Retest variability and patient reliability indices of quantitative fundus autofluorescence in age-related macular degeneration: a MACUSTAR study report

This study aimed to determine the retest variability of quantitative fundus autofluorescence (QAF) in patients with and without age-related macular degeneration (AMD) and evaluate the predictive value of patient reliability indices on retest reliability. A total of 132 eyes from 68 patients were examined, including healthy individuals and those with various stages of AMD. Duplicate QAF imaging was conducted at baseline and 2 weeks later across six study sites. Intraclass correlation (ICC) analysis was used to evaluate the consistency of imaging, and mean opinion scores (MOS) of image quality were generated by two researchers. The contribution of MOS and other factors to retest variation was assessed using mixed-effect linear models. Additionally, a Random Forest Regressor was trained to evaluate the extent to which manual image grading of image quality could be replaced by automated assessment (inferred MOS). The results showed that ICC values were high for all QAF images, with slightly lower values in AMD-affected eyes. The average inter-day ICC was found to be 0.77 for QAF segments within the QAF8 ring and 0.74 for peripheral segments. Image quality was predicted with a mean absolute error of 0.27 on a 5-point scale, and of all evaluated reliability indices, MOS/inferred MOS proved most important. The findings suggest that QAF allows for reliable testing of autofluorescence levels at the posterior pole in patients with AMD in a multicenter, multioperator setting. Patient reliability indices could serve as eligibility criteria for clinical trials, helping identify patients with adequate retest reliability

Artificial intelligence for morphology-based function prediction in neovascular age-related macular degeneration

Spatially-resolved mapping of rod- and cone-function may facilitate monitoring of macular diseases and serve as a functional outcome parameter. However, mesopic and dark-adapted two-color fundus-controlled perimetry (FCP, also called "microperimetry") constitute laborious examinations. We have devised a machine-learning-based approach to predict mesopic and dark-adapted (DA) retinal sensitivity in eyes with neovascular age-related macular degeneration (nAMD). Extensive psychophysical testing and volumetric multimodal retinal imaging data were acquired including mesopic, DA red and DA cyan FCP, spectral-domain optical coherence tomography and confocal scanning laser ophthalmoscopy infrared reflectance and fundus autofluorescence imaging. With patient-wise leave-one-out cross-validation, we have been able to achieve prediction accuracies of (mean absolute error, MAE [95% CI]) 3.94 dB [3.38, 4.5] for mesopic, 4.93 dB [4.59, 5.27] for DA cyan and 4.02 dB [3.63, 4.42] for DA red testing. Partial addition of patient-specific sensitivity data decreased the cross-validated MAE to 2.8 dB [2.51, 3.09], 3.71 dB [3.46, 3.96], and 2.85 dB [2.62, 3.08]. The most important predictive feature was outer nuclear layer thickness. This artificial intelligence-based analysis strategy, termed "inferred sensitivity", herein, enables to estimate differential effects of retinal structural abnormalities on cone- and rod-function in nAMD, and may be used as quasi-functional surrogate endpoint in future clinical trials

Light sensitivity within areas of geographic atrophy secondary to age-related macular degeneration

Purpose: To investigate residual sensitivity within geographic atrophy (GA) secondary to age-related macular degeneration. Methods: Mesopic and dark-adapted (DA) cyan and red light sensitivity (Goldmann III) were investigated using fundus-controlled perimetry (microperimetry). Test points were placed within GA along an “iso-hull” with a distance of −0.645° to the atrophy boundary. The false-positive response rate was determined with suprathreshold stimuli to the optic disc (Heijl-Krakau method) and used to compute the expected sensitivity measurements for the assumption of absolute scotomata. The outermost visible retinal layer on spectral-domain optical coherence tomography at the location of each test point was determined. Results: Thirty eyes of 36 patients (75.55 ± 7.93 years; 19 female) from the prospective natural history study Directional Spread in Geographic Atrophy (NCT02051998), with a total of 1380 threshold determinations were analyzed. The measured sensitivities were significantly (P < 0.01) higher than the expected values for absolute scotomata (mean ± standard error of +6.92 ± 0.86 dB for mesopic, +2.57 ± 0.56 dB for DA cyan, and +4.93 ± 0.74 dB for DA red testing). For mesopic testing and DA red testing, the presence of a residual outer nuclear layer had a significant effect on this discrepancy (P < 0.001). There was no effect of fixation stability or any other reliability index on this discrepancy. Conclusions: Measured sensitivities within the inner junctional zone of GA may not be purely explained by patient-specific false-positive response rates or other reliability indices. The marked influence of the outer retinal configuration on measured sensitivity may be indicative of residual cone function within GA at the inner junctional zone

Determinants of Cone and Rod Functions in Geographic Atrophy: AI-Based Structure-Function Correlation

Purpose To investigate the association between retinal microstructure and cone- and rod-function in geographic atrophy (GA) secondary to age-related macular degeneration (AMD) using artificial-intelligence-(AI) algorithms. Design Prospective, observational case series Methods Forty-one eyes of 41 patients (75.8±8.4 years; 22 female) from a tertiary referral hospital were included (Directional-Spread-in-Geographic-Atrophy (DSGA) natural history study; NCT02051998). Mesopic, dark-adapted (DA) cyan and red sensitivity were assessed using fundus-controlled perimetry (“microperimetry”); retinal microstructure using spectral-domain optical-coherence-tomography (SD-OCT), fundus autofluorescence (FAF) and near-infrared-reflectance (IR) imaging. Layer-thicknesses and -intensities and FAF- and IR-intensities were extracted for each test-point. We evaluated the cross-validated mean absolute error (MAE) for random-forest-based predictions of retinal sensitivity with and without patient-specific training-data and the increase mean-squared error (%IncMSE) as measure of feature-importance. Results Retinal sensitivity was predicted with a MAE of 4.64 dB for mesopic, 4.89 dB for DA cyan and 4.40 dB for DA red testing in absence of patient-specific data. Partial addition of patient-specific sensitivity data to the training sets decreased the MAE to 2.89 dB, 2.86 dB and 2.77 dB. For all three types of testing, the outer nuclear layer-thickness constituted the most important predictive feature (35.0, 42.22 and 53.74 %IncMSE). Spatially-resolved mapping of “inferred sensitivity” revealed regions with differential degrees of mesopic and DA cyan sensitivity loss outside of the GA lesions. Conclusions “Inferred sensitivity” accurately reflected retinal function in patients with GA. Mapping of “inferred sensitivity” could facilitate monitoring of disease progression and serve as “quasi functional” surrogate outcome in clinical trials, especially in consideration of retinal regions beyond areas of GA

Type 1 Choroidal Neovascularization Is Associated with Reduced Localized Progression of Atrophy in Age-Related Macular Degeneration.

PURPOSE To investigate the association between the presence of type 1 choroidal neovascularization (CNV) and the localized progression of atrophy in age-related macular degeneration (AMD). DESIGN Analysis of patients' data collected in the context of 2 noninterventional, prospective studies conducted at the Department of Ophthalmology, University of Bonn, Germany. PARTICIPANTS A total of 98 eyes diagnosed with AMD of 59 patients (40 female, 19 male) with a mean (±standard deviation) age at baseline of 76.60±6.65 years and median (interquartile range) review period of 1.17 years (1.01-1.55) were included. Eyes were subdivided into 3 categories based on multimodal imaging and ocular history: retinal pigment epithelium (RPE) atrophy with treatment-naïve quiescent CNV (n=7), RPE atrophy with a history of exudative CNV (n=10), and RPE atrophy without evidence of coexisting CNV (n=81). METHODS Retinal pigment epithelium atrophy was delineated on the basis of serial fundus-autofluorescence and infrared-reflectance images. If CNV was detected by OCT angiography (OCTA), its location and dimension were spatially mapped to RPE atrophy. The localized progression of RPE atrophy in topographic relation to the CNV lesion was then analyzed using mixed-effects logistic regression. The spatial overlap (Dice coefficient) between predicted and observed RPE atrophy progression was evaluated to estimate the model accuracy. MAIN OUTCOME MEASURES Odds ratio (OR) for localized RPE atrophy progression in areas overlying type 1 CNV. RESULTS The prediction model achieved a high overlap between predicted and observed RPE atrophy progression with a cross-validated Dice coefficient of 0.87 (95% confidence interval [CI], 0.85-0.89) reflecting a high accuracy. The odds for future RPE atrophy involvement were reduced by a factor of 0.21 (95% CI, 0.19-0.24) in the presence of treatment-naïve quiescent type 1 CNV and by a factor of 0.46 (95% CI, 0.41-0.51) in the presence of exudative type 1 CNV. CONCLUSIONS The results indicate that there is markedly reduced RPE atrophy progression in areas co-localizing with quiescent and exudative type 1 CNV. This observation is compatible with a potential protective effect of type 1 CNV on the RPE and overlying neurosensory retina. These results may have relevant clinical implications for the management of CNV and lead to new therapeutic strategies to prevent atrophy progression

Retest variability and patient reliability indices of quantitative fundus autofluorescence in age-related macular degeneration: a MACUSTAR study report

Abstract This study aimed to determine the retest variability of quantitative fundus autofluorescence (QAF) in patients with and without age-related macular degeneration (AMD) and evaluate the predictive value of patient reliability indices on retest reliability. A total of 132 eyes from 68 patients were examined, including healthy individuals and those with various stages of AMD. Duplicate QAF imaging was conducted at baseline and 2 weeks later across six study sites. Intraclass correlation (ICC) analysis was used to evaluate the consistency of imaging, and mean opinion scores (MOS) of image quality were generated by two researchers. The contribution of MOS and other factors to retest variation was assessed using mixed-effect linear models. Additionally, a Random Forest Regressor was trained to evaluate the extent to which manual image grading of image quality could be replaced by automated assessment (inferred MOS). The results showed that ICC values were high for all QAF images, with slightly lower values in AMD-affected eyes. The average inter-day ICC was found to be 0.77 for QAF segments within the QAF8 ring and 0.74 for peripheral segments. Image quality was predicted with a mean absolute error of 0.27 on a 5-point scale, and of all evaluated reliability indices, MOS/inferred MOS proved most important. The findings suggest that QAF allows for reliable testing of autofluorescence levels at the posterior pole in patients with AMD in a multicenter, multioperator setting. Patient reliability indices could serve as eligibility criteria for clinical trials, helping identify patients with adequate retest reliability