Establishment of pregnant-specific intervals for hemoglobin (Hb) A2, HbF and cut-off points for HbA2 for thalassemia in Chongqing, China

Lihua Kang; Siwei Yi; Si Tan; Qiuhong Li; Chunli Li

doi:10.15537/smj.2022.43.4.20210729

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Figure 1
- Schematic diagram of the participating individuals selection process. MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, Hb: hemoglobin, HbA2: hemoglobin A2, HbF: fetal hemoglobin

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Table 1

- Clinical characteristic of subjects.

Groups	Number of cases	Age (years)	MCV (fl)	MCH (pg)	Hb (g/L)	Ferritin (μg/L)
Groups	Mean±SD
Normal subjects for reference intervals
Males	2284	32.1±4.2	90.4±3.4	30.6±1.2	158.2±11.3	84.8±16.7
Females	874	30.5±2.9	91.6±3.7	30.4±1.2	136.2±8.7	66.3±25.4
Pregnant women	1241	29.7±4.6	90.2±3.9	30.9±1.4	131.3±8.0	44.5±13.2
Subjects for cut-off value of HbA2
α-thalassemia carriers	1970	31.2±2.3	79.0±8.9	25.4±3.5	130.9±16.5	101.5±20.3
β-thalassemia carriers	1316	28.9±4.7	74.1±11.0	24.4±4.2	125.0±16.6	98.4±24.1
Non thalassemia	2354	29.6±3.9	90.9±4.1	31.3±2.5	147.5±9.8	76.9±18.6

A p-value of <0.05 for α-thalassemia and β-thalassemia carriers versus normal group. MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, Hb: hemoglobin, HbA2: hemoglobin A2, SD: standard deviation

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Table 2

- The reference values of normal subjects.

Groups	Percentiles
Groups	2.5^th	5^th	10^th	25^th	50^th	75^th	90^th	95^th	97.5^th
HbA2
Normal males	2.3	2.4	2.5	2.6	2.8	2.9	3.0	3.1	3.2
Normal females	2.1	2.2	2.3	2.5	2.7	2.8	3.0	3.0	3.1
Normal pregnant women	1.9	2.2	2.3	2.4	2.4	2.7	2.9	3.0	3.1
HbF
Normal males	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
Normal females	0.0	0.0	0.0	0.0	0.0	0.0	0.5	0.7	0.9
Normal pregnant women	0.0	0.0	0.0	0.0	0.0	1.4	2.8	3.6	4.3

HbA2: hemoglobin A2, HbF: hemoglobin (fetal)

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Table 3

- Optimal cut-off points of hemoglobin A2 used for thalassemia.

Cut-off points	Males	Non pregnant women	Pregnant women	Overall
Cut-off points	Percentages
“Silent” α-thalassemia	2.7	2.7	2.4	2.8
AUC	0.8	0.6	0.5	0.9
α-thalassemia trait	2.6	2.6	2.4	2.6
AUC	0.9	0.8	0.8	0.7
α-thalassemia	2.5	2.6	2.4	2.6
AUC	0.7	0.7	0.6	0.8
β-thalassemia	3.4	3.3	3.3	3.3
AUC	1.0	1.0	1.0	1.0

AUC: area under the curve

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Table 4

- Screening efficiency of hemoglobin A2 for thalassemia.

Groups	Sensitivity	Specificity	PPV	NPV	Youden index
Groups	Precentage
Screening efficiency of HbA2=2.5% for α-thalassemia
Males	55.1	83.0	37.7	40.7	0.381
Non pregnant women	67.9	68.0	81.8	49.9	0.359
Pregnant women	71.3	44.9	74.0	55.7	0.162
Overall	67.9	71.6	50.5	83.9	0.395
Screening efficiency of HbA2=3.2% for β-thalassemia
Males	95.2	98.3	96.4	97.5	0.935
Non pregnant women	94.9	98.6	99.0	92.1	0.935
Pregnant women	94.8	99.1	99.0	94.9	0.939
Total	94.8	98.6	98.2	95.9	0.934

PPV: positive predictive value, NPV: negative predictive value, HbA₂: hemoglobin A2

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Table 5

- Distribution of genotypes.

Genotype	n (%)
α-thalassemia
-α3.7/αα	767 (23.3)
-α4.2/αα	158 (4.8)
ααCS/αα	63 (1.9)
ααQS/αα	35 (1.1)
ααWS/αα	22 (0.7)
--SEA/αα	889 (27.1)
-α3.7/-α3.7	9 (0.3)
-α3.7/-α4.2	3 (0.1)
--SEA/-α3.7	9 (0.3)
--SEA/-α4.2	2 (0.1)
β-thalassemia
CD17 (HBB: c.52A>T)	404 (12.3)
CD41-42 (HBB: c.126-129 delTTCT)	348 (10.6)
IVS-654 (HBB: c.316-197 C>T)	312 (9.5)
-28 (HBB: c. -78 A>G)	79 (2.4)
β E (HBB: c.79G>A)	62 (1.9)
CD71-72 (HBB: c.216_217 insA)	28 (0.8)
-29 (HBB: c.-79A>G)	22 (0.7)
CD27-28 (HBB: c.84_85 insC)	43 (1.3)
CD43(HBB: c.130G>T)	22 (0.7)
CD14-15 (HBB: c.45_46 insG)	4 (0.1)
CAP (HBB: c. -11_8delAAAC)	4 (0.1)
α-complex β-thalassemia	3 (0.1)
Total	3286 (-)