Thomas Booth

Prajwal Ghimire, Junjie Li, Liu Yaou et al.

Background: Radiogenomics allows identification of radiological biomarkers for genomic phenotypes. In glioblastoma, these biomarkers could potentially complement patient stratification strategies. We aim to develop and analytically validate radiological biomarkers that capture immune cell signatures within IDH-wildtype glioblastoma microenvironment using radiogenomic analysis. Methods: This was a retrospective multicenter study using curated open-access anonymized imaging and genomic data from TCGA-GBM, CPTAC, IvyGAP, REMBRANDT and CGGA datasets. Imaging data consisted of MRI-based radiomic features extracted from necrotic core, enhancing and edema regions of deep learning-based auto-segmented tumors. Radiomic feature selections were performed using nested cross-validated LASSO. Support vector machine and ensemble models were trained using seventeen immune and cell-specific score labels extracted from deconvoluted transcriptomic data using pan-cancer and glioblastoma immune signature matrices as reference standards. Seventeen classifier models trained in three cross-cohort strategies were validated on three held-out datasets assessing stability and generalizability. Results: One-hundred-and-seventy-six patients were included in the study. The immune-related radiomic signatures obtained after feature selection were shape, first order and higher order radiomic features. Models predicting macrophage subtype immune signature showed stable mean performance on balanced accuracy (0.67) and precision (0.89) metrics for three independent holdout datasets with ensemble model outperforming support vector machine model. Conclusion: Radiogenomic models non-invasively predicted the macrophage subtype M0 immune signature in IDH-wildtype glioblastoma. These biomarkers have the potential to stratify patients for immunotherapy within prospective glioblastoma clinical trials.

Aaron Kujawa, Thomas Booth, Tom Vercauteren

This work presents novel methods to reduce computational and memory requirements for medical image segmentation with a large number of classes. We curiously observe challenges in maintaining state-of-the-art segmentation performance with all of the explored options. Standard learning-based methods typically employ one-hot encoding of class labels. The computational complexity and memory requirements thus increase linearly with the number of classes. We propose a family of binary encoding approaches instead of one-hot encoding to reduce the computational complexity and memory requirements to logarithmic in the number of classes. In addition to vanilla binary encoding, we investigate the effects of error-correcting output codes (ECOCs), class weighting, hard/soft decoding, class-to-codeword assignment, and label embedding trees. We apply the methods to the use case of whole brain parcellation with 108 classes based on 3D MRI images. While binary encodings have proven efficient in so-called extreme classification problems in computer vision, we faced challenges in reaching state-of-the-art segmentation quality with binary encodings. Compared to one-hot encoding (Dice Similarity Coefficient (DSC) = 82.4 (2.8)), we report reduced segmentation performance with the binary segmentation approaches, achieving DSCs in the range from 39.3 to 73.8. Informative negative results all too often go unpublished. We hope that this work inspires future research of compact encoding strategies for large multi-class segmentation tasks.

Thomas Booth, Bernice Akpinar, Andrei Roman et al.

The aim of the systematic review was to assess recently published studies on diagnostic test accuracy of glioblastoma treatment response monitoring biomarkers in adults, developed through machine learning (ML). Articles were searched for using MEDLINE, EMBASE, and the Cochrane Register. Included study participants were adult patients with high grade glioma who had undergone standard treatment (maximal resection, radiotherapy with concomitant and adjuvant temozolomide) and subsequently underwent follow-up imaging to determine treatment response status. Risk of bias and applicability was assessed with QUADAS 2 methodology. Contingency tables were created for hold-out test sets and recall, specificity, precision, F1-score, balanced accuracy calculated. Fifteen studies were included with 1038 patients in training sets and 233 in test sets. To determine whether there was progression or a mimic, the reference standard combination of follow-up imaging and histopathology at re-operation was applied in 67% of studies. The small numbers of patient included in studies, the high risk of bias and concerns of applicability in the study designs (particularly in relation to the reference standard and patient selection due to confounding), and the low level of evidence, suggest that limited conclusions can be drawn from the data. There is likely good diagnostic performance of machine learning models that use MRI features to distinguish between progression and mimics. The diagnostic performance of ML using implicit features did not appear to be superior to ML using explicit features. There are a range of ML-based solutions poised to become treatment response monitoring biomarkers for glioblastoma. To achieve this, the development and validation of ML models require large, well-annotated datasets where the potential for confounding in the study design has been carefully considered.

Reuben Dorent, Thomas Booth, Wenqi Li et al.

Brain tissue segmentation from multimodal MRI is a key building block of many neuroimaging analysis pipelines. Established tissue segmentation approaches have, however, not been developed to cope with large anatomical changes resulting from pathology, such as white matter lesions or tumours, and often fail in these cases. In the meantime, with the advent of deep neural networks (DNNs), segmentation of brain lesions has matured significantly. However, few existing approaches allow for the joint segmentation of normal tissue and brain lesions. Developing a DNN for such a joint task is currently hampered by the fact that annotated datasets typically address only one specific task and rely on task-specific imaging protocols including a task-specific set of imaging modalities. In this work, we propose a novel approach to build a joint tissue and lesion segmentation model from aggregated task-specific hetero-modal domain-shifted and partially-annotated datasets. Starting from a variational formulation of the joint problem, we show how the expected risk can be decomposed and optimised empirically. We exploit an upper bound of the risk to deal with heterogeneous imaging modalities across datasets. To deal with potential domain shift, we integrated and tested three conventional techniques based on data augmentation, adversarial learning and pseudo-healthy generation. For each individual task, our joint approach reaches comparable performance to task-specific and fully-supervised models. The proposed framework is assessed on two different types of brain lesions: White matter lesions and gliomas. In the latter case, lacking a joint ground-truth for quantitative assessment purposes, we propose and use a novel clinically-relevant qualitative assessment methodology.

David Wood, James Cole, Thomas Booth

Deep learning is attracting significant interest in the neuroimaging community as a means to diagnose psychiatric and neurological disorders from structural magnetic resonance images. However, there is a tendency amongst researchers to adopt architectures optimized for traditional computer vision tasks, rather than design networks customized for neuroimaging data. We address this by introducing NEURO-DRAM, a 3D recurrent visual attention model tailored for neuroimaging classification. The model comprises an agent which, trained by reinforcement learning, learns to navigate through volumetric images, selectively attending to the most informative regions for a given task. When applied to Alzheimer's disease prediction, NEURODRAM achieves state-of-the-art classification accuracy on an out-of-sample dataset, significantly outperforming a baseline convolutional neural network. When further applied to the task of predicting which patients with mild cognitive impairment will be diagnosed with Alzheimer's disease within two years, the model achieves state-of-the-art accuracy with no additional training. Encouragingly, the agent learns, without explicit instruction, a search policy in agreement with standardized radiological hallmarks of Alzheimer's disease, suggesting a route to automated biomarker discovery for more poorly understood disorders.

Thomas Booth, Matthew Williams, Aysha Luis et al.

Aim: To review how machine learning (ML) is applied to imaging biomarkers in neuro-oncology, in particular for diagnosis, prognosis, and treatment response monitoring. Materials and Methods: The PubMed and MEDLINE databases were searched for articles published before September 2018 using relevant search terms. The search strategy focused on articles applying ML to high-grade glioma biomarkers for treatment response monitoring, prognosis, and prediction. Results: Magnetic resonance imaging (MRI) is typically used throughout the patient pathway because routine structural imaging provides detailed anatomical and pathological information and advanced techniques provide additional physiological detail. Using carefully chosen image features, ML is frequently used to allow accurate classification in a variety of scenarios. Rather than being chosen by human selection, ML also enables image features to be identified by an algorithm. Much research is applied to determining molecular profiles, histological tumour grade, and prognosis using MRI images acquired at the time that patients first present with a brain tumour. Differentiating a treatment response from a post-treatment-related effect using imaging is clinically important and also an area of active study (described here in one of two Special Issue publications dedicated to the application of ML in glioma imaging). Conclusion: Although pioneering, most of the evidence is of a low level, having been obtained retrospectively and in single centres. Studies applying ML to build neuro-oncology monitoring biomarker models have yet to show an overall advantage over those using traditional statistical methods. Development and validation of ML models applied to neuro-oncology require large, well-annotated datasets, and therefore multidisciplinary and multi-centre collaborations are necessary.

Thomas Booth

Imaging biomarkers in neuro-oncology are used for diagnosis, prognosis and treatment response monitoring. Magnetic resonance imaging is typically used throughout the patient pathway because routine structural imaging provides detailed anatomical and pathological information and advanced techniques provide additional physiological detail. Following image feature extraction, machine learning allows accurate classification in a variety of scenarios. Machine learning also enables image feature extraction de novo although the low prevalence of brain tumours makes such approaches challenging. Much research is applied to determining molecular profiles, histological tumour grade and prognosis at the time that patients first present with a brain tumour. Following treatment, differentiating a treatment response from a post-treatment related effect is clinically important and also an area of study. Most of the evidence is low level having been obtained retrospectively and in single centres.