Diagnostic performance of red cell parameters and discrimination indices for beta thalassemia trait identification, with a focus on the borderline HbA2 range: a population-based study from Delhi-NCR, India

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Background Beta thalassemia trait (BTT) screening is challenged by a diverse mutation spectrum and by individuals with borderline HbA2 values who may carry pathogenic variants despite near-normal screening results. This study aimed to characterise the genotypic spectrum of BTT carriers in a heterogeneous Indian population, compare hematological parameters across β 0 , β + , and rare HBB variant groups, and assess the diagnostic performance of red cell parameters and discrimination indices for carrier identification, with particular focus on the borderline HbA2 range. Methods Within a population-based cohort of 4,886 young adults (Delhi NCR), 209 individuals (115 with HbA2 4–9%; 94 with borderline HbA2 3.2–3.9%) underwent molecular analysis by ARMS-PCR and Sanger sequencing. Results The β 0 mutations (31.7%) showed the most pronounced thalassemic profile, and MCV, MCH, and HbA2 differed significantly across β 0 , β + , and rare HBB variant groups (p ≤ 0.002). In the full cohort, MCV was the strongest single discriminator (AUC 0.88), followed by HbA2 (0.86) and MCH (0.84); the Shine and Lal index performed best among the indices (AUC 0.88). Within the borderline subgroup, MCH and MCV retained the greatest discriminatory value (AUC 0.84 and 0.83), with high specificity (92.2% and 87.8%) at cut-offs of 20.8 pg and 73.9 fL. Conclusion MCV, MCH, and HbA2 are the most informative first-tier measures for flagging BTT carriers, though molecular confirmation remains essential. In the borderline HbA2 range, MCH and MCV best prioritise individuals for molecular confirmation. Future studies should evaluate better screening criteria for this under-studied group to reliably identify carriers.

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