Circulating microRNAs as biomarkers for diabetic retinopathy stage identification: A DTA systematic review and meta-analysis

Purpose: To evaluate the diagnostic accuracy of circulating miRNAs in distinguishing between different diabetic retinopathy (DR) stages in type 2 diabetes mellitus (T2DM). Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA-DTA and Cochrane guidelines. The protocol was not registeres and no external funding was received. A comprehensive search was performed in PubMed, CENTRAL, Scopus, Web of Science, ScienceDirect, and ClinicalTrials (up to January 2025) to identify diagnostic test accuracy studies on circulating miRNAs for DR. Eligible studies included three predefined comparisons: healthy controls versus DR (CTL vs DR), T2DM without DR versus DR (T2DM vs DR), and non-proliferative versus proliferative DR (NPDR vs PDR). DR diagnosis was confirmed using fundus fluorescein angiography and/or fundus examination. Two reviewers independently conducted study selection, data extraction, and risk of bias assessment with QUADAS-2; certainty of evidence was assessed using GRADE. Data were synthesized using a bivariate random-effects meta-analysis, with subgroup analyses, meta-regression, and sensitivity analyses to explore heterogeneity. Data were synthesized via a bivariate random-effects meta-analysis, with subgroup analyses, meta-regression, and sensitivity tests to explore heterogeneity. Results: Sixteen studies (1849 participants; 21 miRNAs) were included. For CTL vs DR (7 studies), pooled sensitivity was 77% (70–82) and specificity 84% (77–89), AUC 0.86 (0.82–0.89). For T2DM vs DR (9 studies), sensitivity was 81% (75–86) and specificity 80% (71–87), AUC 0.88 (0.84–0.91). For NPDR vs PDR (12 studies), sensitivity was 84% (79–87) and specificity 82% (76–88), AUC 0.90 (0.87–0.93). Heterogeneity arose chiefly from sample matrix, normalization strategies and inter-study expression trends. Patient selection posed the greatest bias risk. Conclusions: Circulating miRNAs exhibit promising diagnostic accuracy for differentiating among various stages of DR. However, future large, prospective studies in diverse populations and standardized pre-analytical protocols are required to confirm and translate these findings.