Screening Intervals for Diabetic Retinopathy and Implications for Care

Purpose of Review The purpose of this study is to review the evidence that lower risk groups who could safely be screened less frequently for sight-threatening diabetic retinopathy (DR) than annually. Recent Findings Data have demonstrated that people with no DR in either eye are at a low risk of progression to sight-threatening DR over a 2-year period (event rate 4.8 per 1000 person years), irrespective of whether the screening method is one-field non-mydriatic or two-field mydriatic digital photography. Low risk has been defined as no retinopathy on two consecutive screening episodes or no retinopathy on one screening episode combined with risk factor data. Summary The risk of an extension to 2 years is less than 5 per 1000 person years in a population with a national screening programme, and the general standard of diabetes care is relatively good, whether low risk is defined as no retinopathy on two consecutive screening episodes or no retinopathy on one screening episode combined with other risk factor data. The definition used in different populations is likely to depend on the availability of data.


Introduction
In the UK, the Office for National Statistics publishes an interesting graph of life expectancy over the last two centuries [1], and this has demonstrated that life expectancy has doubled from 40.2 years for men and 42.2 years for women to 79 and 82.8, respectively. Life expectancy has risen around the world and, although there are still differences between countries, even countries with lower levels of life expectancy have also almost doubled their life expectancy during the last two centuries [2].
The increased life expectancy has led to a change in the nature of the diseases we are treating. There are many more patients in older age groups with chronic diseases such as diabetes and cancer. There is an epidemic of diabetes [3,4] around the world, which has led to an epidemic of diabetic retinopathy (DR) [5].
Various DR screening programmes have been set up around the world. Population-based screening programmes tend to be more successful in countries with state-run nationalised health systems because of the infrastructure and finance that is in place to support these programmes. Early pioneering work on screening for DR was conducted in Iceland [6,7] and Sweden [8], and this was later introduced in the UK [9][10][11], in other European countries [12][13][14] and in Singapore [15]. In the USA and Australia, screening programmes have tended to be in indigenous populations [16][17][18], linked to diabetes clinics [19], in Veterans Administration Healthcare systems [20], or in research programmes [21]. There has also been interest in the development of screening programmes for DR in India [22], China [23], and South America [24]. In England, the epidemic of diabetes has proved to be a problem for the screening programme because of the increasing numbers each year. When screening was introduced in England in 2003, it was believed that there were approximately 1.4 million people with diabetes who needed to be screened, and this number has risen to 2.6 million.
The annual report [25] of National Health Service (NHS) screening programmes in England 2015-2016 reported that there were 2.59 million people with diabetes offered screening with 2.14 million being screened (an uptake of 82.8%) with urgent referrals for proliferative DR of 7593 and routine referrals of 52,597. Routine referrals are either for moderate to severe non-proliferative DR or signs of maculopathy using two-dimensional markers. The rate of referable retinopathy per 100,000 screened was 2807. In the same period (2015-2016), the largest number of new registrations of people with diabetes was recorded-326,587.
In the first and second rounds of screening, the referable retinopathy rate was considerably higher than in subsequent rounds of screening. For example, in the Gloucestershire screening programme, the referable rate of retinopathy was 11.2% in the first round of screening in 1998-2000 [26]. In addition, in populations who are screened for diabetes [27][28][29], which is becoming more common, the rate of any DR is much lower (7.6, 6.8, and 9%) than the prevalence in a known population of people with diabetes. In a review of 35 studies by Yau [30], the overall prevalence of any DR was 34.6% (95% confidence interval (CI) 34.5-34.8), 6.96% (6.87-7.04) for proliferative DR, 6.81% (6.74-6.89) for diabetic macular oedema, and 10.2% (10.1-10.3) for visionthreatening DR.

Purpose of This Review
These factors have all led to the need to re-evaluate the need for annual screening for the whole population of people with diabetes and ascertain whether there are lower risk groups who could safely be seen less frequently.

Methods
The author has conducted an on-going literature review since March 2000 utilising Zetoc [31] which provides access to over 30,000 journals and more than 52 million article citations and conference papers through the British Library's electronic table of contents.
The contents' page lists of 27 journals, considered to be those most likely to publish articles relevant to this topic, are also reviewed each month. Articles of interest identified with this search strategy were sourced from the local NHS Trust library or online from electronic journal resources.

Results
I have identified 26 articles relevant to the purpose of this review. Most of these articles come from established national or regional screening programmes with good population coverage and a relatively high standard of diabetes care, and so these findings may not be applicable to areas where the standard of diabetes care is not as high or where screening is not established.
The study concluded that screening at 2-3-year intervals, rather than annually, for patients without retinopathy in type 1 diabetes is feasible because of the low risk of progression to sight-threatening DR.
In type 2 diabetes [33], 4770 patients underwent 20,570 screening events. Yearly incidence of sight-threatening DR in 3743 patients without retinopathy at baseline was 0.3% (95% CI 0.1-0.5) in the first year, rising to 1.8% (1.2-2.5) in the fifth year; cumulative incidence at 5 years was 3.9% (2.8-5.0). The study concluded that a 3-year screening interval could be safely adopted for patients with no retinopathy.

2.
In 2007, Olafsdottir [34] reported that 296 patients with diabetes in Iceland who had no DR in 1994/1995 were followed with biennial eye examinations until they developed any retinopathy when they were reviewed with annual eye examinations. Over the 10-year period, 172 did not develop any retinopathy, 96 developed mild nonproliferative DR, 6 developed clinically significant macular oedema, 23 developed moderate to severe nonproliferative DR, and 4 developed proliferative DR. All those who developed macular edema or proliferative DR had already been diagnosed with mild non-proliferative DR and entered annual screening before progressing to this level at a subsequent screening event. They concluded that biennials screening for those without retinopathy was safe. 3. In 2009, Misra et al. [35] [37] reported the experience of adopting 3-year screening intervals for sight-threatening retinal vascular lesions in subjects with type 2 diabetes without retinopathy in Sweden. 1691 subjects with type 2 diabetes and no detectable retinopathy in two 50°red-free fundus photographs were scheduled for follow-up with photography 3 years later. Age at diabetes diagnosis was 60 ± 12 years, and known duration of diabetes was 6 ± 6 years. Treatment consisted of diet only (26%), oral agents (54%), and oral agents and/or insulin (20%). Glycated hemoglobin (HbA1c) was 6.4 ± 1.5%. Of the 1322 subjects available for follow-up, 73% were still without retinopathy after 3 years, and 28% had developed mild or moderate retinopathy, but none developed severe non-proliferative or proliferative retinopathy. Macular edema requiring laser coagulation occurred in only one eye. The study concluded that 3-year retinal screening intervals can be recommended in subjects with type 2 diabetes and no retinopathy. 6. In 2013, Scanlon [38] reported that the risk of progression of DR is significantly higher for those with background DR in both eyes than those with background retinopathy in only one or in neither eye. Prior to these low-risk groups were generally regarded to be those people with no DR in either eye. 7. In 2013, Porta [39] published the clinical characteristics influencing screening intervals for DR. The cumulative incidence, time of development, and relative risk of developing referable retinopathy over 6 years following a negative screening for DR were calculated in 4320  [47] reported the sensitivity of DR-associated vision loss to screening interval in an agent-based/discrete event simulation model to examine the effect of changes to screening interval on the incidence of vision loss in a simulated cohort of veterans with DR. DR-associated vision loss increased as the screening interval was extended from 1 to 5 years (p < 0.0001). This increase was concentrated in the third year of the screening interval (p < 0.01). There was no increase in vision loss associated with increasing the screening interval from 1 to 2 years (p = 0.98). 7. In 2016, Lund [48] reported a study to validate a mathematical algorithm [42] that calculates the risk of DR progression in a diabetic population with the UK staging (R0-3; M1) of DR. A cohort of 9690 individuals with diabetes in England was followed for 2 years. The algorithms calculated the individual risk for development of pre-proliferative retinopathy (R2), active proliferative retinopathy (R3A), and diabetic maculopathy (M1) based on clinical data. The algorithm predicts the occurrence of the given DR stages with area under the curve = 80% for patients with type 2 diabetes (CI 0.78 to 0.81). Of the cohort, 64% is at less than 5% risk of progression to R2, R3A, or M1 within 2 years. By applying a 2-year ceiling to the screening interval, patients with type 2 diabetes are screened on average every 20 months, which is a 40% reduction in frequency compared with annual screening.
C. Cost-effectiveness studies a) Long intervals between follow-up visits may lead to difficulties in maintaining contact with patients and may give patients the impression that vision loss is unlikely and therefore not a concern. b) That it might be better to have a conservative guideline of yearly examinations with deviations based on evaluation of risk (glycemic and blood pressure control) rather than having a uniformly long interval. c) The ability to generalise the observations of the Liverpool study to other screening situations will depend on the comparability of the population of people with diabetes being screened to those in the Liverpool study and the sensitivity of the approaches used to detect sightthreatening DR and other ocular conditions.

2.
In 2013, Leese [52] wrote a commentary exploring the evidence for moving towards a biennial retinal screening programme for patients with type 2 diabetes and diabetes duration of less than 10 years. He also explained that a UK-Four Nations group was critically looking at the evidence for any such changes.

E. Studies of patient behavior or opinions of extending the screening interval
In 2012, Yeo conducted two studies [53,54]: a) The first [53] was based on 1550 questionnaires distributed at DR clinics in Wales, with 600 complete responses analysed. Eighty-five percent (n = 507) felt that they should have their eyes screened every year. However, 65% (n = 390) of respondents would accept screening at 2-or 3-year intervals if medical evidence showed that it was safe. b) The second [54] was based on a response rate of 86.4% from the 198 questionnaires administered at clinics, which included a discrete choice experiment contained eight pairwise choices in which screening provision was described by five attributes: frequency of screening, travel time, results time, ability of screening to detect other changes, and explanation of results. Data were analysed using logistic regression techniques. Respondents valued four out of the five attributes [ability of screening to detect other changes (P < 0.001), explanation of results (P = 0.02), frequency of screening (P < 0.001), and travel time (P = 0.007)]. Results time was not significant (P = 0.1). The study concluded that respondents were willing to accept a longer screening interval, as long as preferences for other attributes of service provision (ability of screening to detect other changes, explanation of results and travel time) were made available.
F. Review articles on screening intervals  [57] the evidence available. They recommended a change from 1-to 2-year screening intervals for people at a low risk of sight loss. The definition of low risk is two successive diabetic eye screening appointments with photographic grading of no DR. They recommended that the current annual screening interval should remain for all those with mild retinopathy detected in either eye. They provided four appendices as evidence, which included work by the groups that had previously published [40•, 56]. They also provided a supplementary literature review on 'Does a change in screening interval lead to a subsequent change in uptake?' This review was unable to find sufficient evidence to support the notion that a change in screening interval would result in a change in uptake of a screening programme. There was also an assessment by UK Department of Health Economists that is available on the website, using a cost-utility approach, whether it is cost-effective to change screening intervals, within the NSC diabetic eye screening programme, according to patient risk, using pre-publication results from Health Economists at Oxford University who had worked on the HTA project-Scanlon [50••].

Conclusions
The data from real-world screening programmes has demonstrated that people with diabetes who have no DR in either eye are at the low risk of progression to referable or sightthreatening DR over a 2-year period (event rate 4.8 per 1000 person years). Low event rates appear to be irrespective of whether the diagnosis of no DR is based on one-field nonmydriatic photography as is used in the protocol in Scotland [46] or northern Spain [36] or whether it is based on 2-field mydriatic digital photography as is used in other UK countries [32,33,35] and Sweden [37]. Data was combined between these methods in the Four Nations Study [40•].
It is important to recognise, as pointed out by Professor Klein in his 2003 article [51] that the generalizability of these observations to other screening situations will depend on the comparability of the population of people with diabetes being screened and the sensitivity of the approaches used to detect sight-threatening DR and other ocular conditions.
Cost-effectiveness studies [49, 50••] have suggested that annual screening for all people with diabetes may no longer be cost-effective.
There have been suggestions that the screening interval should be lengthened to 2 years for 'low risk groups' which has been variably defined by the following: 1. Two screening episodes with individualised risk factor data 2. Two screening episodes with no retinopathy 3. One screening episode with individualised risk factor data The only study that compared area under the curve of the receiver operator curves for these three groups was the Health Technology Assessment study by Scanlon [50••] which found the following: 1. Two screening episodes with individualised risk factor data-AUC 0.786 (95% CI 0.759 to 0.813) 2. Two screening episodes with no retinopathy-AUC 0.759 (95% CI 0.732-0.788) 3. One screening episode with individualised risk factor data-AUC 0.774 (95% CI 0.748-0.800) In order to add in the risk factor data to screening data, there needs to be links available to this extra data that are not readily available to many population-based screening programmes. Hence, the UK National Screening Committee has recommended a change from 1-to 2-year screening intervals for people who have two successive diabetic eye screening appointments with photographic grading of no DR.
There is a large gap in knowledge and research on how this will affect individual patient behaviors and attendance for screening programmes. Work by Yeo [53,54] has suggested that respondents would accept screening at 2-or 3-year intervals if medical evidence showed that it was safe and as long as preferences for other attributes of service provision (ability of screening to detect other changes, explanation of results and travel time) were made available. However, there is no current evidence of patient's behavior in these circumstances. There is an on-going concern that if patients are told that they are at the low risk of progression that: 1. They may make less effort in the control of their diabetes and hence put themselves at a greater risk. 2. They may be less likely to attend in the future.
A currently funded project in Liverpool, UK [58] is studying the introduction of personalised screening intervals and may help to answer some of these questions in similar populations.

Compliance with Ethical Standards
Conflict of Interest P.H. Scanlon declares that he has no conflict of interest.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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