Identifying the severity of diabetic retinopathy by visual function measures using both traditional statistical methods and interpretable machine learning: a cross-sectional study.

AIMS/HYPOTHESIS: To determine the extent to which diabetic retinopathy severity stage may be classified using machine learning (ML) and commonly used clinical measures of visual function together with age and sex. METHODS: We measured the visual function of 1901 eyes from 1032 participants in the Northern Ireland Sensory Ageing Study, deriving 12 variables from nine visual function tests. Missing values were imputed using chained equations. Participants were divided into four groups using clinical measures and grading of ophthalmic images: no diabetes mellitus (no DM), diabetes but no diabetic retinopathy (DM no DR), diabetic retinopathy without diabetic macular oedema (DR no DMO) and diabetic retinopathy with DMO (DR with DMO). Ensemble ML models were fitted to classify group membership for three tasks, distinguishing (A) the DM no DR group from the no DM group; (B) the DR no DMO group from the DM no DR group; and (C) the DR with DMO group from the DR no DMO group. More conventional multiple logistic regression models were also fitted for comparison. An interpretable ML technique was used to rank the contribution of visual function variables to predictions and to disentangle associations between diabetic eye disease and visual function from artefacts of the data collection process. RESULTS: The performance of the ensemble ML models was good across all three classification tasks, with accuracies of 0.92, 1.00 and 0.84, respectively, for tasks A-C, substantially exceeding the accuracies for logistic regression (0.84, 0.61 and 0.80, respectively). Reading index was highly ranked for tasks A and B, whereas near visual acuity and Moorfields chart acuity were important for task C. Microperimetry variables ranked highly for all three tasks, but this was partly due to a data artefact (a large proportion of missing values). CONCLUSIONS/INTERPRETATION: Ensemble ML models predicted status of diabetic eye disease with high accuracy using just age, sex and measures of visual function. Interpretable ML methods enabled us to identify profiles of visual function associated with different stages of diabetic eye disease, and to disentangle associations from artefacts of the data collection process. Together, these two techniques have great potential for developing prediction models using untidy real-world clinical data.

Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is characterised by neurovascular degeneration as a result of chronic hyperglycaemia. Proliferative diabetic retinopathy (PDR) is the most serious complication of DR and can lead to total (central and peripheral) visual loss. PDR is characterised by the presence of abnormal new blood vessels, so-called "new vessels," at the optic disc (NVD) or elsewhere in the retina (NVE). PDR can progress to high-risk characteristics (HRC) PDR (HRC-PDR), which is defined by the presence of NVD more than one-fourth to one-third disc area in size plus vitreous haemorrhage or pre-retinal haemorrhage, or vitreous haemorrhage or pre-retinal haemorrhage obscuring more than one disc area. In severe cases, fibrovascular membranes grow over the retinal surface and tractional retinal detachment with sight loss can occur, despite treatment. Although most, if not all, individuals with diabetes will develop DR if they live long enough, only some progress to the sight-threatening PDR stage.  OBJECTIVES: To determine risk factors for the development of PDR and HRC-PDR in people with diabetes and DR. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5), Ovid MEDLINE, and Ovid Embase. The date of the search was 27 May 2022. Additionally, the search was supplemented by screening reference lists of eligible articles. There were no restrictions to language or year of publication.  SELECTION CRITERIA: We included prospective or retrospective cohort studies and case-control longitudinal studies evaluating prognostic factors for the development and progression of PDR, in people who have not had previous treatment for DR. The target population consisted of adults (≥18 years of age) of any gender, sexual orientation, ethnicity, socioeconomic status, and geographical location, with non-proliferative diabetic retinopathy (NPDR) or PDR with less than HRC-PDR, diagnosed as per standard clinical practice. Two review authors independently screened titles and abstracts, and full-text articles, to determine eligibility; discrepancies were resolved through discussion. We considered prognostic factors measured at baseline and any other time points during the study and in any clinical setting. Outcomes were evaluated at three and eight years (± two years) or lifelong.  DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from included studies using a data extraction form that we developed and piloted prior to the data collection stage. We resolved any discrepancies through discussion. We used the Quality in Prognosis Studies (QUIPS) tool to assess risk of bias. We conducted meta-analyses in clinically relevant groups using a random-effects approach. We reported hazard ratios (HR), odds ratios (OR), and risk ratios (RR) separately for each available prognostic factor and outcome, stratified by different time points. Where possible, we meta-analysed adjusted prognostic factors. We evaluated the certainty of the evidence with an adapted version of the GRADE framework.   MAIN RESULTS: We screened 6391 records. From these, we identified 59 studies (87 articles) as eligible for inclusion. Thirty-five were prospective cohort studies, 22 were retrospective studies, 18 of which were cohort and six were based on data from electronic registers, and two were retrospective case-control studies. Twenty-three studies evaluated participants with type 1 diabetes (T1D), 19 with type 2 diabetes (T2D), and 17 included mixed populations (T1D and T2D). Studies on T1D included between 39 and 3250 participants at baseline, followed up for one to 45 years. Studies on T2D included between 100 and 71,817 participants at baseline, followed up for one to 20 years. The studies on mixed populations of T1D and T2D ranged from 76 to 32,553 participants at baseline, followed up for four to 25 years.  We found evidence indicating that higher glycated haemoglobin (haemoglobin A1c (HbA1c)) levels (adjusted OR ranged from 1.11 (95% confidence interval (CI) 0.93 to 1.32) to 2.10 (95% CI 1.64 to 2.69) and more advanced stages of retinopathy (adjusted OR ranged from 1.38 (95% CI 1.29 to 1.48) to 12.40 (95% CI 5.31 to 28.98) are independent risk factors for the development of PDR in people with T1D and T2D. We rated the evidence for these factors as of moderate certainty because of moderate to high risk of bias in the studies.  There was also some evidence suggesting several markers for renal disease (for example, nephropathy (adjusted OR ranged from 1.58 (95% CI not reported) to 2.68 (2.09 to 3.42), and creatinine (adjusted meta-analysis HR 1.61 (95% CI 0.77 to 3.36)), and, in people with T1D, age at diagnosis of diabetes (< 12 years of age) (standardised regression estimate 1.62, 95% CI 1.06 to 2.48), increased triglyceride levels (adjusted RR 1.55, 95% CI 1.06 to 1.95), and larger retinal venular diameters (RR 4.28, 95% CI 1.50 to 12.19) may increase the risk of progression to PDR. The certainty of evidence for these factors, however, was low to very low, due to risk of bias in the included studies, inconsistency (lack of studies preventing the grading of consistency or variable outcomes), and imprecision (wide CIs). There was no substantial and consistent evidence to support duration of diabetes, systolic or diastolic blood pressure, total cholesterol, low- (LDL) and high- (HDL) density lipoproteins, gender, ethnicity, body mass index (BMI), socioeconomic status, or tobacco and alcohol consumption as being associated with incidence of PDR. There was insufficient evidence to evaluate prognostic factors associated with progression of PDR to HRC-PDR.  AUTHORS' CONCLUSIONS: Increased HbA1c is likely to be associated with progression to PDR; therefore, maintaining adequate glucose control throughout life, irrespective of stage of DR severity, may help to prevent progression to PDR and risk of its sight-threatening complications. Renal impairment in people with T1D or T2D, as well as younger age at diagnosis of diabetes mellitus (DM), increased triglyceride levels, and increased retinal venular diameters in people with T1D may also be associated with increased risk of progression to PDR. Given that more advanced DR severity is associated with higher risk of progression to PDR, the earlier the disease is identified, and the above systemic risk factors are controlled, the greater the chance of reducing the risk of PDR and saving sight.

ANTECEDENTES: La retinopatía diabética (RD) se caracteriza por la degeneración neurovascular como consecuencia de la hiperglucemia crónica. La retinopatía diabética proliferativa (RDP) es la complicación más grave de la RD y puede provocar una pérdida total (central y periférica) de la visión. La RDP se caracteriza por la presencia de vasos sanguíneos de neoformación anormales, neovascularización, en la papila óptica (NVP) o en cualquier otra parte de la retina (NVE). La RDP puede evolucionar a una RDP con características de alto riesgo (RDP­CAR), que se define por la presencia de NVP de más de un cuarto a un tercio del área discal más hemorragia vítrea o prerretiniana, o hemorragia vítrea o prerretiniana que oscurece más de un área papilar. En los casos graves, crecen membranas fibrovasculares sobre la superficie retiniana y se puede producir un desprendimiento de retina por tracción con pérdida de la visión, a pesar del tratamiento. Aunque la mayoría de las personas con diabetes, si no todas, desarrollarán RD si viven lo suficiente, solo algunas llegan a la fase de RDP, que pone en peligro la vista. OBJETIVOS: Determinar los factores de riesgo de aparición de la RDP y RDP­CAR en personas con diabetes y RD. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials, CENTRAL; que contiene el Registro de ensayos del Grupo Cochrane de Salud ocular y de la visión [Cochrane Eyes and Vision]; 2022, número 5), Ovid MEDLINE y Ovid Embase. La fecha de búsqueda fue el 27 de mayo de 2022. Además, la búsqueda se complementó con el cribado de las listas de referencias de los artículos elegibles. No hubo restricciones en cuanto al idioma ni al año de publicación. CRITERIOS DE SELECCIÓN: Se incluyeron estudios de cohortes prospectivos o retrospectivos y estudios longitudinales de casos y controles que evaluaran los factores pronósticos para la aparición y la progresión de la RDP, en personas que no habían recibido tratamiento previo para la RD. La población de interés estaba formada por adultos (≥18 años de edad) de cualquier sexo, orientación sexual, etnia, nivel socioeconómico y ubicación geográfica, con retinopatía diabética no proliferativa (RDNP) o RDP sin llegar a RDP­CAR, diagnosticada según la práctica clínica habitual. Dos autores de la revisión examinaron de forma independiente los títulos y resúmenes, así como los artículos completos, para determinar la elegibilidad; las discrepancias se resolvieron mediante debate. Se tuvieron en cuenta los factores pronósticos medidos al inicio del estudio y en cualquier otro punto temporal durante el estudio y en cualquier contexto clínico. Los desenlaces se evaluaron a los tres y ocho años (± dos años) o de por vida. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión extrajeron de forma independiente los datos de los estudios incluidos mediante un formulario de extracción de datos que se desarrolló y evaluó antes de la etapa de obtención de datos. Las discrepancias se resolvieron mediante debate. Para evaluar el riesgo de sesgo se utilizó la herramienta Quality in Prognosis Studies (QUIPS). Se realizaron metanálisis en grupos clínicamente relevantes utilizando un enfoque de efectos aleatorios. Se proporcionaron los cociente de riesgos instantáneos (CRI), los odds ratios (OR) y las razones de riesgos (RR) por separado para cada factor pronóstico y desenlace disponibles, estratificados por diferentes puntos temporales. Cuando fue posible, se realizó un metanálisis de los factores pronósticos ajustados. La certeza de la evidencia se evaluó con una versión adaptada del método GRADE. RESULTADOS PRINCIPALES: Se han examinado 6391 registros. A partir de estos se identificaron 59 estudios (87 artículos) elegibles para inclusión. Treinta y cinco fueron estudios de cohortes prospectivos, 22 fueron estudios retrospectivos, 18 de los cuales fueron de cohortes y 6 se basaron en datos de registros electrónicos, y 2 fueron estudios retrospectivos de casos y controles. Veintitrés estudios evaluaron a participantes con diabetes tipo 1 (DT1), 19 con diabetes tipo 2 (DT2) y 17 incluyeron poblaciones mixtas (DT1 y DT2). Los estudios sobre la DT1 incluyeron entre 39 y 3250 participantes al inicio del estudio, con un seguimiento de 1 a 45 años. Los estudios sobre la DT2 incluyeron entre 100 y 71 817 participantes al inicio del estudio, con un seguimiento de 1 a 20 años. Los estudios sobre poblaciones mixtas de DT1 y DT2 variaron entre 76 y 32 553 participantes al inicio del estudio, con un seguimiento de 4 a 25 años. Se encontró evidencia que indicó que los niveles más altos de hemoglobina glucosilada (hemoglobina A1c [HbA1c]) (OR ajustado que varió de 1,11 [intervalo de confianza (IC) del 95%: 0,93 a 1,32] a 2,10 [IC del 95%: 1,64 a 2,69]) y los estadios más avanzados de retinopatía (OR ajustado que varió entre 1,38 [IC del 95%: 1,29 a 1,48] y 12,40 [IC del 95%: 5,31 a 28,98]) son factores de riesgo independientes para el desarrollo de RDP en personas con DT1 y DT2. La evidencia para estos factores se consideró de certeza moderada debido al riesgo moderado a alto de sesgo en los estudios. También hubo alguna evidencia que indicó varios marcadores de enfermedad renal (por ejemplo, nefropatía [OR ajustado que varió entre 1,58 (IC del 95% no proporcionado) y 2,68 (2,09 a 3,42)] y creatinina [metanálisis ajustado CRI 1,61 (IC del 95%: 0,77 a 3.36)]), y, en las personas con DT1, la edad en el momento del diagnóstico de la diabetes (< 12 años) (estimación de la regresión estandarizada 1,62; IC del 95%: 1,06 a 2,48), el aumento de los niveles de triglicéridos (RR ajustado 1,55; IC del 95%: 1,06 a 1,95) y los diámetros venulares retinianos mayores (RR 4,28; IC del 95%: 1,50 a 12,19) podrían aumentar el riesgo de progresión a RDP. Sin embargo, la certeza de la evidencia para estos factores fue de baja a muy baja, debido al riesgo de sesgo en los estudios incluidos, la inconsistencia (falta de estudios que impide la calificación de consistencia o desenlaces variables) y la imprecisión (IC amplios). No hubo evidencia importante ni consistente que apoyara que la duración de la diabetes, la presión arterial sistólica o diastólica, el colesterol total, las lipoproteínas de baja (LDL) y alta (HDL) densidad, el sexo, el origen étnico, el índice de masa corporal (IMC), el nivel socioeconómico o el consumo de tabaco y alcohol estuvieran asociados con la incidencia de RDP. No hubo evidencia suficiente para evaluar los factores pronósticos asociados con la progresión de la RDP a RDP­CAR. CONCLUSIONES DE LOS AUTORES: Es probable que el aumento de la HbA1c se asocie con la progresión a la RDP; por lo tanto, mantener un control adecuado de la glucosa durante toda la vida, independientemente del estadio de gravedad de la RD, podría ayudar a prevenir la progresión a la RDP y el riesgo de sus complicaciones que ponen en peligro la vista. La insuficiencia renal en personas con DT1 o DT2, así como una menor edad en el momento del diagnóstico de la diabetes mellitus (DM), el aumento de los niveles de triglicéridos y el aumento de los diámetros venulares retinianos en personas con DT1 también se podrían asociar con un mayor riesgo de progresión a RDP. Dado que la gravedad más avanzada de la RD se asocia con un mayor riesgo de progresión a RDP, cuanto antes se identifique la enfermedad y se controlen los factores de riesgo sistémicos mencionados, mayores serán las posibilidades de reducir el riesgo de RDP y conservar la vista.

Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA): health assessment protocol, participant profile and patterns of participation.

BACKGROUND: The Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) is a prospective, longitudinal study of a representative cohort of older adults living in Northern Ireland, United Kingdom. Its aim is to explore the social, behavioural, economic and biological factors of ageing and how these factors change as people age. The study has been designed to maximize comparability with other international studies of ageing thereby facilitating cross-country comparisons. This paper provides an overview of the design and methodology of the health assessment which was carried out as part of Wave 1. METHODS: Three thousand, six hundred and fifty five community dwelling adults, aged 50 years and over participated in the health assessment as part of Wave 1 of NICOLA. The health assessment included a battery of measurements across various domains that addressed key indicators of ageing namely: physical function, vision and hearing, cognitive function, and cardiovascular health. This manuscript describes the scientific rationale for the choice of assessments, provides an overview of the core objective measures carried out in the health assessment and describes the differences in characteristics of participants who took part in the health assessment compared to those who did not take part. RESULTS: The manuscript highlights the importance of incorporating objective measures of health in population based studies as a means of complementing subjective measures and as a way to advance our understanding of the ageing process. The findings contextualize NICOLA as a data resource within Dementias Platform UK (DPUK), the Gateway to Global Ageing (G2G) and other existing networks of population based longitudinal studies of ageing. CONCLUSION: This manuscript can help inform design considerations for other population based studies of ageing and facilitate cross-country comparative analysis of key life-course factors affecting healthy ageing such as educational attainment, diet, the accumulation of chronic conditions (including Alzheimer's disease, dementia and cardiovascular disease) as well as welfare and retirement policies.

Association of reduced inner retinal thicknesses with chronic kidney disease.

BACKGROUND: Tissue derived biomarkers may offer utility as indicators of accumulated damage. Reduced thickness of retinal neuronal tissue and the vascular choroid have previously been associated with vascular damage and diabetes. We evaluated associations between retinal thickness, retinal microvascular and choroidal measures, and renal function in a population with a high burden of comorbidity. METHODS: Participants were recruited from nuclear cardiology or renal medicine clinics. Retinal and choroidal thickness were measured from spectral-domain optical coherence tomograms. Retinal microvascular parameters were assessed from digital fundus photographs using a semi-automated software package. MAIN OUTCOME MEASURE: Chronic kidney disease (CKD) categorised as: CKD stages 1-2, eGFR ≥60 ml/min/1.73m2; CKD stage 3, eGFR 30-59 ml/min/1.73m2, and CKD stages 4-5, eGFR ≤29 ml/min/1.73m2. RESULTS: Participants (n = 241) had a mean age of 65 years and a mean eGFR of 66.9 ml/min/1.73m2. Thirty-nine % of the cohort had diabetes and 27% were using diuretics. Thinning of the inner retina and changes to its microvascular blood supply were associated with lower eGFR and CKD stages 4 and 5, while no associations were found between the outer retinal layers or their choroidal blood supply and CKD of any stage. These associations remained following adjustment for age, mean arterial blood pressure, diabetes status, low-density lipoprotein, body mass index, and sex. CONCLUSIONS: Inner retinal thinning and retinal microvascular variation is associated with advanced CKD (stages 4 & 5) independent of important confounding factors, but not with earlier stage CKD (stage 3) and, therefore, its utility as a biomarker for early CKD is not supported in this study.

Delayed attendance at routine eye examinations is associated with increased probability of general practitioner referral: a record linkage study in Northern Ireland.

PURPOSE: To investigate relationships between health and socio-economic status with delayed attendance at routine eye examinations and risk of subsequent general practitioner (GP) referral in Northern Ireland. METHODS: We constructed a cohort of 132 046 community dwelling individuals aged ≥60 years, drawing contextual information from the 2011 Northern Ireland Census. Using linked administrative records of routine eye examinations between 2009 and 2014, we calculated 311 999 examination intervals. Multinomial models were used to estimate associations between contextual factors and examination interval (classified into three groups: early recall, on-time, delayed attendance). Associations between examination interval and referral risk were estimated using logistic regression. RESULTS: Delayed attendance was recorded for 129 857 (41.6%) examination intervals, 53 759 (17.2%) delayed by ≥6 months. Female sex, poor general or mental health were each associated with delay, as were longer distances to optometry services among those aged ≥70 years (longest vs shortest: Relative Risk Ratio = 1.21 [1.14, 1.28]). Low income and residence in social housing were associated with reduced delay risk. There were 3347 (3.5%) and 11 401 (5.3%) GP referrals in the 60-69 and ≥70 years age groups respectively. Delayed attendance was associated with increased referral risk in both groups (Odds Ratios: 60-69 years = 1.30 [1.04, 1.61]; ≥70 years = 1.07 [1.01, 1.13]). CONCLUSIONS: Poor health and longer distances to optometry services were associated with delayed attendance at routine eye examinations but low income was not. Delayed attendance was associated with increased GP referral risk, indicative of missed opportunities to detect potentially serious eye conditions.

The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data.

TOPIC: To estimate the prevalence of nonrefractive visual impairment and blindness in European persons 55 years of age and older. CLINICAL RELEVANCE: Few visual impairment and blindness prevalence estimates are available for the European population. In addition, many of the data collected in European population-based studies currently are unpublished and have not been included in previous estimates. METHODS: Fourteen European population-based studies participating in the European Eye Epidemiology Consortium (n = 70 723) were included. Each study provided nonrefractive visual impairment and blindness prevalence estimates stratified by age (10-year strata) and gender. Nonrefractive visual impairment and blindness were defined as best-corrected visual acuity worse than 20/60 and 20/400 in the better eye, respectively. Using random effects meta-analysis, prevalence rates were estimated according to age, gender, geographical area, and period (1991-2006 and 2007-2012). Because no data were available for Central and Eastern Europe, population projections for numbers of affected people were estimated using Eurostat population estimates for European high-income countries in 2000 and 2010. RESULTS: The age-standardized prevalence of nonrefractive visual impairment in people 55 years of age or older decreased from 2.22% (95% confidence interval [CI], 1.34-3.10) from 1991 through 2006 to 0.92% (95% CI, 0.42-1.42) from 2007 through 2012. It strongly increased with age in both periods (up to 15.69% and 4.39% in participants 85 years of age or older from 1991 through 2006 and from 2007 through 2012, respectively). Age-standardized prevalence of visual impairment tended to be higher in women than men from 1991 through 2006 (2.67% vs. 1.88%), but not from 2007 through 2012 (0.87% vs. 0.88%). No differences were observed between northern, western, and southern regions of Europe. The projected numbers of affected older inhabitants in European high-income countries decreased from 2.5 million affected individuals in 2000 to 1.2 million in 2010. Of those, 584 000 were blind in 2000, in comparison with 170 000 who were blind in 2010. CONCLUSIONS: Despite the increase in the European older population, our study indicated that the number of visually impaired people has decreased in European high-income countries in the last 20 years. This may be the result of major improvements in eye care and prevention, the decreasing prevalence of eye diseases, or both.

IDENTIFYING FEATURES OF EARLY AND LATE AGE-RELATED MACULAR DEGENERATION: A Comparison of Multicolor Versus Traditional Color Fundus Photography.

PURPOSE: To compare multicolor (MC) and traditional color fundus photography (CFP) in their ability to detect features of early and late age-related macular degeneration (AMD). METHODS: Study design: Observational case series. PARTICIPANTS: fundus images captured using standard CFP and MC imaging from 33 patients attending hospital clinics and 26 participants from the pilot phase of the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). Systematic grading of early and late AMD features; (hard drusen, soft drusen, reticular pseudodrusen, pigment clumping, non-geographic atrophy hypopigmentation, atrophy, hemorrhage, and fibrosis) on CFP and MC. RESULTS: There were 105 eyes with gradable images for comparison. Using CFP as the gold standard, sensitivity values for MC ranged from 100% for atrophy, non-geographic atrophy hypopigmentation, and fibrosis to 69.7% for pigment clumping. Specificity values were high: >80% for all features. On using MC as the comparator, CFP had lower sensitivity for the detection of early AMD features (27.8% for reticular drusen to 77.8% for non-geographic atrophy hypopigmention). Analysis of OCT in discrepant cases showed better agreement with MC for all AMD lesions, except hemorrhage and non-geographic atrophy hypopigmentation. For pigment clumping, CFP and MC were in equal agreement with OCT. CONCLUSION: Multicolor retinal imaging allowed for improved detection and definition of AMD features.

Confocal infrared imaging with optical coherence tomography provides superior detection of a number of common macular lesions compared to colour fundus photography.

PURPOSE: To compare diagnostic accuracy of confocal infrared reflectance (IR), with and without optical coherence tomography (OCT), to colour fundus photography (CFP) in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) Study. METHODS: Cross-sectional observational study of participants in NICOLA. CFP, IR and IR/OCT of 640 eyes were graded for hard, soft and reticular pseudodrusen; geographic atrophy; choroidal neovascularisation; naevus; epiretinal membrane; and haemorrhages. Test characteristics (sensitivity and specificity) for each imaging modality with respect to each retinal feature were calculated. RESULTS: With CFP as the reference standard, sensitivity of IR by itself ranged from 75% for RPD to 93.5% for hard drusen and specificity was above 90% for all features except hard drusen (71.7%). For IR combined with OCT, sensitivity ranged from 80% for choroidal neovascularisation to 96.5% for hard drusen. When IR alone was the reference standard, CFP sensitivity was high for naevi (97.5%) but reduced markedly for epiretinal membrane (48.5%). When the combination of IR and OCT was the reference standard, sensitivity for CFP was least for epiretinal membrane (31.5%), low for geographic atrophy and reticular pseudodrusen (77.8% and 76.2% respectively) and high for all other lesion types. CONCLUSION: Our findings support the use of confocal IR with OCT as a screening tool for a variety of features of macular disease in community optometric practice.

Peripheral blood mononuclear cells from neovascular age-related macular degeneration patients produce higher levels of chemokines CCL2 (MCP-1) and CXCL8 (IL-8).

BACKGROUND: Infiltrating immune cells including monocytes/macrophages have been implicated in the pathogenesis of neovascular age-related macular degeneration (nAMD). The aim of this study was to investigate the cytokine and chemokine expression and secretion profile of peripheral blood mononuclear cells (PBMCs) from nAMD patients and the relationship between the cytokine/chemokine expression profile and clinical phenotype of nAMD, including macular fibrosis, macular atrophy or the responsiveness to anti-VEGF therapy. METHODS: One hundred sixty-one nAMD patients and 43 controls were enrolled in this study. nAMD patients were divided into subgroups based on the presence/absence of (1) macular atrophy, (2) macular fibrosis and (3) responsiveness to anti-VEGF therapy; 25-30 ml of peripheral blood were obtained from all participants and 5 ml were used for serum collection, and the remaining were used for PBMC isolation using density gradient centrifugation. Intracellular cytokine expressions by PBMCs following phorbol 12-myristate 13-acetate (PMA) and ionomycin stimulation were examined using flow cytometry. Cytokine productions in lipopolysaccharides (LPS)-or 1% oxygen -treated PBMC were measured using cytometric bead array (CBA) assay. In addition, cytokine and chemokine levels in the serum were also measured by CBA assay. RESULTS: PBMCs from nAMD patients secreted higher levels of IL-8, CCL2 and VEGF, especially following LPS and 1% oxygen stimulation, than those from controls. 60~80% of IL-8 producing cells were CD11b+CD3- monocytes. The percentage of CD11b+CD3- IL-8+ was significantly increased in nAMD patients compared to controls. PBMCs from nAMD patients without macular fibrosis produced the highest levels of IL-8 and CCL2, whilst PBMCs from nAMD patients with macular atrophy produced highest levels of VEGF. In addition, PBMCs from patients who partially responded to anti-VEGF produced higher levels of IL-8 compared to the cells from complete responders. Interestingly, serum level of CCL2 was not increased in nAMD patients although there was a trend of increased IL-8 in nAMD patients. CONCLUSIONS: PBMCs, in particular monocytes, may contribute to CNV development in nAMD through secreting elevated levels of IL-8, CCL2 and VEGF after they are recruited to the macula. Apart from VEGF, IL-8 and CCL2 may be additional targets for nAMD management.

Mediterranean Diet Score and Its Association with Age-Related Macular Degeneration: The European Eye Study.

PURPOSE: To examine associations between adherence to a Mediterranean diet and prevalence of age-related macular degeneration (AMD) in countries ranging from Southern to Northern Europe. DESIGN: Cross-sectional, population-based epidemiologic study. PARTICIPANTS: Of 5060 randomly sampled people aged 65 years or older from 7 study centers across Europe (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain), full dietary data were available in 4753. The mean age of participants was 73.2 years (standard deviation, 5.6), and 55% were women. METHODS: Participants underwent an eye examination and digital retinal color photography. The images were graded at a single center. Dietary intake during the previous 12 months was assessed by using a semiquantitative food-frequency questionnaire (FFQ). A previously published Mediterranean Diet Score (MDS) was used to classify participants according to their responses on the FFQ. Multivariable logistic regression was used to investigate the association of the MDS score and AMD, taking account of potential confounders and the multicenter study design. MAIN OUTCOME MEASURES: Images were graded according to the International Classification System for age-related maculopathy and stratified using the Rotterdam staging system into 5 exclusive stages (AMD 0-4) and a separate category of large drusen (≥125 µm). Age-related macular degeneration 4 included neovascular AMD (nvAMD) and geographic atrophy (GA). RESULTS: Increasing MDS was associated with reduced odds of nvAMD in unadjusted and confounder-adjusted analysis. Compared with the lowest MDS adherence (≤4 score), those in the highest category MDS adherence (>6 score) showed lower odds of nvAMD (odds ratio, 0.53; 0.27-1.04; P trend = 0.01). The association with MDS did not differ by Y204H risk allele (P = 0.89). For all early AMD (grade 1-3), there was no relationship with MDS (P trend = 0.9). There was a weak trend (P = 0.1) between MDS and large drusen; those in the highest category of MDS had 20% reduced odds compared with those in the lowest (P = 0.05). CONCLUSIONS: This study adds to the limited evidence of the protective effect of adherence to a Mediterranean dietary pattern in those with late AMD, although it does not support previous reports of a relationship with genetic susceptibility. Interventions to encourage the adoption of the Mediterranean diet should be developed, and methods by which such behavior change can be achieved and maintained investigated.

Ophthalmic epidemiology in Europe: the "European Eye Epidemiology" (E3) consortium.

The European Eye Epidemiology (E3) consortium is a recently formed consortium of 29 groups from 12 European countries. It already comprises 21 population-based studies and 20 other studies (case-control, cases only, randomized trials), providing ophthalmological data on approximately 170,000 European participants. The aim of the consortium is to promote and sustain collaboration and sharing of data and knowledge in the field of ophthalmic epidemiology in Europe, with particular focus on the harmonization of methods for future research, estimation and projection of frequency and impact of visual outcomes in European populations (including temporal trends and European subregions), identification of risk factors and pathways for eye diseases (lifestyle, vascular and metabolic factors, genetics, epigenetics and biomarkers) and development and validation of prediction models for eye diseases. Coordinating these existing data will allow a detailed study of the risk factors and consequences of eye diseases and visual impairment, including study of international geographical variation which is not possible in individual studies. It is expected that collaborative work on these existing data will provide additional knowledge, despite the fact that the risk factors and the methods for collecting them differ somewhat among the participating studies. Most studies also include biobanks of various biological samples, which will enable identification of biomarkers to detect and predict occurrence and progression of eye diseases. This article outlines the rationale of the consortium, its design and presents a summary of the methodology.

Higher plasma levels of complement C3a, C4a and C5a increase the risk of subretinal fibrosis in neovascular age-related macular degeneration: Complement activation in AMD.

BACKGROUND: The aim of this study was to investigate the plasma levels of complement C3a, C4a, and C5a in different types of neovascular age-related macular degeneration (nAMD) and whether the levels were related to patients' responsiveness to anti-VEGF therapy. RESULTS: Ninety-six nAMD patients (including 61 with choroidal neovascularisation (CNV), 17 with retinal angiomatous proliferation (RAP), 14 with polypoidal choroidal vasculopathy (PCV) and 4 unclassified patients) and 43 controls were recruited to this case-control study. Subretinal fibrosis was observed in 45 nAMD patients and was absent in 51 nAMD patients. In addition, the responsiveness to anti-VEGF (Lucentis) therapy was also evaluated in nAMD patients. Forty-four patients were complete responders, 48 were partially responders, and only 4 patients did not respond to the therapy. The plasma levels of C3a, C4a and C5a were significantly higher in nAMD patients compared to controls. Further analysis of nAMD subgroups showed that the levels of C3a, C4a and C5a were significantly increased in patients with CNV but not RAP and PCV. Significantly increased levels of C3a, C4a and C5a were also observed in nAMD patients with subretinal fibrosis but not in those without subretinal fibrosis. Higher levels of C3a were observed in nAMD patients who responded partially to anti-VEGF therapy. CONCLUSIONS: Our results suggest increased systemic complement activation in nAMD patients with CNV but not RAP and PCV. Our results also suggest that higher levels of systemic complement activation may increase the risk of subretinal fibrosis in nAMD patients.

Dyslipidemia and Diabetic Macular Edema: A Systematic Review and Meta-Analysis.

TOPIC: A systematic review and meta-analysis of dyslipidemia and diabetic macular edema (DME). CLINICAL RELEVANCE: Diabetic macular edema causes impairment of vision in patients with diabetes, and dyslipidemia has been reported as a risk factor for its development. A systematic review with a meta-analysis was undertaken to examine the evidence of an association between dyslipidemia and DME. METHODS: We defined eligibility criteria as randomized controlled trials (RCTs) and cohort, case-control, and cross-sectional studies reporting on the relationship between blood lipid levels and DME. We performed a literature search in MEDLINE, PubMed, and Embase from inception to September 2014. We used the Newcastle-Ottawa scale to assess the quality of case-control, cross-sectional, and cohort studies, and the Cochrane risk of bias tool for RCTs. RESULTS: The search strategy identified 4959 publications. After screening, we selected 21 articles for review (5 cross-sectional, 5 cohort, 7 case-control, and 4 RCTs). Meta-analysis of case-control studies revealed that mean levels of total serum cholesterol (TC), low-density lipoproteins (LDLs), and serum triglycerides (TGs) were significantly higher in patients with DME compared with those without DME (TC: 30.08; 95% confidence interval [CI], 21.14-39.02; P < 0.001; LDL: 18.62; 95% CI, 5.80-31.43; P < 0.05; TG: 24.82; 95% CI, 9.21-40.42; P < 0.05). Meta-analysis of RCTs did not show significant risk in worsening of hard exudates and severity of DME in the lipid-lowering group compared with placebo (hard exudates: relative risk, 1.00; 95% CI, 0.47-2.11; P = 1.00; DME: relative risk, 1.18; 95% CI, 0.75-1.86; P = 0.48). CONCLUSIONS: Despite evidence from the cohort studies and meta-analysis of the case-control studies suggesting a strong relationship between lipid levels and DME, this was not confirmed by the meta-analysis that included only prospective RCTs. Therefore, given the significant public health relevance of the topic, the relationship between lipid levels and DME deserves further investigation.

Clinical characteristics of reticular pseudodrusen in the fellow eye of patients with unilateral neovascular age-related macular degeneration.

PURPOSE: To describe associations between reticular pseudodrusen, individual characteristics, and retinal function. DESIGN: Cohort study. PARTICIPANTS: We recruited 105 patients (age range, 52-93 years) who had advanced neovascular age-related macular degeneration (AMD) in only 1 eye from 3 clinical centers in Europe. METHODS: Minimum follow-up was 12 months. The eye selected for study was the fellow eye without advanced disease. Clinical measures of vision were distance visual acuity, near visual acuity, and results of the Smith-Kettlewell low-luminance acuity test (SKILL). Fundus imaging included color photography, red-free imaging, blue autofluorescence imaging, fluorescein angiography, indocyanine green angiography, and optical coherence tomography using standardized protocols. These were used to detect progression to neovascular AMD in the study eye during follow-up. All imaging outputs were graded for the presence or absence of reticular pseudodrusen (RPD) using a multimodal approach. Choroidal thickness was measured at the foveal center and at 2 other equidistant locations from the fovea (1500 µm) nasally and temporally. Metrics on retinal thickness and volume were obtained from the manufacturer-supplied automated segmentation readouts. MAIN OUTCOME MEASURES: Presence of RPD, distance visual acuity, near visual acuity, SKILL score, choroidal thickness, retinal thickness, and retinal volume. RESULTS: Reticular pseudodrusen was found in 43 participants (41%) on 1 or more imaging method. The SKILL score was significantly worse in those with reticular drusen (mean score ± standard deviation [SD, 38±12) versus those without (mean score ± SD, 33±9) (P = 0.034). Parafoveal retinal thickness, parafoveal retinal volume, and all of the choroidal thickness parameters measured were significantly lower in those with reticular drusen than in those without. The presence of RPD was associated with development of neovascular AMD when corrected for age and sex (odds ratio, 5.5; 95% confidence interval, 1.1-28.8; P = 0.042). All participants in whom geographic atrophy developed during follow-up had visible RPD at baseline. CONCLUSIONS: Significant differences in retinal and choroidal anatomic features, visual function, and risk factor profile exist in unilateral neovascular AMD patients with RPD compared with those without; therefore, such patients should be monitored carefully because of the risk of developing bilateral disease.

Individual differences provide psychophysical evidence for separate on- and off-pathways deriving from short-wave cones.

Distinct neural populations carry signals from short-wave (S) cones. We used individual differences to test whether two types of pathways, those that receive excitatory input (S+) and those that receive inhibitory input (S-), contribute independently to psychophysical performance. We also conducted a genome-wide association study (GWAS) to look for genetic correlates of the individual differences. Our psychophysical test was based on the Cambridge Color Test, but detection thresholds were measured separately for S-cone spatial increments and decrements. Our participants were 1060 healthy adults aged 16-40. Test-retest reliabilities for thresholds were good (ρ=0.64 for S-cone increments, 0.67 for decrements and 0.73 for the average of the two). "Regression scores," isolating variability unique to incremental or decremental sensitivity, were also reliable (ρ=0.53 for increments and ρ=0.51 for decrements). The correlation between incremental and decremental thresholds was ρ=0.65. No genetic markers reached genome-wide significance (p<5×10(-7)). We identified 18 "suggestive" loci (p<10(-5)). The significant test-retest reliabilities show stable individual differences in S-cone sensitivity in a normal adult population. Though a portion of the variance in sensitivity is shared between incremental and decremental sensitivity, over 26% of the variance is stable across individuals, but unique to increments or decrements, suggesting distinct neural substrates. Some of the variability in sensitivity is likely to be genetic. We note that four of the suggestive associations found in the GWAS are with genes that are involved in glucose metabolism or have been associated with diabetes.

The Double Layer Sign Is Highly Predictive of Progression to Exudation in Age-Related Macular Degeneration.

PURPOSE: The presences of a double layer sign (DLS) and a shallow irregular retinal pigment epithelium (RPE) elevation (SIRE) were investigated using spectral domain-OCT (SD-OCT) imaging to determine their ability to predict progression to exudative macular neovascularization (eMNV) in the unaffected fellow eyes (study eye) of participants with age-related macular degeneration (AMD) with newly diagnosed unilateral eMNV. DESIGN: Retrospective, reanalysis of SD-OCT scans of study eyes from the Early Detection of Neovascular AMD (EDNA) study with 3 years follow-up (FU). PARTICIPANTS: The EDNA study repository of SD-OCT scans was assessed for inclusion. Cases with incomplete data sets, low quality scans, or exhibiting other pathology were excluded, which resulted in 459 eligible cases. METHODS: Spectral domain-OCT volume scans of study eyes were graded for irregular elevation of the RPE (IE), with length, and height measurements made on the most affected B-scan. Eyes with heterogeneous reflectivity within the IE were classified as exhibiting the DLS. Eyes with DLS where the length of separation between RPE and Bruch's membrane was ≥ 1000 µm in length and < 100 µm in height were subclassified as SIRE. MAIN OUTCOME MEASURES: Hazard of progression to eMNV for DLS and SIRE. RESULTS: Of the 459 eyes, 268 had IE, of which 101 were DLS-like and 51 also fulfilled criteria for SIRE. Over the 3 years FU period, 104 (23%) eyes progressed to eMNV. After an FU of 18 months, a significantly higher proportion of study eyes (P < 0.001) with IE, DLS, and SIRE developed eMNV compared with those without these features (IE: 17% vs. no IE 6.3%; DLS: 23% vs. no DLS 9.9%; SIRE: 22% vs. no SIRE 11%). In the adjusted Cox regression models, a significantly greater hazard of progression (P < 0.001) was associated with the presence of IE (adjusted hazard ratio [HR], 3.01; 95% confidence interval [CI], 1.88-4.82), DLS (adjusted HR, 3.41; 95% CI, 2.26-5.14), or SIRE (adjusted HR, 2.83; 95% CI, 1.68-4.75). CONCLUSION: The DLS is a highly sensitive predictor of progression to eMNV, and the use of SIRE does not improve predictability. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Home-Monitoring Vision Tests to Detect Active Neovascular Age-Related Macular Degeneration.

Importance: Most neovascular age-related macular degeneration (nAMD) treatments involve long-term follow-up of disease activity. Home-monitoring would reduce the burden on patients and their caregivers and release clinic capacity. Objective: To evaluate 3 vision home-monitoring tests for patients to use to detect active nAMD compared with diagnosing active nAMD at hospital follow-up during the after-treatment monitoring phase. Design, Setting, and Participants: This was a diagnostic test accuracy study wherein the reference standard was detection of active nAMD by an ophthalmologist at hospital follow-up. The 3 home-monitoring tests evaluated included the following: (1) the KeepSight Journal (KSJ [International Macular and Retinal Foundation]), which contains paper-based near-vision tests presented as word puzzles, (2) the MyVisionTrack (mVT [Genentech]) vision-monitoring mobile app, viewed on an Apple mobile operating system-based device, and (3) the MultiBit (MBT [Visumetrics]) app, viewed on an Apple mobile operating system-based device. Participants were asked to test weekly; mVT and MBT scores were transmitted automatically, and KSJ scores were returned to the research office every 6 months. Raw scores between hospital follow-ups were summarized as averages. Patients were recruited from 6 UK hospital eye clinics and were 50 years and older with at least 1 eye first treated for active nAMD for at least 6 months or longer to a maximum of 42 months before approach. Participants were stratified by time since starting treatment. Study data were analyzed from May to September 2021. Exposures: The KSJ, mVT, and MBT were compared with the reference standard (in-hospital ophthalmologist examination). Main Outcomes and Measures: Estimated area under receiver operating characteristic curve (AUROC). The study had 90% power to detect a difference of 0.06, or 80% power to detect a difference of 0.05, if the AUROC for 2 tests was 0.75. Results: A total of 297 patients (mean [SD] age, 74.9 [6.6] years; 174 female [58.6%]) were included in the study. At least 1 hospital follow-up was available for 312 study eyes in 259 participants (1549 complete visits). Median (IQR) home-monitoring testing frequency was 3 (1-4) times per month. Estimated AUROC was less than 0.6 for all home-monitoring tests, and only the KSJ summary score was associated with lesion activity (odds ratio, 3.48; 95% CI, 1.09-11.13; P = .04). Conclusions and Relevance: Results suggest that no home-monitoring vision test evaluated provided satisfactory diagnostic accuracy to identify active nAMD diagnosed in hospital eye service follow-up clinics. Implementing any of these evaluated tests, with ophthalmologists only reviewing test positives, would mean most active lesions were missed, risking unnecessary sight loss.

Descriptive study of the challenges when implementing an app for patients with neovascular age-related macular degeneration to monitor their vision at home.

OBJECTIVES: Remote monitoring of health has the potential to reduce the burden to patients of face-to-face appointments and make healthcare more efficient. Apps are available for patients to self-monitor vision at home, for example, to detect reactivation of age-related macular degeneration (AMD). Describing the challenges when implementing apps for self-monitoring of vision at home was an objective of the MONARCH study to evaluate two vision-monitoring apps on an iPod Touch (Multibit and MyVisionTrack). DESIGN: Diagnostic Test Accuracy study. SETTING: Six UK hospitals. METHODS: The study provides an example of the real-world implementation of such apps across health sectors in an older population. Challenges described include the following: (1) frequency and reason for incoming calls made to a helpline and outgoing calls made to participants; (2) frequency and duration of events responsible for the tests being unavailable; and (3) other technical and logistical challenges. RESULTS: Patients (n=297) in the study were familiar with technology; 252/296 (85%) had internet at home and 197/296 (67%) had used a smartphone. Nevertheless, 141 (46%) called the study helpline, more often than anticipated. Of 435 reasons for calling, all but 42 (10%) related to testing with the apps or hardware, which contributed to reduced adherence. The team made at least one call to 133 patients (44%) to investigate why data had not been transmitted. Multibit and MyVisionTrack apps were unavailable for 15 and 30 of 1318 testing days for reasons which were the responsibility of the app providers. Researchers also experienced technical challenges with a multiple device management system. Logistical challenges included regulations for transporting lithium-ion batteries and malfunctioning chargers. CONCLUSIONS: Implementation of similar technologies should incorporate a well-resourced helpline and build in additional training time for participants and troubleshooting time for staff. There should also be robust evidence that chosen technologies are fit for the intended purpose. TRIAL REGISTRATION NUMBER: ISRCTN79058224.