Targeting tumor heterogeneity: multiplex-detection-based multiple instance learning for whole slide image classification

Motivation Multiple instance learning (MIL) is a powerful technique to classify whole slide images (WSIs) for diagnostic pathology. The key challenge of MIL on WSI classification is to discover the critical instances that trigger the bag label. However, tumor heterogeneity significantly hinders the algorithm's performance.Results Here, we propose a novel multiplex-detection-based multiple instance learning (MDMIL) which targets tumor heterogeneity by multiplex detection strategy and feature constraints among samples. Specifically, the internal query generated after the probability distribution analysis and the variational query optimized throughout the training process are utilized to detect potential instances in the form of internal and external assistance, respectively. The multiplex detection strategy significantly improves the instance-mining capacity of the deep neural network. Meanwhile, a memory-based contrastive loss is proposed to reach consistency on various phenotypes in the feature space. The novel network and loss function jointly achieve high robustness towards tumor heterogeneity. We conduct experiments on three computational pathology datasets, e.g. CAMELYON16, TCGA-NSCLC, and TCGA-RCC. Benchmarking experiments on the three datasets illustrate that our proposed MDMIL approach achieves superior performance over several existing state-of-the-art methods.