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Validated Prediction Models for Macular Degeneration Progression and Predictors of Visual Acuity Loss Identify High-Risk Individuals.

ABSTRACT: PURPOSE:To determine predictive factors and risk scores for conversion to overall advanced age-related macular degeneration (AMD), geographic atrophy (GA), neovascular disease (NV), and loss of vision, and to validate the model for AMD in an external cohort. METHODS:Progression to advanced AMD was evaluated using stepwise survival analysis. Risk scores including genetic, demographic, behavioral, and ocular factors were derived for 3 AMD endpoints and were validated and calibrated in a large independent cohort. Vision loss of 15 or more letters was evaluated as a new endpoint in genetic analyses. RESULTS:Eight common and rare variants in genes CFH, C3, ARMS2, COL8A1, and HSPH1/B3GALTL conferred a significantly higher risk of transition to advanced AMD. Three loci (C2, CFB, RAD51B) were associated with lower rate of progression. A protective effect was suggested for CTRB1 and PELI3. The age-adjusted area under the curve (AUC) for the composite model including 13 loci model was 0.900 over 12 years (0.896 in the validation cohort). Generally, progressors had a higher risk category and nonprogressors had a lower risk category when genetic factors were considered. Furthermore, there was heterogeneity between models for GA and NV. The model was calibrated in the validation cohort. Determinants of visual loss included age, education, body mass index, smoking, and several common and rare genetic variants. CONCLUSION:Eyes with the same baseline macular grade had a wide range of estimated probability of subsequent progression and visual loss based on the validated risk score. Identifying high-risk individuals at an earlier stage using predictive modeling could lead to improved preventive and therapeutic strategies in the era of precision medicine.

SUBMITTER: Seddon JM

PROVIDER: S-EPMC6469720 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Validated Prediction Models for Macular Degeneration Progression and Predictors of Visual Acuity Loss Identify High-Risk Individuals.

Seddon Johanna M JM Rosner Bernard B

American journal of ophthalmology 20181031

<h4>Purpose</h4>To determine predictive factors and risk scores for conversion to overall advanced age-related macular degeneration (AMD), geographic atrophy (GA), neovascular disease (NV), and loss of vision, and to validate the model for AMD in an external cohort.<h4>Methods</h4>Progression to advanced AMD was evaluated using stepwise survival analysis. Risk scores including genetic, demographic, behavioral, and ocular factors were derived for 3 AMD endpoints and were validated and calibrated ...[more]

PMID: 30389371

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Project description:ImportanceAlthough anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration (AMD) results in improved vision overall, loss of substantial vision can occur. Understanding the processes that lead to loss of vision may lead to preventive strategies.ObjectiveTo determine the incidence, characteristics, causes, and baseline predictors of sustained visual acuity loss after 2 years of treatment with ranibizumab or bevacizumab for neovascular AMD.Design, setting, and participantsA cohort study within a randomized clinical trial of participants in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).InterventionsParticipants were randomly assigned to treatment with ranibizumab or bevacizumab and to 2 years of monthly or as needed injections or monthly injections for 1 year and as needed injections the following year.Main outcomes and measuresSustained visual acuity loss, defined as loss of 15 or more letters from baseline at weeks 88 and 104.ResultsAmong 1030 participants, 61 eyes (5.9%) developed sustained visual acuity loss in 2 years. Within this group, visual acuity decreased gradually over time, with a mean decrease of 2, 19, and 33 letters from baseline at 4 weeks, 1 year, and 2 years, respectively. At 2 years, eyes with sustained visual acuity loss had more scarring (60.0% vs 41.4%, P = .007), more geographic atrophy (GA) (31.6% vs 20.7%, P = .004), larger lesions (16 vs 8 mm2, P < .001), and higher proportions of intraretinal fluid (82.5% vs 51.0%, P < .001), subretinal hyperreflective material (84.5% vs 44.2%, P < .001), retinal thinning (43.3% vs 23.0%, P < .001), and thickening (20.0% vs 12.1%, P < .001). Likely causes of sustained visual acuity loss included foveal scarring (44.3%), pigmentary abnormalities (27.9%), and foveal GA (11.5%). Baseline factors independently associated with a higher incidence of sustained visual acuity loss were the presence of nonfoveal GA (odds ratio [OR], 2.86; 95% CI, 1.35-6.08; P = .006), larger area of choroidal neovascularization (OR for a >4-disc area vs ≤1-disc area, 3.91; 95% CI, 1.70-9.03; P = .007), and bevacizumab treatment (OR, 1.83; 95% CI, 1.07-3.14; P = .03).Conclusions and relevanceSustained visual acuity loss was relatively rare in CATT. The development of foveal scar, pigmentary abnormalities, or GA contributed to most of the sustained visual acuity loss. Risk was 3% higher among eyes treated with bevacizumab. Treatment that targeted the prevention of scarring or GA may improve vision outcomes.Trial registrationclinicaltrials.gov Identifier: NCT00593450.

Project description:ObjectiveTo describe the effects of treatment for 1 year with ranibizumab or bevacizumab on macular morphology and the association of macular morphology with visual acuity (VA) in eyes with neovascular age-related macular degeneration (AMD).DesignProspective cohort study within a randomized clinical trial.ParticipantsParticipants in the Comparison of Age-related Macular Degeneration Treatments Trials.MethodsParticipants were assigned randomly to treatment with ranibizumab or bevacizumab on a monthly or as-needed schedule. Optical coherence tomography (OCT), fluorescein angiography (FA), color fundus photography (FP), and VA testing were performed periodically throughout 52 weeks. Masked readers graded images. General linear models were applied to evaluate effects of time and treatment on outcomes.Main outcome measuresFluid type and location and thickness by OCT, size, and lesion composition on FP, FA, and VA.ResultsIntraretinal fluid (IRF), subretinal fluid (SRF), subretinal pigment epithelium fluid, and retinal, subretinal, and subretinal tissue complex thickness decreased in all treatment groups. A higher proportion of eyes treated monthly with ranibizumab had fluid resolution at 4 weeks, and the difference persisted through 52 weeks. At 52 weeks, there was little association between the presence of fluid of any type (without regard to fluid location) and the mean VA. However, at all time points, eyes with residual IRF, especially foveal IRF, had worse mean VA (9 letters) than those without IRF. Eyes with abnormally thin (<120 μm) or thick (>212 μm) retinas had worse VA than those with normal thickness (120-212 μm). At week 52, eyes with larger neovascular lesions or with foveal scar had worse VA than eyes without these features.ConclusionsAnti-vascular endothelial growth factor (VEGF) therapy reduced lesion activity and improved VA in all treatment groups. At all time points, eyes with residual IRF had worse VA than those without. Eyes with abnormally thin or thick retinas, residual large lesions, and scar also had worse VA. Monthly ranibizumab dosing yielded more eyes with no fluid and an abnormally thin retina, although the long-term significance is unknown. These results have important treatment implications in eyes undergoing anti-VEGF therapy for neovascular AMD.Financial disclosure(s)Proprietary or commercial disclosure may be found after the references.

Project description:ImportanceThe Age-Related Eye Disease Study age-related macular degeneration (AREDS AMD) scale is designed to classify AMD severity. The present cohort study explored whether 2-year progression along this scale was useful for estimating the risk of future progression to late AMD or best-corrected visual acuity (BCVA) loss.ObjectiveTo assess whether 2-year progression along the AREDS AMD scale can be used to estimate the probability of long-term clinically meaningful outcome measures for clinical trials or epidemiologic studies.Design, setting, and participantsAge-Related Eye Disease Study participants enrolled in a clinical trial of oral micronutrient supplements had annual color fundus photographs graded centrally using the AREDS AMD scale. Two-year progression (≥2-step and ≥3-step increases in AMD score between baseline and the 2-year study visit) was evaluated as a method of estimating the risk of long-term progression to late AMD or BCVA loss. The AREDS (1992-2001) was a randomized, placebo-controlled clinical trial based at 11 retinal specialty clinics in the United States. The dates of analysis in the present cohort study were November 1992 through November 2005.Main outcomes and measuresDevelopment of neovascular (NV) AMD, central geographic atrophy (CGA), any geographic atrophy (GA), or BCVA loss of at least 2 lines or at least 3 lines.ResultsAmong 3868 participants in the AREDS free of late AMD at baseline, the mean (SD) age was 68.3 (5.0) years, and 2180 of 3868 (56.4%) were women. In the first 2 years after randomization to the AREDS, 669 of 7458 (9.0%) of eyes had at least 2-step 2-year progression, and 275 of 7458 (3.7%) of eyes had at least 3-step 2-year progression. In the 5-year follow-up period (years 2-7), 486 of 7223 (6.7%) of eyes developed NV AMD, 339 of 7253 (4.7%) developed CGA, 726 of 7246 (10.0%) developed any GA, 2622 of 7095 (37.0%) had at least 2-line BCVA loss, and 1494 of 7155 (20.9%) had at least 3-line BCVA loss. After adjusting for demographic and clinical confounders and stratifying by baseline AMD score, statistically significant associations were observed between at least 2-step and at least 3-step 2-year progression of AMD score and subsequent 5-year development of NV AMD: hazard ratios (HRs) ranged from 3.6 (99% CI, 2.4-5.2) to 19.4 (99% CI, 7.7-48.9). For CGA, HRs ranged from 2.6 (99% CI, 1.7-4.0) to 4.7 (99% CI, 2.5-8.9); the results were similar for any GA. For at least 2-line and at least 3-line BCVA loss, HRs ranged from 1.3 (99% CI, 1.0-1.7) to 2.8 (99% CI, 1.8-4.3). For all outcomes, at least 3-step 2-year progression had stronger associations than at least 2-step 2-year progression. These findings were also validated in the AREDS2 cohort.Conclusions and relevanceTwo-year progression of AMD score was associated with progression to clinically meaningful anatomic (late AMD) and vision (≥2-line or ≥3-line loss) outcomes, suggesting that this scale may be useful for future clinical trials designed to slow the progression of AMD.

Project description:PurposeTo evaluate associations of morphologic features with 5-year visual acuity (VA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).DesignCohort study within a randomized clinical trial.ParticipantsParticipants in CATT.MethodsEyes with age-related macular degeneration-associated choroidal neovascularization (CNV) and VA between 20/25 and 20/320 were eligible. Treatment was assigned randomly to ranibizumab or bevacizumab and to 3 dosing regimens for 2 years and was at the ophthalmologists' discretion thereafter.Main outcome measuresVisual acuity, thickness and morphologic features on OCT, and lesion size and foveal composition on fundus photography (FP) and fluorescein angiography (FA).ResultsVisual acuity and image gradings were available for 523 of 914 participants (57%) alive at 5 years. At 5 years, 60% of eyes had intraretinal fluid (IRF), 38% had subretinal fluid (SRF), 36% had subretinal pigment epithelium (RPE) fluid, and 66% had subretinal hyper-reflective material (SHRM). Mean (standard deviation) foveal center thickness was 148 μm (99) for retina, 5 μm (21) for SRF, 125 μm (107) for subretinal tissue complex, 11 μm (33) for SHRM, and 103 μm (95) for RPE + RPE elevation. The SHRM, thinner retina, greater CNV lesion area, and foveal center pathology (all P < 0.001) and IRF (P < 0.05) were independently associated with worse VA. Adjusted mean VA letters were 62 for no pathology in the foveal center; 61 for CNV, fluid, or hemorrhage; 65 for non-geographic atrophy (GA); 64 for nonfibrotic scar; 53 for GA; and 56 for fibrotic scar. Incidence or worsening of 8 pathologic features (foveal GA, foveal scar, foveal CNV, SHRM, foveal IRF, retinal thinning, CNV lesion area, and GA area) between years 2 and 5 was independently associated with greater loss of VA from years 2 to 5 and VA loss from baseline to year 5.ConclusionsAssociations between VA and morphologic features previously identified through year 1 were maintained or strengthened at year 5. New foveal scar, CNV, intraretinal fluid, SHRM and retinal thinning, development or worsening of foveal GA, and increased lesion size are important contributors to the VA decline from years 2 to 5. A significant need to develop therapies to address these adverse pathologic features remains.

Project description:To describe the association between morphologic features on fundus photography (FP), fluorescein angiography (FA), and optical coherence tomography (OCT) and visual acuity (VA) in the second year of the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).Prospective cohort study within a randomized clinical trial.Participants in the CATT.Study eye eligibility required angiographic and OCT evidence of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) and VA between 20/25 and 20/320. Treatment was assigned randomly to ranibizumab or bevacizumab with 3 different dosing regimens over a 2-year period.Fluid type, location, and thickness; retina and subretinal tissue complex thickness on OCT; size and lesion composition on FP and FA; and VA.Among 1185 CATT participants, 993 (84%) had fluid on OCT at baseline and completed 2 years of follow-up. At 2 years, intraretinal fluid (IRF), subretinal fluid (SRF), sub-retinal pigment epithelium (RPE) fluid, and subretinal tissue complex thickness decreased in all treatment groups. Ranibizumab monthly was best able to resolve each type of fluid. Eyes with SRF in the foveal center on OCT had better mean VA than eyes with no SRF (72.8 vs. 66.6 letters; P = 0.006). Eyes with IRF in the foveal center had worse mean VA than eyes without IRF (59.9 vs. 70.9 letters; P < 0.0001). Eyes with retinal thickness <120 ?m had worse VA compared with eyes with retinal thickness 120 to 212 and >212 ?m (59.4 vs. 71.3 vs. 70.3 letters; P < 0.0001). At 2 years, the mean VA (letters) of eyes varied substantially by the type of subfoveal pathology on FP and FA: 70.6 for no pathology; 74.1 for fluid only; 73.3 for CNV or pigment epithelial (RPE) detachment; 68.4 for nongeographic atrophy; and 62.9 for geographic atrophy, hemorrhage, RPE tear, or scar (P < 0.0001).The associations between VA and morphologic features identified through year 1 were maintained or strengthened during year 2. Eyes with foveal IRF, abnormally thin retina, greater thickness of the subretinal tissue complex on OCT, and subfoveal geographic atrophy or scar on FP/FA had the worst VA. Subretinal fluid was associated with better VA.

Dataset Information

Validated Prediction Models for Macular Degeneration Progression and Predictors of Visual Acuity Loss Identify High-Risk Individuals.

Publications

Validated Prediction Models for Macular Degeneration Progression and Predictors of Visual Acuity Loss Identify High-Risk Individuals.

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