Retinopathy of prematurity (ROP) is a potentially preventable disorder of the retina that occurs predominantly in preterm newborns. Recent evidence suggests that exposure to systemic inflammation might contribute to the etiology and pathogenesis of ROP. In this application, we propose to (objective #1) measure in existing blood samples from a multi-center, NIH-funded cohort study of extremely low gestational age newborns (ELGAN study, U01 NS40069) 18 protein biomarkers in 1,206 ELGANs and add this information to an existing database of 25 biomarkers we have already measured in 924 of the same 1,206 ELGANs. We will also measure these previous 25 markers in the remainder of 282 newborns. The result will be the currently largest biomarker database worldwide of 43 biomarkers (from postnatal days 1, 7, 14, 21, and 28) available for 1,206 newborns with a gestational age <28wks. The new biomarker measurements will be done by the same ELGAN-Co-investigators who measured the initial 25 biomarkers using the Meso Scale Discovery (MSD) multiplex platform. The additional biomarkers were selected specifically for ROP association studies, based on published evidence that the availability of oxygen, the presence of inflammation, the concepts of angiogenesis and erythropoiesis, as well as pre-existing maternal pregnancy conditions such as preeclampsia all appear to play roles in ROP etiology and pathogenesis. We also propose (objective #2) to subsequently perform epidemiologic (risk) analyses using advanced multivariable biostatistical techniques. We will test two specific null-hypotheses: (1) Biomarkers do not predict severe ROP occurrence;and (2) biomarkers do not predict ROP progression. Both hypotheses will be tested by members of the original ELGAN data analysis team in comprehensive multivariable regression models that allow for appropriate control for confounding and for stratified analyses targeted at the discovery of effect modifiers. Pre hoc power analyses suggest that our sample size is large enough to detect appreciable relative risks with sufficient statistical power. The results from our project will have a significnt impact on our current understanding of ROP pathogenesis and will help pave the way towards new prevention and treatment strategies.

Public Health Relevance

Retinopathy of prematurity (ROP) is a disorder of the developing eye that occurs in approximately 15,000 preterm newborns per year in the US and leads to blindness in about 500. Our project will contribute directly to an improved understanding of the causation of ROP by providing novel data on inflammation-associated substances circulating in the preterm baby's blood and their associations with ROP occurrence and progression, thereby elucidating potential target mechanisms for prevention and intervention.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021820-02
Application #
8610316
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Redford, Maryann
Project Start
2013-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$446,001
Indirect Cost
$10,325
Name
Tufts University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Leviton, Alan; Allred, Elizabeth N; Yamamoto, Hidemi et al. (2017) Antecedents and correlates of blood concentrations of neurotrophic growth factors in very preterm newborns. Cytokine 94:21-28
Logan, J W; Dammann, O; Allred, E N et al. (2017) Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm. J Perinatol 37:606-614
Holm, Mari; Austeng, Dordi; Fichorova, Raina N et al. (2017) Postnatal systemic inflammation and neuro-ophthalmologic dysfunctions in extremely low gestational age children. Acta Paediatr 106:454-457
Allred, Elizabeth N; Dammann, Olaf; Fichorova, Raina N et al. (2017) Systemic Inflammation during the First Postnatal Month and the Risk of Attention Deficit Hyperactivity Disorder Characteristics among 10 year-old Children Born Extremely Preterm. J Neuroimmune Pharmacol 12:531-543
Holm, Mari; Morken, Tora S; Fichorova, Raina N et al. (2017) Systemic Inflammation-Associated Proteins and Retinopathy of Prematurity in Infants Born Before the 28th Week of Gestation. Invest Ophthalmol Vis Sci 58:6419-6428
Bright, H Reeve; Babata, Kikelomo; Allred, Elizabeth N et al. (2017) Neurocognitive Outcomes at 10 Years of Age in Extremely Preterm Newborns with Late-Onset Bacteremia. J Pediatr 187:43-49.e1
van der Burg, Jelske W; Sen, Sarbattama; Chomitz, Virginia R et al. (2016) The role of systemic inflammation linking maternal BMI to neurodevelopment in children. Pediatr Res 79:3-12
Leviton, Alan; Allred, Elizabeth N; Fichorova, Raina N et al. (2016) Antecedents of inflammation biomarkers in preterm newborns on days 21 and 28. Acta Paediatr 105:274-80
Dammann, Olaf; Allred, Elizabeth N; Fichorova, Raina N et al. (2016) Duration of Systemic Inflammation in the First Postnatal Month Among Infants Born Before the 28th Week of Gestation. Inflammation 39:672-7
Leviton, Alan; Allred, Elizabeth N; Kuban, Karl C K et al. (2016) The Development of Extremely Preterm Infants Born to Women Who Had Genitourinary Infections During Pregnancy. Am J Epidemiol 183:28-35

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