Protocol: the International Milk Composition (IMiC) Consortium -a Harmonized Secondary Analysis of Human Milk from four Studies

Kelsey Fehr^1,2Andrew Mertens³Chi-Hung Shu⁴Trenton Dailey-Chwalibóg^5,6Liat Shenhav^7,8,9Lindsay Helen Allen^10,11Megan R Beggs^12,13Lars Bode^14,15Rishma Chooniedass¹⁶Mark D Deboer¹⁷Lishi Deng⁵Camilo Espinosa Bernal^18,19,4Daniela Hampel^10,11April Jahual^7,8Fyezah Jehan²⁰Mohit Jain²¹Patrick Kolsteren⁵Puja Kawle²²Kim A Lagerborg²¹Melissa B Manus^1,2,23Samson Mataraso^18,19,4Joann M McDermid²⁴Ameer Muhammad²⁵Payam Peymani^1,2Martin Pham^26,27Setareh Shahab-Ferdows¹¹Yasir Shafiq^28,29,30Vishak Subramoney³¹Daniel Sunko^7,8Laeticia Celine Toe^32,5Stuart Turvey³³Lei Xue⁴Natalie Rodriguez^1,2Alan Hubbard³Nima Aghaeepour^18,19,4Meghan B Azad^1,2*

• ¹Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
• ²Manitoba Interdisciplinary Lactation Centre, Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
• ³Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, California, United States
• ⁴Department of Anesthesiology, Pain, and Perioperative Medicine, Stanford University School of Medicine, Stanford, California, United States
• ⁵Department of Food Technology, Safety and Health, Faculty of Bioscience Engineering, Ghent University, Ghent, East Flanders, Belgium
• ⁶Agence de Formation de Recherche et d’Expertise en Santé pour l’Afrique (AFRICSanté), Bobo-Dioulasso, Burkina Faso
• ⁷Institute for systems genetics, New York Grossman School of Medicine, New York University, New York, United States
• ⁸Department of Microbiology, New York Grossman School of Medicine, New York University, New York, United States
• ⁹Department of Computer Science, New York University, New York, United States
• ¹⁰Department of Nutrition, University of California, Davis, United States
• ¹¹United States Department of Agriculture (USDA), ARS-Western Human Nutrition Research Center, Davis, United States
• ¹²Translational Medicine, The Hospital for Sick Children, Toronto, Canada
• ¹³Department of Nutritional Sciences, University of Toronto, Toronto, Canada
• ¹⁴Larsson-Rosenquist Foundation Mother-Milk-Infant Center of Research Excellence, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California, United States
• ¹⁵Department of Pediatrics, University of California San Diego, San Diego, United States
• ¹⁶School of Nursing, Faculty of Health and Social Development, University of British Columbia, Vancouver, Canada
• ¹⁷Department of Pediatrics, Division of Pediatric Endocrinology, University of Virginia School of Medicine, Charlottesville, United States
• ¹⁸Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States
• ¹⁹Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, United States
• ²⁰Department of Paediatrics & Child Health Medical College, Aga Khan University, Karachi, Pakistan
• ²¹Sapient Bioanalytics, LLC, San Diego, United States
• ²²Cytel, Pune, India
• ²³Department of Anthropology, University of Texas at San Antonio, San Antonio, United States
• ²⁴Consultant, Charlottesville, United States
• ²⁵Vaccines and Other Initiatives to Advance Lives (VITAL) Pakistan Trust, Karachi, Pakistan
• ²⁶Data Aggregation, Translation and Architecture (DATA) Team, University Health Network, Toronto, Canada
• ²⁷Department of Computer Science, University of Toronto, Toronto, Canada
• ²⁸Center of Excellence for Trauma and Emergencies & Community Health Sciences, Aga Khan University, Karachi, Pakistan
• ²⁹Harvard Humanitarian Initiative, Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Cambridge, United States
• ³⁰Global Advancement of Infants and Mothers, Department of Pediatrics, Brigham and Women’s Hospital, Boston, United States
• ³¹DVPL Tech, Dubai, United Arab Emirates
• ³²Unité Nutrition et Maladies Métaboliques, Institut de Recherche en Sciences de la Santé (IRSS), Bobo-Dioulasso, Burkina Faso
• ³³Department of Pediatrics, British Columbia Children's Hospital, Vancouver, British Columbia, Canada

Introduction: Human milk (HM) contains a multitude of nutritive and nonnutritive bioactive compounds that support infant growth, immunity and development, yet its complex composition remains poorly understood. Integrating diverse scientific disciplines from nutrition and global health to data science, the International Milk Composition (IMiC) Consortium was established to undertake a comprehensive harmonized analysis of HM from low, middle and high-resource settings to inform novel strategies for supporting maternal-child nutrition and health.IMiC is a collaboration of HM experts, data scientists and four mother-infant health studies, each contributing a subset of participants: Canada (CHILD Cohort, n=400), Tanzania (ELICIT Trial, n=200), Pakistan (VITAL-LW Trial, n=150), and Burkina Faso (MISAME-3 Trial, n=290). Altogether IMiC includes 1946 HM samples across time-points ranging from birth to 5 months. Using HM-validated assays, we are measuring macronutrients, minerals, B-vitamins, fatsoluble vitamins, HM oligosaccharides, selected bioactive proteins, and untargeted metabolites, proteins, and bacteria. Multi-modal machine learning methods (extreme gradient boosting with late fusion and two-layered cross-validation) will be applied to predict infant growth and identify determinants of HM variation. Feature selection and pathway enrichment analyses will identify key HM components and biological pathways, respectively. While participant data (e.g. maternal characteristics, health, household characteristics) will be harmonized across studies to the extent possible, we will also employ a meta-analytic structure approach where HM effects will be estimated separately within each study, and then meta-analyzed across studies.Ethics and Dissemination: IMiC was approved by the human research ethics board at the University of Manitoba. Contributing studies were approved by their respective primary institutions and local study centers, with all participants providing informed consent. Aiming to inform maternal, newborn, and infant nutritional recommendations and interventions, results will be disseminated through Open Access platforms, and data will be available for secondary analysis.Registration: ClinicalTrials.gov (NCT05119166).