Individualised variable-interval risk-based screening in diabetic retinopathy: the ISDR research programme including RCT
Authors: Harding Simon , Alshukri Ayesh , Appelbe Duncan , Broadbent Deborah , Burgess Philip , Byrne Paula , Cheyne Christopher , Eleuteri Antonio , Fisher Anthony , García-Fiñana Marta , Gabbay Mark , James Marilyn , Lathe James , Moitt Tracy , Rahni Mehrdad Mobayen , Roberts John , Sampson Christopher , Seddon Daniel , Stratton Irene , Thetford Clare , Vazquez-Arango Pilar , Vora Jiten , Wang Amu , Williamson Paula 
Published: November 2023

Background
Systematic annual screening for sight-threatening diabetic retinopathy is established in several countries but is resource intensive. Personalised (individualised) medicine offers the opportunity to extend screening intervals for people at low risk of progression and to target high-risk groups. However, significant concern exists among all stakeholders around the safety of changing programmes. Evidence to guide decisions is limited, with, to the best of our knowledge, no randomised controlled trials to date.

Objectives
To develop an individualised approach to screening for sight-threatening diabetic retinopathy and test its acceptability, safety, efficacy and cost-effectiveness. To estimate the changing incidence of patient-centred outcomes.

Design
A risk calculation engine; a randomised controlled trial, including a within-trial cost-effectiveness study; a qualitative acceptability study; and an observational epidemiological cohort study were developed. A patient and public group was involved in design and interpretation.

Setting
A screening programme in an English health district of around 450,000 people.

Participants
People with diabetes aged ≥ 12 years registered with primary care practices in Liverpool.

Interventions
The risk calculation engine estimated each participant’s risk at each visit of progression to screen-positive diabetic retinopathy (individualised intervention group) and allocated their next appointment at 6, 12 or 24 months (high, medium or low risk, respectively).

Main outcome measures
The randomised controlled trial primary outcome was attendance at first follow-up assessing the safety of individualised compared with usual screening. Secondary outcomes were overall attendance, rates of screen-positive and sight-threatening diabetic retinopathy, and measures of visual impairment. Cost-effectiveness outcomes were cost/quality-adjusted life year and incremental cost savings. Cohort study outcomes were rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy.

Data sources
Local screening programme (retinopathy), primary care (demographic, clinical) and hospital outcomes.

Methods
A seven-person patient and public involvement group was recruited. Data were linked into a purpose-built dynamic data warehouse. In the risk assessment, the risk calculation engine used patient-embedded covariate data, a continuous Markov model, 5-year historical local population data, and most recent individual demographic, retina and clinical data to predict risk of future progression to screen-positive. The randomised controlled trial was a masked, two-arm, parallel assignment, equivalence randomised controlled trial, with an independent trials unit and 1 : 1 allocation to individualised screening (6, 12 or 24 months, determined by risk calculation engine at each visit) or annual screening (control). Cost-effectiveness was assessed using a within-trial analysis over a 2-year time horizon, including NHS and societal perspectives and costs directly observed within the randomised controlled trial. Acceptability was assessed by purposive sampling of 60 people with diabetes and 21 healthcare professionals with semistructured interviews analysed thematically; this was a constant comparative method until saturation. The cohort was an 11-year retrospective/prospective screening population data set.

Results
In the randomised controlled trial, 4534 participants were randomised: 2097 out of 2265 in the individualised arm (92.6%) and 2224 out of 2269 in the control arm (98.0%) remained after withdrawals. Attendance rates at first follow-up were equivalent (individualised 83.6%, control 84.7%) (difference –1.0%, 95% confidence interval –3.2% to 1.2%). Sight-threatening diabetic retinopathy detection rates were non-inferior: individualised 1.4%, control 1.7% (difference –0.3%, 95% confidence interval –1.1% to 0.5%). In the cost-effectiveness analysis, the mean differences in complete-case quality-adjusted life years (EuroQol-5 Dimensions, five-level version, and Health Utilities Index Mark 3) did not significantly differ from zero. Incremental cost savings per person not including treatment costs were from the NHS perspective £17.34 (confidence interval £17.02 to £17.67) and the societal perspective £23.11 (confidence interval £22.73 to £23.53). In the individualised arm, 43.2% fewer screening appointments were required. In terms of acceptability, changing to variable intervals was acceptable for the majority of people with diabetes and health-care professionals. Annual screening was perceived as unsustainable and an inefficient use of resources. Many people with diabetes and healthcare professionals expressed concerns that 2-year screening intervals may detect referable eye disease too late and might have a negative effect on perceptions about the importance of attendance and diabetes care. The 6-month interval was perceived positively. Among people with dementia, there was considerable misunderstanding about eye-related appointments and care. In the cohort study, the numbers of participants (total 28,384) rose over the 11 years (2006/7, n = 6637; 2016/17, n = 14,864). Annual incidences ranged as follows: screen-positive 4.4–10.6%, due to diabetic retinopathy 2.3–4.6% and sight-threatening diabetic retinopathy 1.3–2.2%. The proportions of screen-positive fell steadily but sight-threatening diabetic retinopathy rates remained stable.

Limitations
Our findings apply to a single city-wide established English screening programme of mostly white people with diabetes. The cost-effectiveness analysis was over a short timeline for a long-standing disease; the study, however, was designed to test the safety and effectiveness of the screening regimen, not the cost-effectiveness of screening compared with no screening. Cohort data collection was partly retrospective: data were unavailable on people who had developed sight-threatening diabetic retinopathy or died prior to 2013.

Conclusions
Our randomised controlled trial can reassure stakeholders involved in diabetes care that extended intervals and personalised screening is feasible, where data linkage is possible, and can be safely introduced in established screening programmes with potential cost savings compared with annual screening. Rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy are low and show consistent falls over time. Involvement of patients in research is crucial to success.

Future work
Future work could include external validation with other programmes followed by scale-up of individualised screening outside a research setting and economic modelling beyond the 2-year time horizon.

Trial registration
This trial is registered as ISRCTN87561257.

Funding
This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 6. See the NIHR Journals Library website for further project information.