Abstract
Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Efforts to identify minimally invasive biomarkers of EED reveal an expanding number of candidate analytes. An analytic strategy is reported to select among candidate biomarkers and systematically express the strength of each marker’s association with linear growth in infancy and early childhood. 180 analytes were quantified in fecal, urine and plasma samples taken at 7, 15 and 24 months of age from 258 subjects 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. These were then included with covariates in linear regression models to obtain estimates of each biomarker’s adjusted effect on growth. Transferrin had the largest and most statistically significant adjusted effect on short-term linear growth as measured by LAZ-score–a coefficient value of 0.50 (0.24, 0.75) for each log2 increase in plasma transferrin concentration. Other biomarkers with large effect size estimates included adiponectin, arginine, growth hormone, proline and serum amyloid P-component. The selected subset explained up to 23.0% of the variability in LAZ-score. Penalized regression modeling approaches can be used to select subsets from large panels of candidate biomarkers of EED. There is a need to systematically express the strength of association of biomarkers with linear growth or other outcomes to compare results across studies.
Highlights
Chronic undernutrition affects around one in three children under age five, rendering them susceptible to prolonged and more severe infections and putting them at increased risk of mortality [1]
This study used a large number of candidate biomarkers of immune activation, metabolism and hormones and applied statistical methods to narrow them down from 110 different substances, to the 36 best predictors of growth in 258 Peruvian infants
Transferrin and other proteins, glycoproteins, hormones and antibodies that this study identified, can be measured and affordably in standard laboratories making them feasible to be used broadly as prognostic markers as part of child health and nutrition programs in underresourced settings
Summary
Chronic undernutrition affects around one in three children under age five, rendering them susceptible to prolonged and more severe infections and putting them at increased risk of mortality [1]. Gold standard diagnostic tests for other enteropathies, such as celiac and Crohn’s disease, include endoscopy and gut biopsy, invasive and demanding procedures that cannot feasibly be deployed in resource-constrained settings or to assess disease burden at the population level [10] For this reason, there is considerable interest in identifying and validating biomarkers of EED that can be used as surrogate endpoints in population-based studies and for evaluating nutrition and hygiene interventions [11]. The most widely adopted biomarkers of EED use saccharide-based permeability assays like the lactulose/mannitol test [12] Such tests, while non-invasive, have well-documented limitations to their use in EED-endemic populations, taking hours to administer, requiring samples to be shipped to well-equipped facilities which makes them cumbersome, expensive and impractical for screening and randomization for intervention trials [13]. Several fecal biomarkers, such as alpha-1-antitrypsin, myeloperoxidase and neopterin, have been shown to have complex associations with growth outcomes [9,11], while certain plasma biomarkers
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