Deep learning-based improvement for the outcomes of glaucoma clinical trials

Glaucoma is the leading cause of irreversible blindness worldwide. It is a progressive optic neuropathy in which retinal ganglion cell (RGC) axon loss, probably as a consequence of damage at the optic disc, causes a loss of vision, predominantly affecting the mid-peripheral visual field (VF). Glaucoma results in a decrease in vision-related quality of life and, therefore, early detection and evaluation of disease progression rates is crucial in order to assess the risk of functional impairment and to establish sound treatment strategies. The aim of my research is to improve glaucoma diagnosis by enhancing state of the art analyses of glaucoma clinical trial outcomes using advanced analytical methods. This knowledge would also help better design and analyse clinical trials, providing evidence for re-evaluating existing medications, facilitating diagnosis and suggesting novel disease management. To facilitate my objective methodology, this thesis provides the following contributions: (i) I developed deep learning-based super-resolution (SR) techniques for optical coherence tomography (OCT) image enhancement and demonstrated that using super-resolved images improves the statistical power of clinical trials, (ii) I developed a deep learning algorithm for segmentation of retinal OCT images, showing that the methodology consistently produces more accurate segmentations than state-of-the-art networks, (iii) I developed a deep learning framework for refining the relationship between structural and functional measurements and demonstrated that the mapping is significantly improved over previous techniques, iv) I developed a probabilistic method and demonstrated that glaucomatous disc haemorrhages are influenced by a possible systemic factor that makes both eyes bleed simultaneously. v) I recalculated VF slopes, using the retinal never fiber layer thickness (RNFLT) from the super-resolved OCT as a Bayesian prior and demonstrated that use of VF rates with the Bayesian prior as the outcome measure leads to a reduction in the sample size required to distinguish treatment arms in a clinical trial

Machine learning strategies for diagnostic imaging support on histopathology and optical coherence tomography

Tesis por compendio[ES] Esta tesis presenta soluciones de vanguardia basadas en algoritmos de computer vision (CV) y machine learning (ML) para ayudar a los expertos en el diagnóstico clínico. Se centra en dos áreas relevantes en el campo de la imagen médica: la patología digital y la oftalmología. Este trabajo propone diferentes paradigmas de machine learning y deep learning para abordar diversos escenarios de supervisión en el estudio del cáncer de próstata, el cáncer de vejiga y el glaucoma. En particular, se consideran métodos supervisados convencionales para segmentar y clasificar estructuras específicas de la próstata en imágenes histológicas digitalizadas. Para el reconocimiento de patrones específicos de la vejiga, se llevan a cabo enfoques totalmente no supervisados basados en técnicas de deep-clustering. Con respecto a la detección del glaucoma, se aplican algoritmos de memoria a corto plazo (LSTMs) que permiten llevar a cabo un aprendizaje recurrente a partir de volúmenes de tomografía por coherencia óptica en el dominio espectral (SD-OCT). Finalmente, se propone el uso de redes neuronales prototípicas (PNN) en un marco de few-shot learning para determinar el nivel de gravedad del glaucoma a partir de imágenes OCT circumpapilares. Los métodos de inteligencia artificial (IA) que se detallan en esta tesis proporcionan una valiosa herramienta de ayuda al diagnóstico por imagen, ya sea para el diagnóstico histológico del cáncer de próstata y vejiga o para la evaluación del glaucoma a partir de datos de OCT.[CA] Aquesta tesi presenta solucions d'avantguarda basades en algorismes de *computer *vision (CV) i *machine *learning (ML) per a ajudar als experts en el diagnòstic clínic. Se centra en dues àrees rellevants en el camp de la imatge mèdica: la patologia digital i l'oftalmologia. Aquest treball proposa diferents paradigmes de *machine *learning i *deep *learning per a abordar diversos escenaris de supervisió en l'estudi del càncer de pròstata, el càncer de bufeta i el glaucoma. En particular, es consideren mètodes supervisats convencionals per a segmentar i classificar estructures específiques de la pròstata en imatges histològiques digitalitzades. Per al reconeixement de patrons específics de la bufeta, es duen a terme enfocaments totalment no supervisats basats en tècniques de *deep-*clustering. Respecte a la detecció del glaucoma, s'apliquen algorismes de memòria a curt termini (*LSTMs) que permeten dur a terme un aprenentatge recurrent a partir de volums de tomografia per coherència òptica en el domini espectral (SD-*OCT). Finalment, es proposa l'ús de xarxes neuronals *prototípicas (*PNN) en un marc de *few-*shot *learning per a determinar el nivell de gravetat del glaucoma a partir d'imatges *OCT *circumpapilares. Els mètodes d'intel·ligència artificial (*IA) que es detallen en aquesta tesi proporcionen una valuosa eina d'ajuda al diagnòstic per imatge, ja siga per al diagnòstic histològic del càncer de pròstata i bufeta o per a l'avaluació del glaucoma a partir de dades d'OCT.[EN] This thesis presents cutting-edge solutions based on computer vision (CV) and machine learning (ML) algorithms to assist experts in clinical diagnosis. It focuses on two relevant areas at the forefront of medical imaging: digital pathology and ophthalmology. This work proposes different machine learning and deep learning paradigms to address various supervisory scenarios in the study of prostate cancer, bladder cancer and glaucoma. In particular, conventional supervised methods are considered for segmenting and classifying prostate-specific structures in digitised histological images. For bladder-specific pattern recognition, fully unsupervised approaches based on deep-clustering techniques are carried out. Regarding glaucoma detection, long-short term memory algorithms (LSTMs) are applied to perform recurrent learning from spectral-domain optical coherence tomography (SD-OCT) volumes. Finally, the use of prototypical neural networks (PNNs) in a few-shot learning framework is proposed to determine the severity level of glaucoma from circumpapillary OCT images. The artificial intelligence (AI) methods detailed in this thesis provide a valuable tool to aid diagnostic imaging, whether for the histological diagnosis of prostate and bladder cancer or glaucoma assessment from OCT data.García Pardo, JG. (2022). Machine learning strategies for diagnostic imaging support on histopathology and optical coherence tomography [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182400Compendi

The application of artificial intelligence in glaucoma diagnosis and prediction

Artificial intelligence is a multidisciplinary and collaborative science, the ability of deep learning for image feature extraction and processing gives it a unique advantage in dealing with problems in ophthalmology. The deep learning system can assist ophthalmologists in diagnosing characteristic fundus lesions in glaucoma, such as retinal nerve fiber layer defects, optic nerve head damage, optic disc hemorrhage, etc. Early detection of these lesions can help delay structural damage, protect visual function, and reduce visual field damage. The development of deep learning led to the emergence of deep convolutional neural networks, which are pushing the integration of artificial intelligence with testing devices such as visual field meters, fundus imaging and optical coherence tomography to drive more rapid advances in clinical glaucoma diagnosis and prediction techniques. This article details advances in artificial intelligence combined with visual field, fundus photography, and optical coherence tomography in the field of glaucoma diagnosis and prediction, some of which are familiar and some not widely known. Then it further explores the challenges at this stage and the prospects for future clinical applications. In the future, the deep cooperation between artificial intelligence and medical technology will make the datasets and clinical application rules more standardized, and glaucoma diagnosis and prediction tools will be simplified in a single direction, which will benefit multiple ethnic groups

Machine Learning Techniques, Detection and Prediction of Glaucoma– A Systematic Review

Globally, glaucoma is the most common factor in both permanent blindness and impairment. However, the majority of patients are unaware they have the condition, and clinical practise continues to face difficulties in detecting glaucoma progression using current technology. An expert ophthalmologist examines the retinal portion of the eye to see how the glaucoma is progressing. This method is quite time-consuming, and doing it manually takes more time. Therefore, using deep learning and machine learning techniques, this problem can be resolved by automatically diagnosing glaucoma. This systematic review involved a comprehensive analysis of various automated glaucoma prediction and detection techniques. More than 100 articles on Machine learning (ML) techniques with understandable graph and tabular column are reviewed considering summery, method, objective, performance, advantages and disadvantages. In the ML techniques such as support vector machine (SVM), and K-means. Fuzzy c-means clustering algorithm are widely used in glaucoma detection and prediction. Through the systematic review, the most accurate technique to detect and predict glaucoma can be determined which can be utilized for future betterment

Glaucoma Detection from Raw SD-OCT Volumes: a Novel Approach Focused on Spatial Dependencies

[EN] Background and objective:Glaucoma is the leading cause of blindness worldwide. Many studies based on fundus image and optical coherence tomography (OCT) imaging have been developed in the literature to help ophthalmologists through artificial-intelligence techniques. Currently, 3D spectral-domain optical coherence tomography (SD-OCT) samples have become more important since they could enclose promising information for glaucoma detection. To analyse the hidden knowledge of the 3D scans for glaucoma detection, we have proposed, for the first time, a deep-learning methodology based on leveraging the spatial dependencies of the features extracted from the B-scans. Methods:The experiments were performed on a database composed of 176 healthy and 144 glaucomatous SD-OCT volumes centred on the optic nerve head (ONH). The proposed methodology consists of two well-differentiated training stages: a slide-level feature extractor and a volume-based predictive model. The slide-level discriminator is characterised by two new, residual and attention, convolutional modules which are combined via skip-connections with other fine-tuned architectures. Regarding the second stage, we first carried out a data-volume conditioning before extracting the features from the slides of the SD-OCT volumes. Then, Long Short-Term Memory (LSTM) networks were used to combine the recurrent dependencies embedded in the latent space to provide a holistic feature vector, which was generated by the proposed sequential-weighting module (SWM). Results:The feature extractor reports AUC values higher than 0.93 both in the primary and external test sets. Otherwise, the proposed end-to-end system based on a combination of CNN and LSTM networks achieves an AUC of 0.8847 in the prediction stage, which outperforms other state-of-the-art approaches intended for glaucoma detection. Additionally, Class Activation Maps (CAMs) were computed to highlight the most interesting regions per B-scan when discerning between healthy and glaucomatous eyes from raw SD-OCT volumes. Conclusions:The proposed model is able to extract the features from the B-scans of the volumes and combine the information of the latent space to perform a volume-level glaucoma prediction. Our model, which combines residual and attention blocks with a sequential weighting module to refine the LSTM outputs, surpass the results achieved from current state-of-the-art methods focused on 3D deep-learning architectures.The authors gratefully acknowledge the support of NVIDIA Corporation with the donation of the Titan V GPU used here.This work has been funded by GALAHAD project [H2020-ICT-2016-2017, 732613], SICAP project (DPI2016-77869-C2-1-R) and GVA through project PROMETEO/2019/109. 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Computational methods for new clinical applications using imaging techniques

Esta tesis tiene por objetivo desarrollar diferentes métodos computacionales con aplicación clínica en varias enfermedades. De este modo, la investigación aquí presentada pretende aumentar el conocimiento sobre cómo el análisis y el estudio de los datos procedentes de técnicas de imagen pueden convertirse en un gran valor clínico para los profesionales de la medicina. Por lo tanto, dichos métodos pueden ser incorporados en la práctica clínica, lo que supone un beneficio para el paciente.Por un lado, la mejora de los diferentes dispositivos de imagen aumenta el abanico de posibilidades de análisis y presentación de los datos. Algunas técnicas de imagen arrojan directamente datos numéricos que tradicionalmente sólo se usaban para la monitorización de enfermedades. Sin embargo, dichos datos pueden ser empleados como biomarcadores tanto para el diagnóstico como para la predicción de enfermedades mediante la inteligencia artificial. Hoy en día, la inteligencia artificial se utiliza en muchos campos ya que todo lo que proporciona datos es abordable por estas nuevas tecnologías. Parece que no hay límite y se están desarrollando nuevas aplicaciones que hace sólo unas décadas parecían imposibles.Por otro lado, las técnicas de imagen nos permiten analizar diferentes partes del cuerpo humano en los respectivos pacientes y compararlas con controles sanos. Del mismo modo, con las imágenes se puede realizar el seguimiento de los tratamientos aplicados en dichos pacientes y, así, verificar su eficacia. Además, estas tecnologías, que proporcionan imágenes de alta resolución, son fáciles de usar, rentables y objetivas.Para resumir, esta tesis se ha centrado en desarrollar varias aplicaciones clínicas, basadas en los métodos numéricos descritos, que podrían ser una poderosa herramienta para aportar mayor información que ayude a los clínicos en la toma de decisiones.This thesis aims to develop different computational methods with clinical application in various diseases. In this way, the research presented here aims to increase knowledge on how the analysis and study of data from imaging techniques can be of great clinical value to medical professionals. Therefore, these methods can be incorporated into clinical practice, which is of benefit to the patient. On the one hand, the improvement of different imaging devices increases the range of possibilities for data analysis and presentation. Some imaging techniques directly yield numerical data that were traditionally only used for disease monitoring. However, these data can be used as biomarkers for both diagnosis and disease prediction using artificial intelligence. Today, artificial intelligence is used in many fields as everything that provides data can be addressed by these new technologies. There seems to be no limit and new applications are being developed that only a few decades ago seemed impossible. On the other hand, imaging techniques allow us to analyse different parts of the human body in the respective patients and compare them with healthy controls. In the same way, imaging can be used to monitor the treatments applied to these patients and, thus, verify their efficacy. Moreover, these technologies, which provide high-resolution images, are easy to use, cost-effective and objective. To summarise, this thesis has focused on developing several clinical applications, based on the described numerical methods, which could be a powerful tool to provide further information to help clinicians in decision making.<br /

Extending Bayesian network models for mining and classification of glaucoma

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Glaucoma is a degenerative disease that damages the nerve fiber layer in the retina of the eye. Its mechanisms are not fully known and there is no fully-effective strategy to prevent visual impairment and blindness. However, if treatment is carried out at an early stage, it is possible to slow glaucomatous progression and improve the quality of life of sufferers. Despite the great amount of heterogeneous data that has become available for monitoring glaucoma, the performance of tests for early diagnosis are still insufficient, due to the complexity of disease progression and the diffculties in obtaining sufficient measurements. This research aims to assess and extend Bayesian Network (BN) models to investigate the nature of the disease and its progression, as well as improve early diagnosis performance. The exibility of BNs and their ability to integrate with clinician expertise make them a suitable tool to effectively exploit the available data. After presenting the problem, a series of BN models for cross-sectional data classification and integration are assessed; novel techniques are then proposed for classification and modelling of glaucoma progression. The results are validated against literature, direct expert knowledge and other Artificial Intelligence techniques, indicating that BNs and their proposed extensions improve glaucoma diagnosis performance and enable new insights into the disease process

Automating the eye examination using optical coherence tomography

Optical coherence tomography (OCT) devices are becoming ubiquitous in eye clinics worldwide to aid the diagnosis and monitoring of eye disease. Much of this uptake relates to the ability to non-invasively capture micron-resolution images, enabling objective and quantitative data to be obtained from ocular structures. Although safe and reasonably quick to perform, the costs involved with operating OCT devices are not trivial, and the requirement for OCT and other imaging in addition to other clinical measures is placing increasing demand on ophthalmology clinics, contributing to fragmented patient pathways and often extended waiting times. In this thesis, a novel “binocular optical coherence tomography” system that seeks to overcome some of the limitations of current commercial OCT systems, is clinically evaluated. This device incorporates many aspects of the eye examination into a single patient-operated instrument, and aims to improve the efficiency and quality of eye care while reducing the overall labour and equipment costs. A progressive framework of testing is followed that includes human factors and usability testing, followed by early stage diagnostic studies to assess the agreement, repeatability, and reproducibility of individual diagnostic features. Health economics analysis of the retinal therapy clinic is used to model cost effectiveness of current practice and with binocular OCT implementation. The binocular OCT and development of other low-cost OCT systems may improve accessibility, however there remains a relative shortage of experts to interpret the images. Artificial intelligence (AI) is likely to play a role in rapid and automated image classification. This thesis explores the application of AI within retinal therapy clinics to predict the onset of exudative age-related macular degeneration in fellow eyes of patients undergoing treatment in their first eye. Together with automated and simultaneous imaging of both eyes with binocular OCT and the potential for low-cost patient-facing systems, AI is likely to have a role in personalising management plans, especially in a future where preventive treatments are available

Combining optical coherence tomography with visual field data to rapidly detect disease progression in glaucoma: A diagnostic accuracy study

Background: Progressive optic nerve damage in glaucoma results in vision loss, quantifiable with visual field (VF) testing. VF measurements are, however, highly variable, making identification of worsening vision (‘progression’) challenging. Glaucomatous optic nerve damage can also be measured with imaging techniques such as optical coherence tomography (OCT). Objective: To compare statistical methods that combine VF and OCT data with VF-only methods to establish whether or not these allow (1) more rapid identification of glaucoma progression and (2) shorter or smaller clinical trials. Design: Method ‘hit rate’ (related to sensitivity) was evaluated in subsets of the United Kingdom Glaucoma Treatment Study (UKGTS) and specificity was evaluated in 72 stable glaucoma patients who had 11 VF and OCT tests within 3 months (the RAPID data set). The reference progression detection method was based on Guided Progression Analysis™ (GPA) Software (Carl Zeiss Meditec Inc., Dublin, CA, USA). Index methods were based on previously described approaches [Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement (ANSWERS), Permutation analyses Of Pointwise Linear Regression (PoPLR) and structure-guided ANSWERS (sANSWERS)] or newly developed methods based on Permutation Test (PERM), multivariate hierarchical models with multiple imputation for censored values (MaHMIC) and multivariate generalised estimating equations with multiple imputation for censored values (MaGIC). Setting: Ten university and general ophthalmology units (UKGTS) and a single university ophthalmology unit (RAPID). Participants: UKGTS participants were newly diagnosed glaucoma patients randomised to intraocular pressure-lowering drops or placebo. RAPID participants had glaucomatous VF loss, were on treatment and were clinically stable. Interventions: 24-2 VF tests with the Humphrey Field Analyzer and optic nerve imaging with time-domain (TD) Stratus OCT™ (Carl Zeiss Meditec Inc., Dublin, CA, USA). Main outcome measures: Criterion hit rate and specificity, time to progression, future VF prediction error, proportion progressing in UKGTS treatment groups, hazard ratios (HRs) and study sample size. Results: Criterion specificity was 95% for all tests; the hit rate was 22.2% for GPA, 41.6% for PoPLR, 53.8% for ANSWERS and 61.3% for sANSWERS (all comparisons p ≤ 0.042). Mean survival time (weeks) was 93.6 for GPA, 82.5 for PoPLR, 72.0 for ANSWERS and 69.1 for sANSWERS. The median prediction errors (decibels) when the initial trend was used to predict the final VF were 3.8 (5th to 95th percentile 1.7 to 7.6) for PoPLR, 3.0 (5th to 95th percentile 1.5 to 5.7) for ANSWERS and 2.3 (5th to 95th percentile 1.3 to 4.5) for sANSWERS. HRs were 0.57 [95% confidence interval (CI) 0.34 to 0.90; p = 0.016] for GPA, 0.59 (95% CI 0.42 to 0.83; p = 0.002) for PoPLR, 0.76 (95% CI 0.56 to 1.02; p = 0.065) for ANSWERS and 0.70 (95% CI 0.53 to 0.93; p = 0.012) for sANSWERS. Sample size estimates were not reduced using methods including OCT data. PERM hit rates were between 8.3% and 17.4%. Treatment effects were non-significant in MaHMIC and MaGIC analyses; statistical significance was altered little by incorporating imaging. Limitations: TD OCT is less precise than current imaging technology; current OCT technology would likely perform better. The size of the RAPID data set limited the precision of criterion specificity estimates. Conclusions: The sANSWERS method combining VF and OCT data had a higher hit rate and identified progression more quickly than the reference and other VF-only methods, and produced more accurate estimates of the progression rate, but did not increase treatment effect statistical significance. Similar studies with current OCT technology need to be undertaken and the statistical methods need refinement