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Multicenter Evaluation of Diagnostic Circulating Biomarkers to Detect Sight-Threatening Diabetic Retinopathy

Research output: Contribution to journalArticlepeer-review

Sarega Gurudas, Karen Frudd, Jayapal Jeya Maheshwari, Yeddula Rebecca Revathy, Sobha Sivaprasad, Shruthi Mahalakshmi Ramanathan, Vignesh Pooleeswaran, A. Toby Prevost, Eleni Karatsai, Sandra Halim, Shruti Chandra, Paul Nderitu, Dolores Conroy, Subramanian Krishnakumar, Sowmya Parameswaran, Kuppamuthu Dharmalingam, Kim Ramasamy, Rajiv Raman, Colin Jones, Haralabos Eleftheriadis & 2 more John Greenwood, Patric Turowski

Original languageEnglish
Pages (from-to)587-597
Number of pages11
JournalJAMA Ophthalmology
Issue number6
Early online date22 Mar 2022
Accepted/In press11 Mar 2022
E-pub ahead of print22 Mar 2022
PublishedJun 2022

Bibliographical note

The article was accepted on 15th March 2022 - From: Date: 16 March 2022 at 04:10:23 GMT+5:30 To: Subject: OPH21-2867R Decision Letter Reply-To:  March 15, 2022 Prof Sobha Sivaprasad NIHR Moorfields Biomedical Research Centre Morfields Eye Hospital London United Kingdom RE: Manuscript #OPH21-2867R, Multicenter validation of diagnostic circulating biomarkers to detect sight threatening diabetic retinopathy Dear Prof Sivaprasad: We are pleased to accept your manuscript for publication in JAMA Ophthalmology pending receipt of all authorship forms. Thank you for the prompt and thoughtful revision. Your manuscript is accepted with the understanding that it represents new information, it is not under simultaneous consideration by another publication, and its message has not been published previously in any language. 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King's Authors


Importance: It is a global challenge to provide regular retinal screening for all people with diabetes to detect sight-threatening diabetic retinopathy (STDR). Objective: To determine if circulating biomarkers could be used to prioritize people with type 2 diabetes for retinal screening to detect STDR.

Design, Setting, and Participants: This cross-sectional study collected data from October 22, 2018, to December 31, 2021. All laboratory staff were masked to the clinical diagnosis, assigned a study cohort, and provided with the database containing the clinical data. This was a multicenter study conducted in parallel in 3 outpatient ophthalmology clinics in the UK and 2 centers in India. Adults 40 years and older were categorized into 4 groups: (1) no history of diabetes, (2) type 2 diabetes of at least 5 years' duration with no evidence of DR, (3) nonproliferative DR with diabetic macular edema (DME), or (4) proliferative DR. STDR comprised groups 3 and 4. Exposures: Thirteen previously verified biomarkers were measured using enzyme-linked immunosorbent assay.

Main Outcomes and Measures: Severity of DR and presence of DME were diagnosed using fundus photographs and optical coherence tomography. Weighted logistic regression and receiver operating characteristic curve analysis (ROC) were performed to identify biomarkers that discriminate STDR from no DR beyond the standard clinical parameters of age, disease duration, ethnicity (in the UK) and hemoglobin A1c.

Results: A total of 538 participants (mean [SD] age, 60.8 [9.8] years; 319 men [59.3%]) were recruited into the study. A total of 264 participants (49.1%) were from India (group 1, 54 [20.5%]; group 2, 53 [20.1%]; group 3, 52 [19.7%]; group 4, 105 [39.8%]), and 274 participants (50.9%) were from the UK (group 1, 50 [18.2%]; group 2, 70 [25.5%]; group 3, 55 [20.1%]; group 4, 99 [36.1%]). ROC analysis (no DR vs STDR) showed that in addition to age, disease duration, ethnicity (in the UK) and hemoglobin A1c, inclusion of cystatin C had near-acceptable discrimination power in both countries (area under the receiver operating characteristic curve [AUC], 0.779; 95% CI, 0.700-0.857 in 215 patients in the UK with complete data; AUC, 0.696; 95% CI, 0.602-0.791 in 208 patients in India with complete data). 

Conclusions and Relevance: Results of this cross-sectional study suggest that serum cystatin C had good discrimination power in the UK and India. Circulating cystatin-C levels may be considered as a test to identify those who require prioritization for retinal screening for STDR.

Funding Information:

reported receiving grants from the UK Research and Innovation and Global Challenge Research Fund during the conduct of the study. Dr Sivaprasad reported receiving grants from the UK Research and Innovation and Global Challenge Research Fund and personal fees from Bayer, Novartis, Oxurion, Apellis, Allergan, Roche, and Boehringer Ingelheim outside the submitted work. Dr Prevost reported receiving grants from the UK Research and Innovation and Global Challenge Research Fund through the medical research council during the conduct of the study and personal fees from Roche for being the statistical member of an independent data monitoring committee outside the submitted work. Dr Eleftheriadis reported receiving grants from Bayer and Novartis to attend ophthalmology conferences outside the submitted work. Dr Turowski reported receiving grants from the UK Research and Innovation and Global Challenge Research Fund during the conduct of the study. No other disclosures were reported.

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