Lung vascular changes as biomarkers of severity in systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: It has recently become possible to assess lung vascular and parenchymal changes quantitatively in thoracic CT images using automated software tools. We investigated the vessel parameters of patients with SSc, quantified by CT imaging, and correlated them with interstitial lung disease (ILD) features. METHODS: SSc patients undergoing standard of care pulmonary function testing and CT evaluation were retrospectively evaluated. CT images were analysed for ILD patterns and total pulmonary vascular volume (PVV) extents with Imbio lung texture analysis. Vascular analysis (volumes, numbers and densities of vessels, separating arteries and veins) was performed with an in-house developed software. A threshold of 5% ILD extent was chosen to define the presence of ILD, and commonly used cut-offs of lung function were adopted. RESULTS: A total of 79 patients [52 women, 40 ILD, mean age 56.2 (s.d. 14.2) years, total ILD extent 9.5 (10.7)%, PVV/lung volume % 2.8%] were enrolled. Vascular parameters for total and separated PVV significantly correlated with functional parameters and ILD pattern extents. SSc-associated ILD (SSc-ILD) patients presented with an increased number and volume of arterial vessels, in particular those between 2 and 4 mm of diameter, and with a higher density of arteries and veins of <6 mm in diameter. Considering radiological and functional criteria concomitantly, as well as the descriptive trends from the longitudinal evaluations, the normalized PVVs, vessel numbers and densities increased progressively with the increase/worsening of ILD extent and functional impairment. CONCLUSION: In SSc patients CT vessel parameters increase in parallel with ILD extent and functional impairment, and may represent a biomarker of SSc-ILD severity.

Quantitative CT-derived vessel metrics in idiopathic pulmonary fibrosis: A structure-function study.

BACKGROUND AND OBJECTIVE: This study aimed to investigate whether quantitative lung vessel morphology determined by a new fully automated algorithm is associated with functional indices in idiopathic pulmonary fibrosis (IPF). METHODS: A total of 152 IPF patients had vessel volume, density, tortuosity and heterogeneity quantified from computed tomography (CT) images by a fully automated algorithm. Separate quantitation of vessel metrics in pulmonary arteries and veins was performed in 106 patients. Results were evaluated against readouts from lung function tests. RESULTS: Normalized vessel volume expressed as a percentage of total lung volume was moderately correlated with functional indices on univariable linear regression analysis: forced vital capacity (R2 = 0.27, P < 1 × 10-6 ), diffusion capacity for carbon monoxide (DLCO ; R2 = 0.12, P = 3 × 10-5 ), total lung capacity (TLC; R2 = 0.45, P < 1 × 10-6 ) and composite physiologic index (CPI; R2 = 0.28, P < 1 × 10-6 ). Normalized vessel volume was correlated with vessel density but not with vessel heterogeneity. Quantitatively derived vessel metrics (and artery and vein subdivision scores) were not significantly linked with the transfer factor for carbon monoxide (KCO ), and only weakly with DLCO . On multivariable linear regression analysis, normalized vessel volume and vessel heterogeneity were independently linked with DLCO , TLC and CPI indicating that they capture different aspects of lung damage. Artery-vein separation provided no additional information beyond that captured in the whole vasculature. CONCLUSION: Our study confirms previous observations of links between vessel volume and functional measures of disease severity in IPF using a new vessel quantitation tool. Additionally, the new tool shows independent linkages of normalized vessel volume and vessel heterogeneity with functional indices. Quantitative vessel metrics do not appear to reflect vasculopathic damage in IPF.

Anatomy-Aware Inference of the 3D Standing Spine Posture from 2D Radiographs.

An important factor for the development of spinal degeneration, pain and the outcome of spinal surgery is known to be the balance of the spine. It must be analyzed in an upright, standing position to ensure physiological loading conditions and visualize load-dependent deformations. Despite the complex 3D shape of the spine, this analysis is currently performed using 2D radiographs, as all frequently used 3D imaging techniques require the patient to be scanned in a prone position. To overcome this limitation, we propose a deep neural network to reconstruct the 3D spinal pose in an upright standing position, loaded naturally. Specifically, we propose a novel neural network architecture, which takes orthogonal 2D radiographs and infers the spine's 3D posture using vertebral shape priors. In this work, we define vertebral shape priors using an atlas and a spine shape prior, incorporating both into our proposed network architecture. We validate our architecture on digitally reconstructed radiographs, achieving a 3D reconstruction Dice of 0.95, indicating an almost perfect 2D-to-3D domain translation. Validating the reconstruction accuracy of a 3D standing spine on real data is infeasible due to the lack of a valid ground truth. Hence, we design a novel experiment for this purpose, using an orientation invariant distance metric, to evaluate our model's ability to synthesize full-3D, upright, and patient-specific spine models. We compare the synthesized spine shapes from clinical upright standing radiographs to the same patient's 3D spinal posture in the prone position from CT.

Fast and Low-GPU-memory abdomen CT organ segmentation: The FLARE challenge.

Automatic segmentation of abdominal organs in CT scans plays an important role in clinical practice. However, most existing benchmarks and datasets only focus on segmentation accuracy, while the model efficiency and its accuracy on the testing cases from different medical centers have not been evaluated. To comprehensively benchmark abdominal organ segmentation methods, we organized the first Fast and Low GPU memory Abdominal oRgan sEgmentation (FLARE) challenge, where the segmentation methods were encouraged to achieve high accuracy on the testing cases from different medical centers, fast inference speed, and low GPU memory consumption, simultaneously. The winning method surpassed the existing state-of-the-art method, achieving a 19× faster inference speed and reducing the GPU memory consumption by 60% with comparable accuracy. We provide a summary of the top methods, make their code and Docker containers publicly available, and give practical suggestions on building accurate and efficient abdominal organ segmentation models. The FLARE challenge remains open for future submissions through a live platform for benchmarking further methodology developments at https://flare.grand-challenge.org/.

A Framework for the generation of digital twins of cardiac electrophysiology from clinical 12-leads ECGs.

Cardiac digital twins (Cardiac Digital Twin (CDT)s) of human electrophysiology (Electrophysiology (EP)) are digital replicas of patient hearts derived from clinical data that match like-for-like all available clinical observations. Due to their inherent predictive potential, CDTs show high promise as a complementary modality aiding in clinical decision making and also in the cost-effective, safe and ethical testing of novel EP device therapies. However, current workflows for both the anatomical and functional twinning phases within CDT generation, referring to the inference of model anatomy and parameters from clinical data, are not sufficiently efficient, robust and accurate for advanced clinical and industrial applications. Our study addresses three primary limitations impeding the routine generation of high-fidelity CDTs by introducing; a comprehensive parameter vector encapsulating all factors relating to the ventricular EP; an abstract reference frame within the model allowing the unattended manipulation of model parameter fields; a novel fast-forward electrocardiogram (Electrocardiogram (ECG)) model for efficient and bio-physically-detailed simulation required for parameter inference. A novel workflow for the generation of CDTs is then introduced as an initial proof of concept. Anatomical twinning was performed within a reasonable time compatible with clinical workflows (<4h) for 12 subjects from clinically-attained magnetic resonance images. After assessment of the underlying fast forward ECG model against a gold standard bidomain ECG model, functional twinning of optimal parameters according to a clinically-attained 12 lead ECG was then performed using a forward Saltelli sampling approach for a single subject. The achieved results in terms of efficiency and fidelity demonstrate that our workflow is well-suited and viable for generating biophysically-detailed CDTs at scale.

VerSe: A Vertebrae labelling and segmentation benchmark for multi-detector CT images.

Vertebral labelling and segmentation are two fundamental tasks in an automated spine processing pipeline. Reliable and accurate processing of spine images is expected to benefit clinical decision support systems for diagnosis, surgery planning, and population-based analysis of spine and bone health. However, designing automated algorithms for spine processing is challenging predominantly due to considerable variations in anatomy and acquisition protocols and due to a severe shortage of publicly available data. Addressing these limitations, the Large Scale Vertebrae Segmentation Challenge (VerSe) was organised in conjunction with the International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) in 2019 and 2020, with a call for algorithms tackling the labelling and segmentation of vertebrae. Two datasets containing a total of 374 multi-detector CT scans from 355 patients were prepared and 4505 vertebrae have individually been annotated at voxel level by a human-machine hybrid algorithm (https://osf.io/nqjyw/, https://osf.io/t98fz/). A total of 25 algorithms were benchmarked on these datasets. In this work, we present the results of this evaluation and further investigate the performance variation at the vertebra level, scan level, and different fields of view. We also evaluate the generalisability of the approaches to an implicit domain shift in data by evaluating the top-performing algorithms of one challenge iteration on data from the other iteration. The principal takeaway from VerSe: the performance of an algorithm in labelling and segmenting a spine scan hinges on its ability to correctly identify vertebrae in cases of rare anatomical variations. The VerSe content and code can be accessed at: https://github.com/anjany/verse.

Automated age estimation from MRI volumes of the hand.

Highly relevant for both clinical and legal medicine applications, the established radiological methods for estimating unknown age in children and adolescents are based on visual examination of bone ossification in X-ray images of the hand. Our group has initiated the development of fully automatic age estimation methods from 3D MRI scans of the hand, in order to simultaneously overcome the problems of the radiological methods including (1) exposure to ionizing radiation, (2) necessity to define new, MRI specific staging systems, and (3) subjective influence of the examiner. The present work provides a theoretical background for understanding the nonlinear regression problem of biological age estimation and chronological age approximation. Based on this theoretical background, we comprehensively evaluate machine learning methods (random forests, deep convolutional neural networks) with different simplifications of the image information used as an input for learning. Trained on a large dataset of 328 MR images, we compare the performance of the different input strategies and demonstrate unprecedented results. For estimating biological age, we obtain a mean absolute error of 0.37 ±â€¯0.51 years for the age range of the subjects  ≤  18 years, i.e. where bone ossification has not yet saturated. Finally, we validate our findings by adapting our best performing method to 2D images and applying it to a publicly available dataset of X-ray images, showing that we are in line with the state-of-the-art automatic methods for this task.

Segmenting and tracking cell instances with cosine embeddings and recurrent hourglass networks.

Differently to semantic segmentation, instance segmentation assigns unique labels to each individual instance of the same object class. In this work, we propose a novel recurrent fully convolutional network architecture for tracking such instance segmentations over time, which is highly relevant, e.g., in biomedical applications involving cell growth and migration. Our network architecture incorporates convolutional gated recurrent units (ConvGRU) into a stacked hourglass network to utilize temporal information, e.g., from microscopy videos. Moreover, we train our network with a novel embedding loss based on cosine similarities, such that the network predicts unique embeddings for every instance throughout videos, even in the presence of dynamic structural changes due to mitosis of cells. To create the final tracked instance segmentations, the pixel-wise embeddings are clustered among subsequent video frames by using the mean shift algorithm. After showing the performance of the instance segmentation on a static in-house dataset of muscle fibers from H&E-stained microscopy images, we also evaluate our proposed recurrent stacked hourglass network regarding instance segmentation and tracking performance on six datasets from the ISBI celltracking challenge, where it delivers state-of-the-art results.

Integrating spatial configuration into heatmap regression based CNNs for landmark localization.

In many medical image analysis applications, only a limited amount of training data is available due to the costs of image acquisition and the large manual annotation effort required from experts. Training recent state-of-the-art machine learning methods like convolutional neural networks (CNNs) from small datasets is a challenging task. In this work on anatomical landmark localization, we propose a CNN architecture that learns to split the localization task into two simpler sub-problems, reducing the overall need for large training datasets. Our fully convolutional SpatialConfiguration-Net (SCN) learns this simplification due to multiplying the heatmap predictions of its two components and by training the network in an end-to-end manner. Thus, the SCN dedicates one component to locally accurate but ambiguous candidate predictions, while the other component improves robustness to ambiguities by incorporating the spatial configuration of landmarks. In our extensive experimental evaluation, we show that the proposed SCN outperforms related methods in terms of landmark localization error on a variety of size-limited 2D and 3D landmark localization datasets, i.e., hand radiographs, lateral cephalograms, hand MRIs, and spine CTs.

Automatic Age Estimation and Majority Age Classification From Multi-Factorial MRI Data.

Age estimation from radiologic data is an important topic both in clinical medicine as well as in forensic applications, where it is used to assess unknown chronological age or to discriminate minors from adults. In this paper, we propose an automatic multi-factorial age estimation method based on MRI data of hand, clavicle, and teeth to extend the maximal age range from up to 19 years, as commonly used for age assessment based on hand bones, to up to 25 years, when combined with clavicle bones and wisdom teeth. Fusing age-relevant information from all three anatomical sites, our method utilizes a deep convolutional neural network that is trained on a dataset of 322 subjects in the age range between 13 and 25 years, to achieve a mean absolute prediction error in regressing chronological age of 1.01±0.74 years. Furthermore, when used for majority age classification, we show that a classifier derived from thresholding our regression-based predictor is better suited than a classifier directly trained with a classification loss, especially when taking into account that those cases of minors being wrongly classified as adults need to be minimized. In conclusion, we overcome the limitations of the multi-factorial methods currently used in forensic practice, i.e., dependence on ionizing radiation, subjectivity in quantifying age-relevant information, and lack of an established approach to fuse this information from individual anatomical sites.

Evaluation of algorithms for Multi-Modality Whole Heart Segmentation: An open-access grand challenge.

Knowledge of whole heart anatomy is a prerequisite for many clinical applications. Whole heart segmentation (WHS), which delineates substructures of the heart, can be very valuable for modeling and analysis of the anatomy and functions of the heart. However, automating this segmentation can be challenging due to the large variation of the heart shape, and different image qualities of the clinical data. To achieve this goal, an initial set of training data is generally needed for constructing priors or for training. Furthermore, it is difficult to perform comparisons between different methods, largely due to differences in the datasets and evaluation metrics used. This manuscript presents the methodologies and evaluation results for the WHS algorithms selected from the submissions to the Multi-Modality Whole Heart Segmentation (MM-WHS) challenge, in conjunction with MICCAI 2017. The challenge provided 120 three-dimensional cardiac images covering the whole heart, including 60 CT and 60 MRI volumes, all acquired in clinical environments with manual delineation. Ten algorithms for CT data and eleven algorithms for MRI data, submitted from twelve groups, have been evaluated. The results showed that the performance of CT WHS was generally better than that of MRI WHS. The segmentation of the substructures for different categories of patients could present different levels of challenge due to the difference in imaging and variations of heart shapes. The deep learning (DL)-based methods demonstrated great potential, though several of them reported poor results in the blinded evaluation. Their performance could vary greatly across different network structures and training strategies. The conventional algorithms, mainly based on multi-atlas segmentation, demonstrated good performance, though the accuracy and computational efficiency could be limited. The challenge, including provision of the annotated training data and the blinded evaluation for submitted algorithms on the test data, continues as an ongoing benchmarking resource via its homepage (www.sdspeople.fudan.edu.cn/zhuangxiahai/0/mmwhs/).

Reducing acquisition time for MRI-based forensic age estimation.

Radiology-based estimation of a living person's unknown age has recently attracted increasing attention due to large numbers of undocumented immigrants entering Europe. To avoid the application of X-ray-based imaging techniques, magnetic resonance imaging (MRI) has been suggested as an alternative imaging modality. Unfortunately, MRI requires prolonged acquisition times, which potentially represents an additional stressor for young refugees. To eliminate this shortcoming, we investigated the degree of reduction in acquisition time that still led to reliable age estimates. Two radiologists randomly assessed original images and two sets of retrospectively undersampled data of 15 volunteers (N = 45 data sets) applying an established radiological age estimation method to images of the hand and wrist. Additionally, a neural network-based age estimation method analyzed four sets of further undersampled images from the 15 volunteers (N = 105 data sets). Furthermore, we compared retrospectively undersampled and acquired undersampled data for three volunteers. To assess reliability with increasing degree of undersampling, intra-rater and inter-rater agreement were analyzed computing signed differences and intra-class correlation. While our findings have to be confirmed by a larger prospective study, the results from both radiological and automatic age estimation showed that reliable age estimation was still possible for acquisition times of 15 seconds.

Healthy Lung Vessel Morphology Derived From Thoracic Computed Tomography.

Knowledge of the lung vessel morphology in healthy subjects is necessary to improve our understanding about the functional network of the lung and to recognize pathologic deviations beyond the normal inter-subject variation. Established values of normal lung morphology have been derived from necropsy material of only very few subjects. In order to determine morphologic readouts from a large number of healthy subjects, computed tomography pulmonary angiography (CTPA) datasets, negative for pulmonary embolism, and other thoracic pathologies, were analyzed using a fully-automatic, in-house developed artery/vein separation algorithm. The number, volume, and tortuosity of the vessels in a diameter range between 2 and 10 mm were determined. Visual inspection of all datasets was used to exclude subjects with poor image quality or inadequate artery/vein separation from the analysis. Validation of the algorithm was performed manually by a radiologist on randomly selected subjects. In 123 subjects (men/women: 55/68), aged 59 ± 17 years, the median overlap between visual inspection and fully-automatic segmentation was 94.6% (69.2-99.9%). The median number of vessel segments in the ranges of 8-10, 6-8, 4-6, and 2-4 mm diameter was 9, 34, 134, and 797, respectively. Number of vessel segments divided by the subject's lung volume was 206 vessels/L with arteries and veins contributing almost equally. In women this vessel density was about 15% higher than in men. Median arterial and venous volumes were 1.52 and 1.54% of the lung volume, respectively. Tortuosity was best described with the sum-of-angles metric and was 142.1 rad/m (138.3-144.5 rad/m). In conclusion, our fully-automatic artery/vein separation algorithm provided reliable measures of pulmonary arteries and veins with respect to age and gender. There was a large variation between subjects in all readouts. No relevant dependence on age, gender, or vessel type was observed. These data may provide reference values for morphometric analysis of lung vessels.

Automated integer programming based separation of arteries and veins from thoracic CT images.

Automated computer-aided analysis of lung vessels has shown to yield promising results for non-invasive diagnosis of lung diseases. To detect vascular changes which affect pulmonary arteries and veins differently, both compartments need to be identified. We present a novel, fully automatic method that separates arteries and veins in thoracic computed tomography images, by combining local as well as global properties of pulmonary vessels. We split the problem into two parts: the extraction of multiple distinct vessel subtrees, and their subsequent labeling into arteries and veins. Subtree extraction is performed with an integer program (IP), based on local vessel geometry. As naively solving this IP is time-consuming, we show how to drastically reduce computational effort by reformulating it as a Markov Random Field. Afterwards, each subtree is labeled as either arterial or venous by a second IP, using two anatomical properties of pulmonary vessels: the uniform distribution of arteries and veins, and the parallel configuration and close proximity of arteries and bronchi. We evaluate algorithm performance by comparing the results with 25 voxel-based manual reference segmentations. On this dataset, we show good performance of the subtree extraction, consisting of very few non-vascular structures (median value: 0.9%) and merged subtrees (median value: 0.6%). The resulting separation of arteries and veins achieves a median voxel-based overlap of 96.3% with the manual reference segmentations, outperforming a state-of-the-art interactive method. In conclusion, our novel approach provides an opportunity to become an integral part of computer aided pulmonary diagnosis, where artery/vein separation is important.