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Stratton, I M, Aldington, S J, Taylor, D J, Adler, A I and Scanlon, Peter H ORCID: 0000-0001-8513-710X (2013) A Simple Risk Stratification for Time to Development of Sight-Threatening Diabetic Retinopathy. Diabetes Care, 36 (3). pp. 580-585. doi:10.2337/dc12-0625

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A Simple Risk Stratification for Time toDevelopment of Sight-ThreateningDiabetic RetinopathyIRENE M. STRATTON, MSC, FFPH

1

STEPHEN J. ALDINGTON, DMS1

DAVID J. TAYLOR, BTECH2

AMANDA I. ADLER, MD3

PETER H. SCANLON, MD1

OBJECTIVEdThe American Diabetes Association and the English NHS Diabetic Eye Screen-ing Program recommend annual screening for diabetic retinopathy (DR) with referral to oph-thalmology clinics of patients with sight-threatening DR (STDR). Using only longitudinal datafrom retinal photographs in the population-based NHS Diabetic Eye Screening Program inGloucestershire, we developed a simple means to estimate risk of STDR.

RESEARCH DESIGN AND METHODSdFrom 2005, 14,554 patients with no DR ormild nonproliferative DR only at two consecutive annual digital photographic screenings werecategorized by the presence of DR in neither, one, or both eyes at each screening and werefollowed for a further median 2.8 years.

RESULTSdOf 7,246 with no DR at either screening, 120 progressed to STDR, equivalent to anannual rate of 0.7%. Of 1,778 with no DR in either eye at first screening and in one eye at secondscreening, 80 progressed to STDR, equivalent to an annual rate of 1.9% and to a hazard ratio (HR)of 2.9 (95%CI 2.2–3.8) compared with those with no DR. Of 1,159 with background DR in botheyes at both screenings, 299 progressed to STDR equivalent to an annual rate of 11% and an HRof 18.2 (14.7–22.5) compared with individuals with no DR.

CONCLUSIONSdCombining the results from 2 consecutive years of photographic screen-ing enables estimation of the risk of future development of STDR. In countries with systematicscreening programs, these results could inform decisions about screening frequency.

Diabetes Care 36:580–585, 2013

D iabetic retinopathy (DR) is a com-plication of diabetes that can lead toblindness. The American Diabetes

Association recommends (1) annual eyeexaminations for all people with diabetesmellitus (DM) and the English NHS Di-abetic Eye Screening Program (2) recom-mends annual screening for DR; both setsof recommendations have the goal of re-ferring people with sight-threatening DR(STDR) to ophthalmologists for assess-ment and treatment. Two recent studies(3,4) have shown that since 1985, peoplewith diabetes have experienced lowerrates of progression to proliferative DRand severe visual loss, probably reflectingimprovements in diabetes care. Apart

from the convenience of annual screening,the rationale behind the recommendationsassumes that people should receive annualscreening regardless of their actual risk ofdeveloping retinopathy. Most annual eyeexaminations now include digital retinalphotographs to monitor the presence orabsence of any DR. There has been a debatewhether examinations are required yearlyfor all people with diabetes, with Jameset al. (5) reporting annual photographicscreening to be cost-effective, but Vijanet al. (6) concluding that annual retinalscreening for all patients with type 2 diabe-tes without previously detected retinopa-thy may not be warranted on the basis ofcost-effectiveness and recommended

tailoring the frequency of screening to in-dividual circumstances.

At the time that annual digital photo-graphic screening was introduced in En-gland in 2003, the Department of Healthreported ;1.4 million people known tohave diabetes; as of December 2011, theprevalence reported (7) by screening serv-ices is now 2.5 million. As the publicallyfunded health care system in the U.K. haslimited funds, this has led to challengesproviding retinal screening, a concernshared by both developed and developingnations as the number of people withdiabetes rises (8). In 2004, Kempen et al.(9) reported that, among an estimated 10.2million U.S. adults $40 years known tohave DM, the estimated crude prevalencerates for retinopathy and vision-threateningretinopathy were 40.3 and 8.2%, re-spectively. In November 2011, the Inter-national Diabetes Federation releasedthe 5th edition of the Diabetes Atlas (8),which indicated that the number of peopleliving with diabetes in all age groups in theU.S. had risen to 23.7 million, and thenumber in the world is expected to risefrom 366 million in 2011 to 552 millionby 2030.

In order to more efficiently use limitedfunds, extending the screening intervalfrom annually to longer than annually hasbeen proposed. Two sources of data havebeen considered: 1) a retinal photographfrom one-time screening, and 2) a combi-nation of clinical and demographic riskfactors. Decisions based on retinal photog-raphy from a single visit, although sup-ported by studies (10–12), were rejectedby the American Diabetes Association (1)in 2002, which concluded that the annualeye examination is still warranted, citingthat the evidence (12,13) was not general-izable to the greater population of peoplewith diabetes and that it might lead topatients not attending screening. Deter-mining screening intervals using a combi-nation of clinical and demographic riskfactors combinedwith recent photographicscreening results (14) is equally prob-lematic, as the clinical information maynot be available, may be unreliable (e.g.,reported duration of diabetes), and in

c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c

From the 1Gloucestershire Diabetic Retinopathy Research Group, CheltenhamGeneral Hospital, Cheltenham,Gloucestershire, United Kingdom; the 2National Quality Assurance Team, English NHS Diabetic EyeScreening Programme, Gloucester, Gloucestershire, United Kingdom; and the 3Institute of Metabolic Sci-ences, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, United Kingdom.

Corresponding author: Irene M. Stratton, irene.stratton@nhs.net.Received 1 April 2012 and accepted 13 August 2012.DOI: 10.2337/dc12-0625© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and thework is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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some countries may not be collected (e.g.,HbA1c).

In this study, we used longitudinaldata from the results from retinal photo-graphic images from two annual screen-ing episodes in the population-basedNHS Diabetic Eye Screening Program inGloucestershire, U.K., to evaluate the in-cidence and time to recommended re-ferral of potentially sight-threateningretinopathy.

RESEARCH DESIGN ANDMETHODSdThe patient populationfrom which our cohort was taken com-prised 31,329 people with diabetes fromthe Gloucestershire Diabetic Eye Screen-ing Service who were screened for reti-nopathy between the 4 January 2005 and20 December 2010. Patients invited toretinal screening include all people withdiabetes (type 1 and type 2 or other) aged$12 years in Gloucestershire.

Gloucestershire contains a mixed ruralandurban, predominantlywhiteCaucasianpopulation (15). The Retinal ScreeningProgram invites eligible patients with dia-betes aged$12years to attend aDRscreen-ing clinic in one of 86 locations, wherespecialist staff take a history,measure visualacuity using Early Treatment Diabetic Ret-inopathy Study (ETDRS) logMAR charts,and take digital color retinal photographsof two standard 458 fields (macula and disccentered) per eye after dilation of the pu-pils. Trained assessors in a central locationgrade the presence and severity of DRusing a multilevel, internally and externallyquality-assured reading process that meetsnational recommendations. For these anal-yses, we included patients with at leastthree annual graded image sets, the firsttwo of which have either no retinopathyor only background (mild nonproliferativeDR [NPDR]) in one or both eyes. Back-ground (equivalent to ETDRS mildNPDR) was defined using the R1M0 cate-gory in the English NHS Diabetic EyeScreening Program, namely: presenceof microaneurysm(s), hemorrhage, or exu-date, but having none of the features (16)indicating referral to an ophthalmologistfor STDR, such as features of preprolifera-tive (moderate to severe NPDR) or prolifer-ative DR or photographic markers ofdiabetic maculopathy.

The criteria used for grading in theGloucestershire Diabetic Eye ScreeningProgram and the relationship to the ETDRSseverity scale (17) are described below:

R0 level identifies no detected DR(equivalent to ETDRS level 10).

R1 level (mild NPDR or backgroundDR) identifies a minimum of at least thepresence of one microaneurysm and/orretinal hemorrhage, equivalent to ETDRSlevels 14–35. This is the definition usedby the NHS Diabetic Eye Screening Pro-gram, and it is not possible to identifythose with ETDRS levels 14 and 15. How-ever, the numbers of patients who wouldhave hemorrhages alone would be verysmall.

R2 level (moderate to severe NPDR orpreproliferative DR) identifies the pres-ence of multiple deep, round, or blothemorrhages and/or definite intraretinalmicrovascular abnormality and/or venousbeading and/or reduplication, equivalentto levels 43–53 on the ETDRS scale.

R3 level (proliferative DR) indicatesthe presence of proliferative DR (includ-ing fibrous proliferation), equivalent to aminimum of ETDRS level 61.

M1 (maculopathy) identifies the pres-ence of two-dimensional photographicmarkers of diabetic maculopathy, specif-ically exudate within 1 disc diameter ofthe center of the fovea, circinate, or groupof exudates within the macula or anymicroaneurysm or hemorrhage within 1disc diameter of the center of the fovea,but only if associated with a best visualacuity of worse than 0.3 logMAR (equiv-alent to Snellen 6/12).

M0 describes the absence of any M1features.

We report in this study on 14,554patients with assessable images showingeither no DR (R0M0) or only mild NPDR(R1M0) in one or both eyes at twoconsecutive annual screenings (hereafterreferred to as baseline) and in whom therewas at least one further follow-up screen-ing episode (Fig. 1).

Patients were categorized into groupson the basis of the presence of retinopathyin neither, one, or both eyes at each of thetwo baseline screening episodes. Patientswith unassessable images, with any evi-dence of previous laser treatment or withfeatures of STDR at either baseline screen-ing event were excluded. STDR was de-fined by the presence of any R2 (moderateto severe NPDR), R3 (proliferative DR), orM1 (maculopathy) in either eye. Fig. 2shows the possible grading in the twoeyes at the two screening episodes andthe resultant categorization groups. Pa-tients were then followed until suchtime as they developed features of STDRor until the end of the study period.

We performed survival analysis, de-fining the time to event as the time from

the second screening to the developmentof STDR at a subsequent screening epi-sode; hence this was interval-censored.Specifically, for those people who did notdevelop STDR, the time to event was rightcensored at the date of the last screening,and for those people who developedSTDR, the data were left censored at thedate of the last screening at which noSTDR was found and with event time atthe date of the image set when STDR wasfound. Data were plotted using Kaplan-Meier estimates to show the cumulativepercentage of patients who developedSTDR. We fitted Cox proportional haz-ards models to estimate hazard ratios(HRs). We examined parametric models(g, Weibull, log logistic, logistic, and ex-ponential) that were used to estimate theproportion of patients expected to haveSTDR at 1, 2, 3, 5, and 10 years after base-line. The parametric model with the bestfit (log logistic) was chosen using Akaikeinformation criterion to optimize the fit ofthe model. Proportions were comparedusing x2 tests and continuous data be-tween groups with ANOVA. We per-formed analyses with SAS version 9.1.3(SAS Institute) using Proc LIFEREG forparametric modeling.

RESULTSdThere were 31,329 peopleon the screening register between 2005 and2010 with a median age of 63 years(interquartile range 52–72). Of these, therewere 14,554 people who had two consec-utive baseline screening episodes that bothdemonstrated either no evidence of DR orthe presence of only mild NPDR in one orboth eyes who had at least one furtherepisode with gradable photographs.The median age of the 14,554 patients in-cluded as this cohort was 65 years (56–73).The 16,775 patients who either did notattend for two consecutive screenings orwere otherwise excluded were significantlyyounger (P, 0.0001), median age 60 years(49–72).

There were 14,554 patients whocompleted two consecutive annualscreenings with gradable photographsshowing no DR (R0M0) or mild NPDR(R1M0) who had at least one furtherepisode with gradable photographs.These were characterized into nine pos-sible groups (Table 1). The least severegroup comprised 7,246 patients whohad no DR (R0M0) on both screening epi-sodes, and the most severe baseline groupin this study population were 1,159 pa-tients who had mild NPDR (R1M0) inboth eyes at both screenings. Of the

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remaining patients, 4,240 had mildNPDR (R1M0) in one or both eyes butonly at one of these two screening epi-sodes, 897 had mild NPDR (R1M0) inonly one eye at each screening episode,and 1,012 had mild NPDR (R1M0) inone eye at one episode but in both eyesat the other screening.

The median period between the twobaseline screening episodes was 13.5months (interquartile range 12.0–15.2),and patients were then followed for a me-dian 2.8 years (1.3–3.3). Themedian timeto first follow-up screen in study afterbaseline was 13.6 months (12.3–15.1),to second screen after baseline was 26.6months (24.9–28.3), to third 39.2months (37.4–40.9), and to fourth was51.6 months (50.8–52.1).

Of those excluded from the study,2,458 had more severe retinopathy ateither first or second baseline screeningepisodes, 726 had previously treated DR,949 had at least one unassessable imageset, and the rest had not attended threescreening episodes (Fig. 1).

There was no significant differencein the proportion of men and womenin the categories (P . 0.1). There were

differences (P , 0.001) between the agegroups in that those with mild NPDR inboth eyes at both screenings were youn-ger at 63.0 years (SD 14.6) than thegroups who had either one or both eyeswithout DR at one or both screening epi-sodes. Patients in the three groups thatregressed were older.

Table 1 also shows the outcomes inthe nine baseline categories. Of 7,246with no DR at both screenings (groupA), 120 subsequently progressed toSTDR, equivalent to an annual rate of0.7%. Of 1,778 with no DR in either eyeat first screening but mild NPDR in justone eye at second screening (group D), 80progressed to STDR, equivalent to an an-nual rate of 1.9%. This was associatedwith an HR of 2.9 (95% CI 2.2–3.8) com-pared with those with no DR at bothscreenings. Of 1,159 in the most severecategory (group I) with mild NPDR inboth eyes at both screenings, 299 pro-gressed to STDR, equivalent to 11.0%by 1 year and associated with an HR of18.2 (14.7–22.5) compared with patientswith no DR at both screenings. Those inhigher risk groups were more likely toprogress to more serious DR (P, 0.001).

Fig. 2 shows the Kaplan-Meier plot oftime to detection of STDR from baseline.There are clear differences between theoutcome of the groups and obviously in-creased risk for patients who have mildNPDR in both eyes at both annual screen-ing events (group I) when compared withthose with no DR in either eye at bothscreenings (group A).

CONCLUSIONSdUsing data fromonly two sequential annual photographicscreening visits supported by a quality-controlled grading system,we documentedsignificant differences in the time to de-velopment of retinopathy requiring refer-ral to an ophthalmologist. As most annualeye examinations in people with diabetesin developed countries now include dig-ital retinal photographs to monitor thepresence or absence of DR, these findingssuggest that photographs alone could beused to differentiate levels of risk. Thisimplies that the interval for screeningcould differ by level of risk. We believethat this is the first report identifying aclear differentiation of risk to develop-ment of STDR in patients who had eitherno or only minimal background DR when

Figure 1dCohort identification and inclusion/exclusion flow chart.

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screened: a group normally considered tobe at very low and generally homogenousrisk. The difference in risk between groupsin this study is large. For example, wedemonstrate that a patient who was foundto have no retinopathy on the first occasionbut mild NPDR in both eyes 1 year laterhas a risk of subsequently developingSTDR approximately six times greaterthan does a patient who has no DR onboth occasions. A patient who has bilateralmildNPDR on both occasions has a risk forsubsequent development of STDR thatis 18.2 times higher than an individualwith no retinopathy at either screening(Table 1).

Whereas the risk of progression in themodel by Vijan et al. (6) is based on the

Diabetic Retinopathy Study and ETDRSreports, the risk we define in this studyis based entirely on two sets of digital im-ages taken;1 year apart. With those twoseminal studies dating from the 1980sand 1990s, the possibility exists thatwith the passage of time and the changesin treatment that accompany it, changeswill occur in the rate of progression ofdisease.

This study does not compare risk ofreferable retinopathy defined by retinalphotographs with that defined by clinicalcriteria (e.g., time since diagnosis of di-abetes, HbA1c, blood pressure). It doesnot estimate risk for those in whom as-sessment of DR by retinal photographyis not possible and who have to be

screened using slit-lamp biomicroscopy.It does not test the number of imagesrequired nor does it make explicit rec-ommendations on the frequency orcost-effectiveness of screening. Answer-ing these questions requires further mod-eling that our results could inform byproviding transition probabilities fromnonreferable to referable retinopathy.

Vijan et al. (18) developed a cost-utilitymodel for screening, with the conclusionsthat for patients with good glycemic andblood pressure control (that is, a lowerrisk population), screening every 2 to 3years would be appropriate while at thesame time advocating “close follow-up”for the high-risk patient. They point outthat the costs associated with screeninglow-risk individuals less frequently couldbe better spent achieving close follow-upof patients at higher risk.

Screening low-risk individuals toofrequently implies an inefficient use oflimited health care resources. More effi-cient uses might include spending mon-ey on strategies to bring retinal screeningto people with diabetes who are poorattendees including, as we have shown inthis study, younger patients who tendto be patients at high risk of retinopa-thy (19), spending to prevent retinopathyin people with diabetes, or spendingmoney elsewhere within the health caresystem.

Two of the strengths of this study areits size and that the population screenedaccurately represents the underlying pop-ulation with diabetes. Over 99% of pa-tients with DM are eligible for screeningagainst the criteria of the English NHSDiabetic Eye Screening Program (20). Theeligible population is increasing. In 2005,there were 17,847 patients who were in-vited for screening, but this figure hadrisen to 27,520 by December 2010. Theaverage attendance figures following aninvitation was 74% in any one year, whichcompares favorably to other populationswithin the English NHS Diabetic EyeScreening Program.

A recent report (21) from the DiabeticRetinopathy Screening Service for Walesdescribed the incidence of any and refer-able DR in people with type 2 diabetesmellitus attending the annual screeningservice inWales, whose first screening epi-sode indicated no evidence of retinopathy.Their referable level is higher than in thisstudy, but the results are not directly com-parable, as the definition of retinopathylevels are not the same, and their study isbased on an initial screening episode,

Figure 2dTime to detection of STDR from second baseline screening with none or only mildNPDR in one or both eyes. Significant difference across groups (P , 0.0001).

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whereas this study population is not re-stricted to first screening episode.

This study evaluated people with type1 or type 2 diabetes, most of whom wereof white northern European extraction. Inaddition, the Gloucestershire screeningprogram has a robust quality-control pro-gram of the imaging and grading pro-cesses. Hence, to be generalizable, theresults would need to be validated inother populations.

We propose that estimating risk inthis way can be useful in several ways,either in discussions with patients duringeye examinations or in countries or in-stitutions with systematic screening pro-grams, to develop screening models toallocate limited monies more efficientlyby varying the screening intervals de-pending on an individual’s identified risk.

The results of this study may also helpto design and power clinical trials testinginterventions for DR. Many clinical trialsrequire a three-step progression on theETDRS severity scale. This is equivalent tothe progression from R1 mild NPDR to R2moderate to severe NPDR in this study. Ifpatients were selected who had bilateralmild NPDR on two consecutive screeningappointments, we have demonstrated anoverall progression to sight threatening DRin 29% after 3 years and 40.4% after 5years.

This risk estimator essentially helpsremove the requirement for complexclinical-based data, as even if none of theseare taken into account, we can differenti-ate risk by 18:1. We believe that this is thefirst report identifying a clear differentia-tion of risk to development of STDR inpatients who had either no or only min-imal background DR when screened: agroup normally considered to be at verylow and generally homogenous risk.

AcknowledgmentsdS.J.A. has received con-sulting fees from AstraZeneca (,5 years ago),Takeda (,5 years ago), Eli Lilly (,5 years ago),and Novartis (,1 year ago); received researchsupport fromAstraZeneca andTakeda (both,5years ago); and is currently receiving researchsupport from Novartis. I.M.S. has received feesfor lectures from Novo Nordisk. No other po-tential conflicts of interest relevant to this articlewere reported.I.M.S. raised the research hypothesis, de-

signed and carried out data analyses, andwrote the manuscript. S.J.A. and D.J.T. con-tributed to the discussion and wrote the man-uscript. A.I.A. advised on data analysisprocedures and reviewed the manuscript.P.H.S. contributed to the discussion andT

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584 DIABETES CARE, VOLUME 36, MARCH 2013 care.diabetesjournals.org

Risk of sight-threatening diabetic retinopathy

reviewed and edited the manuscript. I.M.S. isthe guarantor of this work and, as such, had fullaccess to all the data in the study and takesresponsibility for the integrity of the data andthe accuracy of the data analysis.This study was presented in poster form at

the 72nd Scientific Sessions of the AmericanDiabetes Association, Philadelphia, Pennsyl-vania, 8–12 June 2012.The authors thank Mark Histed and the

team of the Gloucestershire Diabetic EyeScreening Service for high-quality screeningand grading and Steve Chave of the samegroup for data extraction and management.

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