Evaluating the Reliability of a Microperimetry-Based Method for Assessing Visual Function in the Junctional Zone of Geographic Atrophy Lesions

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Yasin Alibhai, Eric Moult, Muhammad Usman Jamil, Khadija Raza, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5183845/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Purpose To assess the repeatability of a microperimetry methodology for quantifying visual function changes in the junctional zone of eyes with geographic atrophy (GA) in the clinical trial context. Methods A post hoc analysis of the OAKS phase III trial was conducted, which enrolled patients with GA secondary to age-related macular degeneration. Microperimetry using a standard 10-2 fovea centered grid was performed at baseline and follow-up visits. GA regions were traced on fundus autofluorescence (FAF) images. Two graders independently registered baseline microperimetry images with baseline FAF images in a sampling of 30 eyes from the OAKS study. Agreement between the two graders’ assessments of mean sensitivity and the number of scotomatous points within a ±250 𝜇m GA junctional zone was assessed. Results The intraclass correlation (ICC) and coefficient of repeatability (CoR) for the mean junctional zone sensitivity were 0.994 and 0.349 dB, respectively. The ICC and CoR for the total number of scotomatous points within the junctional zone were 0.997 and 0.218, respectively. Conclusions The repeatability of the methodology and its compatibility with standard MP acquisitions appear to make it well-suited for identifying and analyzing retinal sensitivity within high-risk areas of the retina. microperimetry geographic atrophy fundus auto fluorescence age-related macular degeneration scotomatous points Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Summary Statement We present a microperimetry-based methodology for assessing visual function changes in the junctional zone of geographic atrophy lesions using a standard 10-2 fovea centered grid in a clinical trial context. The approach’s repeatability and compatibility with standard microperimetry grids may make it useful for assessing the effects of GA therapeutics. Introduction Geographic atrophy (GA), the late stage of non-exudative age-related macular degeneration, significantly reduces quality of life 1 , 2 . The consequences of visual impairment in GA patients include an increased risk of falls, difficulty reading, driving, and recognizing faces, and ultimately, the loss of independence 3 , 4 . In 2023, two complement inhibitors were approved by the Food and Drug Administration (FDA), becoming the first approved therapies for treating GA. These therapies were shown to significantly slow the enlargement of GA as measured on fundus autofluorescence (FAF). However, for these and future GA therapeutics, it is important to understand their effects on measures of visual function in addition to structural measures. Sensitive and reliable measurement of visual function in GA patients remains a challenge. The standard assessment of visual acuity is typically performed using eye charts, which is a reliable and reproducible test when patients have a healthy macula and good fixation. In patients with extrafoveal lesions, there can be significant GA growth without any effect on visual acuity, even with patients complaining of worsening visual function. Similarly, once the central fovea is involved, there can be further growth of the GA lesion without additional changes in visual acuity—in this situation, too, the patient’s functional capacity may decline as their scotoma enlarges. Therefore, it is important to develop approaches that can assess the visual function changes that accompany the structural changes that occur as GA lesions enlarge. Microperimetry (MP) provides a functional mapping of the retina that is precisely correlated to fundus anatomy. Because MP assesses light sensitivity at specific, predefined retinal loci that can be longitudinally tracked, MP may be a sensitive measure of visual function changes in patients with GA 5 , 6 . Nevertheless, conventional MP analyses (e.g., mean sensitivity across all stimulus points) are limited in that a substantial proportion of stimuli may fall within the region of atrophy or be located far from the atrophic region over a still healthy retina area, particularly when large sparse grid distribution are selected, and are, therefore, unlikely to change as the GA lesion enlarges. This decoupling may lead to an underestimation of therapeutic effects 7 . Thus, developing and evaluating approaches that analyze MP sensitivities within a junctional zone of the GA lesion may lead to more sensitive measurements of the effects that GA therapeutics have on visual function 5 , 6 . The aim of this study is to assess the repeatability of an MP methodology for quantifying visual function changes in GA junctional zones in a clinical trial context. Methods Study Design The repeatability of our MP analysis workflow was evaluated on a cohort of GA patients from the OAKS study (NCT03525600) 8 . The OAKS study was a 24-month, multicenter, randomized, double-masked, sham-controlled, phase 3 study, which enrolled patients at 110 clinical sites. The study adhered to protocols approved by the institutional review board of each site and complied with the Declaration of Helsinki. The inclusion and exclusion criteria of the OAKS study are described elsewhere 8 . Patients were randomly assigned (2:2:1:1) by a central web-based randomization system to intravitreal 15 mg per 0.1 mL pegcetacoplan or sham either monthly or every other month. MP Testing MP testing was conducted using the Macular Integrity Assessment (MAIA) device (iCare, Padova, Italy) at baseline and every 6 months for up to 24 months. All follow-up MP acquisitions were obtained using a ‘follow-up’ mode to allow registration to the baseline acquisition. MP testing was conducted in a dark room under pharmacologic pupil dilation while the contralateral eye was patched. MP testing was performed using a rectilinear 10 − 2 grid distribution (68 stimulus points; Goldman Size III (0.43º diameter)) centered on the anatomic fovea, with a 4 − 2 staircase threshold strategy and a 1º diameter red central fixation target. The average examination time was 8.8 minutes. All MP testing was performed prior to any imaging to prevent photoreceptor bleaching. Fundus Autofluorescence Imaging Fundus autofluorescence (FAF) imaging was performed using the Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany) at all study visits. In the high-speed mode, a 30° × 30° field centered on the fovea was imaged. FAF images consisted of 768 × 768 pixels. Junctional Zone MP Analysis The workflow for GA junctional zone MP analysis, which follows the approach used by Hariri 9 , is presented in Fig. 1 . In brief, using custom software, baseline MP images (sensitivity maps superimposed on their respective scanning laser ophthalmoscopy (SLO) fundus images) were registered to their corresponding baseline FAF images using fiducial markers manually positioned at corresponding bifurcations of the retinal vasculature. For registration, a similarity-type transformation (translation, rotation, and isotropic scaling) was used. The same transformation was then used to transform the MP stimuli coordinates into the FAF image coordinate frame. GA tracing was performed on the baseline FAF images, with the minimum lesion size defined as 0.05 mm 2 10 , 11 . With the GA tracings and MP measurements in the same coordinate frame (i.e., the FAF coordinate frame), the signed Euclidean (i.e., straight-line) distance from each MP stimulus point to the closest point on the baseline GA margin was computed. Negative and positive distances represent stimuli that lie inside and outside the areas of atrophy, respectively. A junctional zone, defined as all fundus positions within 250 µm of the GA margin (including regions both inside and outside the region of atrophy), was automatically generated. The position and width of the junctional zone used in this study matched that used for the MP analysis of the OAKS trial 12 . Statistical Analysis Two graders (Grader 1 and Grader 2) performed registrations in a systematically stratified sampling of the 637 eyes from the OAKS study. The repeatability of the mean sensitivity and number of scotomatous points within the junctional zone were assessed using Bland–Altman analysis 13 , intraclass correlation coefficients (ICCs) and coefficients of repeatability (CoRs), also referred to as the smallest real difference 14 . To assess the repeatability of our MP analysis workflow without considering a particular junctional zone (e.g., ± 250 µm), we considered two measures, both of which incorporate all 68 stimulus points: (1) the repeatability of the signed-distance from each MP stimulus point to the GA margin (“stimulus-to-margin distance”; distances are negative for points within the GA lesion margin and positive for points outside the GA lesion margin), and (2) the distances between the coordinates of corresponding MP stimulus points when transformed by the two readers into the FAF coordinate frame (“stimulus coordinate difference”). The repeatability of the stimulus-to-margin distance was assessed using Bland-Altman analysis, as well as ICC and CoR. Following Taylor et al. 15 , linear mixed modeling was used to account for repeated measures. Stimulus coordinate differences were summarized with boxplots and descriptive statistics. Note that all repeatability analyses assess only the repeatability of the MP analysis , which is determined by the repeatability of registering the MP SLO images to the FAF images. In particular, the repeatability analyses do not consider the repeatability of the MP acquisition, which have been reported by other authors 16 , or of the GA lesion tracing. Results Images from thirty eyes (24 patients) were registered by two graders. Bland-Altman analysis of the mean sensitivity within the junctional zone showed a bias of 0.37 dB between the two graders, with 90% of the eyes within ± 1.96 SD (95% limit of agreement (LOA): -0.98 dB to 1.73 dB; Fig. 2 ). Bland-Altman analysis of total number of scotomatous points within the junctional zone showed a bias of 0.37 between the two graders, with 94% of the points within ± 1.96 SD (95% limit of agreement (LOA): -0.99 to 0.93; Fig. 3 ). The ICC and CoR for the mean junctional zone sensitivity were 0.994 and 0.349 dB, respectively. The ICC and CoR for the total number of scotomatous points within the junctional zone were 0.997 and 0.218, respectively. Bland-Altman analysis of the stimulus-to-margin distance, measured across all stimulus points (68 per eye), showed a mean shift of -3.24 µm between the two graders, with 94% of the points within ± 1.96 SD from the mean shift (95% limit of agreement (LOA): -87.35 µm to 80.87 µm; Fig. 4 ). Six eyes had larger variabilities (SD of difference > 50 µm) between the two graders and were outside the LOA bounds. The ICC and CoR of the stimulus-to-margin distances between the two graders were 0.969 and 99.85 µm, respectively. The stimulus coordinate differences are summarized in Fig. 5 . The mean stimulus coordinate difference taken across stimulus points for all subjects was 46.87 ± 23.80 µm. Representative images of the registered MP in the FAF coordinate frame are shown in Fig. 6 . Discussion In the present study, we evaluated the repeatability of an MP analysis workflow that is compatible with clinical trial data (10 − 2 MP stimulus grid distribution and FAF imaging for GA tracing) and allows the visual function to be assessed in retinal areas that are most likely to be affected by GA growth—namely, the junctional zone comprised of the regions immediately surrounding the GA lesion margin. The repeatability of the method in the context of the mean junctional zone sensitivity and the number of scotomatous points within the junctional zone was excellent. Assessments of stimulus-to-margin distances and stimulus coordinate difference showed reader differences that were generally small compared to the junctional zone width, although there were some outlier cases (Figs. 4 and 5 ). From a subjective review of grader registrations, we believe that the dominant cause of inter-grader discrepancies were likely due to the similarity-type image transformation not fully capturing the true deformation between the MP SLO and FAF images. To reduce inter-reader discrepancies in future studies, more general transformation types that better approximate the true deformation could be used. However, more general transformation types require more corresponding vessel bifurcations to be selected—in addition to increasing the grading time, selecting more vessel bifurcations can itself be error prone for images with less pronounced vasculature, and may even lead to larger discrepancies. As in Hariri et al., 9 the MP workflow used in this study analyzes junctional zone sensitivities by transforming MP stimulus coordinates into the coordinate frame used for lesion tracing. After this transformation, the position of each MP stimulus point can be directly related to the GA lesion margin. An alternative approach to analyzing MP sensitivities in the junctional zone, proposed by Meleth et al. 17 and recently used in the post hoc analysis of the Spectri and Chroma lampalizumab trials 18 , is to define the junctional zone using the set of scotomatous MP points. Such an approach has the advantage of simplicity (e.g., no image registration required). Furthermore, it can be performed using only MP data, making it particularly well suited to analyses in which GA tracing data are unavailable. However, for standard 10 − 2 MP stimulus grids, the 2-degree stimulus spacing suggests that a junctional zone derived using MP only is likely to be less accurate than a junctional zone derived directly from the registered GA tracing data. Another approach to measuring junctional zone MP sensitivities is to use patient-tailored MP grids wherein the stimuli are distributed around the lesion margin 6 , 19 . An advantage of patient-tailored approaches is that MP measurements are not collected at fundus positions that are decoupled from lesion growth (e.g., regions of atrophy at baseline). Moreover, patient-tailored MP allows stimuli points to be distributed around lesions more uniformly and at higher-density within the junctional zone. A disadvantage is the requirement of customized, lesion-specific grids, which may complicate or be incompatible with current MP workflows and may become complex for certain lesion geometries (e.g., multifocal lesions). Moreover, the optimal grid parameters (e.g., stimulus density and junctional zone dimensions) are not a priori obvious. Indeed, one possible application of the MP approach used in the present study is in helping to design MP grid patterns for future studies using patient-specific MP. An important limitation of our approach, particularly as applied to standard MP grids, is that the MP stimuli are relatively sparse and are randomly distributed relative to regions of atrophy. In addition to the possibility of missing smaller regions of functional impairment, there is a sparse and unequal sampling of the junctional zones, which we expect to increase variances when estimating treatment effects. One potential mitigation strategy is to model, or otherwise adjust for, the spatial distribution of stimulus points within the junctional zone. An alternate approach is to re-sample the MP measurements (e.g., via interpolation 20 ) such that they uniformly tile the junctional zone. While these approaches also have limitations, we hope to explore these approaches in future studies. Conclusion In this paper, we evaluate a microperimetry-based approach for assessing visual function changes in the GA junctional zone in a clinical trial context. The repeatability of the approach and its compatibility with standard MP acquisitions appear to make it well-suited to assessing the effects of GA therapeutics on visual function. Declarations Competing Interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Y.A is an employee at Boston Image Reading Center. M.U.M is an employee at Apellis. C.R.B. is an employee at Apellis. J.G.F. receives research support from Topcon Healthcare, has an equity interest in Optovue, and receives royalties on a patent owned by MIT and licensed to Optovue. N.K.W. receives research support from Carl Zeiss Meditec, Nidek, Regeneron and Topcon. She is Chief Medical Officer at Ocular therapeutics, has received speaker fees from Nidek, has an equity interest in AGTC, Iolyx pharmaceuticals, Valitor and Ocudyne, and is a consultant for Olix Therapeutics, Iolyx pharmaceuticals, Complement Therapeutics, Boehringer Ingelheim, Jansen, and Topcon. J.G.F. and E.M. have a patent (VISTA) with a license option to Topcon Healthcare. The other authors report no disclosures. Funding /Support Supported by the National Institutes of Health (Bethesda, MD, R01EY011289 and R01EY034080); Beckman-Argyros Award in Vision Research (Irvine, CA, USA); Greenberg Prize to End Blindness. The sponsor or funding organizations had no role in the design or conduct of this research. Competing Interest Statement: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Y.A is an employee at Boston Image Reading Center. M.U.M is an employee at Apellis. C.R.B. is an employee at Apellis. J.G.F. receives research support from Topcon Healthcare, has an equity interest in Optovue, and receives royalties on a patent owned by MIT and licensed to Optovue. N.K.W. receives research support from Carl Zeiss Meditec, Nidek, Regeneron and Topcon. She is Chief Medical Officer at Ocular therapeutics, has received speaker fees from Nidek, has an equity interest in AGTC, Iolyx pharmaceuticals, Valitor and Ocudyne, and is a consultant for Olix Therapeutics, Iolyx pharmaceuticals, Complement Therapeutics, Boehringer Ingelheim, Jansen, and Topcon. J.G.F. and E.M. have a patent (VISTA) with a license option to Topcon Healthcare. The other authors report no disclosures. Author Contribution Conception: J.G.F, N.K.W; Data acquisition: A.Y.A, E.M., N.K.W, J.G.F; Analysis and interpretation of data: A.Y.A, E.M, M.U.J, K.R; Figure preparation: A.Y.A, E.M., M.U.J; Software creation: A.Y.A, E.M; Draft writing: E.M., M.U.J; Draft revision: A.Y.A, M.U.M, R.R, C.R.B Acknowledgement We'd like to thank Beacon Therapeutics for statistical support. References Patel PJ, Ziemssen F, Ng E, et al. Burden of Illness in Geographic Atrophy: A Study of Vision-Related Quality of Life and Health Care Resource Use. Clin Ophthalmol. 2020;14:15–28. 10.2147/OPTH.S226425 . PMID: 32021065; PMCID: PMC6955611. Singh RP, Patel SS, Nielsen JS et al. Patient-, Caregiver-, and Eye Care Professional-reported Burden of Geographic Atrophy Secondary to Age-related Macular Degeneration. Am J Ophthalmic Clin Trials [Internet] 2019 Apr 5, 2(1) 1–6. 10.25259/AJOCT-9-2018 Fleckenstein M, Mitchell P, Freund KB, et al. The Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration. Ophthalmology. 2018;125(3):369–90. 10.1016/j.ophtha.2017.08.038 . Epub 2017 Oct 27. PMID: 29110945. Kim A, Bansal A, Devine B. Characterizing the Healthcare Resource Utilization and Costs By Disease Severity Among Patients with Geographic Atrophy Secondary to Age-Related Macular Degeneration. Published online 2019. https://digital.lib.washington.edu:443/researchworks/handle/1773/44687 Csaky KG, Patel PJ, Sepah YJ et al. Microperimetry for geographic atrophy secondary to age-related macular degeneration. Surv Ophthalmol. 2019 May-Jun;64(3):353–364. 10.1016/j.survophthal.2019.01.014 . Epub 2019 Jan 28. PMID: 30703401; PMCID: PMC6532786. Pfau M, Jolly JK, Wu Z et al. Fundus-controlled perimetry (microperimetry): Application as outcome measure in clinical trials. Prog Retin Eye Res. 2021;82:100907. 10.1016/j.preteyeres.2020.100907 . Epub 2020 Oct 3. PMID: 33022378. Markowitz SN, Reyes SV. 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Microperimetry as an Outcome Measure in RPGR-associated Retinitis Pigmentosa Clinical Trials. Transl Vis Sci Technol. 2023;12(6):4. 10.1167/tvst.12.6.4 . PMID: 37294702; PMCID: PMC10259674. Higgins BE, Montesano G, Dunbar HMP, et al. Transl Vis Sci Technol. 2023;12(7):19. 10.1167/tvst.12.7.19 . PMID: 37477933; PMCID: PMC10365139. Test-Retest Variability and Discriminatory Power of Measurements From Microperimetry and Dark Adaptation Assessment in People With Intermediate Age-Related Macular Degeneration - A MACUSTAR Study Report. Meleth AD, Mettu P, Agrón E, et al. Changes in retinal sensitivity in geographic atrophy progression as measured by microperimetry. Invest Ophthalmol Vis Sci. 2011;52(2):1119–26. 10.1167/iovs.10-6075 . PMID: 20926818; PMCID: PMC3053096. Chang DS, Callaway NF, Steffen V, et al. Macular Sensitivity Endpoints in Geographic Atrophy: Exploratory Analysis of Chroma and Spectri Clinical Trials. Ophthalmol Sci. 2023;4(1):100351. 10.1016/j.xops.2023.100351 . PMID: 37869030; PMCID: PMC10587617. Schmitz-Valckenberg S, Bültmann S, Dreyhaupt J et al. Fundus autofluorescence and fundus perimetry in the junctional zone of geographic atrophy in patients with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2004;45(12):4470-6. 10.1167/iovs.03-1311 . Erratum in: Invest Ophthalmol Vis Sci. 2005;46(1):7. PMID: 15557456. Denniss J, Astle AT. Spatial Interpolation Enables Normative Data Comparison in Gaze-Contingent Microperimetry. Invest Ophthalmol Vis Sci. 2016;57(13):5449–5456. 10.1167/iovs.16-20222 . PMID: 27760271. Additional Declarations Competing interest reported. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Y.A is an employee at Boston Image Reading Center. M.U.M is an employee at Apellis. C.R.B. is an employee at Apellis. J.G.F. receives research support from Topcon Healthcare, has an equity interest in Optovue, and receives royalties on a patent owned by MIT and licensed to Optovue. N.K.W. receives research support from Carl Zeiss Meditec, Nidek, Regeneron and Topcon. She is Chief Medical Officer at Ocular therapeutics, has received speaker fees from Nidek, has an equity interest in AGTC, Iolyx pharmaceuticals, Valitor and Ocudyne, and is a consultant for Olix Therapeutics, Iolyx pharmaceuticals, Complement Therapeutics, Boehringer Ingelheim, Jansen, and Topcon. J.G.F. and E.M. have a patent (VISTA) with a license option to Topcon Healthcare. The other authors report no disclosures. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 22 Oct, 2024 Reviews received at journal 21 Oct, 2024 Reviews received at journal 15 Oct, 2024 Reviewers agreed at journal 11 Oct, 2024 Reviewers agreed at journal 08 Oct, 2024 Reviewers invited by journal 07 Oct, 2024 Editor assigned by journal 07 Oct, 2024 Submission checks completed at journal 07 Oct, 2024 First submitted to journal 30 Sep, 2024 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-5183845","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":369307401,"identity":"ab48c6dc-123f-49e9-a11d-1052a2c3808e","order_by":0,"name":"A. 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Fujimoto","email":"","orcid":"","institution":"Massachusetts Institute of Technology","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"G.","lastName":"Fujimoto","suffix":""},{"id":369307412,"identity":"2d666818-d83f-4857-a441-c3e4c0efb877","order_by":8,"name":"Nadia K. Waheed","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYHACgwMMB4AkkCXxAUiwsZOiRXIGSAszEVoYYFqkeUB8QlrM2Q9vPPDjzGF5c/bmg7dtfm2T52NmYPzwMQe3FsuetIKDPTcOG+7sOZZsndt327CNmYFZcuY2fB7JMTjA8+E244YbOWbSuT23GYFa2Jh58Wk5/8bg4J8Pt+033H//Tdqy57Y9YS03cgwO89y4nbjhBg+bNMOP24lEaHlWcFjmzP/kDWfSjC17G24ntzEzNuP3y/nkzR/fHEuz3XD88MMbP/7ctp3f3nzww0c8WlABYxuYbCBWPQj8IUXxKBgFo2AUjBQAAO1NXeY55OxTAAAAAElFTkSuQmCC","orcid":"","institution":"New England Eye Center, Tufts Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Nadia","middleName":"K.","lastName":"Waheed","suffix":""}],"badges":[],"createdAt":"2024-10-01 01:08:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5183845/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5183845/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":72206941,"identity":"dee777c1-86c4-4c6e-ba72-23a4e88e5dcd","added_by":"auto","created_at":"2024-12-23 16:46:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23163478,"visible":true,"origin":"","legend":"\u003cp\u003eWorkflow for longitudinal tracking of microperimetry (MP) sensitivities within the GA junctional zone. Baseline (visit 1) MP scanning laser ophthalmoscopy (SLO) images (panel A) are registered with baseline fundus autofluorescence (FAF) images (panel B), allowing the MP stimulus points to be overlaid on the FAF image (panels C, D). Each MP stimulus point is associated with a signed distance from the lesion margin, as defined by FAF tracing; distances, in micrometers, are shown next to each MP stimulus point. Positive and negative distances correspond to points outside and inside regions of atrophy, respectively. The junctional zone comprising all points within 250 µm of the lesion boundary is shaded red; those MP stimulus positions within the junctional zone have filled markers, and those outside the junctional zone have unfilled markers.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5183845/v1/3cb9a62c89a7d12924278fff.png"},{"id":72206938,"identity":"59cda7ee-ffbe-4986-b7c6-a38bc2abf297","added_by":"auto","created_at":"2024-12-23 16:46:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":215032,"visible":true,"origin":"","legend":"\u003cp\u003eBland-Altman plot of grader agreement for the mean sensitivity within the junctional zone between. (black line: bias; red dashed lines: upper and lower limits of agreement; blue dots: subjects)\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5183845/v1/377dcf5be4e8dc529bfa7a1d.png"},{"id":72206937,"identity":"6b74875e-14fa-42ce-a73d-09290ef2f20b","added_by":"auto","created_at":"2024-12-23 16:46:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":257576,"visible":true,"origin":"","legend":"\u003cp\u003eBland-Altman plot of grader agreement for the total number of scotomatous points within the junctional zone. (black line: bias; ted-dashed lines: upper and lower limits of agreement; blue circles: subjects)\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5183845/v1/f54268a392d91a4b199f544b.png"},{"id":72206939,"identity":"22db9924-7e18-4809-9008-1148ccb76e75","added_by":"auto","created_at":"2024-12-23 16:46:42","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":16141990,"visible":true,"origin":"","legend":"\u003cp\u003eBland-Altman plot of grader agreement of stimulus-to-margin distances across all measured stimulus points (68 per eye).\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5183845/v1/41586b6b20cc996d10d0bcd0.png"},{"id":72206940,"identity":"f6f7369c-1d7c-41a4-b982-7b11b0abd265","added_by":"auto","created_at":"2024-12-23 16:46:42","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":3529346,"visible":true,"origin":"","legend":"\u003cp\u003eBox plot of the mean and standard deviation of the average stimulus coordinate differences over 68 stimulus points for each eye.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5183845/v1/cab54d578b2e9828688ab760.png"},{"id":72206942,"identity":"adb90201-b99b-48f8-a4d8-8b882795a2f7","added_by":"auto","created_at":"2024-12-23 16:46:43","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":37806798,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative Grader 1 and Grader 2 overlays of the microperimetry (MP) stimulus points on the fundus autofluorescence (FAF) images used for GA tracing. MP stimulus points are indicated by circle markers (Grader 1) and star markers (Grader 2). Filled and unfilled markers correspond to MP points inside and outside of the junctional zone, indicated by red shading, respectively. The images correspond to subjects having the 5\u003csup\u003eth\u003c/sup\u003e percentile (Subject 5), 50\u003csup\u003eth\u003c/sup\u003e percentile (subject 19), and 95\u003csup\u003eth\u003c/sup\u003e percentile (Subject 29) mean stimulus coordinate differences (see Fig. 5). Enlargements of regions of interest specified by dashed boxes (top row) are shown in the bottom row. The green arrowheads indicate grader discrepancies in the assignment of points as being inside or outside of the junctional zone.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-5183845/v1/94d50aaabf421fe708ac80ef.png"},{"id":72206955,"identity":"882a31bd-e4f1-4713-86bd-93072f4bf637","added_by":"auto","created_at":"2024-12-23 16:47:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":73969588,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5183845/v1/115f8a56-dd59-482b-a187-e835a23bf9a5.pdf"}],"financialInterests":"Competing interest reported. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Y.A is an employee at Boston Image Reading Center. M.U.M is an employee at Apellis. C.R.B. is an employee at Apellis. J.G.F. receives research support from Topcon Healthcare, has an equity interest in Optovue, and receives royalties on a patent owned by MIT and licensed to Optovue. N.K.W. receives research support from Carl Zeiss Meditec, Nidek, Regeneron and Topcon. She is Chief Medical Officer at Ocular therapeutics, has received speaker fees from Nidek, has an equity interest in AGTC, Iolyx pharmaceuticals, Valitor and Ocudyne, and is a consultant for Olix Therapeutics, Iolyx pharmaceuticals, Complement Therapeutics, Boehringer Ingelheim, Jansen, and Topcon. J.G.F. and E.M. have a patent (VISTA) with a license option to Topcon Healthcare. The other authors report no disclosures.","formattedTitle":"Evaluating the Reliability of a Microperimetry-Based Method for Assessing Visual Function in the Junctional Zone of Geographic Atrophy Lesions","fulltext":[{"header":"Summary Statement","content":"\u003cp\u003eWe present a microperimetry-based methodology for assessing visual function changes in the junctional zone of geographic atrophy lesions using a standard 10-2 fovea centered grid in a clinical trial context. The approach\u0026rsquo;s repeatability and compatibility with standard microperimetry grids may make it useful for assessing the effects of GA therapeutics.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eGeographic atrophy (GA), the late stage of non-exudative age-related macular degeneration, significantly reduces quality of life\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The consequences of visual impairment in GA patients include an increased risk of falls, difficulty reading, driving, and recognizing faces, and ultimately, the loss of independence\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In 2023, two complement inhibitors were approved by the Food and Drug Administration (FDA), becoming the first approved therapies for treating GA. These therapies were shown to significantly slow the enlargement of GA as measured on fundus autofluorescence (FAF). However, for these and future GA therapeutics, it is important to understand their effects on measures of visual function in addition to structural measures.\u003c/p\u003e \u003cp\u003eSensitive and reliable measurement of visual function in GA patients remains a challenge. The standard assessment of visual acuity is typically performed using eye charts, which is a reliable and reproducible test when patients have a healthy macula and good fixation. In patients with extrafoveal lesions, there can be significant GA growth without any effect on visual acuity, even with patients complaining of worsening visual function. Similarly, once the central fovea is involved, there can be further growth of the GA lesion without additional changes in visual acuity\u0026mdash;in this situation, too, the patient\u0026rsquo;s functional capacity may decline as their scotoma enlarges. Therefore, it is important to develop approaches that can assess the visual function changes that accompany the structural changes that occur as GA lesions enlarge.\u003c/p\u003e \u003cp\u003eMicroperimetry (MP) provides a functional mapping of the retina that is precisely correlated to fundus anatomy. Because MP assesses light sensitivity at specific, predefined retinal loci that can be longitudinally tracked, MP may be a sensitive measure of visual function changes in patients with GA\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Nevertheless, conventional MP analyses (e.g., mean sensitivity across all stimulus points) are limited in that a substantial proportion of stimuli may fall within the region of atrophy or be located far from the atrophic region over a still healthy retina area, particularly when large sparse grid distribution are selected, and are, therefore, unlikely to change as the GA lesion enlarges. This decoupling may lead to an underestimation of therapeutic effects\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Thus, developing and evaluating approaches that analyze MP sensitivities within a junctional zone of the GA lesion may lead to more sensitive measurements of the effects that GA therapeutics have on visual function\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The aim of this study is to assess the repeatability of an MP methodology for quantifying visual function changes in GA junctional zones in a clinical trial context.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThe repeatability of our MP analysis workflow was evaluated on a cohort of GA patients from the OAKS study (NCT03525600)\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The OAKS study was a 24-month, multicenter, randomized, double-masked, sham-controlled, phase 3 study, which enrolled patients at 110 clinical sites. The study adhered to protocols approved by the institutional review board of each site and complied with the Declaration of Helsinki. The inclusion and exclusion criteria of the OAKS study are described elsewhere\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Patients were randomly assigned (2:2:1:1) by a central web-based randomization system to intravitreal 15 mg per 0.1 mL pegcetacoplan or sham either monthly or every other month.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMP Testing\u003c/h3\u003e\n\u003cp\u003eMP testing was conducted using the Macular Integrity Assessment (MAIA) device (iCare, Padova, Italy) at baseline and every 6 months for up to 24 months. All follow-up MP acquisitions were obtained using a \u0026lsquo;follow-up\u0026rsquo; mode to allow registration to the baseline acquisition. MP testing was conducted in a dark room under pharmacologic pupil dilation while the contralateral eye was patched. MP testing was performed using a rectilinear 10\u0026thinsp;\u0026minus;\u0026thinsp;2 grid distribution (68 stimulus points; Goldman Size III (0.43\u0026ordm; diameter)) centered on the anatomic fovea, with a 4\u0026thinsp;\u0026minus;\u0026thinsp;2 staircase threshold strategy and a 1\u0026ordm; diameter red central fixation target. The average examination time was 8.8 minutes. All MP testing was performed prior to any imaging to prevent photoreceptor bleaching.\u003c/p\u003e\n\u003ch3\u003eFundus Autofluorescence Imaging\u003c/h3\u003e\n\u003cp\u003eFundus autofluorescence (FAF) imaging was performed using the Spectralis HRA\u0026thinsp;+\u0026thinsp;OCT (Heidelberg Engineering, Heidelberg, Germany) at all study visits. In the high-speed mode, a 30\u0026deg; \u0026times; 30\u0026deg; field centered on the fovea was imaged. FAF images consisted of 768 \u0026times; 768 pixels.\u003c/p\u003e\n\u003ch3\u003eJunctional Zone MP Analysis\u003c/h3\u003e\n\u003cp\u003eThe workflow for GA junctional zone MP analysis, which follows the approach used by Hariri\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In brief, using custom software, baseline MP images (sensitivity maps superimposed on their respective scanning laser ophthalmoscopy (SLO) fundus images) were registered to their corresponding baseline FAF images using fiducial markers manually positioned at corresponding bifurcations of the retinal vasculature. For registration, a similarity-type transformation (translation, rotation, and isotropic scaling) was used. The same transformation was then used to transform the MP stimuli coordinates into the FAF image coordinate frame. GA tracing was performed on the baseline FAF images, with the minimum lesion size defined as 0.05 mm\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. With the GA tracings and MP measurements in the same coordinate frame (i.e., the FAF coordinate frame), the signed Euclidean (i.e., straight-line) distance from each MP stimulus point to the closest point on the baseline GA margin was computed. Negative and positive distances represent stimuli that lie inside and outside the areas of atrophy, respectively. A junctional zone, defined as all fundus positions within 250 \u0026micro;m of the GA margin (including regions both inside and outside the region of atrophy), was automatically generated. The position and width of the junctional zone used in this study matched that used for the MP analysis of the OAKS trial\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eTwo graders (Grader 1 and Grader 2) performed registrations in a systematically stratified sampling of the 637 eyes from the OAKS study. The repeatability of the mean sensitivity and number of scotomatous points within the junctional zone were assessed using Bland\u0026ndash;Altman analysis\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, intraclass correlation coefficients (ICCs) and coefficients of repeatability (CoRs), also referred to as the smallest real difference\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. To assess the repeatability of our MP analysis workflow without considering a particular junctional zone (e.g., \u0026plusmn; 250 \u0026micro;m), we considered two measures, both of which incorporate all 68 stimulus points: (1) the repeatability of the signed-distance from each MP stimulus point to the GA margin (\u0026ldquo;stimulus-to-margin distance\u0026rdquo;; distances are negative for points within the GA lesion margin and positive for points outside the GA lesion margin), and (2) the distances between the coordinates of corresponding MP stimulus points when transformed by the two readers into the FAF coordinate frame (\u0026ldquo;stimulus coordinate difference\u0026rdquo;). The repeatability of the stimulus-to-margin distance was assessed using Bland-Altman analysis, as well as ICC and CoR. Following Taylor et al.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e, linear mixed modeling was used to account for repeated measures. Stimulus coordinate differences were summarized with boxplots and descriptive statistics.\u003c/p\u003e \u003cp\u003eNote that all repeatability analyses assess only the repeatability of the MP \u003cem\u003eanalysis\u003c/em\u003e, which is determined by the repeatability of registering the MP SLO images to the FAF images. In particular, the repeatability analyses do not consider the repeatability of the MP acquisition, which have been reported by other authors\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, or of the GA lesion tracing.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eImages from thirty eyes (24 patients) were registered by two graders. Bland-Altman analysis of the mean sensitivity within the junctional zone showed a bias of 0.37 dB between the two graders, with 90% of the eyes within \u0026plusmn;\u0026thinsp;1.96 SD (95% limit of agreement (LOA): -0.98 dB to 1.73 dB; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Bland-Altman analysis of total number of scotomatous points within the junctional zone showed a bias of 0.37 between the two graders, with 94% of the points within \u0026plusmn;\u0026thinsp;1.96 SD (95% limit of agreement (LOA): -0.99 to 0.93; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The ICC and CoR for the mean junctional zone sensitivity were 0.994 and 0.349 dB, respectively. The ICC and CoR for the total number of scotomatous points within the junctional zone were 0.997 and 0.218, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBland-Altman analysis of the stimulus-to-margin distance, measured across all stimulus points (68 per eye), showed a mean shift of -3.24 \u0026micro;m between the two graders, with 94% of the points within \u0026plusmn;\u0026thinsp;1.96 SD from the mean shift (95% limit of agreement (LOA): -87.35 \u0026micro;m to 80.87 \u0026micro;m; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Six eyes had larger variabilities (SD of difference\u0026thinsp;\u0026gt;\u0026thinsp;50 \u0026micro;m) between the two graders and were outside the LOA bounds. The ICC and CoR of the stimulus-to-margin distances between the two graders were 0.969 and 99.85 \u0026micro;m, respectively. The stimulus coordinate differences are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The mean stimulus coordinate difference taken across stimulus points for all subjects was 46.87\u0026thinsp;\u0026plusmn;\u0026thinsp;23.80 \u0026micro;m. Representative images of the registered MP in the FAF coordinate frame are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, we evaluated the repeatability of an MP analysis workflow that is compatible with clinical trial data (10\u0026thinsp;\u0026minus;\u0026thinsp;2 MP stimulus grid distribution and FAF imaging for GA tracing) and allows the visual function to be assessed in retinal areas that are most likely to be affected by GA growth\u0026mdash;namely, the junctional zone comprised of the regions immediately surrounding the GA lesion margin. The repeatability of the method in the context of the mean junctional zone sensitivity and the number of scotomatous points within the junctional zone was excellent. Assessments of stimulus-to-margin distances and stimulus coordinate difference showed reader differences that were generally small compared to the junctional zone width, although there were some outlier cases (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFrom a subjective review of grader registrations, we believe that the dominant cause of inter-grader discrepancies were likely due to the similarity-type image transformation not fully capturing the true deformation between the MP SLO and FAF images. To reduce inter-reader discrepancies in future studies, more general transformation types that better approximate the true deformation could be used. However, more general transformation types require more corresponding vessel bifurcations to be selected\u0026mdash;in addition to increasing the grading time, selecting more vessel bifurcations can itself be error prone for images with less pronounced vasculature, and may even lead to larger discrepancies.\u003c/p\u003e \u003cp\u003eAs in Hariri et al.,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e the MP workflow used in this study analyzes junctional zone sensitivities by transforming MP stimulus coordinates into the coordinate frame used for lesion tracing. After this transformation, the position of each MP stimulus point can be directly related to the GA lesion margin. An alternative approach to analyzing MP sensitivities in the junctional zone, proposed by Meleth et al.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e and recently used in the post hoc analysis of the Spectri and Chroma lampalizumab trials\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, is to define the junctional zone using the set of scotomatous MP points. Such an approach has the advantage of simplicity (e.g., no image registration required). Furthermore, it can be performed using only MP data, making it particularly well suited to analyses in which GA tracing data are unavailable. However, for standard 10\u0026thinsp;\u0026minus;\u0026thinsp;2 MP stimulus grids, the 2-degree stimulus spacing suggests that a junctional zone derived using MP only is likely to be less accurate than a junctional zone derived directly from the registered GA tracing data.\u003c/p\u003e \u003cp\u003eAnother approach to measuring junctional zone MP sensitivities is to use patient-tailored MP grids wherein the stimuli are distributed around the lesion margin\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. An advantage of patient-tailored approaches is that MP measurements are not collected at fundus positions that are decoupled from lesion growth (e.g., regions of atrophy at baseline). Moreover, patient-tailored MP allows stimuli points to be distributed around lesions more uniformly and at higher-density within the junctional zone. A disadvantage is the requirement of customized, lesion-specific grids, which may complicate or be incompatible with current MP workflows and may become complex for certain lesion geometries (e.g., multifocal lesions). Moreover, the optimal grid parameters (e.g., stimulus density and junctional zone dimensions) are not \u003cem\u003ea priori\u003c/em\u003e obvious. Indeed, one possible application of the MP approach used in the present study is in helping to design MP grid patterns for future studies using patient-specific MP.\u003c/p\u003e \u003cp\u003eAn important limitation of our approach, particularly as applied to standard MP grids, is that the MP stimuli are relatively sparse and are randomly distributed relative to regions of atrophy. In addition to the possibility of missing smaller regions of functional impairment, there is a sparse and unequal sampling of the junctional zones, which we expect to increase variances when estimating treatment effects. One potential mitigation strategy is to model, or otherwise adjust for, the spatial distribution of stimulus points within the junctional zone. An alternate approach is to re-sample the MP measurements (e.g., via interpolation\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e) such that they uniformly tile the junctional zone. While these approaches also have limitations, we hope to explore these approaches in future studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this paper, we evaluate a microperimetry-based approach for assessing visual function changes in the GA junctional zone in a clinical trial context. The repeatability of the approach and its compatibility with standard MP acquisitions appear to make it well-suited to assessing the effects of GA therapeutics on visual function.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003cp\u003eThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Y.A is an employee at Boston Image Reading Center. M.U.M is an employee at Apellis. C.R.B. is an employee at Apellis. J.G.F. receives research support from Topcon Healthcare, has an equity interest in Optovue, and receives royalties on a patent owned by MIT and licensed to Optovue. N.K.W. receives research support from Carl Zeiss Meditec, Nidek, Regeneron and Topcon. She is Chief Medical Officer at Ocular therapeutics, has received speaker fees from Nidek, has an equity interest in AGTC, Iolyx pharmaceuticals, Valitor and Ocudyne, and is a consultant for Olix Therapeutics, Iolyx pharmaceuticals, Complement Therapeutics, Boehringer Ingelheim, Jansen, and Topcon. J.G.F. and E.M. have a patent (VISTA) with a license option to Topcon Healthcare. The other authors report no disclosures.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding /Support\u003c/h2\u003e \u003cp\u003eSupported by the National Institutes of Health (Bethesda, MD, R01EY011289 and R01EY034080); Beckman-Argyros Award in Vision Research (Irvine, CA, USA); Greenberg Prize to End Blindness. The sponsor or funding organizations had no role in the design or conduct of this research.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting Interest Statement:\u003c/strong\u003e \u003cp\u003eThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.Y.A is an employee at Boston Image Reading Center. M.U.M is an employee at Apellis. C.R.B. is an employee at Apellis. J.G.F. receives research support from Topcon Healthcare, has an equity interest in Optovue, and receives royalties on a patent owned by MIT and licensed to Optovue. N.K.W. receives research support from Carl Zeiss Meditec, Nidek, Regeneron and Topcon. She is Chief Medical Officer at Ocular therapeutics, has received speaker fees from Nidek, has an equity interest in AGTC, Iolyx pharmaceuticals, Valitor and Ocudyne, and is a consultant for Olix Therapeutics, Iolyx pharmaceuticals, Complement Therapeutics, Boehringer Ingelheim, Jansen, and Topcon. J.G.F. and E.M. have a patent (VISTA) with a license option to Topcon Healthcare. The other authors report no disclosures.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConception: J.G.F, N.K.W; Data acquisition: A.Y.A, E.M., N.K.W, J.G.F; Analysis and interpretation of data: A.Y.A, E.M, M.U.J, K.R; Figure preparation: A.Y.A, E.M., M.U.J; Software creation: A.Y.A, E.M; Draft writing: E.M., M.U.J; Draft revision: A.Y.A, M.U.M, R.R, C.R.B\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe'd like to thank Beacon Therapeutics for statistical support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePatel PJ, Ziemssen F, Ng E, et al. Burden of Illness in Geographic Atrophy: A Study of Vision-Related Quality of Life and Health Care Resource Use. 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PMID: 18560291; PMCID: PMC2944826.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVaz S, Falkmer T, Passmore AE, et al. The case for using the repeatability coefficient when calculating test-retest reliability. PLoS ONE. 2013;8(9):e73990. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pone.0073990\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0073990\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 24040139; PMCID: PMC3767825.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaylor LJ, Josan AS, Jolly JK, et al. Microperimetry as an Outcome Measure in RPGR-associated Retinitis Pigmentosa Clinical Trials. 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PMID: 27760271.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-retina-and-vitreous","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"IJRV","sideBox":"Learn more about [International Journal of Retina and Vitreous](https://jneurodevdisorders.biomedcentral.com/)","snPcode":"40942","submissionUrl":"https://submission.nature.com/new-submission/40942/3","title":"International Journal of Retina and Vitreous","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"microperimetry, geographic atrophy, fundus auto fluorescence, age-related macular degeneration, scotomatous points","lastPublishedDoi":"10.21203/rs.3.rs-5183845/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5183845/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the repeatability of a microperimetry methodology for quantifying visual function changes in the junctional zone of eyes with geographic atrophy (GA) in the clinical trial context.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA post hoc analysis of the OAKS phase III trial was conducted, which enrolled patients with GA secondary to age-related macular degeneration. Microperimetry using a standard 10-2 fovea centered grid was performed at baseline and follow-up visits. GA regions were traced on fundus autofluorescence (FAF) images. Two graders independently registered baseline microperimetry images with baseline FAF images in a sampling of 30 eyes from the OAKS study.\u003cstrong\u003e \u003c/strong\u003eAgreement between the two graders’ assessments of mean sensitivity and the number of scotomatous points within a ±250 𝜇m GA junctional zone was assessed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe intraclass correlation (ICC) and coefficient of repeatability (CoR) for the mean junctional zone sensitivity were 0.994 and 0.349 dB, respectively. The ICC and CoR for the total number of scotomatous points within the junctional zone were 0.997 and 0.218, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe repeatability of the methodology and its compatibility with standard MP acquisitions appear to make it well-suited for identifying and analyzing retinal sensitivity within high-risk areas of the retina.\u003c/p\u003e","manuscriptTitle":"Evaluating the Reliability of a Microperimetry-Based Method for Assessing Visual Function in the Junctional Zone of Geographic Atrophy Lesions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-23 16:46:38","doi":"10.21203/rs.3.rs-5183845/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-23T03:17:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-21T22:34:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-15T10:49:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128665376728195635423647809733325130511","date":"2024-10-11T18:42:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37748448632313456497428980579318195835","date":"2024-10-08T09:48:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-07T16:54:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-07T16:50:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-07T09:04:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Retina and Vitreous","date":"2024-10-01T01:06:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-retina-and-vitreous","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"IJRV","sideBox":"Learn more about [International Journal of Retina and Vitreous](https://jneurodevdisorders.biomedcentral.com/)","snPcode":"40942","submissionUrl":"https://submission.nature.com/new-submission/40942/3","title":"International Journal of Retina and Vitreous","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a503b744-bf55-49a4-831b-c735ee9c362a","owner":[],"postedDate":"December 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T16:46:38+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-23 16:46:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5183845","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5183845","identity":"rs-5183845","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}