Geographic Atrophy Growth Rate Research Articles

Association Between Quantitative and Qualitative Imaging Biomarkers and Geographic Atrophy Growth Rate

Investigate associations between geographic atrophy (GA) growth rate and multimodal imaging biomarkers and patient demographics in patients with advanced non-neovascular age-related macular degeneration (nnAMD). Prospective cohort study. One hundred twenty-one eyes of 66 patients with advanced nnAMD with GA enrolled in the University of Colorado AMD Registry from August 2014 to June 2021, with follow-up through June 2023. Multimodal images were reviewed by two graders for imaging biomarkers at enrollment. GA growth rate and square-root transformed (SQRT) GA growth rate were measured between enrollment and final visit. Associations between the outcome SQRT GA growth rate and imaging biomarkers, baseline GA lesions characteristics, and patient demographics were evaluated. Average GA growth rate was 1.430 mm2/year and SQRT GA growth rate was 0.268 mm/year over a mean of 3.7 years. SQRT GA growth rate was positively associated with patient age (P = .010) and female sex (0.035), and negatively associated with body mass index (0.041). After adjustment for these demographic factors, SQRT GA growth rate was positively associated with presence of non-exudative subretinal fluid (P < .001), non-exudative subretinal hyperreflective material (P = .037), and incomplete retinal pigment epithelium and outer retina atrophy (P = .022), and negatively associated with subfoveal choroidal thickness (P = .031) and presence of retinal pseudocysts (P = .030). Larger baseline GA size at enrollment was associated with faster GA growth rate (P = .002) but not SQRT GA growth rate. Select patient demographic factors and basic clinically-relevant imaging biomarkers were associated with GA growth rate. These biomarkers may guide patient selection when considering treating GA patients with novel therapeutics.

Geographic Atrophy after Reabsorption of Pigment Epithelial Detachment (GARPED) study

BackgroundTo describe the occurrence, rate of geographic atrophy (GA) expansion, and changes in visual acuity (VA) after reabsorption of subfoveal pigment epithelial detachments (PED).MethodsIncluded patients had reabsorption of a PED followed by GA. Patients underwent clinical examination with SD-OCT. Images were classified by size with grading occurring post reabsorption. VA was recorded pre-reabsorption, post-reabsorption, and over time.ResultsThe average age of the cohort, consisting of 22 eyes from 19 participants, was 86.9 years at reabsorption. Prior to reabsorption, the VA was 20/80 and then declined to 20/200 (p = 0.001) with an average follow-up time of 30.2 months. There was no significant VA change after the initial loss with reabsorption. The average initial lesion size of GA was 0.987 mm2 with an average growth rate of 0.274 mm/year.ConclusionsThis study longitudinally examined GA growth rate in patients with reabsorbed PEDs. These patients started with a drusenoid or serous PED, had a dramatic reduction in vision and GA that occurred in place of the PED. These GA lesions have a slower growth rate and a smaller area of onset compared to rates previously reported in the literature. They do not show significant VA change after reabsorption. As we have entered the era of GA therapy, these patients may not benefit from current treatments.

The Role of the Complement Pathway in Clinical Progression of Geographic Atrophy: Analysis of the Phase III Chroma and Spectri Trials

To investigate the relationship between complement pathway activities and progression of geographic atrophy (GA) secondary to age-related macular degeneration in samples collected from patients enrolled in the Chroma and Spectri trials. Chroma and Spectri were phase III, double-masked, and sham-controlled, 96-week trials. Aqueous humor (AH) samples collected at baseline and week 24 visits from 81 patients with bilateral GA across all 3 treatment groups (intravitreal lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested, along with patient-matched plasma samples collected at baseline. Antibody capture assays using the Simoa platform were used to measure the levels of complement factor B, the Bb fragment of complement factor B, intact complement component 3 (C3), processed C3, intact complement C4, and processed C4. Complement factor D levels were measured using enzyme-linked immunosorbent assay. Correlations of complement levels and activities (i.e., processed:intact ratio of complement component) in AH and plasma with baseline GA lesion size and growth rate. In baseline AH, there were strong correlations (Spearman's rho ≥ 0.80) between intact complement proteins, between processed complement proteins, and between linked processed and intact complement proteins; weak correlations (rho ≤ 0.24) were found between complement pathway activities. There were no strong correlations between complement protein levels and activities measured in AH and plasma at baseline (rho ≤ 0.37). Baseline complement levels and activities in AH and plasma did not correlate with baseline GA lesion size or change from baseline in GA lesion area at week 48 (i.e., annualized growth rate). There were no strong correlations between changes in complement levels/activities in the AH from baseline to week 24 and annualized GA lesion growth rate. Genotype analysis did not reveal a meaningful correlation between complement-related, age-related macular degeneration risk single-nucleotide polymorphisms and complement levels and activities. Complement levels or activities in AH and plasma did not correlate with GA lesion size or growth rate. This suggests that local complement activation as measured in AH does not appear to be related to GA lesion progression. Proprietary or commercial disclosure may be found after the references.

Geographic Atrophy Phenotypes in Subjects of Different Ethnicity: Asia–Pacific Ocular Imaging Society Work Group Report 3

To characterize geographic atrophy (GA) and evaluate differences between Asians and non-Asians. Multicenter, retrospective case series. Subjects aged ≥ 50 years with GA secondary to age-related macular degeneration in the absence of neovascularization in the study eye and follow-up of ≥ 2 years. The GA lesion characterized at baseline and last follow-up based on multimodal imaging (fundus autofluorescence [FAF], near infrared [NIR], and spectral domain-OCT). Patients were grouped as either Asian or non-Asian. Comparison of (1) phenotypes of GA lesions (size, foveal involvement, number of foci, drusen background, and choroid background) and (2) growth rates of GA. A total of 144 patients (169 eyes) with distribution of 50.9% Asians and 49.1% non-Asians. The age and sex were similar between Asians and non-Asians (Asians: mean age, 77.2 ± 10.1 years, 47.9% female; non-Asians: mean age, 79.7 ± 8.4 years, 58.7% female). Asians exhibited thicker choroids (167 ± 74 versus [vs.] 134 ± 56 μm; P < 0.01) and lower prevalence of drusen (40.7% vs. 66.3%; P < 0.01). At baseline, the GA area was smaller in Asians vs. non-Asians (NIR, 3.7 ± 4.6 vs. 6.3 ± 6.8 mm2; P= 0.01: FAF, 2.4 ± 3.4 vs. 8.4 ± 9.6 mm2; P< 0.01). Asians had fewer GA foci (1.7 ± 1.3 vs. 2.7 ± 2.2; P < 0.01) compared to non-Asians. The proportion with diffused or banded FAF junctional zone pattern was similar between Asians and non-Asians (44.2% vs. 60.2%; P= 0.20). Asians had a slower GA lesion growth rate than non-Asians (NIR, 0.7 vs. 1.9 mm2/year; P<0.01: FAF, 0.3 vs. 2.0 mm2/year; P < 0.01: NIR, 0.2 vs. 0.4 mm/year; P < 0.01 square root transformed: FAF, 0.1 vs. 0.3 mm/year; P < 0.01 square root transformed). The factors associated with GA lesion growth rate are (from the highest effect size) ethnicity, junctional zone FAF pattern, baseline GA area, and number of GA foci. Higher GA lesion growth rate was observed in both Asian and non-Asian subgroups, with drusen or lesion size and FAF patterns meeting inclusion criteria of recent therapeutic trials, but growth rate remained significantly slower in Asians. Eyes with baseline lesion ≥ 5 mm2 showed the highest growth rate, and the difference between ethnicities was no longer significant (2.6 vs. 3.3 mm2/year; P= 0.14). There are differences in GA lesion phenotype, associated features, and growth rate between Asians and non-Asian subjects. Proprietary or commercial disclosure may be found after the references.

Deep Learning to Predict Geographic Atrophy Area and Growth Rate from Multimodal Imaging

To develop deep learning models for annualized geographic atrophy (GA) growth rate prediction using fundus autofluorescence (FAF) images and spectral-domain OCT volumes from baseline visits, which can be used for prognostic covariate adjustment to increase power of clinical trials. This retrospective analysis estimated GA growth rate as the slope of a linear fit on all available measurements of lesion area over a 2-year period. Three multitask deep learning models-FAF-only, OCT-only, and multimodal (FAF and OCT)-were developed to predict concurrent GA area and annualized growth rate. Patients were from prospective and observational lampalizumab clinical trials. The 3 models were trained on the development data set, tested on the holdout set, and further evaluated on the independent test sets. Baseline FAF images and OCT volumes from study eyes of patients with bilateral GA (NCT02247479; NCT02247531; and NCT02479386) were split into development (1279 patients/eyes) and holdout (443 patients/eyes) sets. Baseline FAF images from study eyes of NCT01229215 (106 patients/eyes) and NCT02399072 (169 patients/eyes) were used as independent test sets. Model performance was evaluated using squared Pearson correlation coefficient (r2) between observed and predicted lesion areas/growth rates. Confidence intervals were calculated by bootstrap resampling (B= 10 000). On the holdout data set, r2 (95% confidence interval) of the FAF-only, OCT-only, and multimodal models for GA lesion area prediction was 0.96 (0.95-0.97), 0.91 (0.87-0.95), and 0.94 (0.92-0.96), respectively, and for GA growth rate prediction was 0.48 (0.41-0.55), 0.36 (0.29-0.43), and 0.47 (0.40-0.54), respectively. On the 2 independent test sets, r2 of the FAF-only model for GA lesion area was 0.98 (0.97-0.99) and 0.95 (0.93-0.96), and for GA growth rate was 0.65 (0.52-0.75) and 0.47 (0.34-0.60). We show the feasibility of using baseline FAF images and OCT volumes to predict individual GA area and growth rates using a multitask deep learning approach. The deep learning-based growth rate predictions could be used for covariate adjustment to increase power of clinical trials. Proprietary or commercial disclosure may be found after the references.

Growth Modeling for Quantitative, Spatially Resolved Geographic Atrophy Lesion Kinetics.

PurposeTo demonstrate the applicability of a growth modeling framework for quantifying spatial variations in geographic atrophy (GA) lesion kinetics.MethodsThirty-eight eyes from 27 patients with GA secondary to age-related macular degeneration were imaged with a commercial swept source optical coherence tomography instrument at two visits separated by 1 year. Local GA growth rates were computed at 6-µm intervals along each lesion margin using a previously described growth model. Corresponding margin eccentricities, margin angles, and growth angles were also computed. The average GA growth rates conditioned on margin eccentricity, margin angle, growth angle, and fundus position were estimated via kernel regression.ResultsA total of 88,356 GA margin points were analyzed. The average GA growth rates exhibited a hill-shaped dependency on eccentricity, being highest in the 0.5 mm to 1.6 mm range and lower on either side of that range. Average growth rates were also found to be higher for growth trajectories oriented away from (smaller growth angle), rather than toward (larger growth angle), the foveal center. The dependency of average growth rate on margin angle was less pronounced, although lesion segments in the superior and nasal aspects tended to grow faster.ConclusionsOur proposed growth modeling framework seems to be well-suited for generating accurate, spatially resolved GA growth rate atlases and should be confirmed on larger datasets.Translational RelevanceOur proposed growth modeling framework may enable more accurate measurements of spatial variations in GA growth rates.

Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.

Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.

Geographic Atrophy Growth Is Strongly Related to Lesion Perimeter: Unifying Effects of Lesion Area, Number, and Circularity on Growth

To investigate the underlying reason for the previously observed impact of baseline lesion size, number, and circularity on geographic atrophy (GA) growth rate. Retrospective analysis of a multicenter, prospective, randomized controlled trial. Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration. We manually delineated atrophic lesions on color fundus photographs of 318 eyes with GA followed up over at least 2 visits (mean follow-up duration, 5.1 ± 3.0 years). We calculated GA area growth rate for each eye based on the first and last visit. GA perimeter-adjusted growth rate was defined as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye. GA area growth rate, growth rate of the square root of GA area, and GA perimeter-adjusted growth rate. GA area growth rate was correlated strongly with mean GA perimeter (r2= 0.66). GA area growth rate was associated with baseline GA area (r2= 0.39; P < 0.001), lesion number (r2= 0.10; P < 0.001), and circularity index (r2= 0.28; P < 0.001). The use of the square root of GA area reduced the influence of baseline GA area (but not lesion number or circularity) on GA growth rate. In comparison, GA perimeter-adjusted growth rate (0.098 ± 0.062 mm/year) was not correlated with baseline GA area (r2= 0.005; P= 0.20), lesion number (r2= 0.00009; P= 0.86), or circularity index (r2= 0.007; P= 0.14). GA perimeter-adjusted growth rate was 50.0% higher in eyes whose fellow eyes showed GA at any visit (0.102 ± 0.062 mm/year) than in eyes whose fellow eyes never demonstrated GA during follow-up (0.068 ± 0.049 mm/year). The growth rate of GA area is associated strongly with lesion perimeter. This relationship explains the previously observed influences of baseline GA size, lesion number, and circularity on GA growth rate. GA perimeter-adjusted growth rate is uncorrelated with the 3 morphologic factors and may serve as a surrogate outcome measure to monitor GA progression in future studies.

Clinical Course of Treated Choroidal Neovascularization in Eyes with Pre-existing Geographic Atrophy: Case Series and Reappraisal of the Literature

ABSTRACT Purpose: To report the clinical course of choroidal neovascularization (CNV) treated with anti-vascular endothelial growth factor (VEGF) treatment in eyes with pre-existing geographic atrophy (GA). Material and Methods: Multicenter retrospective series. Electronic medical records, clinical notes, and multimodal retinal imaging of patients attending four tertiary referring centers with a diagnosis of unilateral CNV in the context of a pre-existing diagnosis of GA were included. GA was assessed on multimodal retinal imaging including spectral-domain optical coherence tomography (SD-OCT) scan with simultaneous near-infrared (NIR) reflectance imaging (OCT Spectralis, Heidelberg Engineering, Heidelberg, Germany) which was acquired at baseline and every follow-up visit. GA area was measured in treated eyes and fellow eyes using NIR. Results: Fifty-four eyes from 27 patients (23 females, mean age 80.89 ± 7.5) were included. The mean number of injections in the treated eyes was 5.52 ± 1.9 by month 12. From baseline to month 12, stabilization of best-corrected visual acuity (BCVA) and a significant decrease (P = .002) of central macular thickness (CMT) in the treated eyes were observed; there was a slight worsening of BCVA (−2 ETDRS letters) and a non-significant change (P = .4) of CMT in the fellow eyes. GA significantly increased in both treated and untreated eyes (P < .001 and P < .001, respectively) with a similar absolute increase (+2.68 mm2 and +2.59 mm2, respectively) and growth rate (0.4 and 0.34, respectively). Conclusions: In our study anti-VEGF treatment for CNV in eyes with pre-existing GA was effective in terms of decrease of exudative changes and stabilization of VA by month 12. A similar growth rate of GA between treated and untreated eyes does not support a causal relationship between anti-VEGF treatment and GA progression in this subset of patients. Further studies with a longer follow-up are mandatory to confirm these results.

Age-related macular degeneration (AMD): More than meets the eye. The role of multimodal imaging in today's management of AMD-A review.

Multimodal imaging (MMI) allows a more granular grading of age-related macular degeneration (AMD) disease severity, with many novel risk factors having been recently identified. With this imaging information, we are better able to counsel our patients with more accurate and individualized progression scenarios. MMI also allows identification of anatomical features that increase our understanding of disease processes involved in progression to late AMD. Treatment protocols for neovascular AMD (nAMD) depend largely on the optical coherence tomography (OCT) appearance to determine disease activity, which allows us to individualize treatment. In geographic atrophy (GA), new intervention trials require the ability to define the extent of GA, so that GA growth rate can be determined. This is achieved through fundus autofluorescence (FAF) imaging, which allows greater accuracy of border identification, as well as revealing FAF patterns predictive of growth rates. As we strive to bring interventions earlier in the disease course, OCT imaging provides an ability to identify the first signs of atrophy, which may serve as novel surrogate biomarkers for GA, thereby facilitating trials. In the future, the use of artificial intelligence (AI) to automatically identify relevant features on MMI could further enhance our ability to determine disease severity, predict progression and assist in identifying disease activity parameters to support clinical decision making when treating nAMD. Newer developments may allow frequent, remote capturing of images, reducing clinic visits, detecting progression and monitoring neovascular activity in-between clinic visits. Being aware of these new imaging insights in AMD, greatly enhance our clinical management of AMD.

Developing a potential retinal OCT biomarker for local growth of geographic atrophy.

Geographic atrophy (GA), the advanced stage of age-related macular degeneration, is a leading cause of blindness. GA lesions are characterized by anisotropic growth and the ability to predict growth patterns would be valuable in assessing potential therapeutics. In this study, we propose an OCT-based marker of local GA growth rate based on an axial projection of the OCT volume in the Henle fiber layer (HFL) and outer nuclear layer (ONL). We analyze the association between our proposed metric and local GA growth rates in a small longitudinal cohort of patients with AMD. These methods can potentially be used to identify risk markers, stratify patients, or assess response in future therapeutic studies.

Growth Rate of Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Meta-Analysis of Natural History Studies and Implications for Designing Future Trials

Introduction: There is no effective treatment for geographic atrophy (GA). To help design future GA treatment trials, we conducted a meta-analysis for GA growth rate and its variability in natural history studies. Methods: Literatures were searched up to April 30, 2020. Data were extracted independently by 2 authors and analyzed using random-effects models. Results: The pooled mean GA growth rate was 1.66 mm²/year (SD = 1.27 mm²/year, I² = 97.0%, p < 0.001) from 23 studies (3,078 patients) reported with growth rate in mm²/year and 0.33 mm/year (SD = 0.17 mm/year, I² = 83.0%, p < 0.001) from 12 studies (1,808 patients) reported with growth rate in mm/year. Larger mean baseline GA area in mm² was associated with larger mean growth rate in both mm²/year and mm/year (p < 0.001). The sample size at 85% power for detecting 15% reduction in growth rate in a 2-arm GA trial is 464 and 209 patients per arm, respectively, for using mm²/year and mm/year as the primary outcome. Discussion/Conclusion: GA natural history studies had a pooled mean (SD) GA growth rate of 1.66 (1.27) mm²/year or 0.33 (0.17) mm/year. Because GA growth rate using mm/year requires smaller sample size than using mm²/year, GA growth rate in mm/year is recommended as the primary outcome measure for future GA trials.

Effect of Human Central Nervous System Stem Cell Subretinal Transplantation on Progression of Geographic Atrophy Secondary to Nonneovascular Age-Related Macular Degeneration

To evaluate the effect of subretinally transplanted human central nervous system stem cells (HuCNS-SC) on the progression of geographic atrophy (GA) in patients with nonneovascular age-related macular degeneration (AMD). Multicenter, prospective, phase 1 open-label clinical trial. Fifteen patients with bilateral GA solely the result of AMD. The eye with the worst best-corrected visual acuity from each patient was selected for treatment and was considered the study eye; fellow eyes served as controls. A total of 0.25× 106 or 1.0× 106 HuCNS-SCs were infused directly into the subretinal space, superotemporal to the fovea near the junctional zone, outside the area of GA. All patients underwent spectral-domain OCT and fundus autofluorescence imaging using the Spectralis HRA+OCT (Heidelberg Engineering, Inc., Heidelberg, Germany). Total GA area in both eyes was measured at baseline and month 12 by certified reading center graders using the Spectralis Region Finder software. Sectoral (clock hour) per directional radial GA progression rates with respect to the foveal center in both eyes were calculated using the polar transformation method in Image J software (National Institutes of Health, Bethesda, MD). To facilitate comparative analysis across the cohort, all eyes were transformed to a right-eye orientation. Total GA area and sectoral per directional GA progression rates were compared in both study and control eyes. No statistically significant difference was found in mean change in total GA area at month 12 between study and fellow eyes (1.07 ± 0.84 mm2 vs. 2.08 ± 1.97 mm2; P= 0.08). However, the month 12 sectoral per directional radial GA growth rate for the superotemporal region (i.e., the location of HuCNS-SC transplantation) showed a significantly slower progression rate in study eyes than in fellow eyes (0.29 ± 0.58 mm vs.1.08 ± 0.65 mm; P= 0.007). The progression rate in the superotemporal quadrant of the study eye was significantly slower than in the other 3 quadrants combined (P= 0.04). In this small pilot study, HuCNS-SC transplantation seems to be associated with slower expansion of the GA lesion in the transplanted quadrant. Larger confirmatory studies are required. Sectoral or directional analysis of growth rates of GA may be a useful approach for assessing the efficacy of locally delivered therapies.

OCT Angiography to Predict Geographic Atrophy Progression using Choriocapillaris Flow Void as a Biomarker.

PurposeTo investigate the relationship between choriocapillaris (CC) flow void (FV) percentage and geographic atrophy (GA) growth rate, and study how variations in FV percentage surrounding GA predict regional GA growth.MethodsThis prospective, longitudinal study enrolled subjects with GA secondary to nonexudative age-related macular degeneration. Optical coherence tomography angiography imaged the CC and FV percentage was evaluated using a validated algorithm. GA growth rate was measured as the difference in the square root of GA area divided by the months between baseline and follow-up imaging.ResultsTwelve eyes from 7 subjects with a mean age of 80 ± 5 years (range 74–86) were studied once at baseline and 7 to 16 months later. GA expansion rate was positively correlated with increased CC FV percentage (Spearman rank correlation coefficient r = 0.69 [P = 0.038] and 0.76 [P = 0.013]) within the 6 x 6 mm scanned macular region and the 2° margin surrounding each GA lesion, respectively. Regions with CC FV at baseline located within 480 µm from the GA margin showed 33% greater chance of becoming atrophic compared with regions within 480 µm from the GA margin that did not show CC FV at baseline.ConclusionsGA expansion rate and CC FV density throughout the macular region and surrounding the GA margin were significantly correlated. The regional magnitude of FV immediately surrounding GA was associated with GA growth into that region.Translational RelevanceCC FV analysis may facilitate prediction of GA growth over time for patients with advanced nonneovascular age-related macular degeneration.

Progression of Unifocal versus Multifocal Geographic Atrophy in Age-Related Macular Degeneration: A Systematic Review and Meta-analysis

Determining the natural history of unifocal versus multifocal geographic atrophy (GA) secondary to nonexudative age-related macular degeneration. The association between GA focality (i.e., unifocal vs. multifocal lesions) and enlargement rate is inconsistent in the literature. Some studies report a comparable growth rate between unifocal and multifocal GA, whereas others suggest the growth rate varies widely between the 2 groups. We searched 5 literature databases up to May 3, 2019, for studies that classified treatment-naïve GA patients based on lesion focality. We performed a random effects meta-analysis to determine the growth rates of GA. To account for different entry times among cohorts, we introduced a horizontal translation factor to the dataset of each cohort. Heterogeneity and study quality were assessed using the I2 statistic and Quality in Prognosis Studies tool, respectively. Publication bias was evaluated by funnel plots and the Egger test. We included 12 studies with 3489 eyes from 3001 patients. After the introduction of translation factors, the effective radius of unifocal and multifocal GA enlarged linearly over approximately 7 years. The effective radius growth rate of multifocal GA (0.199±0.012 mm/year) was 46.3% higher than the growth rate of unifocal GA (0.136±0.008 mm/year; P < 0.001). Interestingly, unifocal and multifocal GA lesions with the same total baseline area grew at vastly different rates, with an estimated ratio of the growth rate as 1.46 (between 2 and 3). This difference disappeared after we accounted for different baseline total perimeters between unifocal and multifocal groups. The measured GA growth rate was consistent across studies using color fundus photography, fundus autofluorescence, or OCT (P= 0.35-0.99). The effective radius of GA enlarges linearly and steadily over time in both unifocal and multifocal GA. The lesion focality is a significant prognostic factor for the GA effective radius growth rate. We propose that the growth rate of GA area is directly proportional to the total lesion perimeter (a measure of the number of retinal pigment epithelium cells exposed at the lesion border). Additional studies are needed to understand the cellular mechanisms underlying this relationship.

A Deep Learning Model for Segmentation of Geographic Atrophy to Study Its Long-Term Natural History

To develop and validate a deep learning model for the automatic segmentation of geographic atrophy (GA) using color fundus images (CFIs) and its application to study the growth rate of GA. Prospective, multicenter, natural history study with up to 15 years of follow-up. Four hundred nine CFIs of 238 eyes with GA from the Rotterdam Study (RS) and Blue Mountain Eye Study (BMES) for model development, and 3589 CFIs of 376 eyes from the Age-Related Eye Disease Study (AREDS) for analysis of GA growth rate. A deep learning model based on an ensemble of encoder-decoder architectures was implemented and optimized for the segmentation of GA in CFIs. Four experienced graders delineated, in consensus, GA in CFIs from the RS and BMES. These manual delineations were used to evaluate the segmentation model using 5-fold cross-validation. The model was applied further to CFIs from the AREDS to study the growth rate of GA. Linear regression analysis was used to study associations between structural biomarkers at baseline and the GA growth rate. A general estimate of the progression of GA area over time was made by combining growth rates of all eyes with GA from the AREDS set. Automatically segmented GA and GA growth rate. The model obtained an average Dice coefficient of 0.72±0.26 on the BMES and RS set while comparing the automatically segmented GA area with the graders' manual delineations. An intraclass correlation coefficient of 0.83 was reached between the automatically estimated GA area and the graders' consensus measures. Nine automatically calculated structural biomarkers (area, filled area, convex area, convex solidity, eccentricity, roundness, foveal involvement, perimeter, and circularity) were significantly associated with growth rate. Combining all growth rates indicated that GA area grows quadratically up to an area of approximately 12 mm2, after which growth rate stabilizes or decreases. The deep learning model allowed for fully automatic and robust segmentation of GA on CFIs. These segmentations can be used to extract structural characteristics of GA that predict its growth rate.

Topographic Variation of the Growth Rate of Geographic Atrophy in Nonexudative Age-Related Macular Degeneration: A Systematic Review and Meta-analysis.

PurposeTo determine the impact of topographic locations on the progression rate of geographic atrophy (GA).MethodsWe searched in five literature databases up to May 3, 2019, for studies that evaluated the growth rates of GA lesions at different retinal regions. We performed random-effects meta-analyses to determine and compare the GA effective radius growth rates in four location groups defined by two separate classification schemes: (1) macular center point involved (CPI) or spared (CPS) in classification 1, and (2) foveal zone involved (FZI) or spared (FZS) in classification 2. We then estimated the GA growth rate in eight topographic zones and used the data to model the GA expansion.ResultsWe included 11 studies with 3254 unique eyes. In studies that used classification 1, the effective radius growth rate was 30.1% higher in the CPS group (0.203 ± 0.013 mm/year) than in the CPI group (0.156 ± 0.011 mm/year) (P < 0.001). This trend became significantly more prominent in classification 2, where the growth rate was 61.7% higher in the FZS group (0.215 ± 0.012 mm/year) than in the FZI group (0.133 ± 0.009 mm/year) (P < 0.001). The estimated GA effective radius growth rates in eight retinal zones fit a Gaussian function, and the modeling of GA expansion gave rise to various GA configurations comparable to clinical observations.ConclusionsThis study indicates that the GA progression rate varies significantly across different retinal locations. Our analysis may shed light on the natural history and underlying mechanism of GA progression.

Regression to the Mean in Measurements of Growth Rates in Geographic Atrophy

Introduction: Comparison of patients with extremely high and low values of a given characteristic is a common strategy to gain insights into disease mechanisms, but this approach is particularly susceptible to regression to the mean (RTM). Objective: The aim of this work was to determine RTM in growth rate measurements in patients with geographic atrophy (GA) secondary to age-related macular degeneration. Methods: We conducted a retrospective analysis of the GAIN (NCT01694095) and its extension study, in which individuals 50 years or older with pure GA were followed for a minimum of 6 months. Two repeated and masked measurements of area of atrophy, both at baseline and final visits, were made, and growth rates were calculated for each. RTM was determined graphically and statistically, and the percentage of eyes misclassified as having fast and slow progression rates due to RTM was determined for different definitions of “fast” and “slow” growth. Results: We included 112 eyes of 112 patients: 64.3% were females, the mean age was 78.1 (SD ±7.6) years, and the mean follow-up time was 3.2 (±2.2) years. There was RTM, which decreased when the mean of two measurements was used. The magnitude of RTM in growth rates ranged from 2 to 11 µm/year and led to misclassification of eyes considered to have fast and slow growth between 2.9 and 10.3% of the cases, depending on the definition of fast and slow growth. Conclusions: RTM was present in measurements of GA growth rate, but it had a modest impact on patient misclassification. Comparison of features between patients with extreme growth rates is a reasonable strategy, but RTM should be minimized by taking the mean of two measurements.

A Framework for Multiscale Quantitation of Relationships Between Choriocapillaris Flow Impairment and Geographic Atrophy Growth

To develop a multiscale analysis framework for investigating the relationships between geographic atrophy (GA) growth rate and choriocapillaris (CC) blood flow impairment using optical coherence tomography (OCT) and OCT angiography (OCTA). Retrospective case series. We developed an OCT/OCTA analysis framework that quantitatively measures GA growth rates at global and local scales and CC impairment at global, zonal, and local scales. A geometric GA growth model was used to measure local GA growth rates. The utility of the framework was demonstrated on 7 eyes with GA imaged at 2 time points using a prototype 400-kHz, 1050-nm swept-source OCTA system. Qualitatively, there was a trend of increasing GA growth rate with increasing CC impairment. The local analysis model enabled growth rates to be estimated at each point on the GA boundary. However, there was no generally observed trend between local GA growth rates and local CC impairment. The global, zonal, and local analysis framework may be useful for investigating relationships between GA growth and CC impairment at different spatial scales. The geometric GA growth model enables spatially resolved growth measurements that capture the anisotropy of GA growth and may improve the characterization of GA progression.

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial

Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. Prospective, multicenter, randomized, sham-controlled phase 2 study. Two hundred forty-six patients with GA. Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P= 0.008) and 20% (95% CI, 0-40; P= 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P= 0.0004) and 33% (P= 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.