Evis Sala

Tolou Shadbahr, Michael Roberts, Jan Stanczuk et al.

Classifying samples in incomplete datasets is a common aim for machine learning practitioners, but is non-trivial. Missing data is found in most real-world datasets and these missing values are typically imputed using established methods, followed by classification of the now complete, imputed, samples. The focus of the machine learning researcher is then to optimise the downstream classification performance. In this study, we highlight that it is imperative to consider the quality of the imputation. We demonstrate how the commonly used measures for assessing quality are flawed and propose a new class of discrepancy scores which focus on how well the method recreates the overall distribution of the data. To conclude, we highlight the compromised interpretability of classifier models trained using poorly imputed data.

Thomas Buddenkotte, Lorena Escudero Sanchez, Mireia Crispin-Ortuzar et al.

Uncertainty quantification in automated image analysis is highly desired in many applications. Typically, machine learning models in classification or segmentation are only developed to provide binary answers; however, quantifying the uncertainty of the models can play a critical role for example in active learning or machine human interaction. Uncertainty quantification is especially difficult when using deep learning-based models, which are the state-of-the-art in many imaging applications. The current uncertainty quantification approaches do not scale well in high-dimensional real-world problems. Scalable solutions often rely on classical techniques, such as dropout, during inference or training ensembles of identical models with different random seeds to obtain a posterior distribution. In this paper, we show that these approaches fail to approximate the classification probability. On the contrary, we propose a scalable and intuitive framework to calibrate ensembles of deep learning models to produce uncertainty quantification measurements that approximate the classification probability. On unseen test data, we demonstrate improved calibration, sensitivity (in two out of three cases) and precision when being compared with the standard approaches. We further motivate the usage of our method in active learning, creating pseudo-labels to learn from unlabeled images and human-machine collaboration.

Francesca Fati, Felipe Coutinho, Marika Reinius et al.

Purpose. High-grade serous ovarian carcinoma (HGSOC) is characterized by pronounced biological and spatial heterogeneity and is frequently diagnosed at an advanced stage. Neoadjuvant chemotherapy (NACT) followed by delayed primary surgery is commonly employed in patients unsuitable for primary cytoreduction. The Chemotherapy Response Score (CRS) is a validated histopathological biomarker of response to NACT, but it is only available postoperatively. In this study, we investigate whether pre-treatment computed tomography (CT) imaging and clinical data can be used to predict CRS as an investigational decision-support adjunct to inform multidisciplinary team (MDT) discussions regarding expected treatment response. Methods. We proposed a 2.5D multimodal deep learning framework that processes lesion-dense omental slices using a pre-trained Vision Transformer encoder and integrates the resulting visual representations with clinical variables through an intermediate fusion module to predict CRS. Results. Our multimodal model, integrating imaging and clinical data, achieved a ROC-AUC of 0.95 alongside 95% accuracy and 80% precision on the internal test cohort (IEO, n=41 patients). On the external test set (OV04, n=70 patients), it achieved a ROC-AUC of 0.68, alongside 67% accuracy and 75% precision. Conclusion. These preliminary results demonstrate the feasibility of transformer-based deep learning for preoperative prediction of CRS in HGSOC using routine clinical data and CT imaging. As an investigational, pre-treatment decision-support tool, this approach may assist MDT discussions by providing early, non-invasive estimates of treatment response.

Sepideh Hatamikia, Geevarghese George, Florian Schwarzhans et al.

Objectives: High-grade serous ovarian carcinoma (HGSOC) is typically diagnosed at an advanced stage with extensive peritoneal metastases, making treatment challenging. Neoadjuvant chemotherapy (NACT) is often used to reduce tumor burden before surgery, but about 40% of patients show limited response. Radiomics, combined with machine learning (ML), offers a promising non-invasive method for predicting NACT response by analyzing computed tomography (CT) imaging data. This study aimed to improve response prediction in HGSOC patients undergoing NACT by integration different feature selection methods. Materials and methods: A framework for selecting robust radiomics features was introduced by employing an automated randomisation algorithm to mimic inter-observer variability, ensuring a balance between feature robustness and prediction accuracy. Four response metrics were used: chemotherapy response score (CRS), RECIST, volume reduction (VolR), and diameter reduction (DiaR). Lesions in different anatomical sites were studied. Pre- and post-NACT CT scans were used for feature extraction and model training on one cohort, and an independent cohort was used for external testing. Results: The best prediction performance was achieved using all lesions combined for VolR prediction, with an AUC of 0.83. Omental lesions provided the best results for CRS prediction (AUC 0.77), while pelvic lesions performed best for DiaR (AUC 0.76). Conclusion: The integration of robustness into the feature selection processes ensures the development of reliable models and thus facilitates the implementation of the radiomics models in clinical applications for HGSOC patients. Future work should explore further applications of radiomics in ovarian cancer, particularly in real-time clinical settings.

Inês P. Machado, Anna Reithmeir, Fryderyk Kogl et al.

High-grade serous ovarian carcinoma (HGSOC) is characterised by significant spatial and temporal heterogeneity, typically manifesting at an advanced metastatic stage. A major challenge in treating advanced HGSOC is effectively monitoring localised change in tumour burden across multiple sites during neoadjuvant chemotherapy (NACT) and predicting long-term pathological response and overall patient survival. In this work, we propose a self-supervised deformable image registration algorithm that utilises a general-purpose image encoder for image feature extraction to co-register contrast-enhanced computerised tomography scan images acquired before and after neoadjuvant chemotherapy. This approach addresses challenges posed by highly complex tumour deformations and longitudinal lesion matching during treatment. Localised tumour changes are calculated using the Jacobian determinant maps of the registration deformation at multiple disease sites and their macroscopic areas, including hypo-dense (i.e., cystic/necrotic), hyper-dense (i.e., calcified), and intermediate density (i.e., soft tissue) portions. A series of experiments is conducted to understand the role of a general-purpose image encoder and its application in quantifying change in tumour burden during neoadjuvant chemotherapy in HGSOC. This work is the first to demonstrate the feasibility of a self-supervised image registration approach in quantifying NACT-induced localised tumour changes across the whole disease burden of patients with complex multi-site HGSOC, which could be used as a potential marker for ovarian cancer patient's long-term pathological response and survival.

Michael Yeung, Leonardo Rundo, Yang Nan et al.

The Dice similarity coefficient (DSC) is both a widely used metric and loss function for biomedical image segmentation due to its robustness to class imbalance. However, it is well known that the DSC loss is poorly calibrated, resulting in overconfident predictions that cannot be usefully interpreted in biomedical and clinical practice. Performance is often the only metric used to evaluate segmentations produced by deep neural networks, and calibration is often neglected. However, calibration is important for translation into biomedical and clinical practice, providing crucial contextual information to model predictions for interpretation by scientists and clinicians. In this study, we provide a simple yet effective extension of the DSC loss, named the DSC++ loss, that selectively modulates the penalty associated with overconfident, incorrect predictions. As a standalone loss function, the DSC++ loss achieves significantly improved calibration over the conventional DSC loss across six well-validated open-source biomedical imaging datasets, including both 2D binary and 3D multi-class segmentation tasks. Similarly, we observe significantly improved calibration when integrating the DSC++ loss into four DSC-based loss functions. Finally, we use softmax thresholding to illustrate that well calibrated outputs enable tailoring of recall-precision bias, which is an important post-processing technique to adapt the model predictions to suit the biomedical or clinical task. The DSC++ loss overcomes the major limitation of the DSC loss, providing a suitable loss function for training deep learning segmentation models for use in biomedical and clinical practice. Source code is available at: https://github.com/mlyg/DicePlusPlus.

Michael Yeung, Evis Sala, Carola-Bibiane Schönlieb et al.

Automatic segmentation methods are an important advancement in medical image analysis. Machine learning techniques, and deep neural networks in particular, are the state-of-the-art for most medical image segmentation tasks. Issues with class imbalance pose a significant challenge in medical datasets, with lesions often occupying a considerably smaller volume relative to the background. Loss functions used in the training of deep learning algorithms differ in their robustness to class imbalance, with direct consequences for model convergence. The most commonly used loss functions for segmentation are based on either the cross entropy loss, Dice loss or a combination of the two. We propose the Unified Focal loss, a new hierarchical framework that generalises Dice and cross entropy-based losses for handling class imbalance. We evaluate our proposed loss function on five publicly available, class imbalanced medical imaging datasets: CVC-ClinicDB, Digital Retinal Images for Vessel Extraction (DRIVE), Breast Ultrasound 2017 (BUS2017), Brain Tumour Segmentation 2020 (BraTS20) and Kidney Tumour Segmentation 2019 (KiTS19). We compare our loss function performance against six Dice or cross entropy-based loss functions, across 2D binary, 3D binary and 3D multiclass segmentation tasks, demonstrating that our proposed loss function is robust to class imbalance and consistently outperforms the other loss functions. Source code is available at: https://github.com/mlyg/unified-focal-loss

Xiang Bai, Hanchen Wang, Liya Ma et al.

Artificial intelligence (AI) provides a promising substitution for streamlining COVID-19 diagnoses. However, concerns surrounding security and trustworthiness impede the collection of large-scale representative medical data, posing a considerable challenge for training a well-generalised model in clinical practices. To address this, we launch the Unified CT-COVID AI Diagnostic Initiative (UCADI), where the AI model can be distributedly trained and independently executed at each host institution under a federated learning framework (FL) without data sharing. Here we show that our FL model outperformed all the local models by a large yield (test sensitivity /specificity in China: 0.973/0.951, in the UK: 0.730/0.942), achieving comparable performance with a panel of professional radiologists. We further evaluated the model on the hold-out (collected from another two hospitals leaving out the FL) and heterogeneous (acquired with contrast materials) data, provided visual explanations for decisions made by the model, and analysed the trade-offs between the model performance and the communication costs in the federated training process. Our study is based on 9,573 chest computed tomography scans (CTs) from 3,336 patients collected from 23 hospitals located in China and the UK. Collectively, our work advanced the prospects of utilising federated learning for privacy-preserving AI in digital health.

Michael Yeung, Leonardo Rundo, Evis Sala et al.

In recent years, there has been increasing interest to incorporate attention into deep learning architectures for biomedical image segmentation. The modular design of attention mechanisms enables flexible integration into convolutional neural network architectures, such as the U-Net. Whether attention is appropriate to use, what type of attention to use, and where in the network to incorporate attention modules, are all important considerations that are currently overlooked. In this paper, we investigate the role of the Focal parameter in modulating attention, revealing a link between attention in loss functions and networks. By incorporating a Focal distance penalty term, we extend the Unified Focal loss framework to include boundary-based losses. Furthermore, we develop a simple and interpretable, dataset and model-specific heuristic to integrate the Focal parameter into the Squeeze-and-Excitation block and Attention Gate, achieving optimal performance with fewer number of attention modules on three well-validated biomedical imaging datasets, suggesting judicious use of attention modules results in better performance and efficiency.

Michael Yeung, Guang Yang, Evis Sala et al.

Manual segmentation is used as the gold-standard for evaluating neural networks on automated image segmentation tasks. Due to considerable heterogeneity in shapes, colours and textures, demarcating object boundaries is particularly difficult in biomedical images, resulting in significant inter and intra-rater variability. Approaches, such as soft labelling and distance penalty term, apply a global transformation to the ground truth, redefining the loss function with respect to uncertainty. However, global operations are computationally expensive, and neither approach accurately reflects the uncertainty underlying manual annotation. In this paper, we propose the Boundary Uncertainty, which uses morphological operations to restrict soft labelling to object boundaries, providing an appropriate representation of uncertainty in ground truth labels, and may be adapted to enable robust model training where systematic manual segmentation errors are present. We incorporate Boundary Uncertainty with the Dice loss, achieving consistently improved performance across three well-validated biomedical imaging datasets compared to soft labelling and distance-weighted penalty. Boundary Uncertainty not only more accurately reflects the segmentation process, but it is also efficient, robust to segmentation errors and exhibits better generalisation.

Michael Yeung, Evis Sala, Carola-Bibiane Schönlieb et al.

Background: Colonoscopy remains the gold-standard screening for colorectal cancer. However, significant miss rates for polyps have been reported, particularly when there are multiple small adenomas. This presents an opportunity to leverage computer-aided systems to support clinicians and reduce the number of polyps missed. Method: In this work we introduce the Focus U-Net, a novel dual attention-gated deep neural network, which combines efficient spatial and channel-based attention into a single Focus Gate module to encourage selective learning of polyp features. The Focus U-Net further incorporates short-range skip connections and deep supervision. Furthermore, we introduce the Hybrid Focal loss, a new compound loss function based on the Focal loss and Focal Tversky loss, to handle class-imbalanced image segmentation. For our experiments, we selected five public datasets containing images of polyps obtained during optical colonoscopy: CVC-ClinicDB, Kvasir-SEG, CVC-ColonDB, ETIS-Larib PolypDB and EndoScene test set. To evaluate model performance, we use the Dice similarity coefficient (DSC) and Intersection over Union (IoU) metrics. Results: Our model achieves state-of-the-art results for both CVC-ClinicDB and Kvasir-SEG, with a mean DSC of 0.941 and 0.910, respectively. When evaluated on a combination of five public polyp datasets, our model similarly achieves state-of-the-art results with a mean DSC of 0.878 and mean IoU of 0.809, a 14% and 15% improvement over the previous state-of-the-art results of 0.768 and 0.702, respectively. Conclusions: This study shows the potential for deep learning to provide fast and accurate polyp segmentation results for use during colonoscopy. The Focus U-Net may be adapted for future use in newer non-invasive screening and more broadly to other biomedical image segmentation tasks involving class imbalance and requiring efficiency.

Michael Roberts, Derek Driggs, Matthew Thorpe et al.

Machine learning methods offer great promise for fast and accurate detection and prognostication of COVID-19 from standard-of-care chest radiographs (CXR) and computed tomography (CT) images. Many articles have been published in 2020 describing new machine learning-based models for both of these tasks, but it is unclear which are of potential clinical utility. In this systematic review, we search EMBASE via OVID, MEDLINE via PubMed, bioRxiv, medRxiv and arXiv for published papers and preprints uploaded from January 1, 2020 to October 3, 2020 which describe new machine learning models for the diagnosis or prognosis of COVID-19 from CXR or CT images. Our search identified 2,212 studies, of which 415 were included after initial screening and, after quality screening, 61 studies were included in this systematic review. Our review finds that none of the models identified are of potential clinical use due to methodological flaws and/or underlying biases. This is a major weakness, given the urgency with which validated COVID-19 models are needed. To address this, we give many recommendations which, if followed, will solve these issues and lead to higher quality model development and well documented manuscripts.

Changhee Han, Leonardo Rundo, Kohei Murao et al.

Unsupervised learning can discover various unseen abnormalities, relying on large-scale unannotated medical images of healthy subjects. Towards this, unsupervised methods reconstruct a 2D/3D single medical image to detect outliers either in the learned feature space or from high reconstruction loss. However, without considering continuity between multiple adjacent slices, they cannot directly discriminate diseases composed of the accumulation of subtle anatomical anomalies, such as Alzheimer's Disease (AD). Moreover, no study has shown how unsupervised anomaly detection is associated with either disease stages, various (i.e., more than two types of) diseases, or multi-sequence Magnetic Resonance Imaging (MRI) scans. Therefore, we propose unsupervised Medical Anomaly Detection Generative Adversarial Network (MADGAN), a novel two-step method using GAN-based multiple adjacent brain MRI slice reconstruction to detect brain anomalies at different stages on multi-sequence structural MRI: (Reconstruction) Wasserstein loss with Gradient Penalty + 100 L1 loss-trained on 3 healthy brain axial MRI slices to reconstruct the next 3 ones-reconstructs unseen healthy/abnormal scans; (Diagnosis) Average L2 loss per scan discriminates them, comparing the ground truth/reconstructed slices. For training, we use two different datasets composed of 1,133 healthy T1-weighted (T1) and 135 healthy contrast-enhanced T1 (T1c) brain MRI scans for detecting AD and brain metastases/various diseases, respectively. Our Self-Attention MADGAN can detect AD on T1 scans at a very early stage, Mild Cognitive Impairment (MCI), with Area Under the Curve (AUC) 0.727, and AD at a late stage with AUC 0.894, while detecting brain metastases on T1c scans with AUC 0.921.

Maureen van Eijnatten, Leonardo Rundo, K. Joost Batenburg et al.

This study investigates the use of the unsupervised deep learning framework VoxelMorph for deformable registration of longitudinal abdominopelvic CT images acquired in patients with bone metastases from breast cancer. The CT images were refined prior to registration by automatically removing the CT table and all other extra-corporeal components. To improve the learning capabilities of VoxelMorph when only a limited amount of training data is available, a novel incremental training strategy is proposed based on simulated deformations of consecutive CT images. In a 4-fold cross-validation scheme, the incremental training strategy achieved significantly better registration performance compared to training on a single volume. Although our deformable image registration method did not outperform iterative registration using NiftyReg (considered as a benchmark) in terms of registration quality, the registrations were approximately 300 times faster. This study showed the feasibility of deep learning based deformable registration of longitudinal abdominopelvic CT images via a novel incremental training strategy based on simulated deformations.

Changhee Han, Leonardo Rundo, Kohei Murao et al.

Unsupervised learning can discover various unseen diseases, relying on large-scale unannotated medical images of healthy subjects. Towards this, unsupervised methods reconstruct a single medical image to detect outliers either in the learned feature space or from high reconstruction loss. However, without considering continuity between multiple adjacent slices, they cannot directly discriminate diseases composed of the accumulation of subtle anatomical anomalies, such as Alzheimer's Disease (AD). Moreover, no study has shown how unsupervised anomaly detection is associated with disease stages. Therefore, we propose a two-step method using Generative Adversarial Network-based multiple adjacent brain MRI slice reconstruction to detect AD at various stages: (Reconstruction) Wasserstein loss with Gradient Penalty + L1 loss---trained on 3 healthy slices to reconstruct the next 3 ones---reconstructs unseen healthy/AD cases; (Diagnosis) Average/Maximum loss (e.g., L2 loss) per scan discriminates them, comparing the reconstructed/ground truth images. The results show that we can reliably detect AD at a very early stage with Area Under the Curve (AUC) 0.780 while also detecting AD at a late stage much more accurately with AUC 0.917; since our method is fully unsupervised, it should also discover and alert any anomalies including rare disease.