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. 2025 Sep 4;8(5):ooaf086.
doi: 10.1093/jamiaopen/ooaf086. eCollection 2025 Oct.

Data harmonization framework for neonatal hypoxic-ischemic encephalopathy studies

Chuan-Heng Hsiao  1 , Anna N Foster  1 , Scott A McDonald  2 , Rutvi Vyas  1 , Aseelah Ashraf  1 , Rina Bao  1 , Lena Tran  1 , Ankush Kesri  1 , Erfan Darzidehkalani  1 , Matheus D Soldatelli  1   3 , Jeanette O Auman  2 , Janet S Soul  4 , Lina F Chalak  5 , C Michael Cotten  6 , Seetha Shankaran  7   8 , Abbot R Laptook  9   10 , P Ellen Grant  1   3 , Yangming Ou  1   3 ; Consortium Of MRI Biomarkers In Neonatal Encephalopathy (COMBINE)
Collaborators, Affiliations

Data harmonization framework for neonatal hypoxic-ischemic encephalopathy studies

Chuan-Heng Hsiao et al. JAMIA Open. .

Abstract

Objectives: To develop a data harmonization framework for neonatal hypoxic-ischemic encephalopathy (HIE) studies and demonstrate its suitability for prognostic biomarker development.

Materials and methods: Variables were first categorized by chronological stages and then by medical topics. We created a dictionary to harmonize variable names and value coding. We began by merging comprehensive data from 2 landmark nationwide therapeutic hypothermia for HIE trials (2008-2016, 21 sites) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN). The 2 datasets differ in available variables, variable naming and coding, necessitating harmonization. To demonstrate the utility of this data harmonization framework, we computed the distributions of variables and ranked them by the strength of associations with 18- to 22-month outcomes. Associations were measured using Pearson's correlation analysis. Outcomes were defined as (a) a 5-class variable: survivors with normal, mild, moderate, severe disability, or death and (b) the Bayley-III Scales.

Results: We created a dictionary of 1181 variables on 532 patients across 5 chronologic categories and 60 medical subcategories. The distribution of major predictive and outcome variables, and the variables strongly associated with neurodevelopmental outcomes at 18-22 months were presented. The modified Sarnat scores at the Post-intervention and NICU-discharge stage, and the NRN pattern of MRI injury score showed strong associations with outcome variables.

Conclusion: We designed a data harmonization framework specifically for HIE. Our initial effort in merging 2 iconic clinical trials shows strong predictor-outcome associations, allowing subsequent development of advanced prognostic biomarkers of neonatal HIE.

Keywords: biomarker development; common data elements; data harmonization framework; hypoxic-ischemic encephalopathy.

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Conflict of interest statement

All authors declare that they have no financial or non-financial competing interests in relation to this paper.

Figures

Figure 1.
Figure 1.
The 21 sites in the LH and 18 sites in the OC trials. Locations are based on Google Maps.
Figure 2.
Figure 2.
The categorization of variables in the LH and OC trials. The left-most column represents the 5 color-coded categories based on the clinical course. The 60 subcategories are presented with icons and descriptions. The numbers in parentheses represent the number of variables in each category and subcategory. There are 1181 variables in total. MRI, magnetic resonance imaging; GMFCS, Gross Motor Function Classification System.
Figure 3.
Figure 3.
Distributions of the variables in the LH and OC trials.
Figure 4.
Figure 4.
Distributions of 20 variables in the merged database from the LH and OC trials.
See this image and copyright information in PMC

References

    1. Shankaran S. Therapeutic hypothermia for neonatal encephalopathy. Curr Opin Pediatr. 2015;27:152-157. 10.1097/MOP.0000000000000199 - DOI - PubMed
    1. Namusoke H, Nannyonga MM, Ssebunya R, et al. Incidence and short term outcomes of neonates with hypoxic ischemic encephalopathy in a peri urban teaching hospital, Uganda: a prospective cohort study. Matern Health Neonatol Perinatol. 2018;4:6. 10.1186/s40748-018-0074-4 - DOI - PMC - PubMed
    1. Park J, Park SH, Kim C, et al. Growth and developmental outcomes of infants with hypoxic ischemic encephalopathy. Sci Rep. 2023;13:23100. 10.1038/s41598-023-50187-0 - DOI - PMC - PubMed
    1. Peeples ES, Mietzsch U, Molloy E, et al. ; Newborn Brain Society Guidelines and Publications Committee. Data collection variability across neonatal hypoxic-ischemic encephalopathy registries. J Pediatr. 2025;279:114476. 10.1016/j.jpeds.2025.114476 - DOI - PubMed
    1. Shankaran S, Laptook AR, Ehrenkranz RA, et al. ; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy. New Engl J Med. 2005;353:1574-1584. 10.1056/NEJMcps050929 - DOI - PubMed