Treatment heterogeneity of water, sanitation, hygiene, and nutrition interventions on child growth by environmental enteric dysfunction and pathogen status for young children in Bangladesh

Background Water, sanitation, hygiene (WSH), nutrition (N), and combined (N+WSH) interventions are often implemented by global health organizations, but WSH interventions may insufficiently reduce pathogen exposure, and nutrition interventions may be modified by environmental enteric dysfunction (EED), a condition of increased intestinal permeability and inflammation. This study investigated the heterogeneity of these treatments’ effects based on individual pathogen and EED biomarker status with respect to child linear growth. Methods We applied cross-validated targeted maximum likelihood estimation and super learner ensemble machine learning to assess the conditional treatment effects in subgroups defined by biomarker and pathogen status. We analyzed treatment (N+WSH, WSH, N, or control) randomly assigned in-utero, child pathogen and EED data at 14 months of age, and child HAZ at 28 months of age. We estimated the difference in mean child height for age Z-score (HAZ) under the treatment rule and the difference in stratified treatment effect (treatment effect difference) comparing children with high versus low pathogen/biomarker status while controlling for baseline covariates. Results We analyzed data from 1,522 children who had a median HAZ of −1.56. We found that fecal myeloperoxidase (N+WSH treatment effect difference 0.0007 HAZ, WSH treatment effect difference 0.1032 HAZ, N treatment effect difference 0.0037 HAZ) and Campylobacter infection (N+WSH treatment effect difference 0.0011 HAZ, WSH difference 0.0119 HAZ, N difference 0.0255 HAZ) were associated with greater effect of all interventions on anthropometry. In other words, children with high myeloperoxidase or Campylobacter infection experienced a greater impact of the interventions on anthropometry. We found that a treatment rule that assigned the N+WSH (HAZ difference 0.23, 95% CI (0.05, 0.41)) and WSH (HAZ difference 0.17, 95% CI (0.04, 0.30)) interventions based on EED biomarkers and pathogens increased predicted child growth compared to the randomly allocated intervention. Conclusions These findings indicate that EED biomarkers and pathogen status, particularly Campylobacter and myeloperoxidase (a measure of gut inflammation), may be related to the impact of N+WSH, WSH, and N interventions on child linear growth.