightful observation: sparsity in attention, i.e, models tends to localize most of their attention to some prominent patterns in the image. Although attention sparsity can be beneficial in natural images due to these prominent patterns being the object of interest itself, this can be sub-optimal in digital pathology; this is because, unlike natural images, digital pathology scans are not object-centric, but rather a complex phenotype of various spatially intermixed biological components. Inadequate diversification of attention in these complex images could result in crucial information loss. To address this, we leverage cell segmentation to densely extract multiple histopathology-specific representations, and then propose a prior-guided dense pretext task, designed to match the multiple corresponding representations between the views. Through this, the model learns to attend to various components more closely and evenly, thus inducing adequate diversification in attention for capturing context-rich representations. Through quantitative and qualitative analysis on multiple tasks across cancer types, we demonstrate the efficacy of our method and observe that the attention is more globally distributed.

Robust Histopathology Image Analysis: to Label or to Synthesize?

Detection, segmentation and classification of nuclei are fundamental analysis operations in digital pathology. Existing state-of-the-art approaches demand extensive amount of supervised training data from pathologists and may still perform poorly in images from unseen tissue types. We propose an unsupervised approach for histopathology image segmentation that synthesizes heterogeneous sets of training image patches, of every tissue type. Although our synthetic patches are not always of high quality, we harness the motley crew of generated samples through a generally applicable importance sampling method. This proposed approach, for the first time, re-weighs the training loss over synthetic data so that the ideal (unbiased) generalization loss over the true data distribution is minimized. This enables us to use a random polygon generator to synthesize approximate cellular structures (i.e., nuclear masks) for which no real examples are given in many tissue types, and hence, GAN-based methods are not suited. In addition, we propose a hybrid synthesis pipeline that utilizes textures in real histopathology patches and GAN models, to tackle heterogeneity in tissue textures. Compared with existing state-of-the-art supervised models, our approach generalizes significantly better on cancer types without training data. Even in cancer types with training data, our approach achieves the same performance without supervision cost. We release code and segmentation results on over 5000 Whole Slide Images (WSI) in The Cancer Genome Atlas (TCGA) repository, a dataset that would be orders of magnitude larger than what is available today.

Deep Learning on Electronic Health Records to Improve Disease Coding Accuracy.

Characterization of a patient's clinical phenotype is central to biomedical informatics. ICD codes, assigned to inpatient encounters by coders, is important for population health and cohort discovery when clinical information is limited. While ICD codes are assigned to patients by professionals trained and certified in coding there is substantial variability in coding. We present a methodology that uses deep learning methods to model coder decision making and that predicts ICD codes. Our approach predicts codes based on demographics, lab results, and medications, as well as codes from previous encounters. We are able to predict existing codes with high accuracy for all three of the test cases we investigated: diabetes, acute renal failure, and chronic kidney disease. We employed a panel of clinicians, in a blinded manner, to assess ground truth and compared the predictions of coders, model and clinicians. When disparities between the model prediction and coder assigned codes were reviewed, our model outperformed coder assigned ICD codes.

Comparison of Different Classifiers with Active Learning to Support Quality Control in Nucleus Segmentation in Pathology Images.

Segmentation of nuclei in whole slide tissue images is a common methodology in pathology image analysis. Most segmentation algorithms are sensitive to input algorithm parameters and the characteristics of input images (tissue morphology, staining, etc.). Because there can be large variability in the color, texture, and morphology of tissues within and across cancer types (heterogeneity can exist even within a tissue specimen), it is likely that a set of input parameters will not perform well across multiple images. It is, therefore, highly desired, and necessary in some cases, to carry out a quality control of segmentation results. This work investigates the application of machine learning in this process. We report on the application of active learning for segmentation quality assessment for pathology images and compare three classification methods, Support Vector Machine (SVM), Random Forest (RF) and Convolutional Neural Network (CNN), for their performance improvement and efficiency.