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

James M Njunge^{1

2}, Kirkby Tickell³, Abdoulaye Hama Diallo⁴, Abu Sadat Mohammad Sayeem Bin Shahid⁵, Md Amran Gazi⁵, Ali Saleem⁶, Zaubina Kazi⁶, Syed Ali⁶, Caroline Tigoi^{1

2}, Ezekiel Mupere⁷, Christina L Lancioni⁸, Emily Yoshioka³, Mohammod Jobayer Chisti⁵, Moses Mburu^{1

2}, Moses Ngari^{1

2}, Narshion Ngao^{1

2}, Bonface Gichuki^{1

2}, Elisha Omer^{1

2}, Wilson Gumbi^{1

2}, Benson Singa⁹, Robert Bandsma^{10

11}, Tahmeed Ahmed⁵, Wieger Voskuijl^{12

13}, Thomas N Williams^{2

14}, Alex Macharia², Johnstone Makale², Anna Mitchel¹⁵, Jessica Williams¹⁵, Joe Gogain¹⁵, Nebojsa Janjic¹⁵, Rupasri Mandal¹⁶, David S Wishart¹⁶, Hang Wu¹⁷, Lei Xia¹⁷, Michael Routledge^{17

18}, Yun Yun Gong¹⁷, Camilo Espinosa^{19

20

21}, Nima Aghaeepour¹⁹, Jie Liu²², Eric Houpt²², Trevor D Lawley²³, Hilary Browne²³, Yan Shao²³, Doreen Rwigi²⁴, Kevin Kariuki²⁴, Timothy Kaburu²⁴, Holm H Uhlig^{25

26}, Lisa Gartner²⁵, Kelsey Jones^{27

28}, Albert Koulman^{29

30}, Judd Walson^#³, James Berkley^#^{1

2

31}

Affiliations

¹ The Childhood Acute Illness and Nutrition Network, Nairobi, Kenya.
² KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
³ Global Health and Epidemiology, University of Washington, Seattle, Seattle, USA.
⁴ Department of Public Health, Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso.
⁵ Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh.
⁶ Department of Pediatrics and Child Health, Aga Khan University Hospital, Karachi, Karachi, Pakistan.
⁷ Department of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda.
⁸ Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
⁹ Kenya Medical Research Institute, Nairobi, Kenya.
¹⁰ Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Department of Biomedical Sciences, University of Malawi College of Medicine, Blantyre, Malawi.
¹² Amsterdam UMC location, University of Amsterdam, Amsterdam, The Netherlands.
¹³ Amsterdam Centre for Global Child Health & Emma Children's Hospital, Amsterdam, The Netherlands.
¹⁴ Institute of Global Health Innovation, Department of Surgery and Cancer, Imperial College London, London, UK.
¹⁵ SomaLogic, Boulder, Colorado, USA.
¹⁶ Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
¹⁷ School of Food Science and Nutrition, University of Leeds, Leeds, UK.
¹⁸ School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China.
¹⁹ Departments of Anesthesiology, Pain, and Perioperative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
²⁰ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
²¹ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
²² Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.
²³ Wellcome Sanger Institute, Hinxton, UK.
²⁴ The Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya.
²⁵ Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.
²⁶ Department of Paediatrics and Biomedical Research Centre, University of Oxford, Oxford, UK.
²⁷ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
²⁸ Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK.
²⁹ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
³⁰ NIHR BRC Nutritional Biomarker Laboratory, University of Cambridge, Cambridge, UK.
³¹ Center for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.

^# Contributed equally.

PMID: 36415883
PMCID: PMC9646488
DOI: 10.12688/gatesopenres.13635.2

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

James M Njunge et al. Gates Open Res. 2022.

. 2022 Nov 3:6:77.

doi: 10.12688/gatesopenres.13635.2. eCollection 2022.

Authors

Affiliations

¹ The Childhood Acute Illness and Nutrition Network, Nairobi, Kenya.
² KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
³ Global Health and Epidemiology, University of Washington, Seattle, Seattle, USA.
⁴ Department of Public Health, Faculty of Health Sciences, University of Ouagadougou, Ouagadougou, Burkina Faso.
⁵ Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh.
⁶ Department of Pediatrics and Child Health, Aga Khan University Hospital, Karachi, Karachi, Pakistan.
⁷ Department of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda.
⁸ Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
⁹ Kenya Medical Research Institute, Nairobi, Kenya.
¹⁰ Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Department of Biomedical Sciences, University of Malawi College of Medicine, Blantyre, Malawi.
¹² Amsterdam UMC location, University of Amsterdam, Amsterdam, The Netherlands.
¹³ Amsterdam Centre for Global Child Health & Emma Children's Hospital, Amsterdam, The Netherlands.
¹⁴ Institute of Global Health Innovation, Department of Surgery and Cancer, Imperial College London, London, UK.
¹⁵ SomaLogic, Boulder, Colorado, USA.
¹⁶ Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
¹⁷ School of Food Science and Nutrition, University of Leeds, Leeds, UK.
¹⁸ School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China.
¹⁹ Departments of Anesthesiology, Pain, and Perioperative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
²⁰ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
²¹ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
²² Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.
²³ Wellcome Sanger Institute, Hinxton, UK.
²⁴ The Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya.
²⁵ Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.
²⁶ Department of Paediatrics and Biomedical Research Centre, University of Oxford, Oxford, UK.
²⁷ Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
²⁸ Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK.
²⁹ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
³⁰ NIHR BRC Nutritional Biomarker Laboratory, University of Cambridge, Cambridge, UK.
³¹ Center for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.

^# Contributed equally.

PMID: 36415883
PMCID: PMC9646488
DOI: 10.12688/gatesopenres.13635.2

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.

Keywords: Case-Cohort; Children; LMIC; Mortality; Omics; Systems Biology.

PubMed Disclaimer

Conflict of interest statement

No competing interests were disclosed.

Figures

**Figure 1.**
A. Duration of time from sample collection to storage at -80°C. ~80% of the samples (whole blood, plasma, serum, and rectal swabs) achieved a median of 44 minutes from collection to storage at a -80°C freezer. Except for stool, the rest of the samples were frozen at a -80°C freezer within 1 hour of collection. B. Proportion of samples available for analysis within the nested case cohort study. Greater than 90% of the selected study children have available samples for analysis. Approximately 80% of the study participants have stool samples available for analysis. Adm = admission, disch = discharge.

**Figure 2.. Samples collection, processing, storage and shipment workflow.**
Consent and sampling was carried out at the site’s ward or clinic. Samples were collected, pre-processed and stored at the study site -80 °C freezers. The duration from sampling to storage was ~44 minutes. Data curation and visualisation was done in R and the shiny application where queries and reports were transmitted online to sites for prompt and timed resolution. Data for samples was captured in the Kilifi Integrated Data Management System (KIDMS) that was linked to patient data in the clinical database captured on Research Electronic Data Capture (REDCap). Samples were subsequently shipped to the central biobank facility at KEMRI Wellcome Research Programme. CHAIN NCC study samples were analysed in the KEMRI-Wellcome Trust Research laboratories or shipped to consortium partners. CHAIN = Childhood Acute Illness and Nutrition, NCC = Nested Case Cohort, EED = Environmental Enteric Dysfunction, Hb = Haemoglobin, KEMRI-CMR = Kenya Medical Research Institute – Centre for Microbiology Research. TMIC = The Metabolomics Innovation Centre, ICDDR, B = International Centre for Diarrhoeal Disease Research, Bangladesh.

**Figure 3.. Sample selection for the CHAIN Nested Case-Cohort Study.**
Areas are proportional to the number of observations and excluding community participants are not included.

See this image and copyright information in PMC

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical