Adjusting iron and vitamin A status in settings of inflammation: a sensitivity analysis of the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) approach

Abstract

Background: Accurate assessment of iron and vitamin A status is needed to inform public health decisions, but most population-level iron and vitamin A biomarkers are independently influenced by inflammation.

Objectives: We aimed to assess the reproducibility of the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) regression approach to adjust iron [ferritin, soluble transferrin receptor (sTfR)] and vitamin A [retinol-binding protein (RBP), retinol] biomarkers for inflammation (α-1-acid glycoprotein and C-reactive protein).

Methods: We conducted a sensitivity analysis comparing unadjusted and adjusted estimates of iron and vitamin A deficiency using the internal-survey regression approach from BRINDA phase 1 (16 surveys in children, 10 surveys in women) and 13 additional surveys for children and women (BRINDA phase 2).

Results: The relations between inflammation and iron or vitamin A biomarkers were statistically significant except for vitamin A biomarkers in women. Heterogeneity of the regression coefficients across surveys was high. Among children, internal-survey adjustments increased the estimated prevalence of depleted iron stores (ferritin <12 µg/L) by a median of 11 percentage points (pp) (24 pp and 9 pp in BRINDA phase 1 and phase 2, respectively), whereas estimates of iron-deficient erythropoiesis (sTfR >8.3 mg/L) decreased by a median of 15 pp (15 pp and 20 pp in BRINDA phase 1 and phase 2, respectively). Vitamin A deficiency (RBP <0.7 µmol/L or retinol <0.7 µmol/L) decreased by a median of 14 pp (18 pp and 8 pp in BRINDA phase 1 and phase 2, respectively) in children. Adjustment for inflammation in women resulted in smaller differences in estimated iron deficiency than in children.

Conclusions: Our findings are consistent with previous BRINDA conclusions that not accounting for inflammation may result in an underestimation of iron deficiency and overestimation of vitamin A deficiency. Research is needed to understand the etiology of the heterogeneity in the regression coefficients before a meta-analyzed regression correction can be considered.

Keywords: biomarkers; inflammation; iron; meta-analysis; micronutrient; nutritional assessment; vitamin A.

FIGURE 1

Sample sizes for BRINDA project analyses. The total sample size for BRINDA analyses for the reference value calculations is based on surveys with available AGP or CRP data. The total sample size for BRINDA analyses for the adjustment calculations is based on surveys with available data for both AGP and CRP and either ferritin, sTfR, retinol, or RBP concentrations. Pakistan 2011 is included in BRINDA phase 1 for children but included in BRINDA phase 2 for women. Only AGP data were available in BRINDA phase 1 and CRP data became available in BRINDA phase 2 for women. Thus, Pakistan data (8,261 women) were included in the calculations of the AGP reference for BRINDA phase 1 but are counted under BRINDA phase 2 in this flowchart. AGP, α-1-acid glycoprotein; BRINDA, Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia; CRP, C-reactive protein; RBP, retinol-binding protein; sTfR, soluble transferrin receptor.

FIGURE 2

Estimated prevalence of inflammation in children and women, BRINDA project. (A) Estimated prevalence of inflammation for children, (B) estimated prevalence of inflammation for women, with BRINDA phase 1 on the left and BRINDA phase 2 on the right. Estimated prevalence of inflammation defined as CRP >5 mg/L (light gray) and AGP >1 g/L (dark gray), ordered from lowest to highest inflammation amounts based on CRP >5 mg/L. Total sample size in children across surveys is 14,936 and in women 18,817. AGP, α-1-acid glycoprotein; BRINDA, Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia; CRP, C-reactive protein; PNG, Papua New Guinea.

FIGURE 3

Estimated prevalence [% (95% CI)] of depleted iron stores, iron-deficient erythropoiesis, and vitamin A deficiency by inflammation deciles in children, BRINDA project. Estimated unweighted prevalence of depleted iron stores by AGP deciles (A) and CRP deciles (B), iron-deficient erythropoiesis by AGP deciles (C) and CRP deciles (D), and vitamin A deficiency by AGP deciles (E) and CRP deciles (F) in children. Depleted iron stores defined as ferritin <12 µg/L, iron-deficient erythropoiesis as sTfR >8.3 mg/L, and vitamin A deficiency as either retinol or RBP <0.7 µmol/L. Dashed line, pooled BRINDA phase 1 and 2 data; dark gray line, BRINDA phase 1 data; and light gray line, BRINDA phase 2 data. Sample size: (A, B) 8458 for BRINDA phase 1, 5610 for BRINDA phase 2, and 14,068 for BRINDA pooled; (C, D) 9326 for BRINDA phase 1, 4068 for BRINDA phase 2, and 13,394 for BRINDA pooled; (E, F) 8845 for BRINDA phase 1, 5572 for BRINDA phase 2, and 14,417 for BRINDA pooled. AGP, α-1-acid glycoprotein; BRINDA, Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia; CRP, C-reactive protein; RBP, retinol-binding protein; sTfR, soluble transferrin receptor.

FIGURE 4

Estimated prevalence [% (95% CI)] of depleted iron stores, iron-deficient erythropoiesis, and vitamin A insufficiency by inflammation deciles in women, BRINDA project. Estimated prevalence of depleted iron stores by AGP deciles (A) and CRP deciles (B), iron-deficient erythropoiesis by AGP deciles (C) and CRP deciles (D), and vitamin A insufficiency by AGP deciles (E) and CRP deciles (F) in women. Depleted iron stores defined as ferritin <15 µg/L, iron-deficient erythropoiesis as sTfR >8.3 mg/L, and vitamin A insufficiency as either retinol or RBP <1.05 µmol/L. Dashed line, pooled BRINDA phase 1 and 2 data; dark gray line, BRINDA phase 1 data; and light gray line, BRINDA phase 2 data. Sample size: (A, B) 4352 for BRINDA phase 1, 13,719 for BRINDA phase 2, and 18,071 for BRINDA pooled; (C, D) 5098 for BRINDA phase 1, 10,775 for BRINDA phase 2, and 15,873 for BRINDA pooled; (E, F) 4285 for BRINDA phase 1, 13,354 for BRINDA phase 2, and 17,639 for BRINDA pooled. AGP, α-1-acid glycoprotein; BRINDA, Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia; CRP, C-reactive protein; RBP, retinol-binding protein; sTfR, soluble transferrin receptor.