Precision medicine for pandemics: stratification of COVID-19 molecular phenotypes defined by topological analysis of global blood gene expression. (preprint)

Precision medicine offers a promising avenue for better therapeutic responses to pandemics such as COVID-19. This study leverages independent patient cohorts in Florence and Liege gathered under the umbrella of the DRAGON consortium for the stratification of molecular phenotypes associated with COVID-19 using topological analysis of global blood gene expression. Whole blood from 173 patients was collected and RNA was sequenced on the Novaseq platform. Molecular phenotypes were defined through topological analysis of gene expression relative to the biological network using the TopMD algorithm. The two cohorts from Florence and Liege allowed for independent validation of the findings in this study. Clustering of the topological maps of differential pathway activation revealed three distinct molecular phenotypes of COVID-19 in the Florence patient cohort, which were also observed in the Liege cohort. Cluster 1, was characterised by high activation of pathways associated with ESC pluripotency, NRF2, and TGF-B; receptor signalling. Cluster 2 displayed high activation of pathways including focal adhesion-PI3K-Akt-mTOR signalling and type I interferon induction and signalling, while Cluster 3 exhibited low IRF7-related pathway activation. TopMD was also used with the Drug-Gene Interaction Database (DGIdb), revealing pharmaceutical interventions targeting mechanisms across multiple phenotypes and individuals. The data illustrates the utility of molecular phenotyping from topological analysis of blood gene expression, and holds promise for informing personalised therapeutic strategies not only for COVID-19 but also for Disease X. Its potential transferability across multiple diseases highlights the value in pandemic response efforts, offering insights before large-scale clinical studies are initiated.

Post-COVID Highlights: Challenges and Solutions of AI Techniques for Swift Identification of COVID-19 (preprint)

Since the onset of the COVID-19 pandemic in 2019, there has been a concerted effort to develop cost-effective, non-invasive, and rapid AI-based tools. These tools were intended to alleviate the burden on healthcare systems, control the rapid spread of the virus, and enhance intervention outcomes, all in response to this unprecedented global crisis. As we transition into a post-COVID era, we retrospectively evaluate these proposed studies and offer a review of the techniques employed in AI diagnostic models, with a focus on the solutions proposed for different challenges. This review endeavors to provide insights into the diverse solutions designed to address the multifaceted challenges that arose during the pandemic. By doing so, we aim to prepare the AI community for the development of AI tools tailored to address public health emergencies effectively.

Multi-site, Multi-domain Airway Tree Modeling (ATM'22): A Public Benchmark for Pulmonary Airway Segmentation (preprint)

Open international challenges are becoming the de facto standard for assessing computer vision and image analysis algorithms. In recent years, new methods have extended the reach of pulmonary airway segmentation that is closer to the limit of image resolution. Since EXACT'09 pulmonary airway segmentation, limited effort has been directed to quantitative comparison of newly emerged algorithms driven by the maturity of deep learning based approaches and clinical drive for resolving finer details of distal airways for early intervention of pulmonary diseases. Thus far, public annotated datasets are extremely limited, hindering the development of data-driven methods and detailed performance evaluation of new algorithms. To provide a benchmark for the medical imaging community, we organized the Multi-site, Multi-domain Airway Tree Modeling (ATM'22), which was held as an official challenge event during the MICCAI 2022 conference. ATM'22 provides large-scale CT scans with detailed pulmonary airway annotation, including 500 CT scans (300 for training, 50 for validation, and 150 for testing). The dataset was collected from different sites and it further included a portion of noisy COVID-19 CTs with ground-glass opacity and consolidation. Twenty-three teams participated in the entire phase of the challenge and the algorithms for the top ten teams are reviewed in this paper. Quantitative and qualitative results revealed that deep learning models embedded with the topological continuity enhancement achieved superior performance in general. ATM'22 challenge holds as an open-call design, the training data and the gold standard evaluation are available upon successful registration via its homepage.

Adversarial Transformer for Repairing Human Airway Segmentation (preprint)

Discontinuity in the delineation of peripheral bronchioles hinders the potential clinical application of automated airway segmentation models. Moreover, the deployment of such models is limited by the data heterogeneity across different centres, and pathological abnormalities also make achieving accurate robust segmentation in distal small airways difficult. Meanwhile, the diagnosis and prognosis of lung diseases often rely on evaluating structural changes in those anatomical regions. To address this gap, this paper presents a patch-scale adversarial-based refinement network that takes in preliminary segmentation along with original CT images and outputs a refined mask of the airway structure. The method is validated on three different datasets encompassing healthy cases, cases with cystic fibrosis and cases with COVID-19. The results are quantitatively evaluated by seven metrics and achieved more than a 15% rise in detected length ratio and detected branch ratio, showing promising performance compared to previously proposed models. The visual illustration also proves our refinement guided by a patch-scale discriminator and centreline objective functions is effective in detecting discontinuities and missing bronchioles. Furthermore, the generalizability of our refinement pipeline is tested on three previous models and improves their segmentation completeness significantly.

Fuzzy Attention Neural Network to Tackle Discontinuity in Airway Segmentation (preprint)

Airway segmentation is crucial for the examination, diagnosis, and prognosis of lung diseases, while its manual delineation is unduly burdensome. To alleviate this time-consuming and potentially subjective manual procedure, researchers have proposed methods to automatically segment airways from computerized tomography (CT) images. However, some small-sized airway branches (e.g., bronchus and terminal bronchioles) significantly aggravate the difficulty of automatic segmentation by machine learning models. In particular, the variance of voxel values and the severe data imbalance in airway branches make the computational module prone to discontinuous and false-negative predictions. especially for cohorts with different lung diseases. Attention mechanism has shown the capacity to segment complex structures, while fuzzy logic can reduce the uncertainty in feature representations. Therefore, the integration of deep attention networks and fuzzy theory, given by the fuzzy attention layer, should be an escalated solution for better generalization and robustness. This paper presents an efficient method for airway segmentation, comprising a novel fuzzy attention neural network and a comprehensive loss function to enhance the spatial continuity of airway segmentation. The deep fuzzy set is formulated by a set of voxels in the feature map and a learnable Gaussian membership function. Different from the existing attention mechanism, the proposed channel-specific fuzzy attention addresses the issue of heterogeneous features in different channels. Furthermore, a novel evaluation metric is proposed to assess both the continuity and completeness of airway structures. The efficiency, generalization and robustness of the proposed method have been proved by training on normal lung disease while testing on datasets of lung cancer, COVID-19 and pulmonary fibrosis.

CS$^2$: A Controllable and Simultaneous Synthesizer of Images and Annotations with Minimal Human Intervention (preprint)

The destitution of image data and corresponding expert annotations limit the training capacities of AI diagnostic models and potentially inhibit their performance. To address such a problem of data and label scarcity, generative models have been developed to augment the training datasets. Previously proposed generative models usually require manually adjusted annotations (e.g., segmentation masks) or need pre-labeling. However, studies have found that these pre-labeling based methods can induce hallucinating artifacts, which might mislead the downstream clinical tasks, while manual adjustment could be onerous and subjective. To avoid manual adjustment and pre-labeling, we propose a novel controllable and simultaneous synthesizer (dubbed CS$^2$) in this study to generate both realistic images and corresponding annotations at the same time. Our CS$^2$ model is trained and validated using high resolution CT (HRCT) data collected from COVID-19 patients to realize an efficient infections segmentation with minimal human intervention. Our contributions include 1) a conditional image synthesis network that receives both style information from reference CT images and structural information from unsupervised segmentation masks, and 2) a corresponding segmentation mask synthesis network to automatically segment these synthesized images simultaneously. Our experimental studies on HRCT scans collected from COVID-19 patients demonstrate that our CS$^2$ model can lead to realistic synthesized datasets and promising segmentation results of COVID infections compared to the state-of-the-art nnUNet trained and fine-tuned in a fully supervised manner.

Explainable COVID-19 Infections Identification and Delineation Using Calibrated Pseudo Labels (preprint)

The upheaval brought by the arrival of the COVID-19 pandemic has continued to bring fresh challenges over the past two years. During this COVID-19 pandemic, there has been a need for rapid identification of infected patients and specific delineation of infection areas in computed tomography (CT) images. Although deep supervised learning methods have been established quickly, the scarcity of both image-level and pixel-level labels as well as the lack of explainable transparency still hinder the applicability of AI. Can we identify infected patients and delineate the infections with extreme minimal supervision? Semi-supervised learning has demonstrated promising performance under limited labelled data and sufficient unlabelled data. Inspired by semi-supervised learning, we propose a model-agnostic calibrated pseudo-labelling strategy and apply it under a consistency regularization framework to generate explainable identification and delineation results. We demonstrate the effectiveness of our model with the combination of limited labelled data and sufficient unlabelled data or weakly-labelled data. Extensive experiments have shown that our model can efficiently utilize limited labelled data and provide explainable classification and segmentation results for decision-making in clinical routine. The code is available at https://github.com/ayanglab/XAI COVID-19.