Impact of Epigenetic Age Acceleration on Neurodevelopmental Outcomes in Preterm Infants Restricted; Files Only

Abstract

Background Preterm birth poses significant challenges to neonatal health and development, with potential long-term consequences for cognitive and language skills. Epigenetic age acceleration (EAA) has emerged as a potential biomarker for assessing differences in development, but its association with neurodevelopmental cognitive outcomes in preterm infants remains poorly understood.

Aim This study investigated the relationship between EAA and neurodevelopmental outcomes in a cohort of very preterm infants using data from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study.

Methods A total of 525 preterm infants were included in the analysis, with DNA buccal swabs collected at NICU discharge and EAA calculated using the EPIC NEOage post-menstrual age (PMA) and post-natal age (PNA) clocks. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), focusing on cognitive and language domains at 24 and 36 months of age. Further analysis was performed to investigate potential effect modification between EAA and sex, bronchopulmonary dysplasia, and overall neonatal comorbidities.

Results Although no significant correlations were found between EAA and BSID-III scores, both PMA and PNA-based EAA exhibited a positive relationship with both cognitive and language BSID-III scores across all assessment time points, with the association being more pronounced in the PMA clock compared to the PNA clock. Furthermore, sex-specific analyses indicated significant differences in the associations between EAA and neurodevelopment, with males showing stronger associations compared to females.

Discussion This study underscores the complexity of the relationship between EAA and neurodevelopmental outcomes in preterm infants, highlighting the importance of considering factors such as sex and neonatal morbidities. Further epigenetic research should be performed in this vulnerable age group, focusing on longitudinal assessments of neurodevelopment, and evaluating the role of EAA as proxy for stress experienced by preterm infants, leading to it being a potential risk factor for predicting neurodevelopmental delays.

Table of Contents

I.        Introduction................................................................................................. 1

II.       Methods....................................................................................................... 4

Study Population..................................................................................................... 4

Neonatal Morbidities in Study Population ................................................................ 4

Chronological Age Collection................................................................................... 5

Development of Epigenetic Clocks and Epigenetic Age Calculation............................. 5

Assessing Neurodevelopment.................................................................................. 6

Statistical Analysis................................................................................................. 6

III.     Results......................................................................................................... 8

Study Population.................................................................................................... 8

Distribution of Neurodevelopmental Outcomes......................................................... 8

Age Acceleration Estimates...................................................................................... 9

Adjustment for BPD and Multimorbidity Score........................................................... 9

Testing for Interaction with Sex and Neonatal Morbidities.......................................... 9

IV.      Discussion................................................................................................... 11

V.        References...................................................................................................17

VI.      Tables and Figures...................................................................................... 20

VII.    Appendix..................................................................................................... 24

Figure A1: Interaction between Age Acceleration and BPD Status............................... 24

Figure A2: Interaction between Age Acceleration and Multimorbidity Score................ 25

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Epidemiology - MPH & MSPH
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Epidemiology Health Sciences, Human Development
Mot-clé	Preterm Epigenetics Age Acceleration Neurodevelopment
Committee Chair / Thesis Advisor	Todd M. Everson, PhD, MPH, Emory University, Emory University

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