Disease activity and therapeutic response to pegcetacoplan for geographic atrophy identified by deep learning-based analysis of OCT.

PURPOSE: To quantify morphological changes of the photoreceptors (PR) and retinal pigment epithelium (RPE) layers under pegcetacoplan therapy in geographic atrophy (GA) using deep learning-based analysis of optical coherence tomography (OCT) images. DESIGN: Post-hoc longitudinal image analysis SUBJECTS: Patients with GA due to age-related macular degeneration from two prospective randomized phase III clinical trials (OAKS and DERBY) METHODS: Deep learning-based segmentation of RPE loss and PR degeneration, defined as loss of the ellipsoid zone (EZ) layer on OCT, over 24 months on SD-OCT images MAIN OUTCOME MEASURES: Change in the mean area of RPE loss and EZ loss over time in the pooled sham arms and the monthly (PM)/every other month (PEOM) treatment arms RESULTS: 897 eyes of 897 patients were included. There was a therapeutic reduction of RPE loss growth by 22%/20% in OAKS and 27%/21% in DERBY for PM/PEOM compared to sham, respectively, at 24 months. The reduction on the EZ level was significantly higher with 53%/46% in OAKS and 47%/46% in DERBY for PM/PEOM compared to sham at 24 months. The baseline EZ-RPE difference had an impact on disease activity and therapeutic response. The therapeutic benefit for RPE loss growth increased with larger EZ-RPE difference quartiles from 21.9%, 23.1%, 23.9% to 33.6% for PM vs. sham (all p<0.01) and from 13.6% (p=0.11), 23.8%, 23.8% to 20.0% for PEOM vs. sham (p<0.01) in quartiles 1,2,3 and 4, respectively, at 24 months. Regarding EZ layer maintenance, the therapeutic reduction of loss increased from 14.8% (p=0.09), 33.3%, 46.6% to 77.8% (p<0.0001) between PM and sham and from 15.9% (p=0.08), 33.8%, 52.0% to 64.9% (p<0.0001) between PEOM and sham for quartiles 1-4 at 24 months. CONCLUSION: OCT-based AI analysis objectively identifies and quantifies PR and RPE degeneration in GA. Reductions in further PR degeneration consistent with EZ loss on OCT are even higher than the effect on RPE loss in phase 3 trials of pegcetacoplan treatment. The EZ-RPE difference has a strong impact on disease progression and therapeutic response. Identification of patients with higher EZ-RPE loss difference may become an important criterion for the management of GA secondary to AMD.

SYSTEMATIC CORRELATION OF CENTRAL SUBFIELD THICKNESS WITH RETINAL FLUID VOLUMES QUANTIFIED BY DEEP LEARNING IN THE MAJOR EXUDATIVE MACULAR DISEASES.

PURPOSE: To investigate the correlation of volumetric measurements of intraretinal (IRF) and subretinal fluid obtained by deep learning and central retinal subfield thickness (CSFT) based on optical coherence tomography in retinal vein occlusion, diabetic macular edema, and neovascular age-related macular degeneration. METHODS: A previously validated deep learning-based approach was used for automated segmentation of IRF and subretinal fluid in spectral domain optical coherence tomography images. Optical coherence tomography volumes of 2.433 patients obtained from multicenter studies were analyzed. Fluid volumes were measured at baseline and under antivascular endothelial growth factor therapy in the central 1, 3, and 6 mm. RESULTS: Patients with neovascular age-related macular degeneration generally demonstrated the weakest association between CSFT and fluid volume measurements in the central 1 mm (0.107-0.569). In patients with diabetic macular edema, IRF correlated moderately with CSFT (0.668-0.797). In patients with retinal vein occlusion, IRF volumes showed a moderate correlation with CSFT (0.603-0.704). CONCLUSION: The correlation of CSFT and fluid volumes depends on the underlying pathology. Although the amount of central IRF seems to partly drive CSFT in diabetic macular edema and retinal vein occlusion, it has only a limited impact on patients with neovascular age-related macular degeneration. Our findings do not support the use of CSFT as a primary or secondary outcome measure for the quantification of exudative activity or treatment guidance.

IMPACT OF RESIDUAL SUBRETINAL FLUID VOLUMES ON TREATMENT OUTCOMES IN A SUBRETINAL FLUID-TOLERANT TREAT-AND-EXTEND REGIMEN.

PURPOSE: To investigate associations between residual subretinal fluid (rSRF) volumes, quantified using artificial intelligence and treatment outcomes in a subretinal fluid (SRF)-tolerant treat-and-extend (T&E) regimen in neovascular age-related macular degeneration. METHODS: Patients enrolled in the prospective, multicenter FLUID study randomized in an SRF-tolerant T&E regimen were examined by spectral-domain optical coherence tomography and tested for best-corrected visual acuity (BCVA). Intraretinal fluid and SRF volumes were quantified using artificial intelligence tools. In total, 375 visits of 98 patients were divided into subgroups: extended intervals despite rSRF and extended intervals without fluid. Associations between BCVA change, SRF volume, subgroups, and treatment intervals were estimated using linear mixed models. RESULTS: In extended intervals despite rSRF, increased SRF was associated with reduced BCVA at the next visit in the central 1 mm (-0.138 letters per nL; P = 0.014) and 6 mm (-0.024 letters per nL; P = 0.049). A negative association between increased interval and BCVA change was found for rSRF in 1 mm and 6 mm (-0.250 and -0.233 letter per week interval, respectively; both P < 0.001). Extended intervals despite rSRF had significantly higher SRF volumes in the central 6 mm at the following visit (P = 0.002). CONCLUSION: Artificial intelligence-based analysis of extended visits despite rSRF demonstrated increasing SRF volumes associated with BCVA loss at the consecutive visit. This negative association contributes to the understanding of rSRF volumes on treatment outcomes in neovascular age-related macular degeneration.

TOPOGRAPHIC ANALYSIS OF PHOTORECEPTOR LOSS CORRELATED WITH DISEASE MORPHOLOGY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To quantify morphologic photoreceptor integrity during anti-vascular endothelial growth factor (anti-VEGF) therapy of neovascular age-related macular degeneration and correlate these findings with disease morphology and function. METHODS: This presents a post hoc analysis on spectral-domain optical coherence tomography data of 185 patients, acquired at baseline, Month 3, and Month 12 in a multicenter, prospective trial. Loss of the ellipsoid zone (EZ) was manually quantified in all optical coherence tomography volumes. Intraretinal cystoid fluid, subretinal fluid (SRF), and pigment epithelial detachments were automatically segmented in the full volumes using validated deep learning methods. Spatiotemporal correlation of fluid markers with EZ integrity as well as bivariate analysis between EZ integrity and best-corrected visual acuity was performed. RESULTS: At baseline, EZ integrity was predominantly impaired in the fovea, showing progressive recovery during anti-vascular endothelial growth factor therapy. Topographic analysis at baseline revealed EZ integrity to be more likely intact in areas with SRF and vice versa. Moreover, we observed a correlation between EZ integrity and resolution of SRF. Foveal EZ integrity correlated with best-corrected visual acuity at all timepoints. CONCLUSION: Improvement of EZ integrity during anti-VEGF therapy of neovascular age-related macular degeneration occurred predominantly in the fovea. Photoreceptor integrity correlated with best-corrected visual acuity. Ellipsoid zone integrity was preserved in areas of SRF and showed deterioration upon SRF resolution.

[Complement inhibition treatment for geographic atrophy (GA): functional and morphological efficacy and relevant biomarkers in clinical practice]. / Komplementinhibitorentherapie bei geographischer Atrophie (GA): funktionelle und morphologische Wirksamkeit und relevante Biomarker in der klinischen Praxis.

The approval of complement inhibitory therapeutic agents for the treatment of geographic atrophy (GA) has highlighted the need for reliable and reproducible measurement of disease progression and therapeutic efficacy. Due to its availability and imaging characteristics optical coherence tomography (OCT) is the method of choice. Using OCT analysis based on artificial intelligence (AI), the therapeutic efficacy of pegcetacoplan was demonstrated at the levels of both the retinal pigment epithelium (RPE) and photoreceptors (PR). Cloud-based solutions that enable monitoring of GA are already available.

Deep Learning-Based Prediction of Individual Geographic Atrophy Progression from a Single Baseline OCT.

Objective: To identify the individual progression of geographic atrophy (GA) lesions from baseline OCT images of patients in routine clinical care. Design: Clinical evaluation of a deep learning-based algorithm. Subjects: One hundred eighty-four eyes of 100 consecutively enrolled patients. Methods: OCT and fundus autofluorescence (FAF) images (both Spectralis, Heidelberg Engineering) of patients with GA secondary to age-related macular degeneration in routine clinical care were used for model validation. Fundus autofluorescence images were annotated manually by delineating the GA area by certified readers of the Vienna Reading Center. The annotated FAF images were anatomically registered in an automated manner to the corresponding OCT scans, resulting in 2-dimensional en face OCT annotations, which were taken as a reference for the model performance. A deep learning-based method for modeling the GA lesion growth over time from a single baseline OCT was evaluated. In addition, the ability of the algorithm to identify fast progressors for the top 10%, 15%, and 20% of GA growth rates was analyzed. Main Outcome Measures: Dice similarity coefficient (DSC) and mean absolute error (MAE) between manual and predicted GA growth. Results: The deep learning-based tool was able to reliably identify disease activity in GA using a standard OCT image taken at a single baseline time point. The mean DSC for the total GA region increased for the first 2 years of prediction (0.80-0.82). With increasing time intervals beyond 3 years, the DSC decreased slightly to a mean of 0.70. The MAE was low over the first year and with advancing time slowly increased, with mean values ranging from 0.25 mm to 0.69 mm for the total GA region prediction. The model achieved an area under the curve of 0.81, 0.79, and 0.77 for the identification of the top 10%, 15%, and 20% growth rates, respectively. Conclusions: The proposed algorithm is capable of fully automated GA lesion growth prediction from a single baseline OCT in a time-continuous fashion in the form of en face maps. The results are a promising step toward clinical decision support tools for therapeutic dosing and guidance of patient management because the first treatment for GA has recently become available. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Morph-SSL: Self-Supervision With Longitudinal Morphing for Forecasting AMD Progression From OCT Volumes.

The lack of reliable biomarkers makes predicting the conversion from intermediate to neovascular age-related macular degeneration (iAMD, nAMD) a challenging task. We develop a Deep Learning (DL) model to predict the future risk of conversion of an eye from iAMD to nAMD from its current OCT scan. Although eye clinics generate vast amounts of longitudinal OCT scans to monitor AMD progression, only a small subset can be manually labeled for supervised DL. To address this issue, we propose Morph-SSL, a novel Self-supervised Learning (SSL) method for longitudinal data. It uses pairs of unlabelled OCT scans from different visits and involves morphing the scan from the previous visit to the next. The Decoder predicts the transformation for morphing and ensures a smooth feature manifold that can generate intermediate scans between visits through linear interpolation. Next, the Morph-SSL trained features are input to a Classifier which is trained in a supervised manner to model the cumulative probability distribution of the time to conversion with a sigmoidal function. Morph-SSL was trained on unlabelled scans of 399 eyes (3570 visits). The Classifier was evaluated with a five-fold cross-validation on 2418 scans from 343 eyes with clinical labels of the conversion date. The Morph-SSL features achieved an AUC of 0.779 in predicting the conversion to nAMD within the next 6 months, outperforming the same network when trained end-to-end from scratch or pre-trained with popular SSL methods. Automated prediction of the future risk of nAMD onset can enable timely treatment and individualized AMD management.

Deep Neural Networks for Automated Outer Plexiform Layer Subsidence Detection on Retinal OCT of Patients With Intermediate AMD.

Purpose: The subsidence of the outer plexiform layer (OPL) is an important imaging biomarker on optical coherence tomography (OCT) associated with early outer retinal atrophy and a risk factor for progression to geographic atrophy in patients with intermediate age-related macular degeneration (AMD). Deep neural networks (DNNs) for OCT can support automated detection and localization of this biomarker. Methods: The method predicts potential OPL subsidence locations on retinal OCTs. A detection module (DM) infers bounding boxes around subsidences with a likelihood score, and a classification module (CM) assesses subsidence presence at the B-scan level. Overlapping boxes between B-scans are combined and scored by the product of the DM and CM predictions. The volume-wise score is the maximum prediction across all B-scans. One development and one independent external data set were used with 140 and 26 patients with AMD, respectively. Results: The system detected more than 85% of OPL subsidences with less than one false-positive (FP)/scan. The average area under the curve was 0.94 ± 0.03 for volume-level detection. Similar or better performance was achieved on the independent external data set. Conclusions: DNN systems can efficiently perform automated retinal layer subsidence detection in retinal OCT images. In particular, the proposed DNN system detects OPL subsidence with high sensitivity and a very limited number of FP detections. Translational Relevance: DNNs enable objective identification of early signs associated with high risk of progression to the atrophic late stage of AMD, ideally suited for screening and assessing the efficacy of the interventions aiming to slow disease progression.

An interactive task-based method for the avoidance of metal artifacts in CBCT.

PURPOSE: Intraoperative cone-beam CT imaging enables 3D validation of implant positioning and fracture reduction for orthopedic and trauma surgeries. However, the emergence of metal artifacts, especially in the vicinity of metallic objects, severely degrades the clinical value of the imaging modality. In previous works, metal artifact avoidance (MAA) methods have been shown to reduce metal artifacts by adapting the scanning trajectory. Yet, these methods fail to translate to clinical practice due to remaining methodological constraints and missing workflow integration. METHODS: In this work, we propose a method to compute the spatial distribution and calibrated strengths of expected artifacts for a given tilted circular trajectory. By visualizing this as an overlay changing with the C-Arm's tilt, we enable the clinician to interactively choose an optimal trajectory while factoring in the procedural context and clinical task. We then evaluate this method in a realistic human cadaver study and compare the achieved image quality to acquisitions optimized using global metrics. RESULTS: We assess the effectiveness of the compared methods by evaluation of image quality gradings of depicted pedicle screws. We find that both global metrics as well as the proposed visualization of artifact distribution enable a drastic improvement compared to standard non-tilted scans. Furthermore, the novel interactive visualization yields a significant improvement in subjective image quality compared to the state-of-the-art global metrics. Additionally we show that by formulating an imaging task, the proposed method allows to selectively optimize image quality and avoid artifacts in the region of interest. CONCLUSION: We propose a method to spatially resolve predicted artifacts and provide a calibrated measure for artifact strength grading. This interactive MAA method proved practical and effective in reducing metal artifacts in the conducted cadaver study. We believe this study serves as a crucial step toward clinical application of an MAA system to improve image quality and enhance the clinical validation of implant placement.

Sequence of Morphological Changes Preceding Atrophy in Intermediate AMD Using Deep Learning.

Purpose: Investigating the sequence of morphological changes preceding outer plexiform layer (OPL) subsidence, a marker preceding geographic atrophy, in intermediate AMD (iAMD) using high-precision artificial intelligence (AI) quantifications on optical coherence tomography imaging. Methods: In this longitudinal observational study, individuals with bilateral iAMD participating in a multicenter clinical trial were screened for OPL subsidence and RPE and outer retinal atrophy. OPL subsidence was segmented on an A-scan basis in optical coherence tomography volumes, obtained 6-monthly with 36 months follow-up. AI-based quantification of photoreceptor (PR) and outer nuclear layer (ONL) thickness, drusen height and choroidal hypertransmission (HT) was performed. Changes were compared between topographic areas of OPL subsidence (AS), drusen (AD), and reference (AR). Results: Of 280 eyes of 140 individuals, OPL subsidence occurred in 53 eyes from 43 individuals. Thirty-six eyes developed RPE and outer retinal atrophy subsequently. In the cohort of 53 eyes showing OPL subsidence, PR and ONL thicknesses were significantly decreased in AS compared with AD and AR 12 and 18 months before OPL subsidence occurred, respectively (PR: 20 µm vs. 23 µm and 27 µm [P < 0.009]; ONL, 84 µm vs. 94 µm and 98 µm [P < 0.008]). Accelerated thinning of PR (0.6 µm/month; P < 0.001) and ONL (0.8 µm/month; P < 0.001) was observed in AS compared with AD and AR. Concomitant drusen regression and hypertransmission increase at the occurrence of OPL subsidence underline the atrophic progress in areas affected by OPL subsidence. Conclusions: PR and ONL thinning are early subclinical features associated with subsequent OPL subsidence, an indicator of progression toward geographic atrophy. AI algorithms are able to predict and quantify morphological precursors of iAMD conversion and allow personalized risk stratification.

Systematic review of prognostic factors associated with progression to late age-related macular degeneration: Pinnacle study report 2.

There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently, clinicians cannot provide individualised prognoses of disease progression. Moreover, enriching clinical trials with rapid progressors may facilitate delivery of shorter intervention trials aimed at delaying or preventing progression to late AMD. Thus, we performed a systematic review to outline and assess the accuracy of reporting prognostic factors for the progression of intermediate to late AMD. A meta-analysis was originally planned. Synonyms of AMD and disease progression were used to search Medline and EMBASE for articles investigating AMD progression published between 1991 and 2021. Initial search results included 3229 articles. Predetermined eligibility criteria were employed to systematically screen papers by two reviewers working independently and in duplicate. Quality appraisal and data extraction were performed by a team of reviewers. Only 6 studies met the eligibility criteria. Based on these articles, exploratory prognostic factors for progression of intermediate to late AMD included phenotypic features (e.g. location and size of drusen), age, smoking status, ocular and systemic co-morbidities, race, and genotype. Overall, study heterogeneity precluded reporting by forest plots and meta-analysis. The most commonly reported prognostic factors were baseline drusen volume/size, which was associated with progression to neovascular AMD, and outer retinal thinning linked to progression to geographic atrophy. In conclusion, poor methodological quality of included studies warrants cautious interpretation of our findings. Rigorous studies are warranted to provide robust evidence in the future.

3DTINC: Time-Equivariant Non-Contrastive Learning for Predicting Disease Progression From Longitudinal OCTs.

Self-supervised learning (SSL) has emerged as a powerful technique for improving the efficiency and effectiveness of deep learning models. Contrastive methods are a prominent family of SSL that extract similar representations of two augmented views of an image while pushing away others in the representation space as negatives. However, the state-of-the-art contrastive methods require large batch sizes and augmentations designed for natural images that are impractical for 3D medical images. To address these limitations, we propose a new longitudinal SSL method, 3DTINC, based on non-contrastive learning. It is designed to learn perturbation-invariant features for 3D optical coherence tomography (OCT) volumes, using augmentations specifically designed for OCT. We introduce a new non-contrastive similarity loss term that learns temporal information implicitly from intra-patient scans acquired at different times. Our experiments show that this temporal information is crucial for predicting progression of retinal diseases, such as age-related macular degeneration (AMD). After pretraining with 3DTINC, we evaluated the learned representations and the prognostic models on two large-scale longitudinal datasets of retinal OCTs where we predict the conversion to wet-AMD within a six-month interval. Our results demonstrate that each component of our contributions is crucial for learning meaningful representations useful in predicting disease progression from longitudinal volumetric scans.

Metadata-enhanced contrastive learning from retinal optical coherence tomography images.

Deep learning has potential to automate screening, monitoring and grading of disease in medical images. Pretraining with contrastive learning enables models to extract robust and generalisable features from natural image datasets, facilitating label-efficient downstream image analysis. However, the direct application of conventional contrastive methods to medical datasets introduces two domain-specific issues. Firstly, several image transformations which have been shown to be crucial for effective contrastive learning do not translate from the natural image to the medical image domain. Secondly, the assumption made by conventional methods, that any two images are dissimilar, is systematically misleading in medical datasets depicting the same anatomy and disease. This is exacerbated in longitudinal image datasets that repeatedly image the same patient cohort to monitor their disease progression over time. In this paper we tackle these issues by extending conventional contrastive frameworks with a novel metadata-enhanced strategy. Our approach employs widely available patient metadata to approximate the true set of inter-image contrastive relationships. To this end we employ records for patient identity, eye position (i.e. left or right) and time series information. In experiments using two large longitudinal datasets containing 170,427 retinal optical coherence tomography (OCT) images of 7912 patients with age-related macular degeneration (AMD), we evaluate the utility of using metadata to incorporate the temporal dynamics of disease progression into pretraining. Our metadata-enhanced approach outperforms both standard contrastive methods and a retinal image foundation model in five out of six image-level downstream tasks related to AMD. We find benefits in both a low-data and high-data regime across tasks ranging from AMD stage and type classification to prediction of visual acuity. Due to its modularity, our method can be quickly and cost-effectively tested to establish the potential benefits of including available metadata in contrastive pretraining.

Predicting Topographic Disease Progression and Treatment Response of Pegcetacoplan in Geographic Atrophy Quantified by Deep Learning.

PURPOSE: To identify disease activity and effects of intravitreal pegcetacoplan treatment on the topographic progression of geographic atrophy (GA) secondary to age-related macular degeneration quantified in spectral-domain OCT (SD-OCT) by automated deep learning assessment. DESIGN: Retrospective analysis of a phase II clinical trial study evaluating pegcetacoplan in GA patients (FILLY, NCT02503332). SUBJECTS: SD-OCT scans of 57 eyes with monthly treatment, 46 eyes with every-other-month (EOM) treatment, and 53 eyes with sham injection from baseline and 12-month follow-ups were included, in a total of 312 scans. METHODS: Retinal pigment epithelium loss, photoreceptor (PR) integrity, and hyperreflective foci (HRF) were automatically segmented using validated deep learning algorithms. Local progression rate (LPR) was determined from a growth model measuring the local expansion of GA margins between baseline and 1 year. For each individual margin point, the eccentricity to the foveal center, the progression direction, mean PR thickness, and HRF concentration in the junctional zone were computed. Mean LPR in disease activity and treatment effect conditioned on these properties were estimated by spatial generalized additive mixed-effect models. MAIN OUTCOME MEASURES: LPR of GA, PR thickness, and HRF concentration in µm. RESULTS: A total of 31,527 local GA margin locations were analyzed. LPR was higher for areas with low eccentricity to the fovea, thinner PR layer thickness, or higher HRF concentration in the GA junctional zone. When controlling for topographic and structural risk factors, we report on average a significantly lower LPR by -28.0% (95% confidence interval [CI], -42.8 to -9.4; P = 0.0051) and -23.9% (95% CI, -40.2 to -3.0; P = 0.027) for monthly and EOM-treated eyes, respectively, compared with sham. CONCLUSIONS: Assessing GA progression on a topographic level is essential to capture the pathognomonic heterogeneity in individual lesion growth and therapeutic response. Pegcetacoplan-treated eyes showed a significantly slower GA lesion progression rate compared with sham, and an even slower growth rate toward the fovea. This study may help to identify patient cohorts with faster progressing lesions, in which pegcetacoplan treatment would be particularly beneficial. Automated artificial intelligence-based tools will provide reliable guidance for the management of GA in clinical practice.

Clinical validation for automated geographic atrophy monitoring on OCT under complement inhibitory treatment.

Geographic atrophy (GA) represents a late stage of age-related macular degeneration, which leads to irreversible vision loss. With the first successful therapeutic approach, namely complement inhibition, huge numbers of patients will have to be monitored regularly. Given these perspectives, a strong need for automated GA segmentation has evolved. The main purpose of this study was the clinical validation of an artificial intelligence (AI)-based algorithm to segment a topographic 2D GA area on a 3D optical coherence tomography (OCT) volume, and to evaluate its potential for AI-based monitoring of GA progression under complement-targeted treatment. 100 GA patients from routine clinical care at the Medical University of Vienna for internal validation and 113 patients from the FILLY phase 2 clinical trial for external validation were included. Mean Dice Similarity Coefficient (DSC) was 0.86 ± 0.12 and 0.91 ± 0.05 for total GA area on the internal and external validation, respectively. Mean DSC for the GA growth area at month 12 on the external test set was 0.46 ± 0.16. Importantly, the automated segmentation by the algorithm corresponded to the outcome of the original FILLY trial measured manually on fundus autofluorescence. The proposed AI approach can reliably segment GA area on OCT with high accuracy. The availability of such tools represents an important step towards AI-based monitoring of GA progression under treatment on OCT for clinical management as well as regulatory trials.

[Monitoring of the progression of geographic atrophy with optical coherence tomography]. / Monitoring der Progression von geografischer Atrophie in der optischen Kohärenztomographie.

With the prospect of available therapy for geographic atrophy in the near future and consequently increasing patient numbers, appropriate management strategies for the clinical practice are needed. Optical coherence tomography (OCT) as well as automated OCT analysis using artificial intelligence algorithms provide optimal conditions for assessing disease activity as well as the treatment response for geographic atrophy through a rapid, precise and resource-efficient evaluation.

Deep survival modeling of longitudinal retinal OCT volumes for predicting the onset of atrophy in patients with intermediate AMD.

In patients with age-related macular degeneration (AMD), the risk of progression to late stages is highly heterogeneous, and the prognostic imaging biomarkers remain unclear. We propose a deep survival model to predict the progression towards the late atrophic stage of AMD. The model combines the advantages of survival modelling, accounting for time-to-event and censoring, and the advantages of deep learning, generating prediction from raw 3D OCT scans, without the need for extracting a predefined set of quantitative biomarkers. We demonstrate, in an extensive set of evaluations, based on two large longitudinal datasets with 231 eyes from 121 patients for internal evaluation, and 280 eyes from 140 patients for the external evaluation, that this model improves the risk estimation performance over standard deep learning classification models.

Automated deep learning-based AMD detection and staging in real-world OCT datasets (PINNACLE study report 5).

Real-world retinal optical coherence tomography (OCT) scans are available in abundance in primary and secondary eye care centres. They contain a wealth of information to be analyzed in retrospective studies. The associated electronic health records alone are often not enough to generate a high-quality dataset for clinical, statistical, and machine learning analysis. We have developed a deep learning-based age-related macular degeneration (AMD) stage classifier, to efficiently identify the first onset of early/intermediate (iAMD), atrophic (GA), and neovascular (nAMD) stage of AMD in retrospective data. We trained a two-stage convolutional neural network to classify macula-centered 3D volumes from Topcon OCT images into 4 classes: Normal, iAMD, GA and nAMD. In the first stage, a 2D ResNet50 is trained to identify the disease categories on the individual OCT B-scans while in the second stage, four smaller models (ResNets) use the concatenated B-scan-wise output from the first stage to classify the entire OCT volume. Classification uncertainty estimates are generated with Monte-Carlo dropout at inference time. The model was trained on a real-world OCT dataset, 3765 scans of 1849 eyes, and extensively evaluated, where it reached an average ROC-AUC of 0.94 in a real-world test set.

Comparison of Novel Volumetric Microperimetry Metrics in Intermediate Age-Related Macular Degeneration: PINNACLE Study Report 3.

Purpose: To investigate and compare novel volumetric microperimetry (MP)-derived metrics in intermediate age-related macular degeneration (iAMD), as current MP metrics show high variability and low sensitivity. Methods: This is a cross-sectional analysis of microperimetry baseline data from the multicenter, prospective PINNACLE study (ClinicalTrials.gov NCT04269304). The Visual Field Modeling and Analysis (VFMA) software and an open-source implementation (OSI) were applied to calculate MP-derived hill-of-vison (HOV) surface plots and the total volume (VTOT) beneath the plots. Bland-Altman plots were used for methodologic comparison, and the association of retinal sensitivity metrics with explanatory variables was tested with mixed-effects models. Results: In total, 247 eyes of 189 participants (75 ± 7.3 years) were included in the analysis. The VTOT output of VFMA and OSI exhibited a significant difference (P < 0.0001). VFMA yielded slightly higher coefficients of determination than OSI and mean sensitivity (MS) in univariable and multivariable modeling, for example, in association with low-luminance visual acuity (LLVA) (marginal R2/conditional R2: VFMA 0.171/0.771, OSI 0.162/0.765, MS 0.133/0.755). In the multivariable analysis, LLVA was the only demonstrable predictor of VFMA VTOT (t-value, P-value: -7.5, <0.001) and MS (-6.5, <0.001). Conclusions: The HOV-derived metric of VTOT exhibits favorable characteristics compared to MS in evaluating retinal sensitivity. The output of VFMA and OSI is not exactly interchangeable in this cross-sectional analysis. Longitudinal analysis is necessary to assess their performance in ability-to-detect change. Translational Relevance: This study explores new volumetric MP endpoints for future application in therapeutic trials in iAMD and reports specific characteristics of the available HOV software applications.

Developing and validating a multivariable prediction model which predicts progression of intermediate to late age-related macular degeneration-the PINNACLE trial protocol.

AIMS: Age-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD. METHODS: The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55-90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models. CONCLUSIONS: This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.