Clinical performance of predicting late age-related macular degeneration development using multimodal imaging.

BACKGROUND: To examine whether the clinical performance of predicting late age-related macular degeneration (AMD) development is improved through using multimodal imaging (MMI) compared to using colour fundus photography (CFP) alone, and how this compares with a basic prediction model using well-established AMD risk factors. METHODS: Individuals with AMD in this study underwent MMI, including optical coherence tomography (OCT), fundus autofluorescence, near-infrared reflectance and CFP at baseline, and then at 6-monthly intervals for 3-years to determine MMI-defined late AMD development. Four retinal specialists independently assessed the likelihood that each eye at baseline would progress to MMI-defined late AMD over 3-years with CFP, and then with MMI. Predictive performance with CFP and MMI were compared to each other, and to a basic prediction model using age, presence of pigmentary abnormalities, and OCT-based drusen volume. RESULTS: The predictive performance of the clinicians using CFP [AUC = 0.75; 95% confidence interval (CI) = 0.68-0.82] improved when using MMI (AUC = 0.79; 95% CI = 0.72-0.85; p = 0.034). However, a basic prediction model outperformed clinicians using either CFP or MMI (AUC = 0.85; 95% CI = 0.78-91; p ≤ 0.002). CONCLUSIONS: Clinical performance for predicting late AMD development was improved by using MMI compared to CFP. However, a basic prediction model using well-established AMD risk factors outperformed retinal specialists, suggesting that such a model could further improve personalised counselling and monitoring of individuals with the early stages of AMD in clinical practice.

COMPLETE RETINAL PIGMENT EPITHELIAL AND OUTER RETINAL ATROPHY IN AGE-RELATED MACULAR DEGENERATION: A Longitudinal Evaluation.

PURPOSE: There is a need for robust earlier biomarkers of atrophic age-related macular degeneration that could act as surrogate endpoints for geographic atrophy (GA) in early interventional trials. This study sought to examine the risk of progression of complete retinal pigment epithelium and outer retinal atrophy (cRORA) to the traditional atrophic endpoint of GA on color fundus photography. This study also compared the risk of progression for cRORA to that associated with the specific optical coherence tomography features that define nascent GA (nGA), a strong predictor of GA development. METHODS: One hundred forty participants with bilateral large drusen at baseline underwent optical coherence tomography imaging and color fundus photography at 6-month intervals for up to 36 months. Optical coherence tomography volume scans were graded for the presence of cRORA and nGA, and color fundus photographs were graded for the presence of GA. The association and rate of progression to GA for cRORA and nGA were examined. RESULTS: Both cRORA and nGA were significantly associated with GA development (adjusted hazard ratio, 65.7 and 76.8 respectively; both P < 0.001). The probability of progression of cRORA to GA over 24 months (26%) was significantly lower than the probability of progression of nGA (38%; P = 0.039). CONCLUSION: This study confirmed that cRORA was a significant risk factor for developing GA, although its rate of progression was slightly lower compared with nGA. While requiring replication in future studies, these findings suggest that the specific features of photoreceptor degeneration used to define nGA appear important when assessing the risk of progression.

HYPERREFLECTIVE FOCI NOT SEEN AS HYPERPIGMENTARY ABNORMALITIES ON COLOR FUNDUS PHOTOGRAPHS IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the prognostic value of quantifying optical coherence tomography (OCT)-defined hyperreflective foci (HRF) that do not correspond to hyperpigmentary abnormalities (HPAs) on color fundus photographs (CFPs)-HRF (OCT+/CFP-) -when considered in addition to HPA extent, for predicting late age-related macular degeneration development. This study sought to understand the impact of HRF (OCT+/CFP-) extent on visual sensitivity. METHODS: Two hundred eighty eyes from 140 participants with bilateral large drusen underwent imaging and microperimetry at baseline, and then 6-monthly for 3-years. The extent of HPAs on CFPs and HRF (OCT+/CFP-) on OCT was quantified at baseline. Predictive models for progression to late age-related macular degeneration, accounting for drusen volume and age, were developed using HPA extent, with and without HRF (OCT+/CFP-) extent. The association between HPA and HRF (OCT+/CFP-) extent with sector-based visual sensitivity was also evaluated. RESULTS: Incorporating HRF (OCT+/CFP-) extent did not improve the predictive performance for late age-related macular degeneration development ( P ≥ 0.32). Increasing HPA and HRF (OCT+/CFP-) extent in each sector were independently and significantly associated with reduced sector-based visual sensitivity ( P ≤ 0.004). CONCLUSION: The addition of HRF (OCT+/CFP-) extent to HPA extent did not improve the prediction of late age-related macular degeneration development. HRF (OCT+/CFP-) extent was also independently associated with local reductions in visual sensitivity, after accounting for HPAs.

The Diagnostic Yield of Next Generation Sequencing in Inherited Retinal Diseases: A Systematic Review and Meta-analysis.

PURPOSE: Accurate genotyping of individuals with inherited retinal diseases (IRD) is essential for patient management and identifying suitable candidates for gene therapies. This study evaluated the diagnostic yield of next generation sequencing (NGS) in IRDs. DESIGN: Systematic review and meta-analysis. METHODS: This systematic review was prospectively registered (CRD42021293619). Ovid MEDLINE and Ovid Embase were searched on 6 June 2022. Clinical studies evaluating the diagnostic yield of NGS in individuals with IRDs were eligible for inclusion. Risk of bias assessment was performed. Studies were pooled using a random...effects inverse variance model. Sources of heterogeneity were explored using stratified analysis, meta-regression, and sensitivity analysis. RESULTS: This study included 105 publications from 28 countries. Most studies (90 studies) used targeted gene panels. The diagnostic yield of NGS was 61.3% (95% confidence interval: 57.8-64.7%; 51 studies) in mixed IRD phenotypes, 58.2% (51.6-64.6%; 41 studies) in rod-cone dystrophies, 57.7% (46.8-68.3%; eight studies) in macular and cone/cone-rod dystrophies, and 47.6% (95% CI: 41.0-54.3%; four studies) in familial exudative vitreoretinopathy. For mixed IRD phenotypes, a higher diagnostic yield was achieved pooling studies published between 2018-2022 (64.2% [59.5-68.7%]), studies using exome sequencing (73.5% [58.9-86.1%]), and studies using the American College of Medical Genetics variant interpretation standards (65.6% [60.8-70.4%]). CONCLUSION: The current diagnostic yield of NGS in IRDs is between 52-74%. The certainty of the evidence was judged as low or very low. A key limitation of the current evidence is the significant heterogeneity between studies. Adoption of standardized reporting guidelines could improve confidence in future meta-analyses.

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy: Longitudinal Evaluation in Age-Related Macular Degeneration.

PURPOSE: To examine the association between incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) on OCT imaging and the subsequent risk of developing geographic atrophy (GA) defined on conventional color fundus photography (CFP) and to compare this with the specific features that define nascent GA (nGA). DESIGN: Retrospective analysis of data from a longitudinal study. PARTICIPANTS: A total of 280 eyes from 140 participants with bilateral large drusen without specific nGA-defining features or late age-related macular degeneration (AMD) at baseline. METHODS: OCT imaging and CFP were performed at baseline and then at 6-month intervals for up to 36 months. Eyes that developed neovascular AMD were censored on the day it was detected. OCT volume scans were graded for the presence of iRORA and nGA separately, and CFP images were graded for the presence of GA. MAIN OUTCOME MEASURES: Association with and variance explained in time to GA development. RESULTS: A total of 58 eyes (21%) from 46 participants (33%) had iRORA at baseline, and a further 87 eyes (31%) developed iRORA over the follow-up period. Time-to-event analyses demonstrated that prevalent or incident iRORA was associated with an increased rate of GA development (adjusted hazard ratio [HR], 12.1; P = 0.021), as was incident nGA (adjusted HR, 78.6; P < 0.001). However, only the specific nGA features (adjusted P < 0.001), and not iRORA (adjusted P = 0.520), were associated with an increased rate of GA development when both features were included in the same multivariable model. The proportion of variance explained in the time to GA development by iRORA itself (R2 = 43%) was significantly lower than explained by nGA alone (R2 = 91%; P = 0.010). CONCLUSIONS: In this cohort, iRORA is a significant risk factor for GA development, but its association with GA development appears to be accounted for by the development of the specific features that define nGA. Although requiring replication, these findings provide useful guidance on the relative utility of nGA and iRORA as risk factors for GA and as potential surrogate end points for future interventional studies in the early stages of AMD.

Hyperpigmentary abnormalities in age-related macular degeneration: association with progression and impact on visual sensitivity.

BACKGROUND/AIMS: To investigate the additional prognostic value of quantifying the extent of colour fundus photography (CFP)-defined hyperpigmentary abnormalities (HPAs) compared with their presence alone for predicting progression to late-stage age-related macular degeneration (AMD) and to understand their association with visual sensitivity in individuals with intermediate AMD. METHODS: 140 participants with bilateral large drusen underwent multimodal imaging and microperimetry at baseline and then every 6 months for up to 3 years. Baseline CFPs were graded for the presence of HPAs and their extent was quantified. Optical coherence tomography (OCT) scans were used to quantify drusen volume. Predictive models for progression to late AMD (including OCT signs of atrophy) were developed using either HPA presence or extent. The association between HPA extent with mean visual sensitivity (both overall and sector based) was also evaluated. All models were adjusted for the confounders of baseline age and drusen volume. RESULTS: The predictive performance for late AMD development was not significantly different for HPA presence or extent (p=0.92). Increasing HPA extent in each sector, but not its overall extent in an eye, was associated with reduced sector-based visual sensitivity (p<0.001 and p=0.671, respectively). CONCLUSION: In a cohort with bilateral large drusen, quantifying HPA extent did not improve the prediction of late AMD development compared with presence alone. HPA extent was associated with more local, rather than generalised, reductions in visual sensitivity. These findings suggest that quantification of HPA extent adds little to the prediction of AMD progression, but that it provides an imaging biomarker of visual dysfunction.

Cuticular Drusen in Age-Related Macular Degeneration: Association with Progression and Impact on Visual Sensitivity.

PURPOSE: To determine the prognostic significance and impact on visual function of the cuticular drusen phenotype in a cohort with intermediate age-related macular degeneration (AMD). DESIGN: Longitudinal, observational study. PARTICIPANTS: Participants aged 50 years or older, with bilateral large conventional drusen, without late AMD. METHODS: Multimodal imaging (MMI) and microperimetry were performed at baseline and then every 6 months for up to 3 years. Eyes were graded for the MMI-based presence of cuticular drusen at baseline. Color fundus photographs were used to grade for the presence of pigmentary abnormalities. OCT scans were used to calculate drusen volume. The associations between cuticular drusen and progression to MMI-defined late AMD (including OCT signs of atrophy) and the impact on visual sensitivity were examined with and without adjustment for the confounders of baseline age, pigmentary abnormalities, and drusen volume. MAIN OUTCOME MEASURES: Time to develop MMI-defined late AMD and change in mean visual sensitivity. RESULTS: A total of 280 eyes from 140 participants were included, with 70 eyes from 35 individuals (25%) having cuticular drusen at baseline. Cuticular drusen were not significantly associated with an increased rate of progression to late AMD with and without adjustment for confounders (P ≥ 0.784 for both). In an adjusted model, cuticular drusen were not associated with lower baseline visual sensitivity (P = 0.758) or a faster rate of visual sensitivity decline (P = 0.196). CONCLUSIONS: In a cohort with bilateral large conventional drusen, individuals with the cuticular drusen phenotype had neither a higher nor lower risk of developing late AMD over 3 years and were not associated with a difference in rate of visual sensitivity decline compared with those without this phenotype. As such, individuals with this phenotype currently warrant similar monitoring strategies as those with conventional drusen.

A clinical perspective on the expanding role of artificial intelligence in age-related macular degeneration.

In recent years, there has been intense development of artificial intelligence (AI) techniques, which have the potential to improve the clinical management of age-related macular degeneration (AMD) and facilitate the prevention of irreversible vision loss from this condition. Such AI techniques could be used as clinical decision support tools to: (i) improve the detection of AMD by community eye health practitioners, (ii) enhance risk stratification to enable personalised monitoring strategies for those with the early stages of AMD, and (iii) enable early detection of signs indicative of possible choroidal neovascularisation allowing triaging of patients requiring urgent review. This review discusses the latest developments in AI techniques that show promise for these tasks, as well as how they may help in the management of patients being treated for choroidal neovascularisation and in accelerating the discovery of new treatments in AMD.

Hyporeflective Cores within Drusen: Association with Progression of Age-Related Macular Degeneration and Impact on Visual Sensitivity.

PURPOSE: To examine the association between hyporeflective cores within drusen (HCD) and disease progression in age-related macular degeneration (AMD) and with visual function. DESIGN: Longitudinal observational study. PARTICIPANTS: Two hundred and eighty eyes from 140 participants with bilateral large drusen, without late AMD. METHODS: Multimodal imaging and microperimetry were performed at baseline and subsequently every 6 months for up to 3 years. Baseline OCT scans were graded for the presence of HCD and used to calculate drusen volume. The total area of the drusenoid lesions containing hyporeflective cores (HCD extent) on color fundus photographs (CFPs) was calculated. CFPs were also graded for the presence of pigmentary abnormalities. The association between HCD extent with progression to late AMD (including OCT signs of atrophy) and visual sensitivity measured using microperimetry at baseline and its rate of change over time was evaluated with and without adjustment for confounders of drusen volume, pigmentary abnormalities, and age. MAIN OUTCOME MEASURES: Time to develop late AMD and visual sensitivity. RESULTS: Twenty (7%) eyes from 12 (9%) individuals were found to have HCD at baseline, which was associated with a nonsignificantly increased rate of progression to late AMD (unadjusted P = 0.050). HCD extent was significantly associated with an increased rate of progression to late AMD (unadjusted P = 0.034) and lower visual sensitivity at baseline (unadjusted P < 0.001). However, these associations were no longer significant (P ≥ 0.264 for both) after adjusting for known risk factors for AMD progression. HCD extent was also not associated with a faster rate of visual sensitivity decline before the development of late AMD, with or without adjustment (P ≥ 0.674 for both). Increasing age and larger drusen volume were associated with HCD extent (P ≤ 0.041). CONCLUSIONS: In a cohort with bilateral large drusen, HCD presence and extent were not independently associated with an increased rate of progression to late AMD over 3 years, nor with lower visual sensitivity or an increased rate of visual sensitivity decline before the development of late AMD, after adjusting for known risk factors for disease progression.