Imaging Biomarkers To Predict Progression of Intermediate AMD with Avascular Pigment Epithelial Detachment in the University of Colorado AMD Registry

Imaging Biomarkers To Predict Progression of Intermediate AMD with Avascular Pigment Epithelial Detachment in the University of Colorado AMD Registry | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Imaging Biomarkers To Predict Progression of Intermediate AMD with Avascular Pigment Epithelial Detachment in the University of Colorado AMD Registry Soufiane Azargui, Andres Lisker-Cervantes, Jennifer L. Patnaik, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9193520/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: To investigate whether specific imaging biomarkers predict progression to neovascular AMD (nAMD) or geographic atrophy (GA) in eyes with high-risk intermediate age-related macular degeneration (iAMD) and avascular pigment epithelial detachment (PED). Methods: Prospective longitudinal cohort study of eyes with iAMD and avascular PED from the University of Colorado AMD registry (August 2014 - August 2023) with ≥1 month of follow-up through February 2024. Multimodal imaging, including color fundus photos (CFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT), was graded by two reviewers for presence of specific imaging biomarkers. Time-to-progression survival analysis was conducted with hazard ratios calculated. Results: Over a median follow-up period of 35 months, 224 eyes (142 patients) were included. 31 (13.8%) eyes progressed to nAMD, and 63 (28.1%) to GA. Progression to nAMD was significantly predicted by pigmentary changes on CFP (HR=4.43 (95%CI: 1.77, 11.1), p=0.001) and intraretinal hyperreflective foci (iHRF) on OCT (HR=4.90 (95%CI: 2.02, 11.9), p=0.0005). Progression to GA was significantly predicted by pigmentary changes on CFP (HR=3.60 (95%CI: 1.94, 6.67), p<0.0001), iHRF (HR=4.13 (95%CI: 2.14, 7.94), p<0.0001), acquired vitelliform lesions (AVL; (HR=2.97 (95%CI: 1.55, 5.68), p=0.001)) and incomplete retinal pigment epithelium and outer retina atrophy (iRORA; (HR=4.18 (95%CI: 1.52, 11.4), p=0.006)). No other biomarkers demonstrated significance. Conclusion: In eyes with avascular PED, pigmentary changes and iHRF were significantly associated with progression to nAMD and GA, while AVL and iRORA were specifically to GA. We highlight in this study important imaging biomarkers that help identify high-risk eyes that may warrant closer monitoring to ensure timely therapeutic intervention. avascular pigment epithelial detachment intermediate age-related macular degeneration advanced age-related macular degeneration intraretinal hyperreflective foci pigmentary changes acquired vitelliform lesion incomplete retinal pigment epithelium and outer retina atrophy Key Message What is known Avascular PEDs confer substantial risk for late forms of AMD. But these studies of intermediate AMD eyes have not specifically isolated those with avascular PEDs to better understand this high risk subset. This study highlights important imaging biomarkers, such as acquired vitelliform lesions, that can help predict which eyes with avascular PEDs may progress to the advanced vision-threatening forms of AMD and may therefore warrant closer monitoring to ensure timely therapeutic intervention. These findings refine risk stratification within this high-risk phenotype and highlight the value of multimodal imaging biomarkers in anticipating disease trajectory and informing surveillance strategies Introduction Age-related macular degeneration (AMD) is the leading cause of irreversible vision among the elderly population in industrialized nations. Its prevalence is expected to increase to 288 million by 2040. [ 1 , 2 ] Retinal pigment epithelial detachments (PED), occurring between the basal lamina of the retinal pigment epithelial (RPE) cell and the inner collagenous Bruch’s membrane, commonly accompany AMD. [ 3 – 6 ] Avascular PEDs represent a distinct subtype arising from the gradual enlargement and coalescence of pre-existing soft drusen. [ 7 , 8 ] These PEDs are clinically important because they are known to increase the risk of progression to the late forms of AMD: neovascular AMD (nAMD) and geographic atrophy (GA). [ 9 – 12 ] Despite the well-known risk, it remains challenging to predict how quickly a given avascular PED will progress and, critically, to which late AMD form it will progress. Current prognostic tools do not reliably discriminate risk paths between these two forms or provide meaningful temporal information. This has growing clinical relevance given the emergence of novel therapies, such as the Valeda Light Delivery System photobiomodulation therapy, which have made it more important to identify which intermediate AMD (iAMD) patients are at the highest risk for progression and may benefit most from early intervention. [ 13 – 17 ] Although prior studies have examined progression from iAMD to advanced AMD, iAMD encompasses a broad spectrum, and later phenotypes such as those with avascular PEDs have received limited focused investigation, despite their higher risk of progression and the potential value of targeted prediction models. [ 5 , 18 – 21 ] In this study, we investigate whether specific imaging biomarkers can predict faster progression of iAMD eyes with avascular PED to nAMD or GA. Methods This prospective longitudinal study was approved by the Colorado Multiple Institutional Review Board and follows the ethical principles of the Declaration of Helsinki. The study includes patients from the University of Colorado AMD registry, developed by the Department of Ophthalmology at the University of Colorado School of Medicine. Detailed descriptions of the recruitment process, consent procedures, and inclusion and exclusion criteria for patients included in the AMD registry are available in prior publications. [ 18 , 22 – 24 ] Recruitment into this registry started on July 9, 2014 and recruitment is ongoing. Inclusion criteria include participants aged 50–99 years with AMD in one or both eyes and the ability to provide informed consent. The exclusion criteria include a history of concomitant retinal and uveitic disease. [ 23 ] Multi-Modal Imaging Each patient is consented to the collection of medical and ocular history, and review of multimodal imaging (MMI) data collected, including color fundus photos (CFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT). OCT angiography and fluorescein angiography (FA) are also obtained at the discretion of the retina provider. The MMI protocol is as follows: the Eidon True Color Confocal Scanner (iCare Spa, Vantaa, Finland) or Topcon TRC-50DX (Topcon, Tokyo, Japan) device is used to obtain a 60 degree CP centered on the fovea (field 2) and the Heidelberg Spectralis (Heidelberg Engineering Inc) device was used to obtain a 30 or 60 degree FAF with automatic real time-function (ART) of 50 centered on the fovea. The Heidelberg Spectralis device is also used to obtain high resolution horizontal and vertical enhanced-depth imaging line scans (6 mm/30 degree/ART 100) and a 49-line cube scan (6 mm/30 degree/ART 9) centered on the fovea. [ 18 , 25 ] The iAMD longitudinal cohort For this specific study, we limited our analysis to patients with iAMD at enrollment (July 2014 to August 2023) with avascular PED and at least 1 month of follow-up through February 2024. Two retina specialists confirmed the diagnosis of iAMD at enrollment in at least one eye of a patient (and no advanced AMD in either eye), using the classification described by the Beckman Initiative for Macular Research Committee. [ 26 ] Two trained graders reviewed the MMI for presence of avascular PED in each eye. The medical records and MMI of each iAMD eye with avascular PED were then reviewed for date of progression to advanced AMD (defined by the presence of GA or choroidal neovascularization per the Beckman classification), or date of last retina clinic visit if no evidence of progression. Qualitative Imaging Biomarkers The MMIs of patients in the cohort were reviewed by two trained graders for baseline qualitative imaging biomarkers, with any discrepancies resolved by a third trained grader. CFP was evaluated for the presence or absence of hard drusen, soft drusen, calcified drusen, cuticular drusen, pigmentary changes and reticular pseudodrusen (RPD). FAF images were specifically graded for the presence or absence of RPD. OCT images were assessed for the presence or absence of outer retinal tubulations (ORT), retinal pseudocysts, non-neovascular subretinal fluid (nnSRF), acquired vitelliform lesion (AVL), RPD, intraretinal hyper-reflective foci (iHRF) and incomplete retinal pigment epithelium and outer retina atrophy (iRORA). Statistical analysis Statistical analysis was performed using SAS version 9.4 (Cary, North Carolina) software. Characteristics of the cohort, including patient demographics and clinical variables, were compiled with basic frequencies and percentages, along with mean and standard deviations (SD) calculated for continuous variables which were normally distributed and medians and ranges for follow-up time. A survival analysis with time to progression specific to each eye was conducted with hazard ratios calculated. Cox proportional hazard modeling with competing risks was utilized to determine hazard ratios for time to conversion for each type of advanced AMD. Sandwich estimators were included to account for the correlation of the two eyes being included. The p-value cut-point was set at < 0.05. Results Two hundred twenty-four eyes with avascular PEDs of 142 patients were included in this study. The median follow-up period was 35.2 months (range 1.4-118.6). The mean age of patients at study enrollment was 75.5 years (SD = 6.9). There were 47 (33%) male patients and a high proportion of Caucasian patients (135/142, 95%). Average BMI was 27.5 (SD = 5.7). Eighty-five patients (60%) had no history of smoking, 3 (2%) were current smokers, and 54 (38%) were former smokers. Fifty-nine patients (42%) have a known family history of AMD. Thirty-one (13.8%) eyes progressed to nAMD, while 63 (28.1%) eyes progressed to GA. In our cohort, soft drusen, hard drusen, and iHRF were the most common imaging findings (Table 1 ), with similar prevalences among eyes that progressed to nAMD and those that progressed to GA. There were no statistically significant differences in the prevalences of imaging biomarkers between eyes that converted to nAMD and those that progressed to GA. Table 1 Comparison of prevalence of imaging biomarkers between eyes with avascular PED that progress to nAMD or GA Qualitative Imaging Biomarkers Total number of eyes with the imaging biomarker (%) N = 224 Progression to advanced nAMD n = 31 Progression to GA n = 63 Eyes with the imaging biomarker (%) Eyes with the imaging biomarker (%) p-value CFP Hard Drusen 179/213 (84.0%) 26/31 (83.9%) 55/63 (90.2%) 0.39 CFP Soft Drusen 204/213 (95.8%) 30/31 (96.8%) 60/63 (98.4%) 0.63 CFP RPD 23/213 (10.8%) 2/31 (6.4%) 6/63 (9.8%) 0.60 CFP Calcified Drusen 17/213 (8.0%) 1/31 (3.2%) 4/63 (6.6%) 0.51 CFP Cuticular Drusen 12/213 (5.6%) 1/31 (3.2%) 0/63 (0%) NC CFP Pigmentary Change 117/213 (54.9%) 21/31 (67.7%) 42/63 (68.8%) 0.92 FAF RPD 34/216 (15.7%) 5/31 (16.1%) 11/63 (17.5%) 0.86 OCT ORT 1/224 (0.4%) 0/31 (0%) 1/63 (1.8%) NC OCT Retinal Pseudocysts 2/223 (0.9%) 0/31 (0%) 2/63 (3.2%) NC OCT nnSRF 4/224 (1.8%) 1/31 (3.2%) 2/63 (3.2%) 0.99 OCT AVL 34/224 (15.2%) 6/31 (19.4%) 15/63 (23.8%) 0.58 OCT RPD 29/224 (13.0%) 5/31 (16.1%) 11/63 (17.5%) 0.86 OCT iHRF 130/224 (58.0%) 22/31 (71.0%) 44/63 (69.8%) 0.92 OCT iRORA 22/224 (9.8%) 3/31 (9.7%) 9/63 (14.3%) 0.55 NC = not calculable due to zero cell size CFP – Color Fundus Photos FAF – Fundus Autofluorescence OCT – Optical Coherence Tomography RPD – Reticular Pseudodrusen ORT – Outer Retinal Tubulation nnSRF – Non-neovascular Subretinal Fluid AVL – Acquired Vitelliform Lesion iHRF – Intraretinal Hyperreflective Foci iRORA – Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy Among iAMD eyes with avascular PED, time to progression to nAMD was significantly predicted by the presence of pigmentary changes on CFP (HR = 3.39 (95% CI: 1.47, 7.84), p = 0.004) and iHRF on OCT (HR = 3.89 (95% CI: 1.72, 8.80), p = 0.001). Progression to GA was also significantly predicted by presence of pigmentary changes on CFP (HR = 3.78 (95% CI: 2.08, 6.85), p < 0.0001) and iHRF on OCT (HR = 4.14 (95% CI: 2.25, 7.62), p < 0.0001), in addition to AVL (HR = 3.07 (95% CI: 1.67, 5.66), p = 0.0003) and iRORA (HR = 3.57 (95% CI: 1.45, 8.80), p = 0.006) on OCT. No other imaging biomarkers demonstrated a statistically significant association with progression. (Table 2 ) Table 2 The relative hazard of progression for presence of imaging biomarkers to either of the advanced forms of age-related macular degeneration in eyes with avascular PED Qualitative Imaging Biomarkers Total number of eyes with the imaging biomarker (%) Progression to nAMD Progression to GA HR (95% CI) p-value HR (95% CI) p-value CFP Hard Drusen 179/213 (84.0%) 0.67 (0.23, 1.96) 0.469 1.19 (0.44, 3.20) 0.731 CFP Soft Drusen 204/213 (95.8%) 1.25 (0.14, 10.9) 0.840 2.61 (0.34, 19.9) 0.355 CFP RPD 23/213 (10.8%) 0.64 (0.20, 2.02) 0.448 1.17 (0.39, 3.52) 0.779 CFP Calcified Drusen 17/213 (8.0%) 0.78 (0.10, 6.09) 0.813 1.83 (0.50, 6.71) 0.363 CFP Cuticular Drusen 12/213 (5.6%) 0.92 (0.10, 8.16) 0.940 NC - CFP Pigmentary Change 117/213 (54.9%) 3.39 (1.47, 7.84) 0.004 3.78 (2.08, 6.85) < 0.0001 FAF RPD 34/216 (15.7%) 1.23 (0.52, 2.93) 0.636 1.60 (0.75, 3.42) 0.225 OCT ORT 1/224 (0.4%) NC - NC - OCT Retinal Pseudocysts 2/223 (0.9%) NC - NC - OCT nnSRF 4/224 (1.8%) 3.10 (0.31, 30.9) 0.336 3.04 (0.43, 21.5) 0.266 OCT AVL 34/224 (15.2%) 2.02 (0.86, 4.78) 0.108 3.07 (1.67, 5.66) 0.0003 OCT RPD 29/224 (13.0%) 1.43 (0.60, 3.38) 0.421 1.92 (0.89, 4.16) 0.097 OCT iHRF 130/224 (58.0%) 3.89 (1.72, 8.80) 0.001 4.14 (2.25, 7.62) < 0.0001 OCT iRORA 22/224 (9.8%) 1.95 (0.54, 7.11) 0.312 3.57 (1.45, 8.80) 0.006 HR – hazard ratio CI – confidence interval NC – not calculable due to zero cell size CFP – Color Fundus Photos FAF – Fundus Autofluorescence OCT – Optical Coherence Tomography RPD – Reticular Pseudodrusen ORT – Outer Retinal Tubulation nnSRF – Non-neovascular Subretinal Fluid AVL – Acquired Vitelliform Lesion iHRF – Intraretinal Hyperreflective Foci iRORA – Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy Discussion In this iAMD cohort specifically with avascular PEDs, several MMI biomarkers were significantly associated with progression to advanced AMD. Prior AREDS analyses have shown that avascular PEDs confer substantial risk for late AMD, with 42% of eyes progressing within five years (19% to GA and 23% to nAMD), underscoring avascular PED as a high-risk phenotype with heterogeneous progression pathways. [ 20 , 27 – 29 ] The natural history of avascular PEDs generally follows one of three trajectories—collapse with subsequent atrophy, vascularization with exudation, or long-term persistence. In our cohort, pigmentary abnormalities on color fundus photography and iHRF on OCT were associated with progression to both GA and advanced neovascular disease, whereas AVL and iRORA were more specifically associated with progression along the non-neovascular atrophic pathway. Prior studies have shown that large drusen (≥ 125 µm) in the central macula, especially when accompanied by pigmentary abnormalities on color fundus photography, significantly increase the risk of progression to advanced AMD. Eyes with RPE hyperpigmentation and large drusen have a higher 5-year risk of developing either nAMD or GA, while eyes with RPE depigmentation are particularly prone to progressing to GA. [ 30 ] Similarly, iHRF is a key OCT biomarker of AMD progression, defined as discrete, well-demarcated hyperreflective lesions within the neurosensory retina, measuring ≥ 3 pixels and with reflectivity equal to or greater than the RPE band. [ 28 , 31 ] Overlying iHRF is frequently observed with avascular PED, often preceding overt structural breakdown by more than a year and correlating with increased risk of progression. [ 11 , 19 ] Verma et al. reported a 21% higher odds of progression to advanced AMD over 24 months in iAMD eyes with iHRF, while Wakatsuki et al. reported more than a twofold higher odds of progression to nAMD. [ 28 , 31 ] Although these studies did not specifically isolate eyes with avascular PEDs, they collectively support iHRF as a marker of increased progression risk. Notably, in our avascular PED subset, the presence of iHRF conferred substantially higher risk, with over a fourfold increase in odds of progression to GA and a nearly fourfold increase in odds of progression to nAMD, exceeding effect sizes previously reported in broader iAMD cohorts. The higher risk observed in this subgroup likely reflects phenotypic enrichment within the avascular PED cohort, in which the coexistence of iHRF indicates greater structural instability, RPE dysfunction, and heightened disease activity. Our finding that pigmentary change and iHRF were statistically significant predictors of progression to both GA and nAMD is concordant with prior observations and reinforces the prognostic relevance of these biomarkers in risk stratification. In regard to discriminating between which advanced form of AMD an avascular PED will progress to, our study elucidated imaging biomarkers for progression specifically to GA but none exclusively to nAMD. Prior work has examined the prognostic value of these biomarkers for GA progression, AVL and iRORA. AVLs are considered markers of active RPE dysfunction and impaired metabolic exchange between the RPE and overlying neurosensory retina. [ 18 , 32 ] Our finding that AVL significantly predicts progression to GA in iAMD eyes with avascular PEDs is consistent with prior reports in more heterogenous iAMD cohorts. [ 25 ] Mahmoudi et al. observed that approximately 10% of iAMD eyes with AVL progressed to atrophy within 24 months, while earlier studies reported a broader 15–50% risk of AVL collapse to cRORA. [ 33 ] These prior studies did not specifically isolate eyes with avascular PEDs. Therefore, our results build upon prior work, indicating that AVL confers elevated progression risk in the setting of avascular PED. Existing evidence has established iRORA as an atrophic precursor lesion on OCT that frequently progresses to cRORA, a defining feature of GA [ 18 , 34 – 36 ] Reported progression rates have been high, with Corradetti et al. showing that over 90% of eyes with incident iRORA progressed to cRORA within 24 months, and Wu et al. reporting a markedly increased risk of GA in eyes with prevalent or incident iRORA (adjusted HR ≈ 12). [ 34 , 36 ] In contrast, within our avascular PED subset, progression risk appeared substantially lower in the present study: only 14% (9/63) of eyes with both avascular PED and iRORA progressed to GA (HR = 3.57, p = 0.006) during the study period (approximately 3 years). The difference in progression rates between these studies could be due to different patient populations, study follow-up variability, or different thresholds for iRORA classification. Alternatively, iRORA occurring in the presence of an avascular PED may represent an earlier stage of atrophy formation due to persistence of the PED, with a distinct risk profile and potentially slower atrophic trajectory than that reported in broader iAMD cohorts. Strengths of this study include its prospective longitudinal design, the use of well-established enrollment criteria from the University of Colorado AMD Registry, and a standardized multimodal image review process. Trained graders performed AMD staging and image biomarker assessment, with a third independent grader used for adjudication to support consistency and accuracy. In addition, our analysis focused on a specific, well-defined subset of high-risk iAMD eyes, offering a novel perspective within a population that has otherwise not been broadly studied. Several limitations should be acknowledged. This was a single academic center study, and although the overall cohort was large, the number of eyes progressing to advanced AMD was relatively small, with a median follow-up of approximately 3 years. This may have limited our study’s power to uncover significant biomarkers, particularly for progression to nAMD since the sample size was smaller. Furthermore, fluorescein angiography and OCT angiography were not obtained in all patients, as their use was at the clinician's discretion. These modalities were employed in equivocal cases and during research review for progression assessment, and longitudinal multimodal imaging was carefully evaluated to monitor for interval fluid changes suggestive of neovascular conversion. Despite these safeguards, a small number of fibrovascular PEDs without exudation could have been misclassified as avascular PEDs and inadvertently included in the analysis. Finally, while the study was conducted longitudinally, the imaging biomarkers were evaluated only cross-sectionally at enrollment. A longitudinal evaluation of how these biomarkers evolve during the disease progression would provide further information on AMD pathogenesis. Additionally, incorporating quantitative assessment such as PED size metrics or drusen volume may further refine risk stratification. Finally, future studies should explore the use of artificial intelligence to enhance predictive modeling of AMD progression in this high risk iAMD population, potentially incorporating multimodal imaging biomarkers, genetics, and electronic health record data. In conclusion, among eyes with iAMD and avascular PEDs, pigmentary abnormalities and iHRF were strongly associated with progression to both GA and nAMD, while AVL and iRORA were more specifically linked to progression to GA. These findings refine risk stratification within a high-risk phenotype and highlight the value of multimodal imaging biomarkers in anticipating disease trajectory and informing surveillance strategies. Declarations Acknowledgements and Disclosures The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Research Funding Research in this publication was supported by the National Eye Institute of the National Institutes of Health under award number R01EY032456 (AML), the Helene and Marshall Abrahams AMD Research Fund, the Greenwald Family Research Fund, a Research to Prevent Blindness grant to the Department of Ophthalmology, University of Colorado, the Frederic C. Hamilton Macular Degeneration Center, Sue Anschutz-Rodgers Eye Center Research Fund, and by NIH/NCATS Colorado CTSA Grant Number UM1 TR004399. Author Contribution SA and AL-C wrote the main manuscript text and participated in manuscript editing. AL-C also participated in grading/data collection. JP: conducted formal data analysis and manuscript editing. RG: participated in manuscript editing and data collection. NM: participated in manuscript editing and data collection. BG: participated in manuscript editing and data collection. AML: participated in manuscript editing. AGP: participated in manuscript editing. MTM: participated in manuscript editing. N. Manoharan: participated in manuscript editing. N. Mandava: participated in manuscript editing. TdCF: Conceptualized project, participated in data collection, data analysis and reviewed and edited manuscript. References Ambati J et al (2003) Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. 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Ophthalmology 130(2):205–212 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9193520","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":621674854,"identity":"ca2605d7-49cf-45d2-8958-9f65b3edc54a","order_by":0,"name":"Soufiane Azargui","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Soufiane","middleName":"","lastName":"Azargui","suffix":""},{"id":621674855,"identity":"5b0e5227-d529-48f5-9817-048ae3af8f32","order_by":1,"name":"Andres Lisker-Cervantes","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Andres","middleName":"","lastName":"Lisker-Cervantes","suffix":""},{"id":621674857,"identity":"5442bd8f-112f-4229-a677-754306ed1fdd","order_by":2,"name":"Jennifer L. Patnaik","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"L.","lastName":"Patnaik","suffix":""},{"id":621674861,"identity":"1cf899f8-4b01-47e1-8cbb-964e05950f4b","order_by":3,"name":"Ramya Gnanaraj","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ramya","middleName":"","lastName":"Gnanaraj","suffix":""},{"id":621674864,"identity":"eec0a999-6feb-4282-953b-7e030a237d86","order_by":4,"name":"Nihaal Mehta","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Nihaal","middleName":"","lastName":"Mehta","suffix":""},{"id":621674865,"identity":"14c9e6b7-f574-4774-9423-ba0360618e92","order_by":5,"name":"Bill Gange","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Bill","middleName":"","lastName":"Gange","suffix":""},{"id":621674866,"identity":"dd614942-32b2-4453-ab4a-fe1d1bd89903","order_by":6,"name":"Anne M. Lynch","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"M.","lastName":"Lynch","suffix":""},{"id":621674867,"identity":"9285e4dc-a1d5-4e83-af84-d1779a1da82b","order_by":7,"name":"Alan G. Palestine","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Alan","middleName":"G.","lastName":"Palestine","suffix":""},{"id":621674868,"identity":"40abb94b-6fac-4418-aa8b-2fe0280205ba","order_by":8,"name":"Marc T. Mathias","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Marc","middleName":"T.","lastName":"Mathias","suffix":""},{"id":621674869,"identity":"b002b15b-dc7c-4d46-86fe-3cf04ff25e60","order_by":9,"name":"Niranjan Manoharan","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Niranjan","middleName":"","lastName":"Manoharan","suffix":""},{"id":621674870,"identity":"d716e3fb-0863-4b28-855e-be8081b04422","order_by":10,"name":"Naresh Mandava","email":"","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Naresh","middleName":"","lastName":"Mandava","suffix":""},{"id":621674873,"identity":"26bc2f33-1ce4-4602-9153-8b1801ee2927","order_by":11,"name":"Talisa E. Carlo Forest","email":"data:image/png;base64,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","orcid":"","institution":"University of Colorado School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Talisa","middleName":"E. Carlo","lastName":"Forest","suffix":""}],"badges":[],"createdAt":"2026-03-22 20:23:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9193520/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9193520/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106807863,"identity":"e0842e16-a48b-4cfc-be49-84345207c97e","added_by":"auto","created_at":"2026-04-13 15:51:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":917322,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9193520/v1/65298d40-dd88-42e4-b888-47ff2c016f29.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Imaging Biomarkers To Predict Progression of Intermediate AMD with Avascular Pigment Epithelial Detachment in the University of Colorado AMD Registry","fulltext":[{"header":"Key Message","content":"\u003cp\u003eWhat is known\u003c/p\u003e\n\u003cp\u003eAvascular PEDs confer substantial risk for late forms of AMD. But these studies of intermediate AMD eyes have not specifically isolated those with avascular PEDs to better understand this high risk subset.\u003c/p\u003e\n\u003cp\u003eThis study highlights important imaging biomarkers, such as acquired vitelliform lesions, that can help predict which eyes with avascular PEDs may progress to the advanced vision-threatening forms of AMD and may therefore warrant closer monitoring to ensure timely therapeutic intervention.\u003c/p\u003e\n\u003cp\u003eThese findings refine risk stratification within this high-risk phenotype and highlight the value of multimodal imaging biomarkers in anticipating disease trajectory and informing surveillance strategies\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAge-related macular degeneration (AMD) is the leading cause of irreversible vision among the elderly population in industrialized nations. Its prevalence is expected to increase to 288\u0026nbsp;million by 2040.\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e Retinal pigment epithelial detachments (PED), occurring between the basal lamina of the retinal pigment epithelial (RPE) cell and the inner collagenous Bruch\u0026rsquo;s membrane, commonly accompany AMD.\u003csup\u003e[\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e Avascular PEDs represent a distinct subtype arising from the gradual enlargement and coalescence of pre-existing soft drusen.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e These PEDs are clinically important because they are known to increase the risk of progression to the late forms of AMD: neovascular AMD (nAMD) and geographic atrophy (GA).\u003csup\u003e[\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e Despite the well-known risk, it remains challenging to predict how quickly a given avascular PED will progress and, critically, to which late AMD form it will progress. Current prognostic tools do not reliably discriminate risk paths between these two forms or provide meaningful temporal information. This has growing clinical relevance given the emergence of novel therapies, such as the Valeda Light Delivery System photobiomodulation therapy, which have made it more important to identify which intermediate AMD (iAMD) patients are at the highest risk for progression and may benefit most from early intervention.\u003csup\u003e[\u003cspan additionalcitationids=\"CR14 CR15 CR16\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough prior studies have examined progression from iAMD to advanced AMD, iAMD encompasses a broad spectrum, and later phenotypes such as those with avascular PEDs have received limited focused investigation, despite their higher risk of progression and the potential value of targeted prediction models.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e In this study, we investigate whether specific imaging biomarkers can predict faster progression of iAMD eyes with avascular PED to nAMD or GA.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis prospective longitudinal study was approved by the Colorado Multiple Institutional Review Board and follows the ethical principles of the Declaration of Helsinki. The study includes patients from the University of Colorado AMD registry, developed by the Department of Ophthalmology at the University of Colorado School of Medicine. Detailed descriptions of the recruitment process, consent procedures, and inclusion and exclusion criteria for patients included in the AMD registry are available in prior publications.\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e Recruitment into this registry started on July 9, 2014 and recruitment is ongoing. Inclusion criteria include participants aged 50\u0026ndash;99 years with AMD in one or both eyes and the ability to provide informed consent. The exclusion criteria include a history of concomitant retinal and uveitic disease.\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eMulti-Modal Imaging\u003c/h2\u003e\n \u003cp\u003eEach patient is consented to the collection of medical and ocular history, and review of multimodal imaging (MMI) data collected, including color fundus photos (CFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT). OCT angiography and fluorescein angiography (FA) are also obtained at the discretion of the retina provider. The MMI protocol is as follows: the Eidon True Color Confocal Scanner (iCare Spa, Vantaa, Finland) or Topcon TRC-50DX (Topcon, Tokyo, Japan) device is used to obtain a 60 degree CP centered on the fovea (field 2) and the Heidelberg Spectralis (Heidelberg Engineering Inc) device was used to obtain a 30 or 60 degree FAF with automatic real time-function (ART) of 50 centered on the fovea. The Heidelberg Spectralis device is also used to obtain high resolution horizontal and vertical enhanced-depth imaging line scans (6 mm/30 degree/ART 100) and a 49-line cube scan (6 mm/30 degree/ART 9) centered on the fovea.\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eThe iAMD longitudinal cohort\u003c/h3\u003e\n\u003cp\u003eFor this specific study, we limited our analysis to patients with iAMD at enrollment (July 2014 to August 2023) with avascular PED and at least 1 month of follow-up through February 2024. Two retina specialists confirmed the diagnosis of iAMD at enrollment in at least one eye of a patient (and no advanced AMD in either eye), using the classification described by the Beckman Initiative for Macular Research Committee.\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e Two trained graders reviewed the MMI for presence of avascular PED in each eye. The medical records and MMI of each iAMD eye with avascular PED were then reviewed for date of progression to advanced AMD (defined by the presence of GA or choroidal neovascularization per the Beckman classification), or date of last retina clinic visit if no evidence of progression.\u003c/p\u003e\n\u003ch3\u003eQualitative Imaging Biomarkers\u003c/h3\u003e\n\u003cp\u003eThe MMIs of patients in the cohort were reviewed by two trained graders for baseline qualitative imaging biomarkers, with any discrepancies resolved by a third trained grader. CFP was evaluated for the presence or absence of hard drusen, soft drusen, calcified drusen, cuticular drusen, pigmentary changes and reticular pseudodrusen (RPD). FAF images were specifically graded for the presence or absence of RPD. OCT images were assessed for the presence or absence of outer retinal tubulations (ORT), retinal pseudocysts, non-neovascular subretinal fluid (nnSRF), acquired vitelliform lesion (AVL), RPD, intraretinal hyper-reflective foci (iHRF) and incomplete retinal pigment epithelium and outer retina atrophy (iRORA).\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eStatistical analysis was performed using SAS version 9.4 (Cary, North Carolina) software. Characteristics of the cohort, including patient demographics and clinical variables, were compiled with basic frequencies and percentages, along with mean and standard deviations (SD) calculated for continuous variables which were normally distributed and medians and ranges for follow-up time. A survival analysis with time to progression specific to each eye was conducted with hazard ratios calculated. Cox proportional hazard modeling with competing risks was utilized to determine hazard ratios for time to conversion for each type of advanced AMD. Sandwich estimators were included to account for the correlation of the two eyes being included. The p-value cut-point was set at \u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTwo hundred twenty-four eyes with avascular PEDs of 142 patients were included in this study. The median follow-up period was 35.2 months (range 1.4-118.6). The mean age of patients at study enrollment was 75.5 years (SD\u0026thinsp;=\u0026thinsp;6.9). There were 47 (33%) male patients and a high proportion of Caucasian patients (135/142, 95%). Average BMI was 27.5 (SD\u0026thinsp;=\u0026thinsp;5.7). Eighty-five patients (60%) had no history of smoking, 3 (2%) were current smokers, and 54 (38%) were former smokers. Fifty-nine patients (42%) have a known family history of AMD.\u003c/p\u003e\n\u003cp\u003eThirty-one (13.8%) eyes progressed to nAMD, while 63 (28.1%) eyes progressed to GA. In our cohort, soft drusen, hard drusen, and iHRF were the most common imaging findings (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), with similar prevalences among eyes that progressed to nAMD and those that progressed to GA. There were no statistically significant differences in the prevalences of imaging biomarkers between eyes that converted to nAMD and those that progressed to GA.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of prevalence of imaging biomarkers between eyes with avascular PED that progress to nAMD or GA\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\n \u003cp\u003eQualitative Imaging Biomarkers\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\n \u003cp\u003eTotal number of eyes with the imaging biomarker (%)\u003c/p\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;224\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eProgression to advanced nAMD\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;31\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eProgression to GA\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;63\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eEyes with the imaging biomarker (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eEyes with the imaging biomarker (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Hard Drusen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e179/213 (84.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e26/31 (83.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e55/63 (90.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Soft Drusen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e204/213 (95.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e30/31 (96.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e60/63 (98.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP RPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e23/213 (10.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e2/31 (6.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e6/63 (9.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Calcified Drusen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e17/213 (8.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1/31 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e4/63 (6.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Cuticular Drusen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e12/213 (5.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1/31 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0/63 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Pigmentary Change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e117/213 (54.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e21/31 (67.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e42/63 (68.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eFAF RPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e34/216 (15.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e5/31 (16.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e11/63 (17.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT ORT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e1/224 (0.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0/31 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e1/63 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT Retinal Pseudocysts\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e2/223 (0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0/31 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e2/63 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT nnSRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e4/224 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1/31 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e2/63 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT AVL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e34/224 (15.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e6/31 (19.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e15/63 (23.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT RPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e29/224 (13.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e5/31 (16.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e11/63 (17.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT iHRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e130/224 (58.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e22/31 (71.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e44/63 (69.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT iRORA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e22/224 (9.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e3/31 (9.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e9/63 (14.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eNC\u0026thinsp;=\u0026thinsp;not calculable due to zero cell size\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eCFP \u0026ndash; Color Fundus Photos\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eFAF \u0026ndash; Fundus Autofluorescence\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eOCT \u0026ndash; Optical Coherence Tomography\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eRPD \u0026ndash; Reticular Pseudodrusen\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eORT \u0026ndash; Outer Retinal Tubulation\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003ennSRF \u0026ndash; Non-neovascular Subretinal Fluid\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eAVL \u0026ndash; Acquired Vitelliform Lesion\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eiHRF \u0026ndash; Intraretinal Hyperreflective Foci\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eiRORA \u0026ndash; Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy\u003c/p\u003e\n\u003cp\u003eAmong iAMD eyes with avascular PED, time to progression to nAMD was significantly predicted by the presence of pigmentary changes on CFP (HR\u0026thinsp;=\u0026thinsp;3.39 (95% CI: 1.47, 7.84), p\u0026thinsp;=\u0026thinsp;0.004) and iHRF on OCT (HR\u0026thinsp;=\u0026thinsp;3.89 (95% CI: 1.72, 8.80), p\u0026thinsp;=\u0026thinsp;0.001). Progression to GA was also significantly predicted by presence of pigmentary changes on CFP (HR\u0026thinsp;=\u0026thinsp;3.78 (95% CI: 2.08, 6.85), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and iHRF on OCT (HR\u0026thinsp;=\u0026thinsp;4.14 (95% CI: 2.25, 7.62), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), in addition to AVL (HR\u0026thinsp;=\u0026thinsp;3.07 (95% CI: 1.67, 5.66), p\u0026thinsp;=\u0026thinsp;0.0003) and iRORA (HR\u0026thinsp;=\u0026thinsp;3.57 (95% CI: 1.45, 8.80), p\u0026thinsp;=\u0026thinsp;0.006) on OCT. No other imaging biomarkers demonstrated a statistically significant association with progression. (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe relative hazard of progression for presence of imaging biomarkers to either of the advanced forms of age-related macular degeneration in eyes with avascular PED\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\n \u003cp\u003eQualitative Imaging Biomarkers\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\n \u003cp\u003eTotal number of eyes with the imaging biomarker (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\n \u003cp\u003eProgression to nAMD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\n \u003cp\u003eProgression to GA\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Hard Drusen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e179/213 (84.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.67 (0.23, 1.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.469\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.19 (0.44, 3.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.731\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Soft Drusen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e204/213 (95.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1.25 (0.14, 10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.840\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e2.61 (0.34, 19.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.355\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP RPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e23/213 (10.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.64 (0.20, 2.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.448\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.17 (0.39, 3.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.779\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Calcified Drusen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e17/213 (8.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.78 (0.10, 6.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.813\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.83 (0.50, 6.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Cuticular Drusen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e12/213 (5.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e0.92 (0.10, 8.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.940\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFP Pigmentary Change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e117/213 (54.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e3.39 (1.47, 7.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e3.78 (2.08, 6.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eFAF RPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e34/216 (15.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1.23 (0.52, 2.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.636\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.60 (0.75, 3.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.225\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT ORT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e1/224 (0.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT Retinal Pseudocysts\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e2/223 (0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT nnSRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e4/224 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e3.10 (0.31, 30.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.336\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e3.04 (0.43, 21.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.266\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT AVL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e34/224 (15.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e2.02 (0.86, 4.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e3.07 (1.67, 5.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT RPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e29/224 (13.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1.43 (0.60, 3.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.421\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e1.92 (0.89, 4.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e0.097\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT iHRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e130/224 (58.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e3.89 (1.72, 8.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e4.14 (2.25, 7.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOCT iRORA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e22/224 (9.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1.95 (0.54, 7.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e0.312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003e3.57 (1.45, 8.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eHR \u0026ndash; hazard ratio\u003c/p\u003e\n\u003cp\u003eCI \u0026ndash; confidence interval\u003c/p\u003e\n\u003cp\u003eNC \u0026ndash; not calculable due to zero cell size\u003c/p\u003e\n\u003cp\u003eCFP \u0026ndash; Color Fundus Photos\u003c/p\u003e\n\u003cp\u003eFAF \u0026ndash; Fundus Autofluorescence\u003c/p\u003e\n\u003cp\u003eOCT \u0026ndash; Optical Coherence Tomography\u003c/p\u003e\n\u003cp\u003eRPD \u0026ndash; Reticular Pseudodrusen\u003c/p\u003e\n\u003cp\u003eORT \u0026ndash; Outer Retinal Tubulation\u003c/p\u003e\n\u003cp\u003ennSRF \u0026ndash; Non-neovascular Subretinal Fluid\u003c/p\u003e\n\u003cp\u003eAVL \u0026ndash; Acquired Vitelliform Lesion\u003c/p\u003e\n\u003cp\u003eiHRF \u0026ndash; Intraretinal Hyperreflective Foci\u003c/p\u003e\n\u003cp\u003eiRORA \u0026ndash; Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this iAMD cohort specifically with avascular PEDs, several MMI biomarkers were significantly associated with progression to advanced AMD. Prior AREDS analyses have shown that avascular PEDs confer substantial risk for late AMD, with 42% of eyes progressing within five years (19% to GA and 23% to nAMD), underscoring avascular PED as a high-risk phenotype with heterogeneous progression pathways.\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e The natural history of avascular PEDs generally follows one of three trajectories\u0026mdash;collapse with subsequent atrophy, vascularization with exudation, or long-term persistence. In our cohort, pigmentary abnormalities on color fundus photography and iHRF on OCT were associated with progression to both GA and advanced neovascular disease, whereas AVL and iRORA were more specifically associated with progression along the non-neovascular atrophic pathway.\u003c/p\u003e \u003cp\u003ePrior studies have shown that large drusen (\u0026ge;\u0026thinsp;125 \u0026micro;m) in the central macula, especially when accompanied by pigmentary abnormalities on color fundus photography, significantly increase the risk of progression to advanced AMD. Eyes with RPE hyperpigmentation and large drusen have a higher 5-year risk of developing either nAMD or GA, while eyes with RPE depigmentation are particularly prone to progressing to GA.\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e Similarly, iHRF is a key OCT biomarker of AMD progression, defined as discrete, well-demarcated hyperreflective lesions within the neurosensory retina, measuring\u0026thinsp;\u0026ge;\u0026thinsp;3 pixels and with reflectivity equal to or greater than the RPE band.\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e Overlying iHRF is frequently observed with avascular PED, often preceding overt structural breakdown by more than a year and correlating with increased risk of progression.\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e Verma et al. reported a 21% higher odds of progression to advanced AMD over 24 months in iAMD eyes with iHRF, while Wakatsuki et al. reported more than a twofold higher odds of progression to nAMD.\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e Although these studies did not specifically isolate eyes with avascular PEDs, they collectively support iHRF as a marker of increased progression risk. Notably, in our avascular PED subset, the presence of iHRF conferred substantially higher risk, with over a fourfold increase in odds of progression to GA and a nearly fourfold increase in odds of progression to nAMD, exceeding effect sizes previously reported in broader iAMD cohorts. The higher risk observed in this subgroup likely reflects phenotypic enrichment within the avascular PED cohort, in which the coexistence of iHRF indicates greater structural instability, RPE dysfunction, and heightened disease activity. Our finding that pigmentary change and iHRF were statistically significant predictors of progression to both GA and nAMD is concordant with prior observations and reinforces the prognostic relevance of these biomarkers in risk stratification.\u003c/p\u003e \u003cp\u003eIn regard to discriminating between which advanced form of AMD an avascular PED will progress to, our study elucidated imaging biomarkers for progression specifically to GA but none exclusively to nAMD. Prior work has examined the prognostic value of these biomarkers for GA progression, AVL and iRORA. AVLs are considered markers of active RPE dysfunction and impaired metabolic exchange between the RPE and overlying neurosensory retina.\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e Our finding that AVL significantly predicts progression to GA in iAMD eyes with avascular PEDs is consistent with prior reports in more heterogenous iAMD cohorts.\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e Mahmoudi et al. observed that approximately 10% of iAMD eyes with AVL progressed to atrophy within 24 months, while earlier studies reported a broader 15\u0026ndash;50% risk of AVL collapse to cRORA.\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e These prior studies did not specifically isolate eyes with avascular PEDs. Therefore, our results build upon prior work, indicating that AVL confers elevated progression risk in the setting of avascular PED.\u003c/p\u003e \u003cp\u003eExisting evidence has established iRORA as an atrophic precursor lesion on OCT that frequently progresses to cRORA, a defining feature of GA\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e Reported progression rates have been high, with Corradetti et al. showing that over 90% of eyes with incident iRORA progressed to cRORA within 24 months, and Wu et al. reporting a markedly increased risk of GA in eyes with prevalent or incident iRORA (adjusted HR\u0026thinsp;\u0026asymp;\u0026thinsp;12).\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e In contrast, within our avascular PED subset, progression risk appeared substantially lower in the present study: only 14% (9/63) of eyes with both avascular PED and iRORA progressed to GA (HR\u0026thinsp;=\u0026thinsp;3.57, p\u0026thinsp;=\u0026thinsp;0.006) during the study period (approximately 3 years). The difference in progression rates between these studies could be due to different patient populations, study follow-up variability, or different thresholds for iRORA classification. Alternatively, iRORA occurring in the presence of an avascular PED may represent an earlier stage of atrophy formation due to persistence of the PED, with a distinct risk profile and potentially slower atrophic trajectory than that reported in broader iAMD cohorts.\u003c/p\u003e \u003cp\u003e Strengths of this study include its prospective longitudinal design, the use of well-established enrollment criteria from the University of Colorado AMD Registry, and a standardized multimodal image review process. Trained graders performed AMD staging and image biomarker assessment, with a third independent grader used for adjudication to support consistency and accuracy. In addition, our analysis focused on a specific, well-defined subset of high-risk iAMD eyes, offering a novel perspective within a population that has otherwise not been broadly studied.\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. This was a single academic center study, and although the overall cohort was large, the number of eyes progressing to advanced AMD was relatively small, with a median follow-up of approximately 3 years. This may have limited our study\u0026rsquo;s power to uncover significant biomarkers, particularly for progression to nAMD since the sample size was smaller. Furthermore, fluorescein angiography and OCT angiography were not obtained in all patients, as their use was at the clinician's discretion. These modalities were employed in equivocal cases and during research review for progression assessment, and longitudinal multimodal imaging was carefully evaluated to monitor for interval fluid changes suggestive of neovascular conversion. Despite these safeguards, a small number of fibrovascular PEDs without exudation could have been misclassified as avascular PEDs and inadvertently included in the analysis. Finally, while the study was conducted longitudinally, the imaging biomarkers were evaluated only cross-sectionally at enrollment. A longitudinal evaluation of how these biomarkers evolve during the disease progression would provide further information on AMD pathogenesis. Additionally, incorporating quantitative assessment such as PED size metrics or drusen volume may further refine risk stratification. Finally, future studies should explore the use of artificial intelligence to enhance predictive modeling of AMD progression in this high risk iAMD population, potentially incorporating multimodal imaging biomarkers, genetics, and electronic health record data.\u003c/p\u003e \u003cp\u003eIn conclusion, among eyes with iAMD and avascular PEDs, pigmentary abnormalities and iHRF were strongly associated with progression to both GA and nAMD, while AVL and iRORA were more specifically linked to progression to GA. These findings refine risk stratification within a high-risk phenotype and highlight the value of multimodal imaging biomarkers in anticipating disease trajectory and informing surveillance strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements and Disclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\u003cp\u003e \u003ch2\u003eResearch Funding\u003c/h2\u003e \u003cp\u003eResearch in this publication was supported by the National Eye Institute of the National Institutes of Health under award number R01EY032456 (AML), the Helene and Marshall Abrahams AMD Research Fund, the Greenwald Family Research Fund, a Research to Prevent Blindness grant to the Department of Ophthalmology, University of Colorado, the Frederic C. Hamilton Macular Degeneration Center, Sue Anschutz-Rodgers Eye Center Research Fund, and by NIH/NCATS Colorado CTSA Grant Number UM1 TR004399.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSA and AL-C wrote the main manuscript text and participated in manuscript editing. AL-C also participated in grading/data collection. JP: conducted formal data analysis and manuscript editing. RG: participated in manuscript editing and data collection. NM: participated in manuscript editing and data collection. BG: participated in manuscript editing and data collection. AML: participated in manuscript editing. AGP: participated in manuscript editing. MTM: participated in manuscript editing. N. Manoharan: participated in manuscript editing. N. Mandava: participated in manuscript editing. TdCF: Conceptualized project, participated in data collection, data analysis and reviewed and edited manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAmbati J et al (2003) Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol 48(3):257\u0026ndash;293\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWong WL et al (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Global Health 2(2):e106\u0026ndash;e116\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZayit-Soudry S, Moroz I, Loewenstein A (2007) Retinal pigment epithelial detachment. Surv Ophthalmol 52(3):227\u0026ndash;243\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan AC et al (2016) A perspective on the nature and frequency of pigment epithelial detachments. Am J Ophthalmol 172:13\u0026ndash;27\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMrejen S (2013) Multimodal imaging of pigment epithelial detachment: a guide to evaluation. Retina 33(9):1735\u0026ndash;1762\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarampelas M et al (2020) Retinal pigment epithelial detachment in age-related macular degeneration. Ophthalmol Therapy 9(4):739\u0026ndash;756\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCasswell A, Kohen D, Bird A (1985) Retinal pigment epithelial detachments in the elderly: classification and outcome. Br J Ophthalmol 69(6):397\u0026ndash;403\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlein R et al (1997) The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 104(1):7\u0026ndash;21\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeannette JY et al (2019) \u003cem\u003eNatural history of drusenoid pigment epithelial detachment associated with age-related macular degeneration: age-related eye disease study 2 report no. 17.\u003c/em\u003e Ophthalmology, 126(2): pp. 261\u0026ndash;273\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHartnett ME et al (1992) \u003cem\u003eClassification of retinal pigment epithelial detachments associated with drusen.\u003c/em\u003e Graefe's archive for clinical and experimental ophthalmology. 230(1):11\u0026ndash;19\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThavikulwat AT et al (2022) Multimodal assessments of drusenoid pigment epithelial detachments in the age-related eye disease study 2 ancillary spectral-domain optical coherence tomography study cohort. 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Ophthalmol Retina 8(9):863\u0026ndash;871\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorradetti G et al (2021) Natural history of incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration. Can J Ophthalmol 56(5):325\u0026ndash;334\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuymer RH et al (2020) Incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration: classification of atrophy meeting report 4. Ophthalmology 127(3):394\u0026ndash;409\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Z et al (2023) Incomplete retinal pigment epithelial and outer retinal atrophy: longitudinal evaluation in age-related macular degeneration. Ophthalmology 130(2):205\u0026ndash;212\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"avascular pigment epithelial detachment, intermediate age-related macular degeneration, advanced age-related macular degeneration, intraretinal hyperreflective foci, pigmentary changes, acquired vitelliform lesion, incomplete retinal pigment epithelium and outer retina atrophy","lastPublishedDoi":"10.21203/rs.3.rs-9193520/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9193520/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eTo investigate whether specific imaging biomarkers predict progression to neovascular AMD (nAMD) or geographic atrophy (GA) in eyes with high-risk intermediate age-related macular degeneration (iAMD) and avascular pigment epithelial detachment (PED).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eProspective longitudinal cohort study of eyes with iAMD and avascular PED from the University of Colorado AMD registry (August 2014 - August 2023) with ≥1 month of follow-up through February 2024. Multimodal imaging, including color fundus photos (CFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT), was graded by two reviewers for presence of specific imaging biomarkers. Time-to-progression survival analysis was conducted with hazard ratios calculated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOver a median follow-up period of 35 months, 224 eyes (142 patients) were included. 31 (13.8%) eyes progressed to nAMD, and 63 (28.1%) to GA. Progression to nAMD was significantly predicted by pigmentary changes on CFP (HR=4.43 (95%CI: 1.77, 11.1), p=0.001) and intraretinal hyperreflective foci (iHRF) on OCT (HR=4.90 (95%CI: 2.02, 11.9), p=0.0005). Progression to GA was significantly predicted by pigmentary changes on CFP (HR=3.60 (95%CI: 1.94, 6.67), p\u0026lt;0.0001), iHRF (HR=4.13 (95%CI: 2.14, 7.94), p\u0026lt;0.0001), acquired vitelliform lesions (AVL; (HR=2.97 (95%CI: 1.55, 5.68), p=0.001)) and incomplete retinal pigment epithelium and outer retina atrophy (iRORA; (HR=4.18 (95%CI: 1.52, 11.4), p=0.006)). No other biomarkers demonstrated significance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIn eyes with avascular PED, pigmentary changes and iHRF were significantly associated with progression to nAMD and GA, while AVL and iRORA were specifically to GA. We highlight in this study important imaging biomarkers that help identify high-risk eyes that may warrant closer monitoring to ensure timely therapeutic intervention.\u003c/p\u003e","manuscriptTitle":"Imaging Biomarkers To Predict Progression of Intermediate AMD with Avascular Pigment Epithelial Detachment in the University of Colorado AMD Registry","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-13 15:50:35","doi":"10.21203/rs.3.rs-9193520/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fe2f4ab4-f274-474a-8702-234c6f2ce0d1","owner":[],"postedDate":"April 13th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-16T14:21:39+00:00","index":35,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T15:50:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-13 15:50:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9193520","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9193520","identity":"rs-9193520","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}