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Introduction
Diabetic retinopathy (DR) – a complication of diabetes – is caused by high blood sugar levels damaging the retina at the back of the eye*. If left untreated, it can lead to blindness. Treatments are available for the commonest causes of sight-threatening DR: diabetic macular oedema and proliferative DR.
In India, DR is emerging as the leading cause of vision impairment and blindness, affecting an estimated 77 million people with diabetes and another 44 million with undiagnosed diabetesª. Currently, the only way of diagnosing DR is by an annual retinal examination. In the UK, screening for DR costs about £35 per person, or £140 million in total for the four million people with diabetes in the UK. However, India remains without a systematic national or state-wide screening programme for DR, and it remains a challenge to screen the 77 million people with diabetes annually. There is a need to develop alternative approaches for identifying and treating those at risk of visual impairment due to DR, which is what lies behind the ORNATE-India study.
* Information about diabetic retinopathy is available on the Moorfields website here.ª See Raman R, Gella L, Srinivasan S, Sharma T. Diabetic retinopathy: An epidemic at home and around the world. Indian J Ophthalmol 2016; 64: 69-75.
The study is led by Professor Sobha Sivaprasad* and is based jointly at Moorfields Eye Hospital and the UCL Institute of Ophthalmology. It involves collaboration between six UK institutions and seven institutions in India, including the Government of Kerala.
In this Q&A, we talk to Dr Dolores Conroy, ORNATE-India’s Project Manager, who coordinates the activities of diabetologists, ophthalmologists, biostatisticians, health economists, project managers, computer scientists and biomedical researchers from the UK and India. Dr Conroy is based at the UCL Institute of Ophthalmology.
* Professor Sobha Sivaprasad is supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology.
1. Dr Dolores Conroy. Credit: ORNATE-India team
How did the ORNATE-India project come about?
In 2017, the Global Challenges Research Fund (GCRF)* made grants available over 5 years to support cutting-edge research addressing challenges faced by low- to middle-income countries. Professor Shoba Sivaprasad, a consultant ophthalmologist at Moorfields Eye Hospital, was awarded a grant of £6.3 million for the ORNATE-India project to address the burden of blindness due to DR in India, for a period of 51 months from 1 October 2017.
I am responsible for the day-to-day project management of ORNATE-India, supporting and coordinating the research activities to achieve the project’s objectives, including finance and compliance with ethical and data protection regulations. I have developed and implemented robust processes and supporting documents to monitor the project’s progress, which we continuously measure against our objectives. It was a natural evolution for me, having worked for nine years at the charity Fight for Sight.
* Find out more about the GCRF here.
2. Field worker screening for diabetic retinopathy using a Zeiss camera as part of the SMART India workstream. Credit: ORNATE-India team
What are the aims of ORNATE-India?
The main aim of the project is to build research capacity, both in the UK and India, to address blindness due to DR in India*. The project is organised into five inter-related work packages [sub-projects]. Work package 1 is made up of two studies: 1) The SMART-India study, which aims to evaluate the regional prevalence of pre-diabetes, diabetes and DR, and assess ideal tests for holistic screening for diabetes and its complications in 20 areas in India; and 2) the Nayanamrithram study, which aims to pilot a DR care pathway in the public health system in Kerala.
In work package 2, we are developing deep-learning algorithms to grade the retinal images taken by field workers on hand-held non-mydriaticª smartphone-based retinal cameras, as part of the SMART-India study, to facilitate DR screening.
In work package 3, we are investigating whether circulating biomarkersº can be used to identify sight-threatening DR. This prospective, multicentre, case control studyⁿ is being conducted in parallel in the UK and India, and we are currently analysing 12 circulating biomarkers. If any of these biomarkers are found to be predictive of sight-threatening DR, we are planning to incorporate them into affordable biosensors that could be used by patients to monitor DR.
Work package 4 is evaluating the cost of blindness in people with diabetes, the cost-effectiveness of the SMART-India study telemedicine approach, and the DR care pathway in the Nayanamrithram study.
Work package 5 focuses on risk-modelling studies. We are using multiple databases from primary and secondary care – and previous epidemiological studies from diverse ethnic cohorts – to develop, validate and calibrate risk models on various aspects of diabetes and its complications, so that they can be applied to India and other low- and middle-income countries. In addition, we are developing a large India Retinal Research Network to increase research capability in India.
* See: Sivaprasad, S., Raman, R., Conroy, D. et al. The ORNATE India Project: United Kingdom–India Research Collaboration to tackle visual impairment due to diabetic retinopathy. Eye 34, 1279–1286 (2020).
ª ‘Non-mydriatic’ means that the pupils do not need to be dilated, which makes it much easier to take images outside of a clinical setting.
º A ‘biomarker’ is a biological molecule found in the body that shows normal or abnormal processes, or indicates a disease or condition.
ⁿ A ‘case control’ study involves patients who have already been identified as having a disease and looks at factors that may be associated with it.
Can you tell us more about the Nayanamrithram pilot study?
Kerala, in the south, is one of the states with the highest prevalence of diabetes*, with up to 20% of people aged 30 years or above having diagnosed or undiagnosed diabetes . The Government of Kerala had recently innovated in various health sectors, including the non-communicable disease sector. They had initiated screening for end-organ damage in people with diabetes within the public health system, but there was no systematic screening programme for DR.
The Nayanamritham study was a partnership between the ORNATE-India team in the UK and the Government of Kerala. It aimed to pilot a DR care pathway in the public health system, spanning primary, secondary and tertiary care in the Thiruvananthapuram district in Kerala by adapting the NHS Diabetic Eye Screening Programme to the needs of the local population.
Firstly, we set about building capacity to conduct the pilot study. We created an educational programme and trained nurses and doctors in the family health centres on DR management. In addition, the nurses were trained to take retinal images using handheld smartphone-based retinal cameras (Remidio, image 3), provided by the ORNATE-India grant. We had intended do the screening through undilated pupils, but it was necessary to dilate to increase the gradabilityª of the retinal images. Data entry operators were trained to collect the research data, which included demographics, education, personal lifestyle (smoking, alcohol, and physical activity), family history, blood pressure, body mass index, and waist circumference.
* See: Vijayakumar, G., Manghat, S., Vijayakumar, R. et al. Incidence of type 2 diabetes mellitus and prediabetes in Kerala, India: results from a 10-year prospective cohort. BMC Public Health 19, 140 (2019). ª ‘Gradability’ is the ease with which images can be graded (read and interpreted).
3. Portable battery-operated Remidio camera used for diabetic retinopathy screening at the family health centres. Credit: ORNATE-India team
A reading centre was set up at the Regional Institute of Ophthalmology (RIO), a specialist eye care centre, where two accredited optometrists graded the retinal images. The results were sent back to the family health centres. Patients identified with sight-threatening DR, or whose retinal images were ungradable, were referred to four district hospitals. Those with sight-threatening DR received laser treatment. The laser equipment was purchased for each hospital, and the ophthalmologists received training in laser surgery. More complex cases of DR were treated at the RIO.
Patients with diabetes, who attended one of 16 family health centres for their routine clinical care, were invited for screening. They embraced the DR screening programme, and 5,307 patients were screened for DR during this pilot study. Of these, 1,662 (31.3%) were referred to a secondary centre for treatment of sight-threatening DR, or because their images were ungradable.
Based on the successful implementation of this pilot DR care pathway, the Government of Kerala implemented a policy to integrate DR screening in primary care, and decided to up-scale the pathway to other districts in Kerala. We are currently studying the cost and cost-effectiveness of the DR care pathway in the public health system.
Could you tell us more about the teleophthalmology approach used in the SMART-India study?
This cross-sectional, community-based, house-to-house study across 20 sites in India will provide data on the prevalence of diabetes, DR and other complications of diabetes. It will also develop practical and affordable models to (a) diagnose people with diabetes and pre-diabetes and (b) identify those at risk of diabetes complications. The aim is for these models to be applied to the population in low- and middle-income countries, where laboratory tests are unaffordable. The study protocol was developed jointly with our collaborators in India.
Two or more field workers at each of the 20 sites were trained in the study protocol, data collection and entry into the cloud-based database, point-of-care blood tests (random blood glucose, HbA1c*, lipids), urine microalbuminuriaª, blood pressure, anthropometric measurementsº, vision test and obtaining good quality retinal images using a non-mydriatic handheld retinal camera (Zeiss Visuscout 100TM).
* The HbA1c test (also known as the haemoglobin A1c or glycated haemoglobin test) is a blood test that indicates how well a patient’s diabetes is being controlled.ª Also know as ‘urine albumin to creatinine ratio’ (ACR), this helps identify kidney disease that can occur as a complication of diabetes.º Measurements of different parts or tissues of the body.
4. Field workers screening for diabetic retinopathy in a community setting (SMART India workstream) using the Zeiss camera. Credit: ORNATE-India team
A teleophthalmology system was set up whereby the retinal images captured by each fieldworker were uploaded to a cloud-based database and graded by retinal graders, optometrists and ophthalmologists (primary graders) at the local clinical centre. The images were also transferred to four central reading centres, where grading was done by a second ophthalmologist (secondary grader). A senior retinal consultant arbitrated in case of any discrepancies between primary and secondary graders.
Centre administrators at each of the 20 sites were responsible for ensuring completion of retinal image grading, informing participants of the outcome of the grading and coordinating with the participants, who were referred for sight-threatening DR and other findings requiring referral.
We collected data on 57,808 participants across India, from urban, rural and special populations, including high-risk groups, such as cab drivers, and more isolated communities, such as religious orders and tribes. We are currently analysing the data.
Are there any difficulties or challenges that arise from working on an international project?
There are challenges, undoubtedly. Some of the investigators in India had little experience of multidisciplinary collaborative research, developing study protocols, obtaining ethics approvals, data management, etc.
We underestimated the time it would take to build research capacity to execute epidemiological and clinical studies related to DR, especially the number of training sessions required to get field workers/nurses adequately trained in data collection, including retinal imaging and data management. Another difficulty we encountered was the lack of reliable internet access, which meant that it was sometimes necessary for the field workers to collect participants’ data in paper format, rather than entering it directly into the study database.
It was equally difficult to establish a link between DR screening at primary level and treatment in secondary/tertiary care. Furthermore, secondary care hospitals do not maintain any form of outcome register. These are challenges faced by most low- and middle-income countries, as significant resources are required to establish such electronic linkages. In addition, the patients who were referred to secondary care for treatment for sight-threatening DR were often reluctant to attend.
Do you know why is the take-up for treatment is so low?
This is a challenge we faced in both the Nayanamrithram and SMART-India studies. Many of those referred for treatment for sight-threatening DR have been reluctant to get treatment, even though it is provided free of charge.
We conducted interviews with patients in the Nayanamrithram study who attended for treatment and those who did not. The reasons for non-attendance were broadly categorised into knowledge and perception, physical challenges and inconvenience. Interestingly, in the knowledge and perception category, most patients reported that they did not have an eye problem. This is because in the early stages of DR, patients are asymptomatic. Clearly, more work needs to be done to raise public awareness of diabetes-related sight loss in India.
How has COVID-19 affected ORNATE-India?
The project was running to plan until March 2020, when the COVID-19 pandemic affected progress in the UK and India. We successfully completed our pilot DR screening programme in Kerala, with over 5,000 people with diabetes screened for DR in primary care, and those requiring treatment referred to secondary care. However, the upscaling of the DR care pathway across the state of Kerala has been paused while the Government of Kerala concentrates its efforts on the pandemic.
The SMART India study was stopped in March 2020 as it was unsafe for the field workers to continue with the required house-to-house visits. At that stage, we had sufficient sample size for the statistical analyses, with over 57,000 participants recruited to the study, and this analysis is ongoing. However, treatment of participants identified with sight-threatening DR has been delayed due to the closure of most eye clinics, and even when clinics have remained open, lack of transport has been a problem.
In order to continue to build research capacity and engage with our collaborators in India during the lockdown, we embarked on two new studies. In the first study, we evaluated the impact on health and provision of healthcare services during the COVID-19 lockdown on the participants in the SMART India study. This was done by a telephone survey conducted at the 20 clinical sites, following appropriate online training of the health workers. In the second study, we are doing a qualitative study to understand the barriers to accessing treatment for patients with sight-threatening DR.
We have been lucky in the UK, as most of the researchers are doing studies using data, so they have been working remotely. Of course, all face-face training in India has been replaced by virtual training sessions. However, the setting up of UK-India online meetings also boosted more collaborative work and increased publication rates from India.
What are the outputs from ORNATE-India?
The ORNATE-India project is producing significant outputs, with over 40 publications to date*. Of course, the successful implementation of this pilot DR care pathway in the public health system in Kerala, and the upscaling of the pathway by the Government of Kerala to other districts in the state, are major outcomes from the project.
In addition, as a result of ORNATE-India, an India Retinal Disease Study Group has been set up in India to drive high-quality research to answer relevant questions relating to diabetes in India and its complications. This group of retinal specialists from across India is working together to analyse several retrospective and longitudinal studies in diabetes and diabetic-related eye diseases. They are publishing their findings, which will help to develop clinical management guidelines for DR in India.
Working with the All India Ophthalmological Society, we have also developed guidelines for DR screening in India.
The principal aim of ORNATE-India is to build research capacity, and we have up-skilled many healthcare personnel. For example, generalist nurses in the family health centres are now doing DR screening, ophthalmologists have been trained to do laser treatment, and health workers are doing epidemiological studies.
In addition to focusing on capacity-building, ORNATE-India has resulted in fruitful collaborative partnerships built on mutual trust and shared decision-making. We cannot travel to India regularly because of our commitment to reducing our carbon footprint (and limited finances), and now due to the COVID-19 pandemic, but the study group meets virtually on a regular basis.
I believe that our research programme is increasing public awareness of diabetes and diabetic eye disease in India. We also have an advocacy lead for the study in India, and over 400 accredited social health activists (community health workers) have been trained – as part of the Nayanamrithram study – to increase public awareness of diabetes and its complications, and to encourage uptake of DR screening in primary care.
* See a list of publications on the ORNATE-India website here.
Find out more
Visit the ORNATE-India website: http://ornateindia.net/
See a report on the impact of ORNATE-India on the UCL website: https://www.ucl.ac.uk/research/support-staff/global-research-funding/global-impact-ucl-research/ornate-india
See information about diabetic retinopathy on the Moorfields website: https://www.moorfields.nhs.uk/condition/diabetic-retinopathy
See the ORNATE-India research paper (May 2020): Sivaprasad, S., Raman, R., Conroy, D. et al. The ORNATE India Project: United Kingdom–India Research Collaboration to tackle visual impairment due to diabetic retinopathy. Eye 34, 1279–1286 (2020), https://doi.org/10.1038/s41433-020-0854-8
See the SMART India research paper (December 2020): ‘Protocol on a multicentre statistical and economic modelling study of risk-based stratified and personalised screening for diabetes and its complications in India (SMART India)’: https://doi.org/10.1136/bmjopen-2020-039657
6. ORNATE-India logo.
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