Defining the structure-function relationship of specific lesions in early and advanced age-related macular degeneration.

The objective of this study is to define structure-function relationships of pathological lesions related to age-related macular degeneration (AMD) using microperimetry and multimodal retinal imaging. We conducted a cross-sectional study of 87 patients with AMD (30 eyes with early and intermediate AMD and 110 eyes with advanced AMD), compared to 33 normal controls (66 eyes) recruited from a single tertiary center. All participants had enface and cross-sectional optical coherence tomography (Heidelberg HRA-2), OCT angiography, color and infra-red (IR) fundus and microperimetry (MP) (Nidek MP-3) performed. Multimodal images were graded for specific AMD pathological lesions. A custom marking tool was used to demarcate lesion boundaries on corresponding enface IR images, and subsequently superimposed onto MP color fundus photographs with retinal sensitivity points (RSP). The resulting overlay was used to correlate pathological structural changes to zonal functional changes. Mean age of patients with early/intermediate AMD, advanced AMD and controls were 73(SD = 8.2), 70.8(SD = 8), and 65.4(SD = 7.7) years respectively. Mean retinal sensitivity (MRS) of both early/intermediate (23.1 dB; SD = 5.5) and advanced AMD (18.1 dB; SD = 7.8) eyes were significantly worse than controls (27.8 dB, SD = 4.3) (p < 0.01). Advanced AMD eyes had significantly more unstable fixation (70%; SD = 63.6), larger mean fixation area (3.9 mm2; SD = 3.0), and focal fixation point further away from the fovea (0.7 mm; SD = 0.8), than controls (29%; SD = 43.9; 2.6 mm2; SD = 1.9; 0.4 mm; SD = 0.3) (p ≤ 0.01). Notably, 22 fellow eyes of AMD eyes (25.7 dB; SD = 3.0), with no AMD lesions, still had lower MRS than controls (p = 0.04). For specific AMD-related lesions, end-stage changes such as fibrosis (5.5 dB, SD = 5.4 dB) and atrophy (6.2 dB, SD = 7.0 dB) had the lowest MRS; while drusen and pigment epithelial detachment (17.7 dB, SD = 8.0 dB) had the highest MRS. Peri-lesional areas (20.2 dB, SD = 7.6 dB) and surrounding structurally normal areas (22.2 dB, SD = 6.9 dB) of the retina with no AMD lesions still had lower MRS compared to controls (27.8 dB, SD = 4.3 dB) (p < 0.01). Our detailed topographic structure-function correlation identified specific AMD pathological changes associated with a poorer visual function. This can provide an added value to the assessment of visual function to optimize treatment outcomes to existing and potentially future novel therapies.

Extending the diabetic retinopathy screening intervals in Singapore: methodology and preliminary findings of a cohort study.

BACKGROUND: The Diabetic Retinopathy Extended Screening Study (DRESS) aims to develop and validate a new DR/diabetic macular edema (DME) risk stratification model in patients with Type 2 diabetes (DM) to identify low-risk groups who can be safely assigned to biennial or triennial screening intervals. We describe the study methodology, participants' baseline characteristics, and preliminary DR progression rates at the first annual follow-up. METHODS: DRESS is a 3-year ongoing longitudinal study of patients with T2DM and no or mild non-proliferative DR (NPDR, non-referable) who underwent teleophthalmic screening under the Singapore integrated Diabetic Retinopathy Programme (SiDRP) at four SingHealth Polyclinics. Patients with referable DR/DME (> mild NPDR) or ungradable fundus images were excluded. Sociodemographic, lifestyle, medical and clinical information was obtained from medical records and interviewer-administered questionnaires at baseline. These data are extracted from medical records at 12, 24 and 36 months post-enrollment. Baseline descriptive characteristics stratified by DR severity at baseline and rates of progression to referable DR at 12-month follow-up were calculated. RESULTS: Of 5,840 eligible patients, 78.3% (n = 4,570, median [interquartile range [IQR] age 61.0 [55-67] years; 54.7% male; 68.0% Chinese) completed the baseline assessment. At baseline, 97.4% and 2.6% had none and mild NPDR (worse eye), respectively. Most participants had hypertension (79.2%) and dyslipidemia (92.8%); and almost half were obese (43.4%, BMI ≥ 27.5 kg/m2). Participants without DR (vs mild DR) reported shorter DM duration, and had lower haemoglobin A1c, triglycerides and urine albumin/creatinine ratio (all p < 0.05). To date, we have extracted 41.8% (n = 1909) of the 12-month follow-up data. Of these, 99.7% (n = 1,904) did not progress to referable DR. Those who progressed to referable DR status (0.3%) had no DR at baseline. CONCLUSIONS: In our prospective study of patients with T2DM and non-referable DR attending polyclinics, we found extremely low annual DR progression rates. These preliminary results suggest that extending screening intervals beyond 12 months may be viable and safe for most participants, although our 3-year follow up data are needed to substantiate this claim and develop the risk stratification model to identify low-risk patients with T2DM who can be assigned biennial or triennial screening intervals.

DRAC 2022: A public benchmark for diabetic retinopathy analysis on ultra-wide optical coherence tomography angiography images.

We described a challenge named "DRAC - Diabetic Retinopathy Analysis Challenge" in conjunction with the 25th International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI 2022). Within this challenge, we provided the DRAC datset, an ultra-wide optical coherence tomography angiography (UW-OCTA) dataset (1,103 images), addressing three primary clinical tasks: diabetic retinopathy (DR) lesion segmentation, image quality assessment, and DR grading. The scientific community responded positively to the challenge, with 11, 12, and 13 teams submitting different solutions for these three tasks, respectively. This paper presents a concise summary and analysis of the top-performing solutions and results across all challenge tasks. These solutions could provide practical guidance for developing accurate classification and segmentation models for image quality assessment and DR diagnosis using UW-OCTA images, potentially improving the diagnostic capabilities of healthcare professionals. The dataset has been released to support the development of computer-aided diagnostic systems for DR evaluation.

Development and External Validation of Machine Learning Models for Diabetic Microvascular Complications: Cross-Sectional Study With Metabolites.

BACKGROUND: Diabetic kidney disease (DKD) and diabetic retinopathy (DR) are major diabetic microvascular complications, contributing significantly to morbidity, disability, and mortality worldwide. The kidney and the eye, having similar microvascular structures and physiological and pathogenic features, may experience similar metabolic changes in diabetes. OBJECTIVE: This study aimed to use machine learning (ML) methods integrated with metabolic data to identify biomarkers associated with DKD and DR in a multiethnic Asian population with diabetes, as well as to improve the performance of DKD and DR detection models beyond traditional risk factors. METHODS: We used ML algorithms (logistic regression [LR] with Least Absolute Shrinkage and Selection Operator and gradient-boosting decision tree) to analyze 2772 adults with diabetes from the Singapore Epidemiology of Eye Diseases study, a population-based cross-sectional study conducted in Singapore (2004-2011). From 220 circulating metabolites and 19 risk factors, we selected the most important variables associated with DKD (defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2) and DR (defined as an Early Treatment Diabetic Retinopathy Study severity level ≥20). DKD and DR detection models were developed based on the variable selection results and externally validated on a sample of 5843 participants with diabetes from the UK biobank (2007-2010). Machine-learned model performance (area under the receiver operating characteristic curve [AUC] with 95% CI, sensitivity, and specificity) was compared to that of traditional LR adjusted for age, sex, diabetes duration, hemoglobin A1c, systolic blood pressure, and BMI. RESULTS: Singapore Epidemiology of Eye Diseases participants had a median age of 61.7 (IQR 53.5-69.4) years, with 49.1% (1361/2772) being women, 20.2% (555/2753) having DKD, and 25.4% (685/2693) having DR. UK biobank participants had a median age of 61.0 (IQR 55.0-65.0) years, with 35.8% (2090/5843) being women, 6.7% (374/5570) having DKD, and 6.1% (355/5843) having DR. The ML algorithms identified diabetes duration, insulin usage, age, and tyrosine as the most important factors of both DKD and DR. DKD was additionally associated with cardiovascular disease history, antihypertensive medication use, and 3 metabolites (lactate, citrate, and cholesterol esters to total lipids ratio in intermediate-density lipoprotein), while DR was additionally associated with hemoglobin A1c, blood glucose, pulse pressure, and alanine. Machine-learned models for DKD and DR detection outperformed traditional LR models in both internal (AUC 0.838 vs 0.743 for DKD and 0.790 vs 0.764 for DR) and external validation (AUC 0.791 vs 0.691 for DKD and 0.778 vs 0.760 for DR). CONCLUSIONS: This study highlighted diabetes duration, insulin usage, age, and circulating tyrosine as important factors in detecting DKD and DR. The integration of ML with biomedical big data enables biomarker discovery and improves disease detection beyond traditional risk factors.

Medical education and physician training in the era of artificial intelligence.

ABSTRACT: With the rise of generative artificial intelligence (AI) and AI-powered chatbots, the landscape of medicine and healthcare is on the brink of significant transformation. This perspective delves into the prospective influence of AI on medical education, residency training and the continuing education of attending physicians or consultants. We begin by highlighting the constraints of the current education model, challenges in limited faculty, uniformity amidst burgeoning medical knowledge and the limitations in 'traditional' linear knowledge acquisition. We introduce 'AI-assisted' and 'AI-integrated' paradigms for medical education and physician training, targeting a more universal, accessible, high-quality and interconnected educational journey. We differentiate between essential knowledge for all physicians, specialised insights for clinician-scientists and mastery-level proficiency for clinician-computer scientists. With the transformative potential of AI in healthcare and service delivery, it is poised to reshape the pedagogy of medical education and residency training.

Imaging Modalities for Assessing the Vascular Component of Diabetic Retinal Disease: Review and Consensus for an Updated Staging System.

Purpose: To review the evidence for imaging modalities in assessing the vascular component of diabetic retinal disease (DRD), to inform updates to the DRD staging system. Design: Standardized narrative review of the literature by an international expert workgroup, as part of the DRD Staging System Update Effort, a project of the Mary Tyler Moore Vision Initiative. Overall, there were 6 workgroups: Vascular Retina, Neural Retina, Systemic Health, Basic and Cellular Mechanisms, Visual Function, and Quality of Life. Participants: The Vascular Retina workgroup, including 16 participants from 4 countries. Methods: Literature review was conducted using standardized evidence grids for 5 modalities: standard color fundus photography (CFP), widefield color photography (WFCP), standard fluorescein angiography (FA), widefield FA (WFFA), and OCT angiography (OCTA). Summary levels of evidence were determined on a validated scale from I (highest) to V (lowest). Five virtual workshops were held for discussion and consensus. Main Outcome Measures: Level of evidence for each modality. Results: Levels of evidence for standard CFP, WFCP, standard FA, WFFA, and OCTA were I, II, I, I, and II respectively. Traditional vascular lesions on standard CFP should continue to be included in an updated staging system, but more studies are required before they can be used in posttreatment eyes. Widefield color photographs can be used for severity grading within the area covered by standard CFPs, although these gradings may not be directly interchangeable with each other. Evaluation of the peripheral retina on WFCP can be considered, but the method of grading needs to be clarified and validated. Standard FA and WFFA provide independent prognostic value, but the need for dye administration should be considered. OCT angiography has significant potential for inclusion in the DRD staging system, but various barriers need to be addressed first. Conclusions: This study provides evidence-based recommendations on the utility of various imaging modalities for assessment of the vascular component of DRD, which can inform future updates to the DRD staging system. Although new imaging modalities offer a wealth of information, there are still major gaps and unmet research needs that need to be addressed before this potential can be realized. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Blood biomarkers improve the prediction of prevalent and incident severe chronic kidney disease.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is high. Identification of cases with CKD or at high risk of developing it is important to tailor early interventions. The objective of this study was to identify blood metabolites associated with prevalent and incident severe CKD, and to quantify the corresponding improvement in CKD detection and prediction. METHODS: Data from four cohorts were analyzed: Singapore Epidemiology of Eye Diseases (SEED) (n = 8802), Copenhagen Chronic Kidney Disease (CPH) (n = 916), Singapore Diabetic Nephropathy (n = 714), and UK Biobank (UKBB) (n = 103,051). Prevalent CKD (stages 3-5) was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2; incident severe CKD as CKD-related mortality or kidney failure occurring within 10 years. We used multivariable regressions to identify, among 146 blood metabolites, those associated with CKD, and quantify the corresponding increase in performance. RESULTS: Chronic kidney disease prevalence (stages 3-5) and severe incidence were 11.4% and 2.2% in SEED, and 2.3% and 0.2% in UKBB. Firstly, phenylalanine (Odds Ratio [OR] 1-SD increase = 1.83 [1.73, 1.93]), tyrosine (OR = 0.75 [0.71, 0.79]), docosahexaenoic acid (OR = 0.90 [0.85, 0.95]), citrate (OR = 1.41 [1.34, 1.47]) and triglycerides in medium high density lipoprotein (OR = 1.07 [1.02, 1.13]) were associated with prevalent stages 3-5 CKD. Mendelian randomization analyses suggested causal relationships. Adding these metabolites beyond traditional risk factors increased the area under the curve (AUC) by 3% and the sensitivity by 7%. Secondly, lactate (HR = 1.33 [1.08, 1.64]) and tyrosine (HR = 0.74 [0.58, 0.95]) were associated with incident severe CKD among individuals with eGFR < 90 mL/min/1.73 m2 at baseline. These metabolites increased the c-index by 2% and sensitivity by 5% when added to traditional risk factors. CONCLUSION: The performance improvements of CKD detection and prediction achieved by adding metabolites to traditional risk factors are modest and further research is necessary to fully understand the clinical implications of these findings.

Harnessing the potential of large language models in medical education: promise and pitfalls.

OBJECTIVES: To provide balanced consideration of the opportunities and challenges associated with integrating Large Language Models (LLMs) throughout the medical school continuum. PROCESS: Narrative review of published literature contextualized by current reports of LLM application in medical education. CONCLUSIONS: LLMs like OpenAI's ChatGPT can potentially revolutionize traditional teaching methodologies. LLMs offer several potential advantages to students, including direct access to vast information, facilitation of personalized learning experiences, and enhancement of clinical skills development. For faculty and instructors, LLMs can facilitate innovative approaches to teaching complex medical concepts and fostering student engagement. Notable challenges of LLMs integration include the risk of fostering academic misconduct, inadvertent overreliance on AI, potential dilution of critical thinking skills, concerns regarding the accuracy and reliability of LLM-generated content, and the possible implications on teaching staff.

Preconception maternal retinal arteriolar narrowing and fetal growth throughout pregnancy: A prospective cohort study.

OBJECTIVE: To investigate the association between preconception maternal retinal arteriolar calibre and fetal growth. DESIGN, SETTING AND POPULATION: A hospital-based, prospective preconception cohort including 369 women with a singleton live birth. METHODS: We collected detailed information on sociodemographic status, pregnancy history and lifestyle, and performed retinal imaging at the preconception visit. MAIN OUTCOME MEASURES: We retrieved medical records documenting fetal growth biometrics (e.g., abdominal circumference [AC], head circumference [HC], femur length [FL]) at 11-13, 18-21, 24-28, and 32-34 weeks throughout pregnancy. We then computed the z scores for all fetal growth biometrics from 14 weeks of gestation where data were available, referencing the INTERGROWTH-21st fetal growth chart. We used a linear mixed model to estimate the association between maternal preconception retinal arteriolar calibre and fetal growth biometrics z scores throughout pregnancy, with random intercept accounting for repeated measures within individuals. We then performed a multivariable linear regression of maternal preconception retinal arteriolar calibre and z score changes for all fetal growth biometrics between 24-28 weeks and 32-34 weeks of gestation, after full adjustment. RESULTS: Maternal preconception generalised retinal arteriolar narrowing was consistently associated with a reduction in fetal AC z scores (-0.34; 95% CI -0.66 to -0.03) throughout pregnancy. In addition, women with preconception generalised retinal arteriolar narrowing tended to have significantly reduced z score changes in AC (-0.41; 95% CI -0.90 to -0.001) and fetal FL (-0.55; 95% CI -1.00 to -0.10) between 24-28 weeks and 32-34 weeks of gestation, respectively. CONCLUSIONS: Our findings suggest that women with narrower preconception retinal arterioles had smaller fetuses, evidenced by reductions in AC and FL z score throughout pregnancy.

AI-integrated ocular imaging for predicting cardiovascular disease: advancements and future outlook.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Assessing of CVD risk plays an essential role in identifying individuals at higher risk and enables the implementation of targeted intervention strategies, leading to improved CVD prevalence reduction and patient survival rates. The ocular vasculature, particularly the retinal vasculature, has emerged as a potential means for CVD risk stratification due to its anatomical similarities and physiological characteristics shared with other vital organs, such as the brain and heart. The integration of artificial intelligence (AI) into ocular imaging has the potential to overcome limitations associated with traditional semi-automated image analysis, including inefficiency and manual measurement errors. Furthermore, AI techniques may uncover novel and subtle features that contribute to the identification of ocular biomarkers associated with CVD. This review provides a comprehensive overview of advancements made in AI-based ocular image analysis for predicting CVD, including the prediction of CVD risk factors, the replacement of traditional CVD biomarkers (e.g., CT-scan measured coronary artery calcium score), and the prediction of symptomatic CVD events. The review covers a range of ocular imaging modalities, including colour fundus photography, optical coherence tomography, and optical coherence tomography angiography, and other types of images like external eye images. Additionally, the review addresses the current limitations of AI research in this field and discusses the challenges associated with translating AI algorithms into clinical practice.

Development of high-performance point-of-care aqueous VEGF detection system and proof-of-concept validation in RVO patients.

OBJECTIVES: To develop a sensitive point-of-care testing (POCT) aqueous vascular endothelial growth factor (VEGF) detection system, and assess its role for predicting the response to anti-VEGF treatment in macular edema secondary to retinal vein occlusion (RVO-ME) patients. METHODS: An automatic point-of-care aqueous humor Magnetic Particle Chemiluminescence Enzyme Immuno-Assay (MPCLEIA) VEGF detection system was developed. The predictive values of aqueous cytokine levels, in combination with imaging parameters, on anatomical treatment response (ATR, the relative central macular thickness change [ΔCMT/bl-CMT]) were analyzed. RESULTS: The automatic MPCLEIA system was able to provide results in 45 min with only 20 µL sample. Among the 57 eyes with available pre- and post-treatment evaluation, ATR significantly correlated with levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and VEGF measured by Luminex xMAP platform, and VEGF measured by MPCLEIA. Optimal cut-off values for these biomarkers were 13.26 ng/L, 23.57 ng/L, 1,110.12 ng/L, 105.52 ng/L, and 85.39 ng/L, respectively. Univariate analysis showed significant associations between ATR category (good response if ATR≤-25 % or poor response otherwise) and IL-6, IL-8, MCP-1, VEGF-xMAP, and VEGF-MPCLEIA (p<0.05). Multivariate logistic regression revealed that ATR category was significantly associated with aqueous VEGF-MPCLEIA (p=0.006) and baseline(bl)-CMT (p=0.008). Receiver operating characteristics analysis yielded an AUC of 0.959 for the regression model combining VEGF-MPCLEIA and bl-CMT, for predicting ATR category. CONCLUSIONS: Our novel MPCLEIA-based automatic VEGF detection system enables accurate POCT of aqueous VEGF, which shows promise in predicting the treatment response of RVO-ME to anti-VEGF agents when combined with bl-CMT.

Preconception maternal retinal venular widening and steeper resistance increments in the utero-fetoplacental circulation in pregnancy.

We investigated the relationship of preconception maternal retinal vasculature and utero-fetoplacental circulation in ensuing pregnancy. Embedded in a hospital-based, prospective preconception cohort, 396 women with a singleton live birth were included for analysis. We assessed retinal vascular caliber during preconception phase and retrieved ultrasonogram results documenting utero-fetoplacental circulatory indices using Doppler ultrasonography and documented them at 18-21 weeks, 24-28 weeks, and 32-34 weeks where available. We performed a modified Poisson regression to estimate the relative risk of utero-fetoplacental abnormalities, adjusting for major confounders including pre-pregnancy and blood pressure. Per 10 µm increment in maternal preconception retinal venules was associated with over two-fold risks in developing notching (Relative risk [RR]: 2.84; 95% confidence interval [CI]: 1.79, 4.81) and ≥95th percentile umbilical artery pulsatility index (2.36; 1.72, 3.23) during mid-to-late pregnancy, respectively. Women with preconception retinal venular widening tended to demonstrate steeper resistance increments in both maternal uterine arteries and fetal umbilical arteries during mid-to-late pregnancy.

Initiation of China Alliance of Research in High Myopia (CHARM): protocol for an AI-based multimodal high myopia research biobank.

INTRODUCTION: High myopia is a pressing public health concern due to its increasing prevalence, younger trend and the high risk of blindness, particularly in East Asian countries, including China. The China Alliance of Research in High Myopia (CHARM) is a newly established consortium that includes more than 100 hospitals and institutions participating across the nation, aiming to promote collaboration and data sharing in the field of high myopia screening, classification, diagnosis and therapeutic development. METHODS AND ANALYSIS: The CHARM project is an ongoing study, and its initiation is distinguished by its unprecedented scale, encompassing plans to involve over 100 000 Chinese patients. This initiative stands out not only for its extensive scope but also for its innovative application of artificial intelligence (AI) to assist in diagnosis and treatment decisions. The CHARM project has been carried out using a 'three-step' strategy. The first step involves the collection of basic information, refraction, axial length and fundus photographs from participants with high myopia. In the second step, we will collect multimodal imaging data to expand the scope of clinical information, for example, optical coherence tomography and ultra-widefield fundus images. In the final step, genetic testing will be conducted by incorporating patient family histories and blood samples. The majority of data collected by CHARM is in the form of images that will be used to detect and predict the progression of high myopia through the identification and quantification of biomarkers such as fundus tessellation, optic nerve head and vascular parameters. ETHICS AND DISSEMINATION: The study has received approval from the Ethics Committee of Beijing Tongren Hospital (TREC2022-KY045). The establishment of CHARM represents an opportunity to create a collaborative platform for myopia experts and facilitate the dissemination of research findings to the global community through peer-reviewed publications and conference presentations. These insights can inform clinical decision-making and contribute to the development of new treatment modalities that may benefit patients worldwide. TRIAL REGISTRATION NUMBER: ChiCTR2300071219.

Relationship Between Retinal Layer Thickness and Genetic Susceptibility to Age-Related Macular Degeneration in Asian Populations.

Purpose: For OCT retinal thickness measurements to be used as a prodromal age-related macular degeneration (AMD) risk marker, the 3-dimensional (3D) topographic variation of the relationship between genetic susceptibility to AMD and retinal thickness needs to be assessed. We aimed to evaluate individual retinal layer thickness changes and topography at the macula that are associated with AMD genetic susceptibility. Design: Genetic association study. Participants: A total of 1579 healthy participants (782 Chinese, 353 Malays, and 444 Indians) from the multiethnic Singapore Epidemiology of Eye Diseases study were included. Methods: Spectral-domain OCT and automatic segmentation of individual retinal layers were performed to produce 10 retinal layer thickness measurements at each ETDRS subfield, producing 3D topographic information. Age-related macular degeneration genetic susceptibility was represented via single nucleotide polymorphisms (SNPs) and aggregated via whole genome (overall) and pathway-specific age-related macular degeneration polygenic risk score (PRSAMD). Main Outcome Measures: Associations of individual SNPs, overall PRSAMD, and pathway-specific PRSAMD with retinal thickness were analyzed by individual retinal layer and ETDRS subfield. Results: CFH rs10922109, ARMS2-HTRA1 rs3750846, and LIPC rs2043085 were the top AMD susceptibility SNPs associated with retinal thickness of individual layers (P < 1.67 × 10-3), all at the central subfield. The overall PRSAMD was most associated with thinner L9 (outer segment photoreceptor/retinal pigment epithelium complex) thickness at the central subfield (ß = -0.63 µm; P = 5.45 × 10-9). Pathway-specific PRSAMD for the complement cascade (ß = -0.53 µm; P = 9.42 × 10-7) and lipoprotein metabolism (ß = -0.05 µm; P = 0.0061) were associated with thinner photoreceptor layers (L9 and L7 [photoreceptor inner/outer segments], respectively) at the central subfield. The mean PRSAMD score was larger among Indians compared with that of the Chinese and had the thinnest thickness at the L9 central subfield (ß = -1.00 µm; P = 2.91 × 10-7; R2 = 5.5%). Associations at other retinal layers and ETDRS regions were more heterogeneous. Conclusions: Overall genetic susceptibility to AMD and the aggregate effects of the complement cascade and lipoprotein metabolism pathway are associated most significantly with L7 and L9 photoreceptor thinning at the central macula in healthy individuals. Photoreceptor thinning has potential to be a prodromal AMD risk marker, and topographic variation should be considered. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.