Abstract
Background
Preterm birth places infants at higher risk of adverse long-term behavioral and cognitive outcomes. Combining biobehavioral measures and molecular biomarkers may improve tools to predict the risk of long-term developmental delays.
Methods
The Neonatal Neurobehavior and Outcomes in Very Preterm Infants study was conducted at nine neonatal intensive care units between April 2014 and June 2016. Cries were recorded and buccal swabs collected during the neurobehavioral exam. Cry episodes were extracted and analyzed using a computer system and the data were summarized using factor analysis. Genomic DNA was extracted from buccal swabs, quantified using the Qubit Fluorometer, and aliquoted into standardized concentrations. DNA methylation was measured with the Illumina MethylationEPIC BeadArray, and an epigenome-wide association study was performed using cry factors (n = 335).
Results
Eighteen CpGs were associated with the cry factors at genome-wide significance (α = 7.08E − 09). Two CpG sites, one intergenic and one linked to gene TCF3 (important for B and T lymphocyte development), were associated with acoustic measures of cry energy. Increased methylation of TCF3 was associated with a lower energy-related cry factor. We also found that pitch (F0) and hyperpitch (F0 > 1 kHz) were associated with DNA methylation variability at 16 CpG sites.
Conclusions
Acoustic cry characteristics are related to variation in DNA methylation in preterm infants.
Impact
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Preterm birth is a major public health problem and its long-term impact on health is not well understood.
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Cry acoustics, related to prematurity, has been linked to a variety of medical conditions.
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Biobehavioral measures and molecular biomarkers can improve prediction tools for long-term developmental risks of preterm birth.
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Variation in epigenetic modulation in preterm infants provides a potential link between preterm birth and unfavorable developmental outcomes.
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Acknowledgements
This work was funded by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grant R01HD072267 (Lester and O’Shea), R01HD084515 (Lester and Everson), and UH3OD023347 (B.M.L., C.M., and T.M.O’S.), National Center for Advancing Translational Sciences through UCLA CTSI Grant UL1TR001881 and by the National Institute of Environmental Health Sciences HERCULES Center (P30 ES019776).
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Contributions
G.A. designed the study, extracted and processed cry recordings, analyzed and interpreted data, drafted the article and revised critically for important intellectual content, and approved the final version as submitted. S.J.S. developed the acoustic cry system, reviewed and revised critically for important intellectual content, and approved the final version as submitted. C.J.M. performed the laboratory studies, interpreted methylation data, reviewed and revised critically for important intellectual content, and approved the final version as submitted. T.M.E. performed the laboratory studies, analyzed and interpreted methylation data, reviewed and revised critically for important intellectual content, and approved the final version as submitted. H.L. extracted and processed cry recordings, reviewed and revised critically for important intellectual content, and approved the final version as submitted. A.A.B. analyzed methylation data, reviewed and revised critically for important intellectual content, and approved the final version as submitted. B.S.C. reviewed and revised critically for important intellectual content and approved the final version as submitted. J.B.H. reviewed and revised critically for important intellectual content and approved the final version as submitted. J.A.H. reviewed and revised critically for important intellectual content and approved the final version as submitted. E.C.McG. reviewed and revised critically for important intellectual content and approved the final version as submitted. C.R.N. reviewed and revised critically for important intellectual content and approved the final version as submitted. T.M.O’S. conceptualized and designed the study, reviewed and revised critically for important intellectual content, and approved the final version as submitted. S.L.P. reviewed and revised critically for important intellectual content and approved the final version as submitted. L.M.S. reviewed and revised critically for important intellectual content and approved the final version as submitted. A.S. reviewed and revised critically for important intellectual content and approved the final version as submitted. L.M.D. analyzed and interpreted data, reviewed and revised critically for important intellectual content, and approved the final version as submitted. S.A.D. coordinated data collection, reviewed and revised critically for important intellectual content, and approved the final version as submitted. Dr. J.F.P. coordinated laboratory analyses, reviewed and revised critically for important intellectual content, and approved the final version as submitted. B.M.L. conceptualized and designed the study, developed the acoustic cry system, interpreted data, drafted the article and revised critically for important intellectual content, and approved the final version as submitted.
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The study was approved by Western Institutional Review Board, Puyallup, WA (HI site), the John F. Wolf Human Subjects Committee, Los Angeles, CA, Spectrum Health Systems, Inc. IRB, Grand Rapids, MI, Wake Forest University Health Sciences IRB, Winston-Salem, NC, Children’s Mercy Hospital IRB, Kansas City, MO, Women & Infants Hospital IRB, Providence, RI.
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Aghagoli, G., Sheinkopf, S.J., Everson, T.M. et al. Epigenome-wide analysis identifies genes and pathways linked to acoustic cry variation in preterm infants. Pediatr Res 89, 1848–1854 (2021). https://doi.org/10.1038/s41390-020-01172-0
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DOI: https://doi.org/10.1038/s41390-020-01172-0
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