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Ophthalmology

Association of Reading Performance in Geographic Atrophy Secondary to Age-Related Macular Degeneration With Visual Function and Structural Biomarkers

Educational Objective
To prospectively evaluate reading performance in geographic atrophy and to assess its association with established visual function assessments and structural biomarkers.

1 Credit CME

JAMA Ophthalmology

Published Online: September 30, 2021

Original Investigation

Article Information and Disclosures

Sandrine H. Künzel, MD¹;

Moritz Lindner, MD^2,3;

Josua Sassen, MSc⁴;

Philipp T. Möller, MD¹;

Lukas Goerdt, MD¹;

Matthias Schmid, PhD⁵;

Steffen Schmitz-Valckenberg, MD^1,6;

Frank G. Holz, MD¹;

Monika Fleckenstein, MD⁶;

Maximilian Pfau, MD^1,7

Author Affiliations

¹Department of Ophthalmology, University of Bonn, Bonn, Germany
²Nuffield Laboratory of Ophthalmology, Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
³Institute for Physiology and Pathophysiology, Department of Neurophysiology, Philipps-University Marburg, Marburg, Germany
⁴Institute for Numerical Simulation, University of Bonn, Bonn, Germany
⁵Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany
⁶John A. Moran Eye Center, University of Utah, Salt Lake City
⁷Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland

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Key Points

Question What is the association of reading performance in patients with geographic atrophy secondary to age-related macular degeneration with established visual function and structural biomarkers?

Findings In this cohort study of 150 eyes of 85 participants, reading acuity was most strongly associated with best-corrected visual acuity and geographic atrophy area in the central and inner-right Early Treatment Diabetic Retinopathy Study subfield. Regarding reading speed, the most associated variables were best-corrected visual acuity, low-luminance visual acuity, and geographic atrophy area in the central, the inner-right, and the inner-upper Early Treatment Diabetic Retinopathy Study subfields.

Meaning The association of reading performance with visual functional and structural biomarkers supports the validity of reading performance as an end point in clinical trials.

Abstract

Importance As a disabling and frequent disease, geographic atrophy secondary to age-related macular degeneration (AMD) constitutes an important study subject. Emerging clinical trials require suitable end points. The characterization and validation of reading performance as a functional outcome parameter is warranted.

Objective To prospectively evaluate reading performance in geographic atrophy and to assess its association with established visual function assessments and structural biomarkers.

Design, Setting, and Participants The noninterventional, prospective natural history Directional Spread in Geographic Atrophy study included patients with geographic atrophy secondary to AMD who were recruited at the University Hospital in Bonn, Germany. Participants were enrolled from June 2013 to June 2016. Analysis began December 2019 and ended January 2021.

Main Outcomes and Measures Reading acuity and reading speed were assessed using Radner charts. Longitudinal fundus autofluorescence and infrared reflectance images were semiautomatically annotated for geographic atrophy, followed by extraction of shape-descriptive variables. Linear mixed-effects models were applied to investigate the association of those variables with reading performance.

Results A total of 150 eyes of 85 participants were included in this study (median [IQR] age, 77.9 [72.4-82.1] years; 51 women [60%]; 34 men [40%]). Reading performance was impaired with a median (IQR) monocular reading acuity of 0.9 (0.4-1.3) logarithm of the reading acuity determination and a reading speed of 52.8 (0-123) words per minute. In the multivariable cross-sectional analysis, best-corrected visual acuity, area of geographic atrophy in the central Early Treatment Diabetic Retinopathy Study (ETDRS) subfield, classification of noncenter vs center-involving geographic atrophy, and area of geographic atrophy in the inner-right ETDRS subfield showed strongest associations with reading acuity (cross-validated R²for reading acuity = 0.69). Regarding reading speed, the most relevant variables were best-corrected visual acuity, low-luminance visual acuity, area of geographic atrophy in the central ETDRS subfield, in the inner-right ETDRS subfield, and in the inner-upper ETDRS subfield (R² for reading speed = 0.67). In the longitudinal analysis, a similar prediction accuracy for reading performance was determined (R² for reading acuity = 0.73; R² for reading speed = 0.70). Prediction accuracy did not improve when follow-up time was added as an independent variable. Binocular reading performance did not differ from reading performance in the better-seeing eye.

Conclusions and Relevance The association of reading acuity and speed with visual functional and structural biomarkers supports the validity of reading performance as a meaningful end point in clinical trials. These findings suggest that measures in clinical and low-vision care for patients with geographic atrophy should focus primarily on the better-seeing eye.

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Article Information

Corresponding Author: Monika Fleckenstein, MD, John A. Moran Eye Center, 65 N Mario Capecchi, Salt Lake City, UT 84132 (mfleckenstein@web.de).

Accepted for Publication: August 7, 2021.

Published Online: September 30, 2021. doi:10.1001/jamaophthalmol.2021.3826

Author Contributions: Drs Künzel and Fleckenstein had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Künzel, Lindner, Möller, Fleckenstein, Pfau.

Acquisition, analysis, or interpretation of data: Künzel, Lindner, Sassen, Goerdt, Schmid, Schmitz-Valckenberg, Holz, Fleckenstein, Pfau.

Drafting of the manuscript: Künzel, Fleckenstein.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Künzel, Sassen, Schmid, Pfau.

Obtained funding: Künzel, Lindner, Fleckenstein, Pfau.

Administrative, technical, or material support: Goerdt, Schmitz-Valckenberg, Fleckenstein, Pfau.

Supervision: Schmitz-Valckenberg, Holz, Fleckenstein, Pfau.

Conflict of Interest Disclosures: Dr Künzel reported other doctoral fellowship from Deutsche Ophthalmologische Gesellschaft during the conduct of the study and nonfinancial support from Heidelberg Engineering, Carl Zeiss Meditec, and Optos. Drs Lindner, Möller, and Goerdt reported nonfinancial support from Heidelberg Engineering, Carl Zeiss Meditec, and Optos during the conduct of the study. Dr Schmid reported personal fees from Pixium Vision outside the submitted work. Dr Schmitz-Valckenberg reported contracted research from Acucela, Bioeq/Formycon, Apellis Pharmaceuticals, Katairo, Novartis, Pixium Vision, Roche, and SparingVision; consulting for Apellis Pharmaceuticals, Roche, and Oxurion; nonfinancial support from Carl Zeiss Meditec and Heidelberg Engineering; grants from Allergan; and personal fees from Allergan, Bayer, CenterVue and Galimedix Therapeutics outside the submitted work. Dr Holz reported grants from Heidelberg Engineering and CenterVue during the conduct of the study; grants from Apellis Pharmaceuticals, Novartis, Bayer, Genentech, Alcon, Allergan, Optos, Formycon, Iveric Bio, Kanhong, Zeiss, Acucela, Geuder, and Roche; personal fees from Pixium Vision, Gyroscope, Novartis, Bayer, Genentech, Acucela, Boehringer Ingelheim, Alcon, and Allergan; grants, personal fees, and nonfinancial support from Heidelberg Engineering; grants and nonfinancial support from Optos; and nonfinancial support from Carl Zeiss Meditec outside the submitted work. Dr Fleckenstein reported grants from German Research Foundation during the conduct of the study; grants and personal fees from Novartis; grants and personal fees from Bayer; grants, personal fees, and nonfinancial support from Heidelberg Engineering; personal fees from Roche/Genentech; nonfinancial support from Carl Zeiss Meditec; grants and nonfinancial support from Optos; and a pending patent (US20140303013 A1) outside the submitted work. Dr Pfau reported grants from German Research Foundation during the conduct of the study; personal fees from Apellis outside the submitted work; and nonfinancial support from Heidelberg Engineering, Carl Zeiss Meditec, and Optos. No other disclosures were reported.

Funding/Support: This work was supported by the German Ophthalmological Society (dissertation grant to Dr Künzel), the German Research Foundation (grant PF 950/1-1 to Dr Pfau and grants 658/4-1 and 658/4-2 to Dr Fleckenstein), University Hospital Gießen and Marburg Research Funds (grant 15/2020MR to Dr Lindner), and the Bonfor Gerok Program of the Faculty of Medicine, University of Bonn (grants O-137.0022 and O-137.0025 to Dr Pfau). Drs Fleckenstein and Schmitz-Valckenberg were in part supported by a National Institutes of Health (grant EY014800) and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology & Visual Sciences, University of Utah. CenterVue SpA provided research material for the conduct of this study. CenterVue had no role in the design or conduct of the experiments.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Joanna Czauderna, Verena Bonn, and Ruth Hassenrik (Department of Ophthalmology, University of Bonn) for patient coordination and data acquisition. Compensation was not received outside their salary as employees.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.