Multiomics characterization of acute child illness and mortality in Africa and South Asia

Childhood illnesses from infectious diseases in low- and middle-income countries contribute substantially to the global under-five mortality. Many hospitalised children experience incomplete recovery, readmission, and post-discharge mortality despite guideline-directed care. However, targeted interventions remain elusive due to a limited understanding of underlying mechanisms. In this work, we employ multiomic profiling and multivariate modeling to investigate biological drivers of inpatient and post-discharge mortality in 3,101 acutely ill children across nine sites in sub-Saharan Africa and South Asia. In a nested case-cohort (N=1,008), we generate plasma proteomics, serum metabolomics and lipidomics, stool metagenomics, and fecal pathogen data at admission and discharge. Additionally, we profile 270 geographically matched community children for biological baselines. We identify a generalizable mortality signature marked by immune, inflammatory, and metabolic dysregulation with gut dy..., The study population consisted of a nested case-cohort (NCC) study (the discovery cohort) within the Childhood Acute Illness and Nutrition (CHAIN) Network cohort. The CHAIN study recruited 3,101 children from nine sites across six countries: Bangladesh, Burkina Faso, Kenya, Malawi, Pakistan, and Uganda. Children were stratified by nutritional status using mid-upper arm circumference (MUAC) during enrolment at hospital admission, and followed up for 180 days after discharge. Geographically-matched community participants were included as a comparison group. The study was approved by the institutional review boards of all partner sites. The discovery cohort consisted of a random 24% sub-cohort of children stratified by site, including 658 survivors (non-cases) and 109 deaths (cases). Additionally, all remaining deaths (241 cases) not included in the random sub-cohort were added, resulting in a total of 350 cases. Another 30 randomly selected community participants from each site (a to..., , # Multiomics characterization of acute child illness and mortality in Africa and South Asia

#### Data Accessibility Statement

Due to the sensitive nature of the data collected for this study, access to the underlying data is restricted and overseen by the relevant Data Governance Committee. The dataset and detailed access instructions are available via the Harvard Dataverse ([https://doi.org/10.7910/DVN/X6FAGX)](https://doi.org/10.7910/DVN/X6FAGX\)). The code files included in this submission are compatible with the CC0 waiver required by Dryad for publication; however, the input files required to run the code are not included due to data sensitivity constraints. If there are any questions or concerns regarding data or code availability, readers are encouraged to contact the corresponding author of this dataset.

#### Scripts

The set of scripts (scripts.zip) to analyze the data from this study and generate all the results and figures presented in the manuscript are contained in the s..., All caregivers provided written informed consent for their child to participate in the study and for the data produced to be accessible after de-identification. Caregivers were assured that any report or publications on this study would not use participant’s names or identities. They agreed to information being shared with other researchers in ways that do not reveal individual participants’ identities. Any information that could identify people, such as their names and general locations, were replaced with number codes.