Ian Y. Wong

Development and Validation of a Deep Learning System for Diabetic Retinopathy and Related Eye Diseases Using Retinal Images From Multiethnic Populations With Diabetes

Importance A deep learning system (DLS) is a machine learning technology with potential for screening diabetic retinopathy and related eye diseases. Objective To evaluate the performance of a DLS in detecting referable diabetic retinopathy, vision-threatening diabetic retinopathy, possible glaucoma, and age-related macular degeneration (AMD) in community and clinic-based multiethnic populations with diabetes. Design, Setting, and Participants Diagnostic performance of a DLS for diabetic retinopathy and related eye diseases was evaluated using 494 661 retinal images. A DLS was trained for detecting diabetic retinopathy (using 76 370 images), possible glaucoma (125 189 images), and AMD (72 610 images), and performance of DLS was evaluated for detecting diabetic retinopathy (using 112 648 images), possible glaucoma (71 896 images), and AMD (35 948 images). Training of the DLS was completed in May 2016, and validation of the DLS was completed in May 2017 for detection of referable diabetic retinopathy (moderate nonproliferative diabetic retinopathy or worse) and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse) using a primary validation data set in the Singapore National Diabetic Retinopathy Screening Program and 10 multiethnic cohorts with diabetes. Exposures Use of a deep learning system. Main Outcomes and Measures Area under the receiver operating characteristic curve (AUC) and sensitivity and specificity of the DLS with professional graders (retinal specialists, general ophthalmologists, trained graders, or optometrists) as the reference standard. Results In the primary validation dataset (n = 14 880 patients; 71 896 images; mean [SD] age, 60.2 [2.2] years; 54.6% men), the prevalence of referable diabetic retinopathy was 3.0%; vision-threatening diabetic retinopathy, 0.6%; possible glaucoma, 0.1%; and AMD, 2.5%. The AUC of the DLS for referable diabetic retinopathy was 0.936 (95% CI, 0.925-0.943), sensitivity was 90.5% (95% CI, 87.3%-93.0%), and specificity was 91.6% (95% CI, 91.0%-92.2%). For vision-threatening diabetic retinopathy, AUC was 0.958 (95% CI, 0.956-0.961), sensitivity was 100% (95% CI, 94.1%-100.0%), and specificity was 91.1% (95% CI, 90.7%-91.4%). For possible glaucoma, AUC was 0.942 (95% CI, 0.929-0.954), sensitivity was 96.4% (95% CI, 81.7%-99.9%), and specificity was 87.2% (95% CI, 86.8%-87.5%). For AMD, AUC was 0.931 (95% CI, 0.928-0.935), sensitivity was 93.2% (95% CI, 91.1%-99.8%), and specificity was 88.7% (95% CI, 88.3%-89.0%). For referable diabetic retinopathy in the 10 additional datasets, AUC range was 0.889 to 0.983 (n = 40 752 images). Conclusions and Relevance In this evaluation of retinal images from multiethnic cohorts of patients with diabetes, the DLS had high sensitivity and specificity for identifying diabetic retinopathy and related eye diseases. Further research is necessary to evaluate the applicability of the DLS in health care settings and the utility of the DLS to improve vision outcomes.

Choroidal thickness in relation to hypercholesterolemia on enhanced depth imaging optical coherence tomography.

Purpose: To investigate the relationship of hypercholesterolemia and choroidal thickness in normal healthy volunteers. Method: This was a cross-sectional observational study. Volunteers with no ocular abnormalities were examined using enhanced depth imaging optical coherence tomography. Choroidal and retinal thicknesses were measured at the fovea, and at 4 different locations 1 mm superior, inferior, temporal, and nasal to the fovea. Subjects were further divided into those with hypercholesterolemia (Group 1) and normal control subjects (Group 2) for subgroup analysis regarding the effect of hypercholesterolemia on choroidal thickness. Subjects with hypertension and diabetes were excluded. Results: A total of 322 eyes of 161 subjects were studied. Mean age was 59.9 years (range, 24–84 years). The mean subfoveal choroidal thickness was 261 ± 98.7 &mgr;m. Mean subfoveal choroidal thickness negatively correlated with age (r = −0.326; P = 0.001). The mean serum total cholesterol was 5.02 ± 0.98 mmol/L. In Group 1, it was 5.65 ± 1.15 mmol/L, while in Group 2, it was 4.72 ± 0.73 mmol/L. The difference was statistically significant (P = 0.003). Subjects in Group 1 tended to be older and have worse vision, although the difference did not reach statistical significance. The mean subfoveal choroidal thickness in Group 1 was 306 ± 111 &mgr;m, while that in Group 2 was 258 ± 97 &mgr;m. The difference was statistically significant (P = 0.041). The same difference was also found at the 1 mm nasal (P = 0.041) and 1 mm superior (P = 0.040). Conclusion: The subfoveal choroidal thickness was found to be significantly higher in subjects with hypercholesterolemia. This has to be taken into account when analyzing choroidal thickness.

Enhanced depth imaging optical coherence tomography.

Imaging the choroid with conventional commercial spectral-domain optical coherence tomography (SD-OCT) has been difficult, mainly because of difficulty in signal transmission beyond the retinal pigment epithelium. A recent modification to the standard technique, termed enhanced depth imaging optical coherence tomography (EDI-OCT), was able to image the choroid with reasonable clarity using commercial SD-OCTs. The aim of this article was to review the technique, principle, recent findings, and possible future developments regarding EDI-OCT. A MEDLINE search on all published articles on EDI-OCT was performed up to December 2010. The principle behind EDI-OCT was discussed. Modification to the conventional technique in image acquisition was described and illustrated with figures. EDI-OCT findings in various retinal and choroidal diseases were discussed. Advantages and disadvantages were also discussed. EDI-OCT has proved to be a promising novel technique in imaging the choroid.

The inner segment/outer segment junction: what have we learnt so far?

Purpose of review The advancement of optical coherence tomography has improved the resolution of in-vivo images of the retina. This has led to a wealth of novel knowledge regarding the microstructures of the photoreceptor layer and its relationship with visual functions under different pathological diseases. Recent findings Identification of the hyperreflective lines in the photoreceptor layer has been made possible by spectral domain optical coherence tomography. The inner segment/outer segment junction, external limiting membrane, cone outer segment tips, and the retinal pigment epithelium were thought to be the origins of the four hyperreflective lines seen in the photoreceptor layer. Integrity of these lines has been linked with visual functions in various retinopathies, and has been suggested to carry prognostic implications. Recovery of initially interrupted lines has been documented following successful treatment. Summary Identification of these hyperreflective lines may have clinical implications as visual function was found to correlate closely with their integrity. Restoration of these lines may indicate treatment response and potential visual recovery.

Choroidal imaging: A review

Being the most vascular tissue of the eye, importance of the choroid has been very well established in various retinal and chorio-retinal diseases. Understanding of the choroidal structures has improved significantly since the evolution of enhanced depth imaging. Quantitative assessment of choroidal measurements has been found to be reproducible using different devices. This review article describes factors affecting choroidal thickness and choroidal changes in several diseases and reports its clinical importance. Evaluation of choroid would provide insight into the pathogenesis, treatment planning and follow up in chorioretinal diseases.

Central serous chorioretinopathy: what we have learnt so far.

Central serous chorioretinopathy (CSCR) is a common retinal cause of visual loss. The mainstays of management are observation, photodynamic therapy (PDT) and laser procedures. Over the past decade, there has been rapid development in the existing and novel imaging techniques, functional testing and management of CSCR. However, there is no convincing treatment designed for CSCR yet. In recent years, the advances in PDT, with various adjustments in fluence and verteporfin dosage, and the comparisons between different types of PDT for acute and chronic CSCR in recent studies have provided greater insights into the role of PDT in treating CSCR. Novel laser procedures, such as the diode micropulse laser, have shown comparable efficacy to conventional lasers without laser‐induced damage. Antivascular endothelial growth factor, which was originally developed for treating cancers, has emerged to be a potentially effective treatment for CSCR. The potential role of mineralocorticoid receptor antagonists in treating CSCR has provided greater understanding of the pathogenesis. Based on the relevant studies, mainly from the past decade, we discuss updates to the management of CSCR according to the risk factor modifications, pharmacological interventions, PDT and laser procedures and concluded that PDT is the current best option for CSCR.

Novel Parameter of Corneal Biomechanics That Differentiate Normals From Glaucoma.

Purpose:To identify novel corneal biomechanical parameters differentiating glaucomatous from normal eyes. Patients and Methods:Sixty subjects with varying degrees of glaucoma severity and 61 normal controls underwent corneal biomechanical measurements including corneal deformation amplitude, inward and outward applanation length and velocity, and highest concavity time in 1 eye per subject at Queen Mary Hospital, Hong Kong. Measurements were taken with the Corvis ST device, a noncontact tonometer coupled with a high-speed Scheimpflug camera. The intraocular pressure (IOP) and central corneal thickness (CCT) were also measured. Results:Significant findings included differences in outward applanation velocity (glaucoma: −0.37±0.01 m/s; control: −0.32±0.01 m/s; P=0.001), peak distance (glaucoma: 2.37±0.03 mm; control: 2.30±0.02 mm; P=0.005), and highest concavity time (glaucoma: 16.75±0.08 ms; control: 17.05±0.07 ms; P=0.002) between the 2 groups, after correcting for IOP, CCT, and age. Both outward applanation velocity and peak distance were moderately correlated with IOP and CCT. However, highest concavity time was not correlated with either IOP or CCT (R2=0.0140 and 0.000055, respectively). Age was not correlated with any of the 3 parameters. Conclusions:Glaucomatous eyes have a greater mean outward applanation velocity and peak distance, but shorter time to highest concavity than eyes without glaucoma. The difference in time to highest concavity does not correlate with age, IOP, or CCT, suggesting that this parameter may be a marker of increased pressure susceptibility that is independently associated with glaucoma risk.

Inhibition of RAP1 enhances corneal recovery following alkali injury.

PURPOSE Recently, RAP1 (Telomeric Repeat Binding Factor 2, Interacting Protein [TERF2IP]) was discovered as a modulator that selectively regulates nuclear factor light chain kappa enhancer of activated B cells (NFκB) signaling. The roles of RAP1 in regulation of inflammation and angiogenesis for corneal recovery following corneal injury remain poorly understood. The effects of RAP1 deletion on corneal resurfacing and neovascularization in a corneal alkali burn mouse model were examined. METHODS Corneal defects and neovascularization were induced in vivo by infliction of an alkali burn to the cornea with 1 N sodium hydroxide solution in RAP1 knock-out (RKO) and wild-type (RWT) mice. Corneal resurfacing was evaluated using slit-lamp biomicroscopy. Neovascularization following injury was evaluated by bright view biomicroscopy and immunofluorescence staining with the endothelial marker platelet endothelial cell adhesion molecule (PECAM). The cytokine profiles of corneal tissue involved in inflammation and neovascularization following injury was compared between RKO and RWT mice. Corneal epithelial cells were isolated for classic scratch wound healing assay and further testing with lipopolysaccharide stimulation. RESULTS Resurfacing of the burned cornea was accelerated and angiogenesis was suppressed, faster recovery of corneal epithelial cells from classic scratch wound healing and superior tolerance of lipopolysaccharides challenge was observed in the RKO compared to RWT. Molecular investigation revealed that deletion of RAP1 reduced upregulation of inflammatory cytokine (IL1A), finely regulated the expression of angiogenic factor (VEGF), and antiangiogenic factor (PEDF), following injury for better corneal recovery. CONCLUSIONS Deficiency of RAP1 facilitates corneal recovery after injury. Specificity of RAP1 inhibition may lead to design of specific inhibitors of NFκB in the treatment of ocular injuries.

Corneal collagen cross-linking for infectious keratitis: an update of clinical studies

Collagen cross‐linking (CXL) with ultraviolet light‐activated riboflavin is a corneal surface procedure developed for the treatment of keratoconus and corneal ectasia. With the known microbicidal and corneal stiffening effects of ultraviolet irradiation and photoactivated riboflavin, it has recently been introduced for the management of infectious keratitis, especially for ulcers resistant to antimicrobial therapy or associated with corneal melting. Various authors have attempted to use CXL as an adjunctive, salvage or even as the sole treatment for infectious corneal ulcers. The aim of this review was to provide a summary of the clinical studies in the literature. It is worth noting that there is still no consensus on the treatment protocol of CXL against infectious keratitis. The disparities in outcome measures, treatment protocol and study design can confound the interpretation and hamper the generalization of the study results. Based on current evidence, the role of CXL in infectious keratitis remained unclear despite the reported success in some clinical cases. Further investigations are warranted concerning the efficacy and safety of treating infectious keratitis with CXL.

Reemergence of syphilitic uveitis masquerading as other diseases: a report of two cases.

During a 6-month period in 2010, 2 patients with uveitis were examined at our department and diagnosed with ocular syphilis. They initially presented with symptoms and signs resembling Harada’s disease and Behçet’s disease and were therefore treated with systemic steroids with suboptimal responses. When laboratory workup revealed neurosyphilis, they were given a course of intravenous penicillin G, which led to significant clinical and visual improvement. Epidemiological data indicates a worldwide reemergence of syphilis and a high degree of suspicion is necessary in view of its multitude of presenting ocular signs without pathognomonic features.