Detection and Classification of Diabetic Retinopathy Pathologies in Fundus Images

Diabetic Retinopathy (DR) is a disease that affects up to 80% of diabetics around the world. It is the second greatest cause of blindness in the Western world, and one of the leading causes of blindness in the U.S. Many studies have demonstrated that early treatment can reduce the number of sight-threatening DR cases, mitigating the medical and economic impact of the disease. Accurate, early detection of eye disease is important because of its potential to reduce rates of blindness worldwide. Retinal photography for DR has been promoted for decades for its utility in both disease screening and clinical research studies. In recent years, several research centers have presented systems to detect pathology in retinal images. However, these approaches apply specialized algorithms to detect specific types of lesion in the retina. In order to detect multiple lesions, these systems generally implement multiple algorithms. Furthermore, some of these studies evaluate their algorithms on a single dataset, thus avoiding potential problems associated with the differences in fundus imaging devices, such as camera resolution. These methodologies primarily employ bottom-up approaches, in which the accurate segmentation of all the lesions in the retina is the basis for correct determination. A disadvantage of bottom-up approaches is that they rely on the accurate segmentation of all lesions in order to measure performance. On the other hand, top-down approaches do not depend on the segmentation of specific lesions. Thus, top-down methods can potentially detect abnormalities not explicitly used in their training phase. A disadvantage of these methods is that they cannot identify specific pathologies and require large datasets to build their training models. In this dissertation, I merged the advantages of the top-down and bottom-up approaches to detect DR with high accuracy. First, I developed an algorithm based on a top-down approach to detect abnormalities in the retina due to DR. By doing so, I was able to evaluate DR pathologies other than microaneurysms and exudates, which are the main focus of most current approaches. In addition, I demonstrated good generalization capacity of this algorithm by applying it to other eye diseases, such as age-related macular degeneration. Due to the fact that high accuracy is required for sight-threatening conditions, I developed two bottom-up approaches, since it has been proven that bottom-up approaches produce more accurate results than top-down approaches for particular structures. Consequently, I developed an algorithm to detect exudates in the macula. The presence of this pathology is considered to be a surrogate for clinical significant macular edema (CSME), a sight-threatening condition of DR. The analysis of the optic disc is usually not taken into account in DR screening systems. However, there is a pathology called neovascularization that is present in advanced stages of DR, making its detection of crucial clinical importance. In order to address this problem, I developed an algorithm to detect neovascularization in the optic disc. These algorithms are based on amplitude-modulation and frequency-modulation (AM-FM) representations, morphological image processing methods, and classification algorithms. The methods were tested on a diverse set of large databases and are considered to be the state-of the art in this field

Visual field and structural alterations in age-related macular degeneration

The thesis investigated progression of the central 10° visual field with structural changes at the macula in a cross-section of patients with varying degrees of agerelated macular degeneration (AMD). The relationships between structure and function were investigated for both standard and short-wavelength automated perimetry (SWAP). Factors known to influence the measure of visual field progression were considered, including the accuracy of the refractive correction on SWAP thresholds and the learning effect. Techniques of assessing the structure to function relationships between fundus images and the visual field were developed with computer programming and evaluated for repeatability. Drusen quantification of fundus photographs and retro-mode scanning laser ophthalmoscopic images was performed. Visual field progression was related to structural changes derived from both manual and automated methods. Principal Findings: • Visual field sensitivity declined with advancing stage of AMD. SWAP showed greater sensitivity to progressive changes than standard perimetry. • Defects were confined to the central 5°. SWAP defects occurred at similar locations but were deeper and wider than corresponding standard perimetry defects. • The central field became less uniform as severity of AMD increased. SWAP visual field indices of focal loss were of more importance when detecting early change in AMD, than indices of diffuse loss. • The decline in visual field sensitivity over stage of severity of AMD was not uniform, whereas a linear relationship was found between the automated measure of drusen area and visual field parameters. • Perimetry exhibited a stronger relationship with drusen area than other measures of visual function. • Overcorrection of the refraction for the working distance in SWAP should be avoided in subjects with insufficient accommodative facility. • The perimetric learning effect in the 10° field did not differ significantly between normal subjects and AMD patients. • Subretinal deposits appeared more numerous in retro-mode imaging than in fundus photography

Modeling, Pattern Analysis and Feature-Based Retrieval on Retinal Images

Inexpensive high quality fundus camera systems enable imaging of retina for vision related health management and diagnosis at large scale. A computer based analysis system can help establish the general baseline of normal conditions vs. anomalous ones, so that different classes of retinal conditions can be classified. Advanced applications, ranging from disease screening algorithms, aging vs. disease trend modeling and prediction, and content-based retrieval systems can be developed. In this dissertation, I propose an analytical framework for the modeling of retina blood vessels to capture their statistical properties, so that based on these properties one can develop blood vessel mapping algorithms with self-optimized parameters. Then, other image objects can be registered based on vascular topology modeling techniques. On the basis of these low level analytical models and algorithms, the third major element of this dissertation is a high level population statistics application, in which texture classification of macular patterns is correlated with vessel structures, which can also be used for retinal image retrieval. The analytical models have been implemented and tested based on various image sources. Some of the algorithms have been used for clinical tests. The major contributions of this dissertation are summarized as follows: (1) A concise, accurate feature representation of retinal blood vessel on retinal images by proposing two feature descriptors Sp and Ep derived from radial contrast transform. (2) A new statistical model of lognormal distribution, which captures the underlying physical property of the levels of generations of the vascular network on retinal images. (3) Fast and accurate detection algorithms for retinal objects, which include retinal blood vessel, macular-fovea area and optic disc, and (4) A novel population statistics based modeling technique for correlation analysis of blood vessels and other image objects that only exhibit subtle texture changes

To Investigate the Foveal Avascular Zone in a Young Healthy Population Using Optical Coherence Tomography Angiography

Introduction/Aims Inflammatory diseases such as diabetes, glaucoma and age-related macular degeneration (AMD) can alter the size and shape of the foveal avascular zone (FAZ). Macular pigment (MP), a powerful antioxidant, located at the macula can protect the eye from oxidative stress damage. This study aims to investigate possible factors affecting the FAZ, such as vessel perfusion and overweight/obesity, in association with MP status in a young, healthy population. Normative values for FAZ size/shape and vascularity will also be proposed. Methods One hundred and fifty-four subjects aged 18-35 years old were recruited. Superficial FAZ area, diameter, ganglion cell layer, central macular thickness (CMT), vascular perfusion and density were measured by Optical Coherence Tomography Angiography (OCTA). FAZ area/vascularity were assessed in relation to body mass index (BMI), trunk fat % and macular pigment optical density (MPOD). Results Mean FAZ area was 0.22±0.07millimetres squared (mm2). Reduced vessel perfusion central (≤ 24%), low MPOD (≤ 0.4optical density units (OD)) and high BMI (\u3e 25kilograms (kg)/metre (m2)) were associated with a larger FAZ area on multivariate analysis. Age, vessel perfusion and CMT were all negative predictors of FAZ area. Trunk fat % was a positive predictor of FAZ area (p = 0.03) while BMI was positively correlated with FAZ area, (Pearson’s r = 0.18, p = 0.03). Conclusions Optical Coherence Tomography Angiography has potential as a screening tool aiding in the earlier detection and monitoring of eye diseases associated with oxidative stress i.e., hypertensive and diabetic retinopathy (DR), glaucoma and AMD. FAZ size in association with MPOD assessment, may be useful in detecting and advising patients at risk of retinal oxidative stress damage

Ethnic differences in the spatial distribution of macular pigment and its association with foveal anatomy

Macular pigment (MP) at the centre of the retina is thought to serve a protective function shielding the photoreceptors from damaging effects of blue light. The amount of MP and its spatial density distribution across the macula i.e. its spatial profile varies among individuals. Lower levels of MP and certain MP spatial profile phenotypes are believed to be associated with increased risk of age-related macular degeneration (AMD). There is suggestion that MP spatial profiles differ between ethnicities, with non-exponential profiles occurring more frequently in non-whites. This may explain some of the ethnic variations seen in AMD prevalence. However, previous investigations have used several methodologies to measure MP. In addition, inconsistent MP spatial profile definitions have been used; thus comparing data between studies is difficult. Nevertheless, it has been hypothesised that variations in MP spatial distribution could be due to differences in foveal architecture, in particular at the foveal centre where MP levels peak. A study was designed to investigate the effect of ethnicity on MP spatial density distribution and its relation to foveal architecture. The influence of known risk factors for AMD was also considered. Young (18 to 39 years), healthy volunteers of white (n = 76), South Asian (n = 80) and black (n = 70) ethnic origin were recruited to take part. MP measurements were obtained using a method based on heterochromatic flicker photometry (HFP) and foveal morphology measurements were taken from optical coherence tomography (OCT) scans. The coefficients of repeatability of each of these were confirmed in a sub-study. A systematic objective MP spatial profile classification technique was implemented throughout. The feasibility of applying this to MP measurements obtained with different techniques such as HFP and fundus autofluorescence (FAF) was also explored in a sub-study. The results showed that measures of MP optical density (MPOD) over the central retinal area were statistically significantly increased in South Asian and black compared to white subjects, whereby ethnicity explained around 10% of the variation (P < 0.0005). Non-exponential MP spatial profiles (ring-like and central dip respectively) were significantly more prevalent in South Asian and black compared with white subjects (χ2 (4, n = 226) = 13.4, P = 0.009). Integrated MPOD up to 1.8º was significantly increased in ring-like and central dip compared to exponential profiles (P < 0.0005) irrespective of ethnicity. South Asian and black individuals presented thinner central retinas and wider foveas compared to white individuals (P < 0.0005). However, while accounting for these ethnic variations, foveal architecture provided no predictive values for the MP spatial profile phenotype

Structure function correlation in retinal ischaemia and macular oedema

Diabetic retinopathy (DR) and retinal vein occlusion (RVO) are the two most prevalent retinal vascular diseases which affect macular perfusion, altering visual function. Firstly, healthy eyes [eyes with no structural pathology identified on Optical coherence tomography (OCT) and OCT angiogram (OCTA)] were assessed for the foveal parameters to identify the reliability of structural markers before studying pathological changes. The white ethnic group had a smaller foveal avascular zone area and perimeter compared to the Asian and Afro-Caribbean (AFC) ethnic groups, respectively in our study. Retinal capillary loss is an irreversible complication of DR. We analysed patients with advanced DR and found higher parafoveal capillary vessel density (VD) at the level of superficial capillary plexus (SCP) was associated with better best corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) while for radial peripapillary capillary plexus (RPCP) only VD of temporal sector was the predictor of LLVA. Disorganization of the retinal inner layers (DRIL), a potential biomarker of focal ischaemia affects LLVA more than BCVA. In a final adjusted model, the SCP density of the parafoveal area was the only parameter that most accurately ascertained BCVA and LLVA. In the next section of this thesis, functional assessment of the effect of treatment (anti-vascular endothelial growth factor [VEGF] versus laser) on active proliferative diabetic retinopathy (PDR) showed BCVA and LLVA are well correlated before and after treatment. Our findings suggest ten letters difference between BCVA-LLVA; however, this difference becomes more remarkable for a lower level of BCVA, suggesting more advanced ischaemia affects LLVA aggressively. Next analysing, OCTA changes at the macula for PDR, and central retinal vein occlusion (CRVO), I found capillary loss was more pronounced in PDR than CRVO. The final chapter of the thesis looked at the baseline demographic and morphological changes in CRVO patients to predict vision outcomes. Baseline retinal central subfield thickness (CST) up to 900 microns can be expected to improve by 2 or more lines on Early Treatment Diabetic Retinopathy Study (ETDRS) chart or achieve >70 letters visual acuity (VA) at 100 weeks of follow up and treatment. Age of the patient and vision at the time of diagnosis of CRVO and intact ellipsoid zone can predict BCVA at 100 weeks following initiation of treatment in CRVO eyes

Visual field and structural alterations in age-related macular degeneration

The thesis investigated progression of the central 10° visual field with structural changes at the macula in a cross-section of patients with varying degrees of agerelated macular degeneration (AMD). The relationships between structure and function were investigated for both standard and short-wavelength automated perimetry (SWAP). Factors known to influence the measure of visual field progression were considered, including the accuracy of the refractive correction on SWAP thresholds and the learning effect. Techniques of assessing the structure to function relationships between fundus images and the visual field were developed with computer programming and evaluated for repeatability. Drusen quantification of fundus photographs and retro-mode scanning laser ophthalmoscopic images was performed. Visual field progression was related to structural changes derived from both manual and automated methods. Principal Findings: • Visual field sensitivity declined with advancing stage of AMD. SWAP showed greater sensitivity to progressive changes than standard perimetry. • Defects were confined to the central 5°. SWAP defects occurred at similar locations but were deeper and wider than corresponding standard perimetry defects. • The central field became less uniform as severity of AMD increased. SWAP visual field indices of focal loss were of more importance when detecting early change in AMD, than indices of diffuse loss. • The decline in visual field sensitivity over stage of severity of AMD was not uniform, whereas a linear relationship was found between the automated measure of drusen area and visual field parameters. • Perimetry exhibited a stronger relationship with drusen area than other measures of visual function. • Overcorrection of the refraction for the working distance in SWAP should be avoided in subjects with insufficient accommodative facility. • The perimetric learning effect in the 10° field did not differ significantly between normal subjects and AMD patients. • Subretinal deposits appeared more numerous in retro-mode imaging than in fundus photography.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Dynamic features of the mature retinal pigment epithelium

The retinal pigment epithelium (RPE) is a monolayer of cells that are vital for visual function and play a key role in the maintenance of the photoreceptors. Within RPE cells are melanin granules which absorb stray light and minimise scatter within the eye, therefore, protecting the RPE from damage. Albinos lack this protective capacity of melanin as a result of mutations of the tyrosinase gene. The first half of this thesis investigates heterogeneity within the RPE in both pigmentation phenotypes. Furthermore, the effect of ageing on the RPE is examined. Immunohistochemistry highlighted the molecular heterogeneity of the RPE and how this varies with pigmentation phenotype. In aged animals, SEM revealed abnormalities occurring within the photoreceptor outer segments of albinos, while ERGs and QRT-PCR illustrated that albinos show the signs of an age-related decline in visual function much sooner than pigmented animals. These studies revealed that in the outer retina, albinism is a progressive disease and not simply a congenital abnormality. The second half of this thesis investigates migration and proliferation of RPE cells in healthy pigmented animals. Using BrdU and DiI it was established that individual RPE cells have the ability to migrate. In addition, the effect of inducing lesions in different retinal locations was studied to determine whether this affects the response of RPE cells to the damaged area. The results conveyed that a single unilateral lesion in the RPE caused an upregulation of proliferating cells not only in the lasered eye, but also the contralateral unlasered eye in a quadrant specific manner. An additional experiment investigated the effect of treating rats with Glatiramer Acetate and found that it elevates levels of cell proliferation in the RPE of treated animals. Together, the data presented in this thesis demonstrate that the mature RPE is a dynamic heterogeneous epithelial cell layer

Engineering data compendium. Human perception and performance. User's guide

The concept underlying the Engineering Data Compendium was the product of a research and development program (Integrated Perceptual Information for Designers project) aimed at facilitating the application of basic research findings in human performance to the design and military crew systems. The principal objective was to develop a workable strategy for: (1) identifying and distilling information of potential value to system design from the existing research literature, and (2) presenting this technical information in a way that would aid its accessibility, interpretability, and applicability by systems designers. The present four volumes of the Engineering Data Compendium represent the first implementation of this strategy. This is the first volume, the User's Guide, containing a description of the program and instructions for its use