One and Two Year Visual Outcomes from the Moorfields AMD Database - an Open Science Resource for the Study of Neovascular Age-related Macular Degeneration

Objectives To analyse treatment outcomes and share clinical data from a large, single-center, well-curated database (8174 eyes / 6664 patients with 120,756 single entries) of patients with neovascular age related macular degeneration (AMD) treated with anti-vascular endothelial growth factor (VEGF). By making our depersonalised raw data openly available, we aim to stimulate further research in AMD, as well as setting a precedent for future work in this area. Setting Retrospective, comparative, non-randomised electronic medical record (EMR) database cohort study of the UK Moorfields AMD database with data extracted between 2008 and 2018. Participants 3357 eyes/patients (61% female). Extraction criteria were ≥ 1 ranibizumab or aflibercept injection, entry of “AMD” in the diagnosis field of the EMR, and a minimum of one year of follow-up. Exclusion criteria were unknown date of first injection and treatment outside of routine clinical care at Moorfields before the first recorded injection in the database. Main outcome measures Primary outcome measure was change in VA at one and two years from baseline as measured in Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Secondary outcomes were the number of injections and predictive factors for VA gain. Results Mean VA gain at one-year and two years were +5.5±0.5 and +4.9±0.68 letters respectively. Fifty-four percent of eyes gained ≥5 letters at two years, 63% had stable VA (±≤14 letters), forty-four percent of eyes maintained good VA (≥70 letters). Patients received a mean of 7.7±0.06 injections during year one and 13.0±0.2 injections over two years. Younger age, lower baseline VA, and more injections were associated with higher VA gain at two years. Conclusion This study benchmarks high quality EMR study results of real life AMD treatment and promotes open science in clinical AMD research by making the underlying data publicly available. Strengths and limitations of this study - Large sample size, retrospective, single centre, electronic medical record database study - High quality real life data - Open science approach with sharing of depersonalised raw data


Disclosure / Funding
Results: Mean VA gain at one-year and two years were +5.5±0. 5

Statistical Analysis:
The data were analysed using the statistics software R (https://www.r-project.org/; provided in the public domain by R Core team 2017 R Foundation for Statistical Computing, Vienna, Austria).
The ggplot2 package was used for plots. The eye was defined as unit of analysis. Descriptive statistics included mean +/-95% confidence interval (CI), and median, where appropriate.
Differences between groups were evaluated using Mann Whitney U test and Pearson Chi-Square. Regression analysis was performed to assess relationship of predictive factors and VA gains. A p value of < 0.05 was interpreted as statistically significant.

Patient and Public Involvement:
Patients and public were not involved in the study as this was a retrospective cohort study.

Data Sharing Statement:
De-personalised data for this study will be openly available from the Dryad Digital Repository https://doi.org/10.5061/dryad.97r9289. Depersonalisation was carried out through hash function anonymisation of patient identification numbers, replacement of appointment dates with follow-up days to baseline, and categorising extreme age groups into age categories.

Approval of adequate depersonalisation was obtained by Moorfields Information
Governance.

Patient Demographics:
The

Visual outcomes at one and two years
Mean VA gain at one and two years were +5.5±0. 5

Determinants of change in VA at one and two years
Regression to predict change in VA at one and two years from gender, baseline age,  Figure 3).

DISCUSSION
In this study, we show that patients treated with ranibizumab and/or aflibercept for neovascular AMD at Moorfields Eye Hospital achieve good visual outcomes, particularly those patients who present at an earlier age with better visual acuity, and who subsequently receive frequent intravitreal injections.
The Moorfields AMD Database is a large, consistent, and clean dataset of neovascular AMD treatment and visual outcomes, perhaps the largest single-center dataset of its kind worldwide. We have made this freely available to download with this manuscript in an effort to benefit the AMD research community. At a minimum this will allow for use of alternative statistical approaches and facilitate research reproducibility. (21) We also hope it will allow for the testing of new hypotheses and thus provide new insights into the treatment of this condition. (27) We have also developed systems so that the Moorfields AMD Database is automatically updated over time, with minimal need for manual cleaning of data.
Just under 1000 new cases of neovascular AMD present to Moorfields Eye Hospital on a yearly basis -this may be particularly useful as new therapeutics for AMD continue to be introduced. Additionally, we plan on releasing data for long-term follow-up of these (five years and beyond), as well as their associated raw imaging data (colour fundus photography and optical coherence tomography (OCT) imaging in every eye at every visit).
At one and two years, our results of mean VA gains confirm the existing evidence in real-life studies, e.g., the Fight Retinal Blindness (FRB) group in Australia/New Zealand for ranibizumab/aflibercept with nearly identical baseline characteristics and visual acuity outcomes for mixed ranibizumab/aflibercept treatment (   vision has deteriorated and rendered further treatment unreasonable, or they are not able to further attend clinics. We deliberately did not perform any imputational replacement of missing data, but clearly describe the baseline characteristics and compare the one year results of the cohort LTFU before two years. (12) VA gain over time is dependent on baseline characteristics and injection frequency. (12,14,29) Increasing age diminishes the VA gain expected as does a higher baseline acuity due to ceiling effect. (30) Baseline VA could even emerge as a surrogate measure for accessibility to treatment and quality of care, since simply looking at VA gains would underestimate centers that achieve short time from diagnosis to first treatment resulting in above average baseline VA but ceiling effect on VA gains. (8,12,16) Injection frequency has been recognised as another significant factor influencing VA gain and has been hypothesised to be the major factor in studies comparing ranibizumab and aflibercept due to the change in posology from treatment as needed to treat-and-extend concomitant with the change from ranibizumab to aflibercept in clinical practice. (14,29,31,32).
The retrospective nature and EMR-based data collection of our study introduce several limiting factors. Smoking status of our patients was not consistently available and thus, could not be included in the prediction model. Smoking has been identified as a risk factor for the development of neovascular AMD, but might also impact treatment response. (33) There is invariably survival bias within the data, as LTFU cannot be assumed to occur at random. However, baseline characteristics of LTFU as well as differences in outcomes for one and two year follow-up cohorts have been clearly described to address this. To date, there is no systematic collection of patient-reported outcome measures (mobility and independence, emotional well-being, as well as reading and accessing information questionnaires) as suggested by ICHOM. (22) The main advantages of this study are the quality and amount of data coming from one single center and one database.
Moorfields Eye Hospital has a standardised treatment protocol for neovascular AMD, formerly treatment as needed, and fixed-first year/treat-and extend regimen with the introduction of aflibercept in 2014 (flow chart for aflibercept use is shown in Supplementary   2). The extensive manual cleaning and the homogeneous standards of data input (VA in ETDRS letters, mandatory fields) have formed a highly reliable resource which will be enhanced in the future with an automated update and validation to allow for continued growth and quality improvement of clinical AMD data.
In conclusion, this study shows that with a diligent approach, analysis of well maintained EMR data can lead to high quality real-life results and electronic availability of data facilitates maximisation of its potential in sharing research resources with the community, ultimately with the goal of improving patient care in real-life. In the near future, we plan to report on long-term visual outcomes (e.g., after 5-years), anatomic outcomes, and fellow-eye involvement, as well as the differential therapeutic effects of ranibizumab and aflibercept. In each case, we plan to release the raw data that underpins these reports -we hope that this will help promote an open-science approach to the study of neovascular AMD, and thus to direct patient benefit in the longer term.

Author / contributorship statement
Katrin Fasler has drafted the manuscript and contributed to data acquisition, analysis, and interpretation of data. She is accountable for all aspects of the work and has approved for the final version to be published.   Bars represent 95% confidence intervals.