Automatic Screening and Classification of Diabetic Retinopathy Eye Fundus Image

Diabetic Retinopathy (DR) is a disorder of the retinal vasculature. It develops to some degree in nearly all patients with long-standing diabetes mellitus and can result in blindness. Screening of DR is essential for both early detection and early treatment. This thesis aims to investigate automatic methods for diabetic retinopathy detection and subsequently develop an effective system for the detection and screening of diabetic retinopathy. The presented diabetic retinopathy research involves three development stages. Firstly, the thesis presents the development of a preliminary classification and screening system for diabetic retinopathy using eye fundus images. The research will then focus on the detection of the earliest signs of diabetic retinopathy, which are the microaneurysms. The detection of microaneurysms at an early stage is vital and is the first step in preventing diabetic retinopathy. Finally, the thesis will present decision support systems for the detection of diabetic retinopathy and maculopathy in eye fundus images. The detection of maculopathy, which are yellow lesions near the macula, is essential as it will eventually cause the loss of vision if the affected macula is not treated in time. An accurate retinal screening, therefore, is required to assist the retinal screeners to classify the retinal images effectively. Highly efficient and accurate image processing techniques must thus be used in order to produce an effective screening of diabetic retinopathy. In addition to the proposed diabetic retinopathy detection systems, this thesis will present a new dataset, and will highlight the dataset collection, the expert diagnosis process and the advantages of the new dataset, compared to other public eye fundus images datasets available. The new dataset will be useful to researchers and practitioners working in the retinal imaging area and would widely encourage comparative studies in the field of diabetic retinopathy research. It is envisaged that the proposed decision support system for clinical screening would greatly contribute to and assist the management and the detection of diabetic retinopathy. It is also hoped that the developed automatic detection techniques will assist clinicians to diagnose diabetic retinopathy at an early stage

Computational models for stuctural analysis of retinal images

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University LondonThe evaluation of retina structures has been of great interest because it could be used as a non-intrusive diagnosis in modern ophthalmology to detect many important eye diseases as well as cardiovascular disorders. A variety of retinal image analysis tools have been developed to assist ophthalmologists and eye diseases experts by reducing the time required in eye screening, optimising the costs as well as providing efficient disease treatment and management systems. A key component in these tools is the segmentation and quantification of retina structures. However, the imaging artefacts such as noise, intensity homogeneity and the overlapping tissue of retina structures can cause significant degradations to the performance of these automated image analysis tools. This thesis aims to provide robust and reliable automated retinal image analysis technique to allow for early detection of various retinal and other diseases. In particular, four innovative segmentation methods have been proposed, including two for retinal vessel network segmentation, two for optic disc segmentation and one for retina nerve fibre layers detection. First, three pre-processing operations are combined in the segmentation method to remove noise and enhance the appearance of the blood vessel in the image, and a Mixture of Gaussians is used to extract the blood vessel tree. Second, a graph cut segmentation approach is introduced, which incorporates the mechanism of vectors flux into the graph formulation to allow for the segmentation of very narrow blood vessels. Third, the optic disc segmentation is performed using two alternative methods: the Markov random field image reconstruction approach detects the optic disc by removing the blood vessels from the optic disc area, and the graph cut with compensation factor method achieves that using prior information of the blood vessels. Fourth, the boundaries of the retinal nerve fibre layer (RNFL) are detected by adapting a graph cut segmentation technique that includes a kernel-induced space and a continuous multiplier based max-flow algorithm. The strong experimental results of our retinal blood vessel segmentation methods including Mixture of Gaussian, Graph Cut achieved an average accuracy of 94:33%, 94:27% respectively. Our optic disc segmentation methods including Markov Random Field and Compensation Factor also achieved an average sensitivity of 92:85% and 85:70% respectively. These results obtained on several public datasets and compared with existing methods have shown that our proposed methods are robust and efficient in the segmenting retinal structures such the blood vessels and the optic disc.Brunel University Londonhttp://bura.brunel.ac.uk/bitstream/2438/10387/1/FulltextThesis.pd

Early screening and diagnosis of diabetic retinopathy

Diabetic retinopathy (DR) is a chronic, progressive and possibly vision-threatening eye disease. Early detection and diagnosis of DR, prior to the development of any lesions, is paramount for more efficiently dealing with it and managing its consequences. This thesis investigates and proposes a number of candidate geometric and haemodynamic biomarkers, derived from fundus images of the retinal vasculature, which can be reliably utilised for identifying the progression from diabetes to DR. Numerous studies exist in literature that investigate only some of these biomarkers in independent normal, diabetic and DR cohorts. However, none exist, to the best of my knowledge, that investigates more than 100 biomarkers altogether, both geometric and haemodynamic ones, for identifying the progression to DR, by also using a novel experimental design, where the same exact matched junctions and subjects are evaluated in a four year period that includes the last three years pre-DR (still diabetic eye) and the onset of DR (progressors’ group). Multiple additional conventional experimental designs, such as non-matched junctions, non-progressors’ group, and a combination of them are also adopted in order to present the superiority of this type of analysis for retinal features. Therefore, this thesis aims to present a complete framework and some novel knowledge, based on statistical analysis, feature selection processes and classification models, so as to provide robust, rigorous and meaningful statistical inferences, alongside efficient feature subsets that can identify the stages of the progression. In addition, a new and improved method for more accurately summarising the calibres of the retinal vessel trunks is also presented. The first original contribution of this thesis is that a series of haemodynamic features (blood flow rate, blood flow velocity, etc.), which are estimated from the retinal vascular geometry based on some boundary conditions, are applied to studying the progression from diabetes to DR. These features are found to undoubtedly contribute to the inferences and the understanding of the progression, yielding significant results, mainly for the venular network. The second major contribution is the proposed framework and the experimental design for more accurately and efficiently studying and quantifying the vascular alterations that occur during the progression to DR and that can be safely attributed only to this progression. The combination of the framework and the experimental design lead to more sound and concrete inferences, providing a set of features, such as the central retinal artery and vein equivalent, fractal dimension, blood flow rate, etc., that are indeed biomarkers of progression to DR. The third major contribution of this work is the new and improved method for more accurately summarising the calibre of an arterial or venular trunk, with a direct application to estimating the central retinal artery equivalent (CRAE), the central retinal vein equivalent (CRVE) and their quotient, the arteriovenous ratio (AVR). Finally, the improved method is shown to truly make a notable difference in the estimations, when compared to the established alternative method in literature, with an improvement between 0.24% and 0.49% in terms of the mean absolute percentage error and 0.013 in the area under the curve. I have demonstrated that some thoroughly planned experimental studies based on a comprehensive framework, which combines image processing algorithms, statistical and classification models, feature selection processes, and robust haemodynamic and geometric features, extracted from the retinal vasculature (as a whole and from specific areas of interest), provide altogether succinct evidence that the early detection of the progression from diabetes to DR can be indeed achieved. The performance that the eight different classification combinations achieved in terms of the area under the curve varied from 0.745 to 0.968

Glaucoma

This book addresses the basic and clinical science of glaucomas, a group of diseases that affect the optic nerve and visual fields and is usually accompanied by increased intraocular pressure. The book incorporates the latest development as well as future perspectives in glaucoma, since it has expedited publication. It is aimed for specialists in glaucoma, researchers, general ophthalmologists and trainees to increase knowledge and encourage further progress in understanding and managing these complicated diseases

Zebrafish and mouse models for studying deubiquitinating enzyme genes as candidates for retinal dystrophies

[eng] The retina consists of several structured layers of highly specialized neurons that capture and process light stimuli enabling vision. Such a fine architecture turns retinal differentiation into an extremely complex event that must be accurately regulated. The ubiquitin-proteasome system (UPS) is considered one of the most dynamic and versatile mechanisms of protein regulation in eukaryotic cells. As ubiquitination is reversible, deubiquitinating enzymes (DUBs) play a major regulatory role in the UPS. Despite the importance of proteostasis and the UPS in health and disease, a more comprehensive in-depth analysis of DUB expression and function on particular tissues or organs, such as the retina, is still missing. Combining expression quantification, mRNA localization assays and functional analyses in animal and cellular models, we analyzed the function of several DUB genes in the retina to identify DUBs that regulate important retinal cell mechanisms, explore their relevance in retinal function in health and disease, and finally, posit them as new potential candidate genes for retinal dystrophies. Taking into consideration our results in the expression levels and pattern of DUBs in the retina, we first selected USP45 to perform functional assays in animal models in order to define its role and function in the retina. By morpholino-knockdown of usp45 in zebrafish embryos, our results showed moderate to severe eye morphological defects, eye size reduction, small body size with small tail or without tail, and disruption in notochord formation. There is also defective lamination and formation of the retinal structures, with no distinguishable layers and smaller retinas. Overall, our results supported the relevance of USP45 in the normal development and formation of the vertebrate retina, and we proposed this gene as a good candidate for causing hereditary retinal dystrophies, as later confirmed by other authors in several families. We also selected ATXN3, a DUB gene that causes the dominant polyQ disease Spinocerebellar ataxia type 3 (SCA3), and we aimed to analyze its function in the retina. We showed that depletion of Atxn3 in zebrafish and mice caused retinal morphological and functional alterations with photoreceptor outer segment elongation, cone opsin mislocalization, and cone hyperexcitation upon light stimuli. A pool of ATXN3 resides at the basal body and axoneme of the photoreceptor cilium, where it controls the levels and recruitment of the regulatory proteins KEAP1 and HDAC6. Abrogation of Atxn3 expression causes delayed phagosome maturation in the retinal pigment epithelium. We propose that ATXN3 regulates two relevant biological processes in the retina, ciliogenesis and phagocytosis, by modulating microtubule polymerization and microtubule-dependent retrograde transport, and propose ATXN3 as a causative or modifier gene in retinal/macular dystrophies. We further aimed to explore whether the SCA3 humanized mouse model showed specific retinal phenotype traits. We showed that polyQ-expanded ATXN3 protein formed a high number of progressive pathogenic aggregates in the retinal layers of transgenic Atxn3Q84 mice, and caused a decrease in the number of cone photoreceptors. Optical coherence tomography revealed a general decrease in the thickness of the retinal layers whereas retinal electrophysiological analyses showed a strong decrease in photoreceptor response to light, thus supporting severe retinal dysfunction in Atxn3Q84 mice. Similar analyses in human patients detected a correlation of retinal alterations with the number of CAG repeats and the age of onset of SCA3 symptoms. We propose that retinal alterations detected by non-invasive eye examination and electroretinography tests in SCA3 patients could serve as a valuable early-onset symptom and a biological marker of disease progression. As a conclusion, our work posits several DUB genes as candidates for inherited retinal dystrophies, but further investigation is needed to dissect the function of DUBs in retinal cell differentiation, photoreceptor function, and retinal homeostasis

iPS Cells for Modelling and Treatment of Human Diseases

The field of reprogramming somatic cells into induced pluripotent stem cells (iPSC) has moved very quickly, from bench to bedside in just eight years since its first discovery. The best example of this is the RIKEN clinical trial this year in Japan, which will use iPSC derived retinal pigmented epithelial (RPE) cells to treat macular degeneration (MD). This is the first human disease to be tested for regeneration and repair by iPSC-derived cells and others will follow in the near future. Currently, there is an intense worldwide research effort to bring stem cell technology to the clinic for application to treat human diseases and pathologies. Human tissue diseases (including those of the lung, heart, brain, spinal cord, and muscles) drive organ bioengineering to the forefront of technology concerning cell replacement therapy. Given the critical mass of research and translational work being performed, iPSCs may very well be the cell type of choice for regenerative medicine in the future. Also, basic science questions, such as efficient differentiation protocols to the correct cell type for regenerating human tissues, the immune response of iPSC replacement therapy and genetic stability of iPSC-derived cells, are currently being investigated for future clinical applications

Abstracts of 51st EASD Annual Meeting

Background and aims: Presence and frequency of beta cell (BC) dysfunction(BCD) and insulin resistance (IR) in patients with newly diagnosedtype 2 diabetes mellitus (NDT2D) are imperfectly known, becauseprevious studies used small cohorts and/or only surrogate indexes of BCfunction and IR.We sought to assess BC function and IR with state-of-artmethods in the VNDS.Materials and methods: In 712 GADA-negative, drug naïve, consecutiveItalian NDT2D patients we assessed: 1. standard parameters; 2. insulinsensitivity (IS) by the euglycaemic insulin clamp); 3. BC functionby state-of-art modeling of prolonged (5 hours) OGTT-derived glucose/C-peptide curves. Thresholds for BCD and IR were the 25th percentilesof BC function and IS assessed with the same methods of the VNDS inItalian subjects with normal glucose regulation of the GENFIEV (n=340)and GISIR (n=386) studies, respectively.Results: In the VNDS, 89.8% [95% C.I.: 87.6 - 92.0%] and87.8% [85.4 - 90.2] patients had BCD and IR, respectively. Patientswith only one defect were 19.7% [16.8 - 22.6]. IsolatedBCD and isolated IR were present in 10.9% [8.6 - 13.2] and8.9% [6.8 - 11.0] patients, respectively. Coexistence of BCDand IR was observed in 78.9% [75.9 - 81.9] of the patients.1.4% [0.5 - 2.3] of the patients had no detectable alterations inBC function and IS. Patients (19.7%) with only one metabolicdefect had lower BMI, fasting glucose, HbA1c, triglycerides andBC function, and higher HDL-cholesterol and IS than patientswith both BCD and IR (p<0.01 or less after Bonferroni’scorrection).Conclusion: In conclusion, in NDT2DM patients: 1. at least 75.9% haveboth BCD and IR; 2. At least 87.6% and 85.4% have BCD and IR,respectively; 3. At least 16.8% have only one defect and a significantlydifferent (milder) metabolic phenotype compared to patients with bothdefects. These findings may be relevant to therapeutic strategies centeredon the metabolic phenotype of the patient.Clinical Trial Registration Number: NCT00879801; NCT01526720Supported by: University of Veron

XXIV congreso anual de la sociedad española de ingeniería biomédica (CASEIB2016)

En la presente edición, más de 150 trabajos de alto nivel científico van a ser presentados en 18 sesiones paralelas y 3 sesiones de póster, que se centrarán en áreas relevantes de la Ingeniería Biomédica. Entre las sesiones paralelas se pueden destacar la sesión plenaria Premio José María Ferrero Corral y la sesión de Competición de alumnos de Grado en Ingeniería Biomédica, con la participación de 16 alumnos de los Grados en Ingeniería Biomédica a nivel nacional. El programa científico se complementa con dos ponencias invitadas de científicos reconocidos internacionalmente, dos mesas redondas con una importante participación de sociedades científicas médicas y de profesionales de la industria de tecnología médica, y dos actos sociales que permitirán a los participantes acercarse a la historia y cultura valenciana. Por primera vez, en colaboración con FENIN, seJane Campos, R. (2017). XXIV congreso anual de la sociedad española de ingeniería biomédica (CASEIB2016). Editorial Universitat Politècnica de València. http://hdl.handle.net/10251/79277EDITORIA