LNDb challenge on automatic lung cancer patient management.

Lung cancer is the deadliest type of cancer worldwide and late detection is the major factor for the low survival rate of patients. Low dose computed tomography has been suggested as a potential screening tool but manual screening is costly and time-consuming. This has fuelled the development of automatic methods for the detection, segmentation and characterisation of pulmonary nodules. In spite of promising results, the application of automatic methods to clinical routine is not straightforward and only a limited number of studies have addressed the problem in a holistic way. With the goal of advancing the state of the art, the Lung Nodule Database (LNDb) Challenge on automatic lung cancer patient management was organized. The LNDb Challenge addressed lung nodule detection, segmentation and characterization as well as prediction of patient follow-up according to the 2017 Fleischner society pulmonary nodule guidelines. 294 CT scans were thus collected retrospectively at the Centro Hospitalar e Universitrio de So Joo in Porto, Portugal and each CT was annotated by at least one radiologist. Annotations comprised nodule centroids, segmentations and subjective characterization. 58 CTs and the corresponding annotations were withheld as a separate test set. A total of 947 users registered for the challenge and 11 successful submissions for at least one of the sub-challenges were received. For patient follow-up prediction, a maximum quadratic weighted Cohen's kappa of 0.580 was obtained. In terms of nodule detection, a sensitivity below 0.4 (and 0.7) at 1 false positive per scan was obtained for nodules identified by at least one (and two) radiologist(s). For nodule segmentation, a maximum Jaccard score of 0.567 was obtained, surpassing the interobserver variability. In terms of nodule texture characterization, a maximum quadratic weighted Cohen's kappa of 0.733 was obtained, with part solid nodules being particularly challenging to classify correctly. Detailed analysis of the proposed methods and the differences in performance allow to identify the major challenges remaining and future directions - data collection, augmentation/generation and evaluation of under-represented classes, the incorporation of scan-level information for better decision-making and the development of tools and challenges with clinical-oriented goals. The LNDb Challenge and associated data remain publicly available so that future methods can be tested and benchmarked, promoting the development of new algorithms in lung cancer medical image analysis and patient follow-up recommendation.

Automated Cell Counts on Tissue Sections by Deep Learning and Unbiased Stereology.

In recent decades stereology-based studies have played a significant role in understanding brain aging and developing novel drug discovery strategies for treatment of neurological disease and mental illness. A major obstacle to further progress in a wide range of neuroscience sub-disciplines remains the lack of high-throughput technology for stereology analyses. Though founded on methodologically unbiased principles, commercially available stereology systems still rely on well-trained humans to manually count hundreds of cells within each region of interest (ROI). Even for a simple study with 10 controls and 10 treated animals, cell counts typically require over a month of tedious labor and high costs. Furthermore, these studies are prone to errors and poor reproducibility due to human factors such as subjectivity, variable training, recognition bias, and fatigue. Here we propose a deep neural network-stereology combination to automatically segment and estimate the total number of immunostained neurons on tissue sections. Our three-step approach consists of (1) creating extended-depth-of-field (EDF) images from z-stacks of images (disector stacks); (2) applying an adaptive segmentation algorithm (ASA) to label stained cells in the EDF images (i.e., create masks) for training a convolutional neural network (CNN); and (3) use the trained CNN model to automatically segment and count the total number of cells in test disector stacks using the optical fractionator method. The automated stereology approach shows less than 2% error and over 5× greater efficiency compared to counts by a trained human, without the subjectivity, tedium, and poor precision associated with conventional stereology.

Predicting breast tumor proliferation from whole-slide images: The TUPAC16 challenge.

Tumor proliferation is an important biomarker indicative of the prognosis of breast cancer patients. Assessment of tumor proliferation in a clinical setting is a highly subjective and labor-intensive task. Previous efforts to automate tumor proliferation assessment by image analysis only focused on mitosis detection in predefined tumor regions. However, in a real-world scenario, automatic mitosis detection should be performed in whole-slide images (WSIs) and an automatic method should be able to produce a tumor proliferation score given a WSI as input. To address this, we organized the TUmor Proliferation Assessment Challenge 2016 (TUPAC16) on prediction of tumor proliferation scores from WSIs. The challenge dataset consisted of 500 training and 321 testing breast cancer histopathology WSIs. In order to ensure fair and independent evaluation, only the ground truth for the training dataset was provided to the challenge participants. The first task of the challenge was to predict mitotic scores, i.e., to reproduce the manual method of assessing tumor proliferation by a pathologist. The second task was to predict the gene expression based PAM50 proliferation scores from the WSI. The best performing automatic method for the first task achieved a quadratic-weighted Cohen's kappa score of κ = 0.567, 95% CI [0.464, 0.671] between the predicted scores and the ground truth. For the second task, the predictions of the top method had a Spearman's correlation coefficient of r = 0.617, 95% CI [0.581 0.651] with the ground truth. This was the first comparison study that investigated tumor proliferation assessment from WSIs. The achieved results are promising given the difficulty of the tasks and weakly-labeled nature of the ground truth. However, further research is needed to improve the practical utility of image analysis methods for this task.

A framework for nucleus and overlapping cytoplasm segmentation in cervical cytology extended depth of field and volume images.

We propose a framework to detect and segment nuclei and segment overlapping cytoplasm in cervical cytology images. This is a challenging task due to folded cervical cells with spurious edges, poor contrast of cytoplasm and presence of neutrophils and artifacts. The algorithm segments nuclei and cell clumps in extended depth of field (EDF) images and uses volume images to segment overlapping cytoplasm. The boundaries are first approximated by a defined similarity metric and are refined in two steps by reducing concavity, iterative smoothing and outliers removal. We evaluated our framework on two public datasets provided in the first and second overlapping cervical cell segmentation challenges (ISBI 2014 and 2015). The results show that our method outperforms other state-of-the-art algorithms on both datasets. The results on the ISBI 2014 dataset show that our method missed less than 5% of cells when the pairwise cell overlapping degree was not higher than 0.3 and it missed only 7% of cells on average in a dataset of 810 synthetic images with 4860 (overlapping) cells. On the same dataset, it outperforms other state-of-the-art methods in nucleus detection with precision 0.961 and recall 0.933. The results on the ISBI 2015 dataset containing real cervical EDF images show that our method misses around 20% of cells in EDF images where a segmentation is considered a miss if it has dice similarity coefficient not greater than 0.7. The 20% miss rate is around half of the miss rate of two other recent methods.

Unbiased estimation of cell number using the automatic optical fractionator.

A novel stereology approach, the automatic optical fractionator, is presented for obtaining unbiased and efficient estimates of the number of cells in tissue sections. Used in combination with existing segmentation algorithms and ordinary immunostaining methods, automatic estimates of cell number are obtainable from extended depth of field images built from three-dimensional volumes of tissue (disector stacks). The automatic optical fractionator is more accurate, 100% objective and 8-10 times faster than the manual optical fractionator. An example of the automatic fractionator is provided for counts of immunostained neurons in neocortex of a genetically modified mouse model of neurodegeneration. Evidence is presented for the often overlooked prerequisite that accurate counting by the optical fractionator requires a thin focal plane generated by a high optical resolution lens.