Harmonizing multisite neonatal diffusion-weighted brain MRI data for developmental neuroscience

Large diffusion-weighted brain MRI (dMRI) studies in neonates are crucial for developmental neuroscience. Our aim was to investigate the utility of ComBat, and empirical Bayes tool for multisite harmonization, for removing site effects from white matter (WM) dMRI measures in healthy infants born 37-42+6 weeks from the Theirworld Edinburgh Birth Cohort (n=86) and Developing Human Connectome Project (n=287). Skeletonized fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD, RD) maps were harmonized. The differences between voxel-wise metrics, skeleton means and histogram widths (5th-95th percentile) were assessed before and after harmonization, as well as variance associated with gestational age at birth. Before harmonization, large cohort differences were observed in all measures. Harmonization removed all voxel-wise differences from MD maps and all metric means and histogram widths, however small voxel-wise differences (<1.5% of voxels) remained in FA, AD and RD. We detected significant relationships between GA at birth and all metrics. When comparing single site and multi-site harmonized datasets of equal sample sizes, harmonized data resulted in smaller standardized regression coefficients. ComBat will enable unprecedented sample sizes in developmental neuroscience, offering new horizons for biomarker discovery and validation, understanding typical and atypical brain development, and assessment of neuroprotective therapies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by the Harold Hyam Wingate Foundation and Medical Research Council UK (MR/V002465/1). JPB acknowledges funding from the UKRI MRC programme grant (MR/X003434/1) and Theirworld (). The Developing Human Connectome Project was funded by the European Research Council under the European Union Seventh Framework Program (FP7/20072013)/European Research Council grant agreement no. 319456. This research was supported by core funding from the Wellcome/EPSRC Centre for Medical Engineering (WT203148/Z/16/Z) and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust and Kings College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The National Research Ethics Service Research Ethics Committees in West London (Developing Human Connectome Project (dHCP) 14/LO/1169) and South East Scotland (Theirworld Edinburgh Birth Cohort (TEBC) 16/SS/0154) provided ethical approvals. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes