A Precision Screening Framework for Thalassemia in a High-Mobility Population: Integrating 3D Phenotypic Mapping and Genotype-Specific Thresholds
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Objective In regions characterized by high hemoglobinopathy prevalence and significant population mobility, defining population-specific diagnostic thresholds is critical to overcoming "phenotypic masking" in complex thalassemia genotypes. This study evaluates the diagnostic utility of hematological indices and HbA 2 through a novel 3D topographical framework to refine screening protocols for the South China population. Methods A retrospective analysis was conducted on 1,672 genetically confirmed thalassemia carriers 1,090 α -thalassemia, 522 β -thalassemia, 60 αβ -compound) and 5,051 healthy controls from January 2018 to June 2025. We utilized Receiver Operating Characteristic (ROC) curves and 3D spatial clustering analysis of Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), and Hemoglobin A 2 ( HbA 2 ) to define optimal cut-off values and diagnostic performance. Results The molecular landscape was dominated by the -- SEA /αα (54.5%) and β CD41–42 /β N (30.5%) genotypes, reflecting a distinct regional mutational spectrum. While HbA 2 functioned as a near-perfect biomarker for β -thalassemia (AUC 0.984) and αβ -compound states (AUC 0.964), it lacked discriminatory power for silent α -carriers (AUC 0.563). Notably, αβ -coinheritances demonstrated "phenotypic masking," where concurrent α -globin defects partially "normalized" erythrocyte indices compared to pure β -thalassemia (22.00 ± 2.11 vs. 20.60 ± 1.96 pg). Our 3D topographical model revealed significant spatial overlap between controls and silent α -carriers, representing a critical diagnostic "blind spot". Conclusion To mitigate the risk of occult carrier transmission, we propose a hierarchical precision framework: indices HbA 2 > 3.75% for primary β -thalassemia screening. MCH < 28.5 pg combined with HbA 2 < 2.77% as a trigger for reflex α -molecular testing to capture silent carriers. This multidimensional approach addresses the limitations of traditional single-parameter thresholds and provides a robust scientific basis for thalassemia prevention in high-prevalence urban environments.
