The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia

Abstract

Introduction: Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network (www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and 270/1140 well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination. The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT03208725.

Plasma proteomic signatures of enteric permeability among hospitalized and community children in Kenya and Pakistan

“…This study included acutely ill children aged 2−23 months enrolled in the CHAIN study. 15 , 16 , 21 , 22 Two CHAIN sites, Migori County Referral Hospital in western Kenya and Civil Hospital in Karachi, Pakistan, participated in the LRR sub-study. No gender or sex bias was introduced in the enrolling strategy for these children, but the effect of sex in this dataset has been previously explored.…”

“…The CHAIN Cohort was a prospective study which enrolled acutely ill children aged 2−23 months across nine sites in six countries in Africa and South Asia at admission to hospital. 15 , 16 , 21 , 22 Children were enrolled across a range of rural and urban environments and differing malaria and HIV endemicities. Two CHAIN sites, Migori County Referral Hospital in western Kenya and Civil Hospital in Karachi, Pakistan, participated in the LRR sub-study.…”

“…The proteomic approach was implemented by Somalogic, Inc using an aptamer-based technology, which assesses the concentration of 7,500 proteins. 15 , 23 , 24 …”

“…TACman quantitative PCR for 32 enteric pathogens was conducted on these rectal swabs. 15 Cycle threshold values under 30 were considered positive detections. These data were aggregated into variables for detection of any pathogen within specific groups at either admission or discharge.…”

“…We combine clinical data from the Childhood Acute Illness and Nutrition (CHAIN) Cohort with LRR results collected on a subset of CHAIN children, a proteomic panel of 7,500 plasma biomarkers covering a broad range of biological processes, and a quantitative polymerase chain reaction for 34 enteric pathogens detected on rectal swabs. 15 , 16 Using supervised machine learning we identify plasma proteins associated with the LRR among the community and hospitalized children and we describe the associations between the identified plasma proteins, enteric pathogens, and known clinical and demographic risk factors for increased enteric permeability.…”