Table 3.
Mediation Analyses
| Direct Effect of Iron Stores (95%CI) P value |
Indirect Effect of Iron Stores through Mediator (95%CI) P Value |
Total Effect of Iron Stores (95%CI) P value |
*Proportion Mediated (%) (95%CI) P value |
|
|---|---|---|---|---|
| FGF23 as mediator | ||||
| Mortality | ||||
| Iron Deficiency | 0.96 (0.77, 1.20) 0.74 |
1.32 (1.24, 1.40) <0.001 |
1.27 (1.02, 1.57) 0.03 |
115% (50, 635) 0.04 |
| Mixed Iron Deficiency | 1.41 (1.11, 1.80) 0.005 |
1.10 (1.05, 1.15) < 0.001 |
1.56 (1.22, 1.99) <0.001 |
20% (10, 43) < 0.001 |
| High Iron | 1.57 (1.26, 1.96) < 0.001 |
0.98 (0.94, 1.02) 0.34 |
1.54 (1.24, 1.92) <0.001 |
−5% (−24, 5) 0.31 |
| Heart Failure | ||||
| Iron Deficiency | 0.98 (0.76, 1.28) 0.90 |
1.34 (1.25, 1.45) <0.001 |
1.32 (1.03, 1.70) 0.03 |
112% (51, 579) 0.03 |
| Mixed Iron Deficiency | 1.20 (0.89, 1.63) 0.23 |
1.11 (1.05, 1.17) <0.001 |
1.33 (0.98, 1.81) 0.07 |
35% (−70, 235) 0.06 |
| High Iron | 1.60 (1.23, 2.09) <0.001 |
0.98 (0.94, 1.02) 0.34 |
1.57 (1.20, 2.06) 0.001 |
−6% (−31, 5) 0.29 |
| PTH as mediator | ||||
| Mortality | ||||
| Iron Deficiency | 1.27 (1.02, 1.58) 0.03 |
1.00 (0.98, 1.01) 0.79 |
1.27 (1.02, 1.57) 0.03 |
2% (−12, 21) 0.55 |
| Mixed Iron Deficiency | 1.62 (1.27, 2.06) <0.001 |
1.01 (0.99, 1.02) 0.50 |
1.62 (1.28, 2.07) <0.001 |
0.6% (−5, 6) 0.80 |
| High Iron | 1.55 (1.24, 1.92) <0.001 |
0.99 (0.98, 1.01) 0.27 |
1.53 (1.23, 1.91) <0.001 |
−2% (−11, 3) 0.35 |
| Heart Failure | ||||
| Iron Deficiency | 1.36 (1.06, 1.74) 0.02 |
1.00 (0.99, 1.01) 0.79 |
1.35 (1.06, 1.73) 0.02 |
2% (−7, 16) 0.52 |
| Mixed Iron Deficiency | 1.28 (0.94, 1.74) 0.12 |
1.00 (0.99, 1.02) 0.51 |
1.28 (0.94, 1.74) 0.11 |
1% (−40, 40) 0.82 |
| High Iron | 1.59 (1.22, 2.08) <0.001 |
0.99 (0.98, 1.00) 0.30 |
1.58 (1.21, 2.07) <0.001 |
−2% (−12, 3) 0.35 |
| Hemoglobin as mediator | ||||
| Mortality | ||||
| Iron Deficiency | 1.19 (0.96, 1.48) 0.11 |
1.05 (1.02, 1.09) 0.003 |
1.26 (1.01, 1.56) 0.04 |
23% (4, 130) 0.04 |
| Mixed Iron Deficiency | 1.54 (1.21, 1.96) <0.001 |
1.02 (1.00, 1.04) 0.03 |
1.57 (1.24, 2.00) <0.001 |
5% (1, 13) 0.003 |
| High Iron | 1.51 (1.22, 1.88) <0.001 |
1.00 (0.99, 1.01) 0.77 |
1.52 (1.22, 1.88) <0.001 |
0.4% (−4, 5) 0.81 |
| Heart Failure | ||||
| Iron Deficiency | 1.26 (0.98, 1.62) 0.07 |
1.10 (1.05, 1.15) <0.001 |
1.38 (1.08, 1.77) 0.01 |
31% (13, 138) 0.02 |
| Mixed Iron Deficiency | 1.29 (0.95, 1.74) 0.10 |
1.04 (1.01, 1.07) 0.009 |
1.34 (0.99, 1.81) 0.06 |
14% (−69, 113) 0.09 |
| High Iron | 1.59 (1.22, 2.08) <0.001 |
1.00 (0.98, 1.02) 0.77 |
1.60 (1.23, 2.09) <0.001 |
0.6% (−6, 7) 0.80 |
Estimates for direct, indirect and total effects are hazard ratios. The direct effect refers to the effect of iron stores on the outcome independent of the mediator. The indirect effect refers to the effect of iron stores on the outcome that acts through the mediator. Total effects are computed as the product of the direct and indirect effects.
Proportion mediated is computed using R package mediation based on a Weibull model and presented as percentages.
Covariates included in the model: center, age, sex, race, ethnicity, diabetes, smoking, systolic blood pressure, body mass index, history of cardiovascular disease, estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, and erythropoietin use.
Abbreviations: PTH, parathyroid hormone; FGF23, fibroblast growth factor 23