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G. Kanuri et al.
Table 2. Properties of selected hepcidin and ZPP/H cut-off values for iron deficiency anemia diagnosis.
Study group
Children Women
Children
Women
Biomarker Sensitivity Cut-off Value
ZPP/H mmol/mol heme
>90 81 >107 73
Hepcidin ng/mL
≤6.85 86 ≤4.52 90
95% CI Specificity
71.9 - 88.2 96 63.2 - 81.4 93
77.6 - 92.1 94
82.4 - 95.1 94
95% CI
90.1 - 98.9 85.9 - 97.5
87.4 - 97.8
87.5 - 98.2
LR+ LR–
20.25 0.2 10.83 0.29
14.33 0.15
16.2 0.11
Youden Positive Index Predictive
0.77 95.29 0.66 91.25
0.80 93.48
0.84 93.75
Negative Predictive
83.48 77.5
85.45
90.38
CI: confidence interval; +LR: positive likelihood ratio; -LR: negative likelihood ratio; ZPP/H: zinc protoporphyrin/heme.
(Children: 9.6 ± 0.8g/dL vs. 11.9 ± 0.6g/dL; Women: 10 ± 1.2g/dL vs. 13.2 ± 0.7 g/dL), mean corpuscular volume (Children: 65 vs. 77fl, Women: 74 vs. 86fl) and median fer- ritin (Children: 3.8 vs. 35ng/mL, Women: 3.7 vs. 39ng/mL) compared with non-anemic women and children, respec- tively (Table 1).
There were no differences in white blood cell and platelet counts between the two study groups (Table 1). Serum CRP values were low in both study groups (Table 1). As expected, sTfR was significantly higher in children
and women with IDA compared with their non-anemic counterparts (Children: 3.9 vs. 1.7mg/L; Mothers: 3 vs. 1.3mg/L) (Table 1). Moreover, sTfR/log ferritin index val- ues >2 in women and children with IDA confirmed a diag- nosis of IDA and ruled out coexisting anemia of inflam- mation (Table 1).
Erythrocyte ZPP/H and serum hepcidin values in anemic and non-anemic groups
The median ZPP/H in children and women with IDA was higher when compared with their non-anemic coun- terparts (children: 151 mmol/mol heme [IQR: 104, 263] vs. 49 mmol/mol heme [IQR: 39, 60] and women: 155 mmol/mol heme [IQR: 101, 243] vs. 66 mmol/mol heme [IQR: 53, 83], P<0.001 for both) (Table 1). Median hep- cidin concentration was markedly higher in non-anemic children and women when compared with their counter- parts who had IDA (children: 42ng/mL [IQR: 25, 62] vs.
Figure 2. Receiver operating charac- teristic curves for ferritin, hepcidin and ZPP/H. Pairwise comparison of area under ROC curves of hepcidin and ZPP/H with ferritin as a gold standard for IDA diagnosis in (A) chil- dren and in (B) women. As noted, the AUC is similar between the gold stan- dard (ferritin) and either hepcidin or ZPP/H indicating the inherent ability of these two biomarker tests to dis- criminate between the non-anemic and IDA groups. ZPP: zinc protopor- phyrin.
1.2ng/mL [IQR: 0.5, 3.6] and women: 17.7ng/mL [IQR: 9, 38] vs. 0.6ng/mL [IQR: 0.2, 1.3], P<0.05 for both) (Table 1).
Diagnostic cut-off for erythrocyte ZPP/H
ZPP/H >90 μmole/mole heme resulted in IDA diagnosis in children with 81% sensitivity and 96% specificity (Table 2). This cut-off had a positive likelihood ratio of 20.25 and a positive predictive value of 95.2% (Table 2). In women, a higher ZPP/H >107 μmole/mole heme resulted in IDA diagnosis with 73% sensitivity and 93% specifici- ty. This cut-off in women yielded a positive likelihood ratio of 10.8 and a positive predictive value of 91.2% (Table 2). ROC curves for ZPP/H to diagnose IDA revealed an area under the curve (AUC)ROC of 0.94 in children (Figure 2A) and 0.89 (P<0.0001) in women (Figure 2B).
Diagnostic cut-off for serum hepcidin
Serum hepcidin value ≤6.85ng/mL yielded an IDA diag- nosis in children with 86% sensitivity and 94% specifici- ty (Table 2). This cut-off had a likelihood ratio of 14.3 with a positive predictive value of 93.4% (Table 2). In women, a hepcidin value of ≤4.5ng/mL resulted in an IDA diagnosis with 90% sensitivity and 94% specificity (Table 2). This cut-off corresponded with a likelihood ratio of 16.2 and a positive predictive value of 93.7%. ROC curves for hepcidin to diagnose IDA revealed an AUCROC of 0.97 in children (Figure 2A) and 0.96 (P<0.0001) in women (Figure 2B).
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B