European Association for the Study of Diabetic Eye Complications

Annual Meeting Rome 26-27th May 2007

Free Paper Abstracts 1 - 12

Saturday 26th May 2007

Free Paper Session: 0910 - 1100

Free Paper Abstract 1

REDUCED RESPONSE OF RETINAL VESSELS TO FLICKER LIGHT STIMULATION IN DIABETIC PATIENTS WITHOUT RETINOPATHY. A Lecleire-Collet, J_F Girmens, A Erginay, R Sofroni, J Conrath, J-A Sahel, A Gaudric, P Massin. Dept of Ophthalmology, Hôpital Lariboisière, PARIS, France

Purpose: In healthy subjects, retinal stimulation with flicker light induces retinal vessel dilatation, via a still partially understood neurovascular mechanism. The aim of the study was to determine if this vasomotive response due to retinal neural cell stimulation is impaired early in diabetes, before the occurrence of diabetic retinopathy.
Methods: Twenty-eight patients with diabetes (17 patients with type 1 diabetes, 11 patients with type 2 diabetes) without diabetic retinopathy on fundus examination, and 28 age- and sex-matched healthy volunteers were included. The diameter of retinal arteries and veins was measured using the commercially available Zeiss Retinal Vessel Analyzer (RVA). During the examination, three periods of flicker light stimulation (530-600 nm, 12.5 Hz, 20 seconds) were performed. Flicker light-induced retinal arterial and venous responses were assessed using three different calculation methods (R1, R2, R3).
Results: The arterial response to flicker light was significantly reduced in diabetic patients compared with healthy volunteers (Student Test, p < 10-4, p < 10-5, p <0.001, for R1, R2, R3, respectively). In healthy volunteers, flicker light stimulation increases arterial diameter by (mean ± SD) 9.39% ± 2.51%, 4.14% ±1.78%, and 4.91% ± 2.40%, for R1, R2, and R3, respectively, compared with 5.97% ± 2.89 %, 1.88 % ±1.42 %, and 2.92 % ±2.07 %, for diabetic patients. Venous response was also decreased in diabetic patients compared with healthy volunteers (Student test, p < 0.05, p < 0.01, p < 0.05, for R1, R2, R3, respectively). In healthy volunteers, flicker light stimulation increases venous diameter (mean ±SD) by 5.90 % ±2.35 %, 4.41 % ±2.21 %, and 4.57 % ±2.02 %, for R1, R2, and R3, respectively, compared with 4.23 % ±1.87 %, 2.58 % ±1.86 %, and 3.03 % ±1.79 %, for diabetic patients.
Conclusions: Flicker light-induced retinal arterial and venous responses are reduced in diabetic patients without diabetic retinopathy. This decrease in retinal vasomotive response may be due to an early decrease of retinal vascular reactivity and/or retinal neural activity.

Free Paper Abstract 2

ATP- AND ADENOSINE-INDUCED RELAXATION OF PORCINE RETINAL ARTERIOLES DEPENDS ON PERIVASCULAR RETINAL TISSUE AND ACTS VIA AN ADENOSINE RECEPTOR. K Holmgaard, C Aalkjær, JDC Lambert, T Bek. Dept. of Ophthalmology, Aarhus University Hospital / Dept. of Physiology, Aarhus University, Denmark.

Background: Disturbances in the tone regulation of retinal arterioles is assumed to be involved in the pathophysiology of diabetic retinopathy, an effect that may be related to disturbances in the metabolism of purinergic compounds and prostaglandins. However, it is unknown whether the perivascular retinal tissue is involved in these effects.
Methods: Adenosine and ATP induced vasodilation of porcine retinal arterioles were studied in a wire myograph before and after removal of the perivascular tissue. Additionally, the effect of adding the prostaglandin synthesis inhibitor ibuprofen was studied.
Results: Both adenosine and ATP induced relaxation of the studied arterioles. This effect depended on the perivascular tissue and could be blocked by antagonists, but only ATP induced relaxation was affected by ibuprofen.
Conclusions: The relaxation of porcine retinal arterioles induced by purinergic compounds is modulated by the perivascular retinal tissue. The disturbances in the purinergic metabolism observed in diabetes mellitus may contribute to the disturbances in retinal blood flow that lead to diabetic retinopathy. This reaction pattern depends on an interplay between the retinal blood vessel and the perivascular retina.

Free Paper Abstract 3

E Beltramo,1 K Nizheradze,2 E Berrone,1 S Tarallo,1 M Porta.1
1Dept. of Internal Medicine, University of Turin - Italy
2Laboratory of Biomarkers, Institute of Colloid and Water Chemistry, Kiev - Ukraine.

Purpose: Capillary pericytes are selectively lost in diabetic retinopathy. We have reported reduced adhesion of bovine retinal pericytes (BRP) cultured on extracellular matrix (ECM) produced by human vascular endothelial cells (HUVEC) in high hexose concentrations, probably due to glycation of matrix proteins, but no changes in their apoptosis. Some observations suggest, however, that human and bovine pericytes may behave differently in experimental conditions mimicking the diabetic milieu. The aim of this study was to verify human retinal pericytes (HRP) behaviour, when cultured on altered ECMs.
Methods: Conditioned ECMs were obtained by growing HUVEC for 7 days in culture media containing normal (5.6 mmol/l) or high (28 mmol/l) D-glucose. Cells were then lysed and ECM fixed by NH4OH. HRP were cultured in normal or high glucose on these conditioned ECMs or plastic alone. Pericyte adhesion was evaluated after 12-18 hours. After 7 days of culture, cell proliferation was assessed by cell counts and BrdU incorporation. DNA fragmentation was evaluated by ELISA, as a marker of early apoptosis, and the expression of three genes involved in apoptosis, p53, Bax and Bcl-2, was determined by RT-PCR.
Results: HRP adhered less on high glucose-conditioned ECM and plastic than on normal glucose-conditioned ECM, while there were no significant differences, after 7 days, in their number, nor in DNA synthesis, when grown in physiological glucose. In contrast, DNA synthesis was impaired in HRP cultured in high glucose on the three different matrixes, in comparison with HRP cultured in normal glucose. Apoptosis was greatly enhanced by high glucose-conditioned matrix, both in HRP grown in normal and high glucose and this was confirmed by p53, Bcl-2 and Bax mRNA expression.
Conclusions: Human pericyte apoptosis seems to be strongly affected by matrix produced in high glucose. This behaviour is different from that observed with bovine pericytes, underlining the importance of establishing a cell model as similar as possible to the human diabetic eye.

Free Paper Abstract 4

INCREASED SHEDDING OF VASCULAR ENDOTHELIAL MICROPARTICLES IN PROLIFERATIVE DIABETIC RETINOPATHY. P Massin, S Chahed, M Benzerroug, C Nguyen, A Gaudric, A Tedgui, CM Boulanger. Ophthalmology Department and Cardio Vascular Unit, Lariboisière Hospital, Paris, France.

Background: Diabetic retinopathy (DR), the main cause for visual loss in adults, is associated with vascular proliferation, oedema and capillary occlusions. We hypothesized that microparticles (MP), submicron membrane vesicles released following cell activation or apoptosis, accumulate in vitreous fluid from patients with DRP.
Methods and results: 60 patients needing eye surgery were classed as non-diabetic (ND, n=26, 68±2 yrs) or diabetic (D, n=34, 60±2 yrs, 7.5±0.2% HbA1c, 28 with proliferative and 6 non-proliferative DR). Levels and cellular origins of MP in platelet-free plasma and cell-free vitreous fluid were analyzed by flow cytometry, using annexinV (AnnV) labelling as a marker of apoptotic origin and specific markers for platelet (CD41) and endothelial (CD144) origins. Plasma MP levels were not different in ND and D patients (1605 ±309 vs 1561 ±276 AnnV+MP/ml, 1265 ±254 vs 843 ±147 CD41+MP/ml, 198 ±45 vs 291 ±129 CD144+MP/ml, respectively). However vitreous MP levels were all markedly increased in D compared with ND patients (131 ±41 vs 54 ±24 AnnV+MP/ml, p=0.035; 94 ±25 vs 31 ±8 CD41+MP/ml, p=0.018; 197 ±38 vs 63 ±15 CD144+MP/ml, p<0.001, respectively). The ratio of vitreous to plasma MP levels indicates the importance of local formation versus potential plasma leakage of MP from microvessels in vitreous fluid. This ratio for CD144+MP was markedly greater than 1 in proliferative DR (p=0.020), clearly indicating local accumulation of endothelial MP. For all markers the ratio was increased in proliferative DR compared to ND.
Conclusion: Proliferative DR is associated with a specific ocular increase in MP shed from activated or apoptotic vascular endothelial cells.

Free Paper Abstract 5

DIFFERENTIAL ROLES OF CTGF AND VEGF IN ANGIOGENESIS AND FIBROSIS IN PROLIFERATIVE DIABETIC RETINOPATHY. RO Schlingemann,1 EJ Kuiper,1 P Roestenberg,2 MD. de Smet,1 JC van Meurs,3 MW Tanck,4 N Oliver,5 I Klaassen,1 CJF van Noorden,1 R Goldschmeding.2
1Ocular Angiogenesis Group, Departments of Ophthalmology and Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2Department of Pathology, Academic Medical Centre of Utrecht, Utrecht, The Netherlands; 3Department of Ophthalmology, Rotterdam Eye Hospital, Rotterdam, The Netherlands; 4Department of Clinical Epidemiological Statistics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 5Fibrogen, Inc., San Francisco, CA., USA.

Purpose: Vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) may be causal factors of neovascularisation and fibrosis in diabetic retinopathy (DR), but their relative contribution to angiogenesis and fibrosis is unknown. We hypothesised that there is an association of VEGF and CTGF levels in vitreous with retinal neovascularisation and/or fibrosis when there is a causal relation, and reduced CTGF expression limits (VEGF-induced) angiogenesis when angiogenesis is CTGF dependent.
Methods: VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, n=32), macular hole (n=13) or macular pucker (n=23) and related to clinical data, including degree of intra-ocular neovascularisation and fibrosis. The effects of reduced CTGF gene expression on angiogenesis was investigated in heterozygous and homozygous CTGF knockout mice in oxygen-induced retinopathy, laser-induced choroidal neovascularisation and in an in vitro angiogenic assay in metatarsal explant cultures.
Results: In PDR patients but not the other patients, vitreous CTGF levels correlated significantly with degree of fibrosis and with VEGF levels, but not with neovascularisation, whereas VEGF levels correlated only with neovascularisation. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. In mice, CTGF deletion did not inhibit angiogenesis induced by hypoxia, wound healing or VEGF levels, respectively.
Conclusions: CTGF is primarily a pro-fibrotic factor in the eye and a shift in the balance between CTGF and VEGF levels causes the switch from angiogenesis to fibrosis.

Free Paper Abstract 6

I Klaassen,1 JM Hughes,1 EJ Kuiper,1 P Canning,2 AW Stitt,2 J van Bezu,3 CG Schalkwijk,3 CJF van Noorden,1 RO Schlingemann.1 1Ocular Angiogenesis Group, Departments of Ophthalmology and Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; 2Department of Ophthalmology, The Queen's University of Belfast, The Royal Victoria Hospital, Belfast, Northern Ireland, UK; 3Department of Clinical Chemistry and Institute of Cardiovascular Research, VU University Medical Centre, Amsterdam, The Netherlands.

Purpose: Referred to as CCN, the family of growth factors consisting of cystein-rich protein 61 (CYR61, also known as CCN1), connective tissue growth factor (CTGF, also known as CCN2), nephroblastoma overexpressed gene (NOV, also known as CCN3) and WNT1-inducible signalling pathway proteins 1, 2 and 3 (WISP1, -2 and -3; also known as CCN4, -5 and -6) affects cellular growth, differentiation, adhesion and locomotion in wound repair, fibrotic disorders, inflammation and angiogenesis. AGEs formed in the diabetic milieu affect the same processes, leading to diabetic complications including diabetic retinopathy. We hypothesised that pathological effects of AGEs in the diabetic retina are a consequence of AGE induced alterations in CCN family expression.
Methods: CCN gene expression levels were studied at the mRNA and protein level in retinas of control and diabetic rats using real-time quantitative PCR, western blotting and immunohistochemistry at 6 and 12 weeks of streptozotocin-induced diabetes in the presence or absence of aminoguanidine, an AGE inhibitor. In addition, C57BL/6 mice were repeatedly injected with exogenously formed AGE to establish whether AGE modulate retinal CCN growth factors in vivo.
Results: After 6 weeks of diabetes, Cyr61 expression levels were increased more than threefold. At 12 weeks of diabetes, Ctgf expression levels were increased twofold. Treatment with aminoguanidine inhibited Cyr61 and Ctgf expression in diabetic rats, with reductions of 31 and 36%, respectively, compared with untreated animals. Western blotting showed a twofold increase in CTGF production, which was prevented by aminoguanidine treatment. In mice infused with exogenous AGE, Cyr61 expression increased fourfold and Ctgf expression increased twofold in the retina.
Conclusions: CTGF and CYR61 are downstream effectors of AGE in the diabetic retina, implicating them as possible targets for future intervention strategies against the development of diabetic retinopathy.

Free Paper Abstract 7

1 Ocular Angiogenesis Group, Departments of Ophthalmology and Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2 Department of Pathology, Academic Medical Center of Utrecht, Utrecht, The Netherlands.

Purpose: Vascular endothelial growth factor-A (VEGF) causes increased vascular permeability and leukocyte adhesion in preclinical diabetic retinopathy (PCDR). Another hallmark of PCDR is thickening of the capillary basement membrane (BM). Recently, VEGF was shown to induce expression of pro-fibrotic genes such as transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF or CCN2) in cultured endothelial cells. Moreover, neutralization of VEGF prevented BM thickening in diabetic mice in vivo. Therefore, we hypothesize that VEGF directly contributes to BM thickening in the diabetic retina by inducing expression of pro-fibrotic growth factors and extracellular matrix (ECM) components.
Methods: Transcription and protein levels of ECM-related genes were evaluated in the rat retina after intravitreal VEGF injection by real-time quantitative PCR, Western blotting and immunohistochemistry, respectively. In addition, expression profiles of the same genes in response to VEGF stimulation were investigated in bovine retinal vascular cells in vitro.
Results: Intravitreal VEGF injection induced retinal transcription of CYR61 (CCN1), CTGF, TGF-β1, tissue inhibitor of metalloproteases-1 (TIMP-1) and fibronectin, and protein expression of CYR61, CTGF and fibronectin. In bovine retinal endothelial cells and pericytes stimulated by VEGF in vitro, gene expression profiles were similar to those in the intact retina in vivo.
Conclusions: VEGF induces pro-fibrotic growth factors and extracellular matrix genes in the retina in vivo, as well as in cultured retinal vascular cells in vitro. Our findings may have relevance for understanding the pathogenesis of preclinical DR, where early upregulation of VEGF may cause BM thickening by induction of ECM-related genes.

Free Paper Session: 1200-1300

Free Paper Abstract 8

CROSSTALK BETWEEN TNF-α, NADPH OXIDASE, PKCβ2, AND CORE 2 TRANSFERASE IN DIABETIC LEUKOCYTES. BM Ben-Mahmud, EM Kohner, R Chibber. Cardiovascular Division, James Black Centre, King's Denmark Hill Campus, London, UK

Purpose: Increasing evidence suggests that chronic, sub-clinical inflammation plays an important role in diabetic retinopathy. We have recently reported that a glycosylating enzyme, core 2 β-1, 6-N-acetylglucosaminyltransferase (core 2 GlcNAc-T), is implicated in increased leukocyte-endothelial cell adhesion in retinopathy via an up-regulation mechanism controlled by tumour necrosis factor-alpha (TNF-α) (Ben-Mahmud et al., 2006). The aim of the present study was to elucidate the potential role of NADPH oxidase signalling pathway in the raised activity of core 2 GlcNAc-T in diabetic leukocytes. NADPH oxidase is the most important source of cellular reactive oxygen species (ROS) in leukocytes and blood vessels.
Methods: Human leukocytes (U937 cells) and a lymphoblastoid cell-line deficient in p47phox were cultured in RPMI medium containing norml (5.6 mM glucose). The cells were exposed to TNF-α (8 pg/ml) for 24 h in the presence and absence of (i) NADPH oxidase inhibitors, 30 µM apocynin and 1µM of scrambled and unscrambled gp91ds-tat (ii) 50 nM LY379196, a specific PKCβ1/2 inhibitor and (iii) antioxidants, 15 mM N-acetyl cysteine (NAC, 15 mM) and 5 mM Tiron. NADPH oxidase activity was measured using cytochrome c reduction assay. PKC β1/2 activity was measured using TruLight™ PKC- β1/2 assay kit (Calbiochem, UK).
Results: Compared to control medium, exposure to TNF- α (8pg/ml; 24h) raised core 2 GlcNAc-T activity in human leukocytes [1722 ± 255.3 (n = 10) vs. 374 ± 80.3 (n = 10), P<0.0001] that was significantly reversed with apocynin and LY379196. These findings were further supported with (i) significant reversal of TNF-α-induced core 2 GlcNAc-T activity with unscrambled and not scrambled gp91ds-tat, a specific NADPH oxidase inhibitor, (ii) use of a lymphoblastoid cell-line deficient in p47phox, a major subunit of NADPH oxidase, and (iii) reversal with NAC and Tiron.
Conclusion: Our results demonstrate a novel signalling crosstalk between TNF-α, core 2 GlcNAc-T, NADPH oxidase and PKCβ1/2 in diabetic leukocytes.
The study was supported by EFSD/Servier

Free Paper Abstract 9

THE ROLE OF ADVANCED STRUCTURAL AND FUNCTIONAL RETINAL TESTING IN THE DIAGNOSIS OF EARLY RETINOPATHY IN TYPE 1 DIABETES. M Parravano,1 F Oddone,1 D Mineo,3 M Centofanti,2 P Borboni,3 R Lauro,3 GL Manni.2 Fondazione GB Bietti per lo Studio e la Ricerca in Oftalmologia- IRCCS- Rome
1 Dipartimento di Biopatologia e Diagnostica per Immagini, University of Rome Tor Vergata,2 Internal Medicine Department, 3University of Rome Tor Vergata.

Purpose: To investigate early structural and functional retinal impairment in patients with type 1 diabetes (DM1).
Methods: Thirty long-term and well-controlled DM1 patients, without fluorescein angiographic signs of retinal vasculopathy, and 15 healthy control subjects, performed structural tests included peripapillary retinal nerve fiber layer (RNFL) thickness measurement by Scanning Laser Polarimetry (GDx VCC) and by Optical Coherence Tomography (OCT3), and macular thickness evaluation by OCT3. Functional tests included retinal sensitivity evaluations by white-on-white Humphrey visual Field Analyser (HFA), Frequency Doubling Technology (Humphrey Matrix) and MP1 Microperimetry.
Results: TSNIT average, superior and inferior RNFL thicknesses at GDx VCC were significantly reduced in DM1 respect to healthy subjects. All OCT-3 parameters were similar between groups. HFA pattern standard deviation, Humphrey Matrix mean deviation, and temporal and infero-temporal retinal sensitivity at MP1 were significantly reduced in DM1 compared to control group.
Conclusion: DM1 patients showed a specific reduction in RNFL thickness and retinal sensitivity, despite the presence of any retinal vasculopathy, suggesting that advanced structural and functional retinal testing may be useful in the diagnosis of early diabetic retinal impairment.

Free Paper Abstract 10


Purpose: Recent studies have demonstrated that good metabolic control (glycosylated haemoglobin (HbA1c) level less than 7%) achieved with insulin therapy (IT) can delay the onset and progression of diabetic retinopathy (DR). Often IT is unavailable or unsuitably used, despite being listed by WHO as an essential drug. IT is indicated when insulin resistance is present, it happens when oral drugs become ineffective, and large daily doses of insulin (0.5-1.2 U/kg) may be needed (even more than 1.5 U/kg, at least initially) to overcome prevailing insulin resistance.
Methods: We observed 3 groups of patients with type 2 diabetes and indications for IT to value progression of DR in 3 year period. Patients from the first group (n=75) had indications for IT, but refused over 3 years. Patients from the second group (n=215) were switched to IT at the beginning of the study and continued IT for 3 years. Patients from the third group (62) were treated with IT for more than 4 years. All were examined at baseline and 1, 2 and 3 years. DR was graded by biomicroscopy using the ETDRS scale. At baseline patients had either no DR or nonproliferative DR (≤level 47). Duration of diabetes, HbA1c, blood pressure, lipids, BMI, presence of nephropathy, neuropathy and insulin dose were recorded.
Results: We found high progression levels in all groups: 73.3% in the first, 60.9% in the second and 41.9% in the third. IT switch was made after 13.4 ±0.7 years of diabetes, medium daily dose of insulin was less than 0.4 U/kg. 3-year progression in all groups was associated with the following risk factors: HbA1C level, duration of diabetes, initial degree of retinopathy, systolic hypertension, high cholesterol level, high BMI level, age and sex (p<0.001).
Conclusions: Our research provides clear evidence of low effectiveness of IT in type 2 diabetes in real clinical practice. The delay of IT and low insulin dose leads to an uncontrolled course of diabetes and its complications. IT in real clinical practice does not prevent long-term complications of diabetes, including blindness.

Free Paper Abstract 11

Center of Diabetology, Institute for Clinical and Experimental Medicine, Prague;1 Thomayer Memorial Hospital, Prague,2 Czech Republic.

Purpose: To identify the potential long-term role of successful pancreas transplantation on the course of different levels of diabetic retinopathy (DR).
Methods: We retrospectively evaluated all our patients who underwent combined kidney and pancreas transplantation (KPTx) or pancreas transplantation (PTx) and who had stable graft function for at least one year. Patients were divided into four groups according to the level of DR (modified ETDRS scale) at the time of transplantation. Blind patients were excluded. Besides these factors, we also assessed diabetic macular edema (DME), visual acuity (VA), the need for laser treatment (LT) and pars plana vitrectomy (PPV). Other parameters such as cataract progression and glaucoma were also evaluated. We took into account also other risk factors for the progression DR before and after TX, e.g.; duration of diabetes, nephropathy before TX, blood pressure (BP), dyslipidemia, etc.
Results: Out of 300 transplanted patients, 189 KPTx were included into the study (mean follow-up 89 months); 17 patients after PTx were followed for up to 31 months on average. At the time of Tx the distribution of patients between the various levels of DR was (KPTx, PTx): grade 0 ( no retinopathy) 1, 4; I. (mild non-proliferative DR) 21, 6; II. (moderate NPDR) 53,4; III. (severe NPDR) 53, 1; IV. (proliferative DR) 61,2. DME was present in 38 KPTx and 0 PTx patients. Progression of DR was recorded predominately in the advanced levels (III – IV) of the KPTx group (35%), compared only one case in level IV in the PTx group. VA outcomes were similar in each groups. LT before and need for LT after Tx was in KPTx patients 65 and 38 respectively and in PTx 2 and 1. PPV before and after Tx was required in 22 and 1 patients respectively. Cataract surgery in 2 years after Tx was required in 17 KTPx patients and 1 PTx. Duration of diabetes before Tx was nearly 3x longer in KPTx patients, and these patients had a higher incidence of nephropathy and hypertension.
Conclusions: Transplantation does not have a dramatic effect on pre-established DR. In patients with advanced forms of DR transplantation is not able in itself to prevent deterioration. In contrast, worsening is not generally seen in earlier levels of DR.

Free Paper Session: 14.30 – 15.45

Free Paper Abstract 12

Foresight Eye Care, Dundalk, Ireland,1 Coolport Grading and Management,2 Ocuco-Relcon,3 Health Service Executive Dublin,4 North East Ireland

Purpose: To establish the level of inter-grader agreement between graders of digital retinal images acquired by a mobile retinal screening service
Methods: The retinal images of 835 type II diabetics were submitted for grading by up to 3 separate graders as recommended by the National Screening Committee on Diabetic Retinopathy (NSC) in the UK. Sensitivity and specificity levels were established for primary grading carried out by non-clinical personnel performing first stage grading. The results of the initial grader were masked when the same images were submitted to second and in some instances third line grading by an accredited optometric grader and medical ophthalmologist respectively. The sensitivity and specificity of initial grading (test grading) on all cases were calculated by reference to the final grading decision which was taken as the true grading for each case. Of those cases identified as having disease greater than minimal background diabetic retinopathy and hence requiring hospital referral, the decision as to priority of referral was based on strict agreed criteria and referrals were classified as either routine hospital or fast-track hospital referral. The levels of inter-grader agreement for those cases which were graded as either routine hospital referral or fast-track referral were subsequently calculated.
Results: The results for specificity and sensitivity were: number of patients with some disease at first level grade = 289, number of patients with some disease at final level grade (true +ve) = 204 (TP), number of patients with no disease at first level grade = 212, number of patients initially graded as disease that were subsequently graded as no disease (false +ve) = 85 (FP), number of patients who were graded as no disease at final grade (true-ve) = 266 (TN), number initially graded as no disease who subsequently were graded as disease (false-ve) = 8 (FN), sensitivity = TP/TP+FN = 204/204+8 = 204/212 = 96.2%, specificity = TN/TN+FP = 266/266+85 = 266/351 = 76%. The level of inter-grader agreement between either routine and fast-track referral based on those 104 cases requiring hospital referral for more than minimal retinopathy was 94%.
Conclusions: Trained accredited graders can be recruited from non-clinical personnel and achieve adequate grading standards to be useful in the establishment of a national retinopathy screening service.



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