Objectives : The objective of this analysis was to identify clinically relevant biomarkers of the precursors of EE that can inform early intervention. To this end, penalized regression approaches for variable subset selection were applied to a large panel of candidate biomarkers measured in a cohort of Peruvian infants to identify the optimal subset that are most predictive of nutritional status (length-for-age Z-score – LAZ-score) over a two-month lag.
Panels of biomarkers totaling 180 distinct analytes were quantified in fecal, urine and plasma samples taken at 7, 15 and 24 months of age from 258 subjects enrolled in a birth cohort in Peru. Treating the subjects’ length-for-age Z-score (LAZ-score) over a 2-month lag as the outcome, penalized linear regression models with different shrinkage methods were fitted to determine the best-fitting subset of biomarkers, which were then included with covariates in linear regression models to estimate each biomarker’s adjusted effect.
Transferrin had the largest and most statistically significant adjusted effect on LAZ-score – a coefficient value of 0.76 (0.48, 1.05) for each doubling of plasma transferrin concentration relative to the sample mean. This translated to an estimated difference in height at 17 months of age of 0.93 cm between children at the 75th and 25th percentile of that biomarker’s distribution. Other biomarkers with large effect size estimates included 4-hydroxyproline (Hyp), tumor necrosis factor receptor 2 (TNFR2), beta-2-microglobulin (B2M), proline, serum amyloid P-component (SAP) and adiponectin.
Penalized regression modeling approaches can be used to select subsets from large panels of candidate biomarkers of EED that both provide further evidence for known markers and generate hypotheses about new ones. Transferrin, Hyp, TNFR2, B2M, proline, SAP and adiponectin, among others, are promising plasma biomarkers of EE.
Funding Sources :
The Bill & Melinda Gates Foundation (BMGF).
The Foundation for the National Institutes of Health
The National Institutes of Health, Fogarty International Center
The Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases of the Johns Hopkins School of Medicine.