Iterative multiple instance learning for weakly annotated whole slide image classification.

Objective.Whole slide images (WSIs) play a crucial role in histopathological analysis. The extremely high resolution of WSIs makes it laborious to obtain fine-grade annotations. Hence, classifying WSIs with only slide-level labels is often cast as a multiple instance learning (MIL) problem where a WSI is regarded as a bag and tiled into patches that are regarded as instances. The purpose of this study is to develop a novel MIL method for classifying WSIs with only slide-level labels in histopathology analysis.Approach.We propose a novel iterative MIL (IMIL) method for WSI classification where instance representations and bag representations are learned collaboratively. In particular, IMIL iteratively finetune the feature extractor with selected instances and corresponding pseudo labels generated by attention-based MIL pooling. Additionally, three procedures for robust training of IMIL are adopted: (1) the feature extractor is initialized by utilizing self-supervised learning methods on all instances, (2) samples for finetuning the feature extractor are selected according to the attention scores, and (3) a confidence-aware loss is applied for finetuning the feature extractor.Main results.Our proposed IMIL-SimCLR archives the optimal classification performance on Camelyon16 and KingMed-Lung. Compared with the baseline method CLAM, IMIL-SimCLR significantly outperforms it by 3.71% higher average area under curve (AUC) on Camelyon16 and 4.25% higher average AUC on KingMed-Lung. Additionally, our proposed IMIL-ImageNet achieve the optimal classification performance on TCGA-Lung with the average AUC of 96.55% and the accuracy of 96.76%, which significantly outperforms the baseline method CLAM by 1.65% higher average AUC and 2.09% higher average accuracy respectively.Significance.Experimental results on a public lymph node metastasis dataset, a public lung cancer diagnosis dataset and an in-house lung cancer diagnosis datasets show the effectiveness of our proposed IMIL method across different WSI classification tasks compared with other state-of-the-art MIL methods.

Multi-scale cascaded networks for synthesis of mammogram to decrease intensity distortion and increase model-based perceptual similarity.

PURPOSE: Synthetic digital mammogram (SDM) is a 2D image generated from digital breast tomosynthesis (DBT) and used as a substitute for a full-field digital mammogram (FFDM) to reduce the radiation dose for breast cancer screening. The previous deep learning-based method used FFDM images as the ground truth, and trained a single neural network to directly generate SDM images with similar appearances (e.g., intensity distribution, textures) to the FFDM images. However, the FFDM image has a different texture pattern from DBT. The difference in texture pattern might make the training of the neural network unstable and result in high-intensity distortion, which makes it hard to decrease intensity distortion and increase perceptual similarity (e.g., generate similar textures) at the same time. Clinically, radiologists want to have a 2D synthesized image that feels like an FFDM image in vision and preserves local structures such as both mass and microcalcifications (MCs) in DBT because radiologists have been trained on reading FFDM images for a long time, while local structures are important for diagnosis. In this study, we proposed to use a deep convolutional neural network to learn the transformation to generate SDM from DBT. METHOD: To decrease intensity distortion and increase perceptual similarity, a multi-scale cascaded network (MSCN) is proposed to generate low-frequency structures (e.g., intensity distribution) and high-frequency structures (e.g., textures) separately. The MSCN consist of two cascaded sub-networks: the first sub-network is used to predict the low-frequency part of the FFDM image; the second sub-network is used to generate a full SDM image with textures similar to the FFDM image based on the prediction of the first sub-network. The mean-squared error (MSE) objective function is used to train the first sub-network, termed low-frequency network, to generate a low-frequency SDM image. The gradient-guided generative adversarial network's objective function is to train the second sub-network, termed high-frequency network, to generate a full SDM image with textures similar to the FFDM image. RESULTS: 1646 cases with FFDM and DBT were retrospectively collected from the Hologic Selenia system for training and validation dataset, and 145 cases with masses or MC clusters were independently collected from the Hologic Selenia system for testing dataset. For comparison, the baseline network has the same architecture as the high-frequency network and directly generates a full SDM image. Compared to the baseline method, the proposed MSCN improves the peak-to-noise ratio from 25.3 to 27.9 dB and improves the structural similarity from 0.703 to 0.724, and significantly increases the perceptual similarity. CONCLUSIONS: The proposed method can stabilize the training and generate SDM images with lower intensity distortion and higher perceptual similarity.

Generating Full-Field Digital Mammogram From Digitized Screen-Film Mammogram for Breast Cancer Screening With High-Resolution Generative Adversarial Network.

Purpose: Developing deep learning algorithms for breast cancer screening is limited due to the lack of labeled full-field digital mammograms (FFDMs). Since FFDM is a new technique that rose in recent decades and replaced digitized screen-film mammograms (DFM) as the main technique for breast cancer screening, most mammogram datasets were still stored in the form of DFM. A solution for developing deep learning algorithms based on FFDM while leveraging existing labeled DFM datasets is a generative algorithm that generates FFDM from DFM. Generating high-resolution FFDM from DFM remains a challenge due to the limitations of network capacity and lacking GPU memory. Method: In this study, we developed a deep-learning-based generative algorithm, HRGAN, to generate synthesized FFDM (SFFDM) from DFM. More importantly, our algorithm can keep the image resolution and details while using high-resolution DFM as input. Our model used FFDM and DFM for training. First, a sliding window was used to crop DFMs and FFDMs into 256 × 256 pixels patches. Second, the patches were divided into three categories (breast, background, and boundary) by breast masks. Patches from the DFM and FFDM datasets were paired as inputs for training our model where these paired patches should be sampled from the same category of the two different image sets. U-Net liked generators and modified discriminators with two-channels output, one channel for distinguishing real and SFFDMs and the other for representing a probability map for breast mask, were used in our algorithm. Last, a study was designed to evaluate the usefulness of HRGAN. A mass segmentation task and a calcification detection task were included in the study. Results: Two public mammography datasets, the CBIS-DDSM dataset and the INbreast dataset, were included in our experiment. The CBIS-DDSM dataset includes 753 calcification cases and 891 mass cases with verified pathology information, resulting in a total of 3568 DFMs. The INbreast dataset contains a total of 410 FFDMs with annotations of masses, calcifications, asymmetries, and distortions. There were 1784 DFMs and 205 FFDM randomly selected as Dataset A. The remaining DFMs from the CBIS-DDSM dataset were selected as Dataset B. The remaining FFDMs from the INbreast dataset were selected as Dataset C. All DFMs and FFDMs were normalized to 100µm × 100µm in our experiments. A study with a mass segmentation task and a calcification detection task was performed to evaluate the usefulness of HRGAN. Conclusions: The proposed HRGAN can generate high-resolution SFFDMs from DFMs. Extensive experiments showed the SFFDMs were able to help improve the performance of deep-learning-based algorithms for breast cancer screening on DFM when the size of the training dataset is small.

Conservation in China of a novel group of HCV variants dating to six centuries ago.

UNLABELLED: We characterized a novel group of HCV variants that are genetically related but distinct from each other belonging to genotype 6 (HCV-6). From 26 infected Austronesian-descended aborigines on Hainan Island, China, HCV sequences were determined followed by genetic analyses. Six nearly full-length genomes and 20 E1 sequences of HCV were obtained, which differ from each other and from all known HCV lineages by nucleotides above the intra-subtype level of 13%. Together with subtypes 6g and 6w, they constitute a phylogenetic group sharing a common ancestor dating from the end of the 12th century. CONCLUSION: Our data indicate the maintenance of an isolated HCV-6 indigenous circulation on Hainan Island at least for six centuries.