A Deep Learning Approach to Denoise Optical Coherence Tomography Images of the Optic Nerve Head

Purpose: To develop a deep learning approach to de-noise optical coherence tomography (OCT) B-scans of the optic nerve head (ONH). Methods: Volume scans consisting of 97 horizontal B-scans were acquired through the center of the ONH using a commercial OCT device (Spectralis) for both eyes of 20 subjects. For each eye, single-frame (without signal averaging), and multi-frame (75x signal averaging) volume scans were obtained. A custom deep learning network was then designed and trained with 2,328 "clean B-scans" (multi-frame B-scans), and their corresponding "noisy B-scans" (clean B-scans + gaussian noise) to de-noise the single-frame B-scans. The performance of the de-noising algorithm was assessed qualitatively, and quantitatively on 1,552 B-scans using the signal to noise ratio (SNR), contrast to noise ratio (CNR), and mean structural similarity index metrics (MSSIM). Results: The proposed algorithm successfully denoised unseen single-frame OCT B-scans. The denoised B-scans were qualitatively similar to their corresponding multi-frame B-scans, with enhanced visibility of the ONH tissues. The mean SNR increased from $4.02 \pm 0.68$ dB (single-frame) to $8.14 \pm 1.03$ dB (denoised). For all the ONH tissues, the mean CNR increased from $3.50 \pm 0.56$ (single-frame) to $7.63 \pm 1.81$ (denoised). The MSSIM increased from $0.13 \pm 0.02$ (single frame) to $0.65 \pm 0.03$ (denoised) when compared with the corresponding multi-frame B-scans. Conclusions: Our deep learning algorithm can denoise a single-frame OCT B-scan of the ONH in under 20 ms, thus offering a framework to obtain superior quality OCT B-scans with reduced scanning times and minimal patient discomfort

Machine Learning Approaches for Automated Glaucoma Detection using Clinical Data and Optical Coherence Tomography Images

Glaucoma is a multi-factorial, progressive blinding optic-neuropathy. A variety of factors, including genetics, vasculature, anatomy, and immune factors, are involved. Worldwide more than 80 million people are affected by glaucoma, and around 300,000 in Australia, where 50% remain undiagnosed. Untreated glaucoma can lead to blindness. Early detection by Artificial intelligence (AI) is crucial to accelerate the diagnosis process and can prevent further vision loss. Many proposed AI systems have shown promising performance for automated glaucoma detection using two-dimensional (2D) data. However, only a few studies had optimistic outcomes for glaucoma detection and staging. Moreover, the automated AI system still faces challenges in diagnosing at the clinicians’ level due to the lack of interpretability of the ML algorithms and integration of multiple clinical data. AI technology would be welcomed by doctors and patients if the "black box" notion is overcome by developing an explainable, transparent AI system with similar pathological markers used by clinicians as the sign of early detection and progression of glaucomatous damage. Therefore, the thesis aimed to develop a comprehensive AI model to detect and stage glaucoma by incorporating a variety of clinical data and utilising advanced data analysis and machine learning (ML) techniques. The research first focuses on optimising glaucoma diagnostic features by combining structural, functional, demographic, risk factor, and optical coherence tomography (OCT) features. The significant features were evaluated using statistical analysis and trained in ML algorithms to observe the detection performance. Three crucial structural ONH OCT features: cross-sectional 2D radial B-scan, 3D vascular angiography and temporal-superior-nasal-inferior-temporal (TSNIT) B-scan, were analysed and trained in explainable deep learning (DL) models for automated glaucoma prediction. The explanation behind the decision making of DL models were successfully demonstrated using the feature visualisation. The structural features or distinguished affected regions of TSNIT OCT scans were precisely localised for glaucoma patients. This is consistent with the concept of explainable DL, which refers to the idea of making the decision-making processes of DL models transparent and interpretable to humans. However, artifacts and speckle noise often result in misinterpretation of the TSNIT OCT scans. This research also developed an automated DL model to remove the artifacts and noise from the OCT scans, facilitating error-free retinal layers segmentation, accurate tissue thickness estimation and image interpretation. Moreover, to monitor and grade glaucoma severity, the visual field (VF) test is commonly followed by clinicians for treatment and management. Therefore, this research uses the functional features extracted from VF images to train ML algorithms for staging glaucoma from early to advanced/severe stages. Finally, the selected significant features were used to design and develop a comprehensive AI model to detect and grade glaucoma stages based on the data quantity and availability. In the first stage, a DL model was trained with TSNIT OCT scans, and its output was combined with significant structural and functional features and trained in ML models. The best-performed ML model achieved an area under the curve (AUC): 0.98, an accuracy of 97.2%, a sensitivity of 97.9%, and a specificity of 96.4% for detecting glaucoma. The model achieved an overall accuracy of 90.7% and an F1 score of 84.0% for classifying normal, early, moderate, and advanced-stage glaucoma. In conclusion, this thesis developed and proposed a comprehensive, evidence-based AI model that will solve the screening problem for large populations and relieve experts from manually analysing a slew of patient data and associated misinterpretation problems. Moreover, this thesis demonstrated three structural OCT features that could be added as excellent diagnostic markers for precise glaucoma diagnosis

Deep learning analysis of eye fundus images to support medical diagnosis

Machine learning techniques have been successfully applied to support medical decision making of cancer, heart diseases and degenerative diseases of the brain. In particular, deep learning methods have been used for early detection of abnormalities in the eye that could improve the diagnosis of different ocular diseases, especially in developing countries, where there are major limitations to access to specialized medical treatment. However, the early detection of clinical signs such as blood vessel, optic disc alterations, exudates, hemorrhages, drusen, and microaneurysms presents three main challenges: the ocular images can be affected by noise artifact, the features of the clinical signs depend specifically on the acquisition source, and the combination of local signs and grading disease label is not an easy task. This research approaches the problem of combining local signs and global labels of different acquisition sources of medical information as a valuable tool to support medical decision making in ocular diseases. Different models for different eye diseases were developed. Four models were developed using eye fundus images: for DME, it was designed a two-stages model that uses a shallow model to predict an exudate binary mask. Then, the binary mask is stacked with the raw fundus image into a 4-channel array as an input of a deep convolutional neural network for diabetic macular edema diagnosis; for glaucoma, it was developed three deep learning models. First, it was defined a deep learning model based on three-stages that contains an initial stage for automatically segment two binary masks containing optic disc and physiological cup segmentation, followed by an automatic morphometric features extraction stage from previous segmentations, and a final classification stage that supports the glaucoma diagnosis with intermediate medical information. Two late-data-fusion methods that fused morphometric features from cartesian and polar segmentation of the optic disc and physiological cup with features extracted from raw eye fundus images. On the other hand, two models were defined using optical coherence tomography. First, a customized convolutional neural network termed as OCT-NET to extract features from OCT volumes to classify DME, DR-DME and AMD conditions. In addition, this model generates images with highlighted local information about the clinical signs, and it estimates the number of slides inside a volume with local abnormalities. Finally, a 3D-Deep learning model that uses OCT volumes as an input to estimate the retinal thickness map useful to grade AMD. The methods were systematically evaluated using ten free public datasets. The methods were compared and validated against other state-of-the-art algorithms and the results were also qualitatively evaluated by ophthalmology experts from Fundación Oftalmológica Nacional. In addition, the proposed methods were tested as a diagnosis support tool of diabetic macular edema, glaucoma, diabetic retinopathy and age-related macular degeneration using two different ocular imaging representations. Thus, we consider that this research could be potentially a big step in building telemedicine tools that could support medical personnel for detecting ocular diseases using eye fundus images and optical coherence tomography.Las técnicas de aprendizaje automático se han aplicado con éxito para apoyar la toma de decisiones médicas sobre el cáncer, las enfermedades cardíacas y las enfermedades degenerativas del cerebro. En particular, se han utilizado métodos de aprendizaje profundo para la detección temprana de anormalidades en el ojo que podrían mejorar el diagnóstico de diferentes enfermedades oculares, especialmente en países en desarrollo, donde existen grandes limitaciones para acceder a tratamiento médico especializado. Sin embargo, la detección temprana de signos clínicos como vasos sanguíneos, alteraciones del disco óptico, exudados, hemorragias, drusas y microaneurismas presenta tres desafíos principales: las imágenes oculares pueden verse afectadas por artefactos de ruido, las características de los signos clínicos dependen específicamente de fuente de adquisición, y la combinación de signos locales y clasificación de la enfermedad no es una tarea fácil. Esta investigación aborda el problema de combinar signos locales y etiquetas globales de diferentes fuentes de adquisición de información médica como una herramienta valiosa para apoyar la toma de decisiones médicas en enfermedades oculares. Se desarrollaron diferentes modelos para diferentes enfermedades oculares. Se desarrollaron cuatro modelos utilizando imágenes de fondo de ojo: para DME, se diseñó un modelo de dos etapas que utiliza un modelo superficial para predecir una máscara binaria de exudados. Luego, la máscara binaria se apila con la imagen de fondo de ojo original en una matriz de 4 canales como entrada de una red neuronal convolucional profunda para el diagnóstico de edema macular diabético; para el glaucoma, se desarrollaron tres modelos de aprendizaje profundo. Primero, se definió un modelo de aprendizaje profundo basado en tres etapas que contiene una etapa inicial para segmentar automáticamente dos máscaras binarias que contienen disco óptico y segmentación fisiológica de la copa, seguido de una etapa de extracción de características morfométricas automáticas de segmentaciones anteriores y una etapa de clasificación final que respalda el diagnóstico de glaucoma con información médica intermedia. Dos métodos de fusión de datos tardíos que fusionaron características morfométricas de la segmentación cartesiana y polar del disco óptico y la copa fisiológica con características extraídas de imágenes de fondo de ojo crudo. Por otro lado, se definieron dos modelos mediante tomografía de coherencia óptica. Primero, una red neuronal convolucional personalizada denominada OCT-NET para extraer características de los volúmenes OCT para clasificar las condiciones DME, DR-DME y AMD. Además, este modelo genera imágenes con información local resaltada sobre los signos clínicos, y estima el número de diapositivas dentro de un volumen con anomalías locales. Finalmente, un modelo de aprendizaje 3D-Deep que utiliza volúmenes OCT como entrada para estimar el mapa de espesor retiniano útil para calificar AMD. Los métodos se evaluaron sistemáticamente utilizando diez conjuntos de datos públicos gratuitos. Los métodos se compararon y validaron con otros algoritmos de vanguardia y los resultados también fueron evaluados cualitativamente por expertos en oftalmología de la Fundación Oftalmológica Nacional. Además, los métodos propuestos se probaron como una herramienta de diagnóstico de edema macular diabético, glaucoma, retinopatía diabética y degeneración macular relacionada con la edad utilizando dos representaciones de imágenes oculares diferentes. Por lo tanto, consideramos que esta investigación podría ser potencialmente un gran paso en la construcción de herramientas de telemedicina que podrían ayudar al personal médico a detectar enfermedades oculares utilizando imágenes de fondo de ojo y tomografía de coherencia óptica.Doctorad

Tools for creating wide-field views of the human retina using Optical Coherence Tomography

Optical Coherence Tomography (OCT) has allowed in-vivo viewing of details of retinal layers like never before. With the development of spectral domain OCT (SD-OCT) details of nearly 2µm axial resolution and higher imaging speed have been reported. Nevertheless, a single volume scan of the retina is typically restricted to 6mm x 6mm in size. Having a larger field of view of the retina will definitely enhance the clinical utility of the OCT. A tool was developed for creating wide-field thickness maps of the retina by combining the use of already available tools like i2k Retina (DualAlign, LLC, Clifton Park, NY) and the thickness maps from Cirrus HD-OCT research browser (Carl Zeiss Meditec, Dublin, California, USA). Normal subjects (n=20) were imaged on Zeiss Cirrus HD-OCT using 512x128 Macular Cube scanning protocol. Sixteen overlapping volumetric images were obtained by moving the internal fixation target around such that the final stitched maps were 12mm x 14mm in size. The thickness maps were corrected for inter-individual differences in axial lengths measured using Zeiss IOL Master and averaged to obtain a normative map. An algorithm was also developed for montaging 3-D volume scans. Using this algorithm two OCT volume scans can be registered and stitched together to obtain a larger volume scan. The algorithm can be described as a two step process involving 3-D phase-correlation and 2-D Pseudo-polar Fourier transform (PPFT). In the first step, 3-D phase-correlation provides translation values in the x, y and z axis. The second step involves applying PPFT on each overlapping pair of B-scans to find rotation in the x-y plane. Subsequent volumes can be stitched to obtain a large field of view. We developed a simple and robust method for creating wide-field views of the retina using existing SD-OCT hardware. As segmentation algorithms improve, this method could be expanded to produce wide-field maps of retinal sub-layers, such as the outer nuclear layer or retinal nerve fiber layer. These wide-field views of the retina may prove useful in evaluating retinal diseases involving the peripheral retina (e.g., retinitis pigmentosa and glaucoma)

Automatic Segmentation of the Retinal Nerve Fiber Layer by Means of Mathematical Morphology and Deformable Models in 2D Optical Coherence Tomography Imaging

[EN] Glaucoma is a neurodegenerative disease process that leads to progressive damage of the optic nerve to produce visual impairment and blindness. Spectral-domain OCT technology enables peripapillary circular scans of the retina and the measurement of the thickness of the retinal nerve fiber layer (RNFL) for the assessment of the disease status or progression in glaucoma patients. This paper describes a new approach to segment and measure the retinal nerve fiber layer in peripapillary OCT images. The proposed method consists of two stages. In the first one, morphological operators robustly detect the coarse location of the layer boundaries, despite the speckle noise and diverse artifacts in the OCT image. In the second stage, deformable models are initialized with the results of the previous stage to perform a fine segmentation of the boundaries, providing an accurate measurement of the entire RNFL. The results of the RNFL segmentation were qualitatively assessed by ophthalmologists, and the measurements of the thickness of the RNFL were quantitatively compared with those provided by the OCT inbuilt software as well as the state-of-the-art methods.This work was partially funded by Spanish National projects AES2017-PI17/00771 and AES2017-PI17/00821 (Instituto de Salud Carlos III), PID2019-105142RB-C21 (AI4SKIN) (Spanish Ministry of Economy and Competitiveness), PTA2017-14610-I (State Research Spanish Agency), regional project 20901/PI/18 (Fundacion Seneca) and Polytechnic University of Valencia (PAID-01-20).Berenguer-Vidal, R.; Verdú-Monedero, R.; Morales-Sánchez, J.; Sellés-Navarro, I.; Del Amor, R.; García-Pardo, JG.; Naranjo Ornedo, V. (2021). Automatic Segmentation of the Retinal Nerve Fiber Layer by Means of Mathematical Morphology and Deformable Models in 2D Optical Coherence Tomography Imaging. Sensors. 21(23):1-30. https://doi.org/10.3390/s21238027S130212

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

Artificial Intelligence Algorithms to Diagnose Glaucoma and Detect Glaucoma Progression: Translation to Clinical Practice

Purpose: This concise review aims to explore the potential for the clinical implementation of artificial intelligence (AI) strategies for detecting glaucoma and monitoring glaucoma progression. / Methods: Nonsystematic literature review using the search combinations "Artificial Intelligence," "Deep Learning," "Machine Learning," "Neural Networks," "Bayesian Networks," "Glaucoma Diagnosis," and "Glaucoma Progression." Information on sensitivity and specificity regarding glaucoma diagnosis and progression analysis as well as methodological details were extracted. / Results: Numerous AI strategies provide promising levels of specificity and sensitivity for structural (e.g. optical coherence tomography [OCT] imaging, fundus photography) and functional (visual field [VF] testing) test modalities used for the detection of glaucoma. Area under receiver operating curve (AROC) values of > 0.90 were achieved with every modality. Combining structural and functional inputs has been shown to even more improve the diagnostic ability. Regarding glaucoma progression, AI strategies can detect progression earlier than conventional methods or potentially from one single VF test. / Conclusions: AI algorithms applied to fundus photographs for screening purposes may provide good results using a simple and widely accessible test. However, for patients who are likely to have glaucoma more sophisticated methods should be used including data from OCT and perimetry. Outputs may serve as an adjunct to assist clinical decision making, whereas also enhancing the efficiency, productivity, and quality of the delivery of glaucoma care. Patients with diagnosed glaucoma may benefit from future algorithms to evaluate their risk of progression. Challenges are yet to be overcome, including the external validity of AI strategies, a move from a "black box" toward "explainable AI," and likely regulatory hurdles. However, it is clear that AI can enhance the role of specialist clinicians and will inevitably shape the future of the delivery of glaucoma care to the next generation. / Translational Relevance: The promising levels of diagnostic accuracy reported by AI strategies across the modalities used in clinical practice for glaucoma detection can pave the way for the development of reliable models appropriate for their translation into clinical practice. Future incorporation of AI into healthcare models may help address the current limitations of access and timely management of patients with glaucoma across the world

Optical designs and image processing algorithms for optical coherence tomography detection of glaucoma

textOptical Coherence Tomography (OCT) is an optical tomography technique which provides high resolution non-invasive three-dimensional (3D) structural images of the sample based on coherent properties of light. The dissertation focuses on the use of OCT systems for detecting glaucoma, which is the second leading cause of blindness worldwide. First, as a prerequisite of analyzing ophthalmologic OCT images, a retinal sublayer segmentation algorithm is presented and implemented with GPU assisted computation. Then, a polarization-sensitive optical coherence tomography (PS-OCT) system was constructed for the study of glaucoma. Three closely related clinical and animal studies on early-stage glaucoma detection using either OCT or PS-OCT were performed. Statistical analysis of the study results indicates that the scattering property of retinal nerve fiber layer (RNFL) is the earliest indicator for glaucoma. Finally, to investigate the scattering properties of RNFL, a pathlength-multiplexed scattering-angle-diverse optical coherence tomography (PM-SAD-OCT) system was designed and built. PM-SAD-OCT images were collected from human and rodent retina as well as earthworm nerve cord. PM-SAD-OCT system shows promising potentials to detect neurodegenerative diseases including glaucoma.Biomedical Engineerin

Precision Medicine in Glaucoma: Artificial Intelligence, Biomarkers, Genetics and Redox State

Glaucoma is a multifactorial neurodegenerative illness requiring early diagnosis and strict monitoring of the disease progression. Current exams for diagnosis and prognosis are based on clinical examination, intraocular pressure (IOP) measurements, visual field tests, and optical coherence tomography (OCT). In this scenario, there is a critical unmet demand for glaucoma-related biomarkers to enhance clinical testing for early diagnosis and tracking of the disease’s development. The introduction of validated biomarkers would allow for prompt intervention in the clinic to help with prognosis prediction and treatment response monitoring. This review aims to report the latest acquisitions on biomarkers in glaucoma, from imaging analysis to genetics and metabolic markers