Automatic analysis of retinal images to aid in the diagnosis and grading of diabetic retinopathy

Diabetic retinopathy (DR) is the most common complication of diabetes mellitus and one of the leading causes of preventable blindness in the adult working population. Visual loss can be prevented from the early stages of DR, when the treatments are effective. Therefore, early diagnosis is paramount. However, DR may be clinically asymptomatic until the advanced stage, when vision is already affected and treatment may become difficult. For this reason, diabetic patients should undergo regular eye examinations through screening programs. Traditionally, DR screening programs are run by trained specialists through visual inspection of the retinal images. However, this manual analysis is time consuming and expensive. With the increasing incidence of diabetes and the limited number of clinicians and sanitary resources, the early detection of DR becomes non-viable. For this reason, computed-aided diagnosis (CAD) systems are required to assist specialists for a fast, reliable diagnosis, allowing to reduce the workload and the associated costs. We hypothesize that the application of novel, automatic algorithms for fundus image analysis could contribute to the early diagnosis of DR. Consequently, the main objective of the present Doctoral Thesis is to study, design and develop novel methods based on the automatic analysis of fundus images to aid in the screening, diagnosis, and treatment of DR. In order to achieve the main goal, we built a private database and used five retinal public databases: DRIMDB, DIARETDB1, DRIVE, Messidor and Kaggle. The stages of fundus image processing covered in this Thesis are: retinal image quality assessment (RIQA), the location of the optic disc (OD) and the fovea, the segmentation of RLs and EXs, and the DR severity grading. RIQA was studied with two different approaches. The first approach was based on the combination of novel, global features. Results achieved 91.46% accuracy, 92.04% sensitivity, and 87.92% specificity using the private database. We developed a second approach aimed at RIQA based on deep learning. We achieved 95.29% accuracy with the private database and 99.48% accuracy with the DRIMDB database. The location of the OD and the fovea was performed using a combination of saliency maps. The proposed methods were evaluated over the private database and the public databases DRIVE, DIARETDB1 and Messidor. For the OD, we achieved 100% accuracy for all databases except Messidor (99.50%). As for the fovea location, we also reached 100% accuracy for all databases except Messidor (99.67%). The joint segmentation of RLs and EXs was accomplished by decomposing the fundus image into layers. Results were computed per pixel and per image. Using the private database, 88.34% per-image accuracy (ACCi) was reached for the RL detection and 95.41% ACCi for EX detection. An additional method was proposed for the segmentation of RLs based on superpixels. Evaluating this method with the private database, we obtained 84.45% ACCi. Results were validated using the DIARETDB1 database. Finally, we proposed a deep learning framework for the automatic DR severity grading. The method was based on a novel attention mechanism which performs a separate attention of the dark and the bright structures of the retina. The Kaggle DR detection dataset was used for development and validation. The International Clinical DR Scale was considered, which is made up of 5 DR severity levels. Classification results for all classes achieved 83.70% accuracy and a Quadratic Weighted Kappa of 0.78. The methods proposed in this Doctoral Thesis form a complete, automatic DR screening system, contributing to aid in the early detection of DR. In this way, diabetic patients could receive better attention for their ocular health avoiding vision loss. In addition, the workload of specialists could be relieved while healthcare costs are reduced.La retinopatía diabética (RD) es la complicación más común de la diabetes mellitus y una de las principales causas de ceguera prevenible en la población activa adulta. El diagnóstico precoz es primordial para prevenir la pérdida visual. Sin embargo, la RD es clínicamente asintomática hasta etapas avanzadas, cuando la visión ya está afectada. Por eso, los pacientes diabéticos deben someterse a exámenes oftalmológicos periódicos a través de programas de cribado. Tradicionalmente, estos programas están a cargo de especialistas y se basan de la inspección visual de retinografías. Sin embargo, este análisis manual requiere mucho tiempo y es costoso. Con la creciente incidencia de la diabetes y la escasez de recursos sanitarios, la detección precoz de la RD se hace inviable. Por esta razón, se necesitan sistemas de diagnóstico asistido por ordenador (CAD) que ayuden a los especialistas a realizar un diagnóstico rápido y fiable, que permita reducir la carga de trabajo y los costes asociados. El objetivo principal de la presente Tesis Doctoral es estudiar, diseñar y desarrollar nuevos métodos basados en el análisis automático de retinografías para ayudar en el cribado, diagnóstico y tratamiento de la RD. Las etapas estudiadas fueron: la evaluación de la calidad de la imagen retiniana (RIQA), la localización del disco óptico (OD) y la fóvea, la segmentación de RL y EX y la graduación de la severidad de la RD. RIQA se estudió con dos enfoques diferentes. El primer enfoque se basó en la combinación de características globales. Los resultados lograron una precisión del 91,46% utilizando la base de datos privada. El segundo enfoque se basó en aprendizaje profundo. Logramos un 95,29% de precisión con la base de datos privada y un 99,48% con la base de datos DRIMDB. La localización del OD y la fóvea se realizó mediante una combinación de mapas de saliencia. Los métodos propuestos fueron evaluados sobre la base de datos privada y las bases de datos públicas DRIVE, DIARETDB1 y Messidor. Para el OD, logramos una precisión del 100% para todas las bases de datos excepto Messidor (99,50%). En cuanto a la ubicación de la fóvea, también alcanzamos un 100% de precisión para todas las bases de datos excepto Messidor (99,67%). La segmentación conjunta de RL y EX se logró descomponiendo la imagen del fondo de ojo en capas. Utilizando la base de datos privada, se alcanzó un 88,34% de precisión por imagen (ACCi) para la detección de RL y un 95,41% de ACCi para la detección de EX. Se propuso un método adicional para la segmentación de RL basado en superpíxeles. Evaluando este método con la base de datos privada, obtuvimos 84.45% ACCi. Los resultados se validaron utilizando la base de datos DIARETDB1. Finalmente, propusimos un método de aprendizaje profundo para la graduación automática de la gravedad de la DR. El método se basó en un mecanismo de atención. Se utilizó la base de datos Kaggle y la Escala Clínica Internacional de RD (5 niveles de severidad). Los resultados de clasificación para todas las clases alcanzaron una precisión del 83,70% y un Kappa ponderado cuadrático de 0,78. Los métodos propuestos en esta Tesis Doctoral forman un sistema completo y automático de cribado de RD, contribuyendo a ayudar en la detección precoz de la RD. De esta forma, los pacientes diabéticos podrían recibir una mejor atención para su salud ocular evitando la pérdida de visión. Además, se podría aliviar la carga de trabajo de los especialistas al mismo tiempo que se reducen los costes sanitarios.Escuela de DoctoradoDoctorado en Tecnologías de la Información y las Telecomunicacione

Deep Learning in Medical Image Analysis

The accelerating power of deep learning in diagnosing diseases will empower physicians and speed up decision making in clinical environments. Applications of modern medical instruments and digitalization of medical care have generated enormous amounts of medical images in recent years. In this big data arena, new deep learning methods and computational models for efficient data processing, analysis, and modeling of the generated data are crucially important for clinical applications and understanding the underlying biological process. This book presents and highlights novel algorithms, architectures, techniques, and applications of deep learning for medical image analysis

Harmonic Analysis and Machine Learning

This dissertation considers data representations that lie at the interesection of harmonic analysis and neural networks. The unifying theme of this work is the goal for robust and reliable machine learning. Our specific contributions include a new variant of scattering transforms based on a Haar-type directional wavelet, a new study of deep neural network instability in the context of remote sensing problems, and new empirical studies of biomedical applications of neural networks

Recent Clinical Research on Glaucoma

In the past few years, knowledge about glaucoma diagnosis and follow up has evolved dramatically through advances in intraocular pressure (IOP) measurement, corneal biomechanics, structural and functional assessment of the ocular surface, anterior chamber, retina, optic nerve and intracranial visual pathways, as well as the advent of artificial intelligence. In addition, the development of new modalities of IOP-lowering and non-IOP-lowering drugs, alternative deliveries, refined laser technologies, and minimally invasive glaucoma surgery (MIGS) techniques with different implants have widened the therapeutic possibilities for treating this disease. Finally, current insights into risk factors and quality of life in relation to glaucomatous impairment are emerging. The purpose of this Special Issue is to present the latest exciting clinical developments that are taking place in the field of glaucoma

Big Data: Potential as an Ocular Epidemiology and Public Health Tool

Refractive error is a significant cause of vision impairment both through the limited access to correction in some areas and the associated ocular diseases for which refractive errors are risk factors. Having timely, regular access to population level estimates of refractive error and vision impairment is necessary to adequately plan public health resources and resource appropriate interventions. A lack of access to current and regularly updated refractive error and vision impairment prevalence data has been identified as a significant limitation in predicting future population trends with many countries lacking any prevalence data or available data being outdated. This project addresses this gap by utilising the untapped potential of Big Data in the form of spectacle lens sales data and optometric electronic medical record data and assesses the potential of these data sources as a public health tool. Chapter 5 contains a review of the application of Big Data and Artificial Intelligence to the field of eyecare and describes the revolutionary potential these new technologies may hold. Chapter 6 describes the data used in this project and the steps taken to acquire and clean the data. Chapter 7 and 8 compare the prevalence of refractive error found using spectacle lens sales data and optometric electronic medical record data to a large population survey of refractive error and demonstrate that with careful analysis an accurate estimation of population distribution of refractive error can be obtained from both types of data. Chapter 8 also estimates the likely level of vision impairment by age 75 given the distribution of myopia in the spectacle lens sales data. Chapter 9 analyses visual acuity data within the optometric electronic medical records which allowed the optimum recall interval and visual acuity threshold for driving licence renewal to be determined. Chapter 10 provides a summary and conclusion on the work, and contains recommendations for future research

Object Recognition

Vision-based object recognition tasks are very familiar in our everyday activities, such as driving our car in the correct lane. We do these tasks effortlessly in real-time. In the last decades, with the advancement of computer technology, researchers and application developers are trying to mimic the human's capability of visually recognising. Such capability will allow machine to free human from boring or dangerous jobs

Anwendungen maschinellen Lernens für datengetriebene Prävention auf Populationsebene

Healthcare costs are systematically rising, and current therapy-focused healthcare systems are not sustainable in the long run. While disease prevention is a viable instrument for reducing costs and suffering, it requires risk modeling to stratify populations, identify high- risk individuals and enable personalized interventions. In current clinical practice, however, systematic risk stratification is limited: on the one hand, for the vast majority of endpoints, no risk models exist. On the other hand, available models focus on predicting a single disease at a time, rendering predictor collection burdensome. At the same time, the den- sity of individual patient data is constantly increasing. Especially complex data modalities, such as -omics measurements or images, may contain systemic information on future health trajectories relevant for multiple endpoints simultaneously. However, to date, this data is inaccessible for risk modeling as no dedicated methods exist to extract clinically relevant information. This study built on recent advances in machine learning to investigate the ap- plicability of four distinct data modalities not yet leveraged for risk modeling in primary prevention. For each data modality, a neural network-based survival model was developed to extract predictive information, scrutinize performance gains over commonly collected covariates, and pinpoint potential clinical utility. Notably, the developed methodology was able to integrate polygenic risk scores for cardiovascular prevention, outperforming existing approaches and identifying benefiting subpopulations. Investigating NMR metabolomics, the developed methodology allowed the prediction of future disease onset for many common diseases at once, indicating potential applicability as a drop-in replacement for commonly collected covariates. Extending the methodology to phenome-wide risk modeling, elec- tronic health records were found to be a general source of predictive information with high systemic relevance for thousands of endpoints. Assessing retinal fundus photographs, the developed methodology identified diseases where retinal information most impacted health trajectories. In summary, the results demonstrate the capability of neural survival models to integrate complex data modalities for multi-disease risk modeling in primary prevention and illustrate the tremendous potential of machine learning models to disrupt medical practice toward data-driven prevention at population scale.Die Kosten im Gesundheitswesen steigen systematisch und derzeitige therapieorientierte Gesundheitssysteme sind nicht nachhaltig. Angesichts vieler verhinderbarer Krankheiten stellt die Prävention ein veritables Instrument zur Verringerung von Kosten und Leiden dar. Risikostratifizierung ist die grundlegende Voraussetzung für ein präventionszentri- ertes Gesundheitswesen um Personen mit hohem Risiko zu identifizieren und Maßnah- men einzuleiten. Heute ist eine systematische Risikostratifizierung jedoch nur begrenzt möglich, da für die meisten Krankheiten keine Risikomodelle existieren und sich verfüg- bare Modelle auf einzelne Krankheiten beschränken. Weil für deren Berechnung jeweils spezielle Sets an Prädiktoren zu erheben sind werden in Praxis oft nur wenige Modelle angewandt. Gleichzeitig versprechen komplexe Datenmodalitäten, wie Bilder oder -omics- Messungen, systemische Informationen über zukünftige Gesundheitsverläufe, mit poten- tieller Relevanz für viele Endpunkte gleichzeitig. Da es an dedizierten Methoden zur Ex- traktion klinisch relevanter Informationen fehlt, sind diese Daten jedoch für die Risikomod- ellierung unzugänglich, und ihr Potenzial blieb bislang unbewertet. Diese Studie nutzt ma- chinelles Lernen, um die Anwendbarkeit von vier Datenmodalitäten in der Primärpräven- tion zu untersuchen: polygene Risikoscores für die kardiovaskuläre Prävention, NMR Meta- bolomicsdaten, elektronische Gesundheitsakten und Netzhautfundusfotos. Pro Datenmodal- ität wurde ein neuronales Risikomodell entwickelt, um relevante Informationen zu extra- hieren, additive Information gegenüber üblicherweise erfassten Kovariaten zu quantifizieren und den potenziellen klinischen Nutzen der Datenmodalität zu ermitteln. Die entwickelte Me-thodik konnte polygene Risikoscores für die kardiovaskuläre Prävention integrieren. Im Falle der NMR-Metabolomik erschloss die entwickelte Methodik wertvolle Informa- tionen über den zukünftigen Ausbruch von Krankheiten. Unter Einsatz einer phänomen- weiten Risikomodellierung erwiesen sich elektronische Gesundheitsakten als Quelle prädik- tiver Information mit hoher systemischer Relevanz. Bei der Analyse von Fundusfotografien der Netzhaut wurden Krankheiten identifiziert für deren Vorhersage Netzhautinformationen genutzt werden könnten. Zusammengefasst zeigten die Ergebnisse das Potential neuronaler Risikomodelle die medizinische Praxis in Richtung einer datengesteuerten, präventionsori- entierten Medizin zu verändern

Smoking and Second Hand Smoking in Adolescents with Chronic Kidney Disease: A Report from the Chronic Kidney Disease in Children (CKiD) Cohort Study

The goal of this study was to determine the prevalence of smoking and second hand smoking [SHS] in adolescents with CKD and their relationship to baseline parameters at enrollment in the CKiD, observational cohort study of 600 children (aged 1-16 yrs) with Schwartz estimated GFR of 30-90 ml/min/1.73m2. 239 adolescents had self-report survey data on smoking and SHS exposure: 21 [9%] subjects had “ever” smoked a cigarette. Among them, 4 were current and 17 were former smokers. Hypertension was more prevalent in those that had “ever” smoked a cigarette (42%) compared to non-smokers (9%), p\u3c0.01. Among 218 non-smokers, 130 (59%) were male, 142 (65%) were Caucasian; 60 (28%) reported SHS exposure compared to 158 (72%) with no exposure. Non-smoker adolescents with SHS exposure were compared to those without SHS exposure. There was no racial, age, or gender differences between both groups. Baseline creatinine, diastolic hypertension, C reactive protein, lipid profile, GFR and hemoglobin were not statistically different. Significantly higher protein to creatinine ratio (0.90 vs. 0.53, p\u3c0.01) was observed in those exposed to SHS compared to those not exposed. Exposed adolescents were heavier than non-exposed adolescents (85th percentile vs. 55th percentile for BMI, p\u3c 0.01). Uncontrolled casual systolic hypertension was twice as prevalent among those exposed to SHS (16%) compared to those not exposed to SHS (7%), though the difference was not statistically significant (p= 0.07). Adjusted multivariate regression analysis [OR (95% CI)] showed that increased protein to creatinine ratio [1.34 (1.03, 1.75)] and higher BMI [1.14 (1.02, 1.29)] were independently associated with exposure to SHS among non-smoker adolescents. These results reveal that among adolescents with CKD, cigarette use is low and SHS is highly prevalent. The association of smoking with hypertension and SHS with increased proteinuria suggests a possible role of these factors in CKD progression and cardiovascular outcomes