title: Transcriptomics of maternal and fetal membranes can discriminate between gestational-age matched preterm neonates with and without cognitive impairment diagnosed at 18-24 months.
abstract: BACKGROUND
  Neurocognitive impairment among children born preterm may arise from complex interactions between genes and the intra-uterine environment.
  
  
  OBJECTIVE
  (1) To characterize the transcriptomic profiles of chorioamniotic membranes in preterm neonates with and without neurocognitive impairment via microarrays and (2) to determine if neonates with neurocognitive impairment can be identified at birth.
  
  
  METHODS
  A retrospective case-control study was conducted to examine the chorioamniotic transcriptome of gestational-age matched very preterm neonates with and without neurocognitive impairment at 18-24 months' corrected-age defined by a Bayley-III Cognitive Composite Score <80 (n = 14 each). Pathway analysis with down-weighting of overlapping genes (PADOG) was performed to identify KEGG pathways relevant to the phenotype. Select differentially expressed genes were profiled using qRT-PCR and a multi-gene disease prediction model was developed using linear discriminant analysis. The model's predictive performance was tested on a new set of cases and controls (n = 19 each).
  
  
  RESULTS
  1) 117 genes were differentially expressed among neonates with and without subsequent neurocognitive impairment (p<0.05 and fold change >1.5); 2) Gene ontology analysis indicated enrichment of 19 biological processes and 3 molecular functions; 3)PADOG identified 4 significantly perturbed KEGG pathways: oxidative phosphorylation, Parkinson's disease, Alzheimer's disease and Huntington's disease (q-value <0.1); 4) 48 of 90 selected differentially expressed genes were confirmed by qRT-PCR, including genes implicated in energy metabolism, neuronal signaling, vascular permeability and response to injury (e.g., up-regulation of SEPP1, APOE, DAB2, CD163, CXCL12, VWF; down-regulation of HAND1, OSR1)(p<0.05); and 5) a multi-gene model predicted 18-24 month neurocognitive impairment (using the ratios of OSR1/VWF and HAND1/VWF at birth) in a larger, independent set (sensitivity = 74%, at specificity = 83%).
  
  
  CONCLUSIONS
  Gene expression patterns in the chorioamniotic membranes link neurocognitive impairment in preterm infants to neurodegenerative disease pathways and might be used to predict neurocognitive impairment. Further prospective studies are needed.
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America; Department of Pediatrics, Division of Neonatal and Perinatal Medicine, Wayne State University, Detroit, MI, United States of America.
authors.forename: Athina
authors.initials: A
authors.lastname: Pappas
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States of America.
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States of America; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, United States of America.
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States of America; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, United States of America.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Korzeniewski
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America; Department of Pediatrics, Division of Neonatal and Perinatal Medicine, Wayne State University, Detroit, MI, United States of America.
authors.forename: Josef C
authors.initials: JC
authors.lastname: Cortez
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhatti
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States of America; Department of Immunology and Microbiology, Wayne State University, Detroit, MI, United States of America.
authors.forename: Nardhy
authors.initials: N
authors.lastname: Gomez-Lopez
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States of America.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America; Department of Pediatrics, Division of Neonatal and Perinatal Medicine, Wayne State University, Detroit, MI, United States of America.
authors.forename: Seetha
authors.initials: S
authors.lastname: Shankaran
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development / NIH / DHHS, Bethesda, MD and Detroit, MI, United States of America; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, United States of America.
authors.forename: Adi L
authors.initials: AL
authors.lastname: Tarca
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002675:Child, Preschool; D003072:Cognition Disorders / Q000175:diagnosis* / Q000235:genetics*; D019295:Computational Biology; D005321:Extraembryonic Membranes / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D058977:Molecular Sequence Annotation; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012372:ROC Curve; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012307:Risk Factors; D059467:Transcriptome; D055815:Young Adult
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