Brain growth charts of “clinical controls” for quantitative analysis of clinically acquired brain MRI

Background Brain MRIs acquired in clinical settings represent a valuable and underutilized scientific resource for investigating neurodevelopment. Utilization of these clinical scans has been limited because of their clinical acquisition and technical heterogeneity. These barriers have curtailed the interpretability and scientific value of retrospective studies of clinically acquired brain MRIs, compared to studies of prospectively acquired research quality brain MRIs. Purpose To develop a scalable and rigorous approach to generate clinical brain growth chart models, to benchmark neuroanatomical differences in clinical MRIs, and to validate clinically-derived brain growth charts against those derived from large-scale research studies. Materials and Methods We curated a set of clinical MRI S cans with L imited I maging P athology (SLIP) – so-called “clinical controls” – from an urban pediatric healthcare system acquired between 2005 and 2020. The curation process included manual review of signed radiology reports, as well as automated and manual quality review of images without gross pathology. We measured global and regional volumetric imaging phenotypes in the SLIP sample using two alternative, advanced image processing pipelines, and quantitatively compared clinical brain growth charts to research brain growth charts derived from >123,000 MRIs. Results The curated SLIP dataset included 372 patients scanned between the ages of 28 days post-birth and 22.2 years across nine 3T MRI scanners. Clinical brain growth charts were highly similar to growth charts derived from large-scale research datasets, in terms of the normative developmental trajectories predicted by the models. The clinical indication of the scans did not significantly bias the output of clinical brain charts. Tens of thousands of additional healthcare system scans meet inclusion criteria to be included in future brain growth charts. Conclusion Brain charts derived from clinical-controls are highly similar to brain charts from research-controls, suggesting that curated clinical scans could be used to supplement research datasets. Summary Statement Brain growth charts of pediatric clinical MRIs with limited imaging pathology (N=372) are highly correlated with charts from a large aggregated set of research controls (N>120,000). Key Results A cohort of brain MRI scans with limited reported imaging pathology (N=372, 186 female; ages 0.07 - 22.2 years, median = 10.2) were identified using signed radiology reports and processed using two segmentation pipelines. Growth charts generated from these scans are highly correlated with growth charts from a large aggregated set of research controls (r range 0.990 - 0.999). There was no evidence of bias due to the reason for each scan. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement JMS, JS, and AAB were supported in part by K08MH120564. TDS was supported in part by R01MH120482. RTS was supported by R01MH123550, R01NS112274, and R01MH112847. JEI and BB were supported in part by the European Research Council (ERC Starting Grant 677697), and the EPSRC-funded UCL Centre for Doctoral Training in Medical Imaging (EP/L016478/1). SRW was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) and UKRI Medical Research Council (MC\_UU\_00002/2). All research at the Department of Psychiatry in the University of Cambridge is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) and NIHR Applied Research Centre. ### 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 Institutional Review Board of the Children's Hospital of Philadelphia waived ethical approval for this work. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are currently unable to be shared but may be in the future. * SLIP : Scans with Limited Imaging Pathology LBCC : Lifespan Brain Chart Consortium GMV : cortical Gray Matter Volume WMV : White Matter Volume sGMV : Subcortical Gray Matter Volume CSF : ventricular volume (Cerebrospinal Fluid) TCV : Total Cerebrum Volume