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

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; John Greenwood; Patric Turowski

doi:10.1001/jamaophthalmol.2022.1175

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

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 EleftheriadisJohn Greenwood, Patric Turowski

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Abstract

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 A_1c. 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 A_1c, 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.

Original language	English
Pages (from-to)	587-597
Number of pages	11
Journal	JAMA Ophthalmology
Volume	140
Issue number	6
Early online date	5 May 2022
DOIs	https://doi.org/10.1001/jamaophthalmol.2022.1175
Publication status	E-pub ahead of print - 5 May 2022
Externally published	Yes

Bibliographical note

This is an open access article distributed under the terms of the CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium. You are not required to obtain permission to reuse this article content, provided that you credit the author and journal.
© 2022 Gurudas S et al. JAMA Ophthalmology

Funder

Ms Gurudas 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.

Publisher Copyright:
© 2022 American Medical Association. All rights reserved.

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Ophthalmology

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Gurudas, S., Frudd, K., Maheshwari, J. J., Revathy, Y. R., Sivaprasad, S., Ramanathan, S. M., Pooleeswaran, V., Prevost, A. T., Karatsai, E., Halim, S., Chandra, S., Nderitu, P., Conroy, D., Krishnakumar, S., Parameswaran, S., Dharmalingam, K., Ramasamy, K., Raman, R., Jones, C., ... Turowski, P. (2022). Multicenter Evaluation of Diagnostic Circulating Biomarkers to Detect Sight-Threatening Diabetic Retinopathy. JAMA Ophthalmology, 140(6), 587-597. Advance online publication. https://doi.org/10.1001/jamaophthalmol.2022.1175

Gurudas, S, Frudd, K, Maheshwari, JJ, Revathy, YR, Sivaprasad, S, Ramanathan, SM, Pooleeswaran, V, Prevost, AT, Karatsai, E, Halim, S, Chandra, S, Nderitu, P, Conroy, D, Krishnakumar, S, Parameswaran, S, Dharmalingam, K, Ramasamy, K, Raman, R, Jones, C, Eleftheriadis, H, Greenwood, J & Turowski, P 2022, 'Multicenter Evaluation of Diagnostic Circulating Biomarkers to Detect Sight-Threatening Diabetic Retinopathy', JAMA Ophthalmology, vol. 140, no. 6, pp. 587-597. https://doi.org/10.1001/jamaophthalmol.2022.1175

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abstract = "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.",

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AU - Frudd, Karen

AU - Maheshwari, Jayapal Jeya

AU - Revathy, Yeddula Rebecca

AU - Sivaprasad, Sobha

AU - Ramanathan, Shruthi Mahalakshmi

AU - Pooleeswaran, Vignesh

AU - Prevost, A. Toby

AU - Karatsai, Eleni

AU - Halim, Sandra

AU - Chandra, Shruti

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N2 - 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.

AB - 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.

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

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