Extremely Low Gestational Age Newborns Research Articles

Early Salivary miRNA Expression in Extreme Low Gestational Age Newborns.

Background: MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression playing a key role in organogenesis. MiRNAs are studied in tracheal aspirates (TA) of preterm infants. However; this is difficult to obtain in infants who are not intubated. This study examines early salivary miRNA expression as non-invasive early biomarkers in extremely low gestational age newborns (ELGANs). Methods: Saliva was collected using DNA-genotek swabs, miRNAs were analyzed using RNA seq and RT PCR arrays. Salivary miRNA expression was compared to TA using RNA seq at 3 days of age, and longitudinal changes at 28 days of age were analyzed using RT PCR arrays in ELGANs. Results: Approximately 822 ng of RNA was extracted from saliva of 7 ELGANs; Of the 757 miRNAs isolated, 161 miRNAs had significant correlation in saliva and TA at 3 days of age (r = 0.97). Longitudinal miRNA analysis showed 29 miRNAs downregulated and 394 miRNAs upregulated at 28 days compared to 3 days of age (adjusted p < 0.1). Bioinformatic analysis (Ingenuity Pathway Analysis) of differentially expressed miRNAs identified organismal injury and abnormalities and cellular development as the top physiological system development and cellular function. Conclusion: Salivary miRNA expression are source for early biomarkers of underlying pathophysiology in ELGANs.

Effects of High-Frequency Oscillatory Ventilation With Volume Guarantee During Surfactant Treatment in Extremely Low Gestational Age Newborns With Respiratory Distress Syndrome: An Observational Study.

ObjectiveTo evaluate the effect of volume guarantee (VG) combined with high-frequency oscillatory ventilation (HFOV) on respiratory and other physiological parameters immediately after lung recruitment and surfactant administration in HFOV elective ventilated extremely low gestational age newborns (ELGAN) with respiratory distress syndrome (RDS).DesignObservational study.SettingTertiary neonatal intensive care unit.PatientsTwenty-two ELGANs of 25.5 ± 1.1 weeks of gestational age requiring invasive mechanical ventilation and surfactant administration for RDS during the first 6 h of life.InterventionsAll infants intubated in delivery room, were managed with elective HFOV and received surfactant after a lung recruitment manoeuver. Eleven infants received HFOV + VG and were compared with a control group of 11 infants receiving HFOV alone. HFOV was delivered in both groups by Dräger Babylog VN500 ventilator (Dräger, Lubeck, Germany).Main Outcome MeasuresVariations and fluctuations of delivered high-frequency tidal volume (VThf), fluctuation of pressure amplitude (ΔP) and partial pressure of CO2 (pCO2) levels after recruitment manoeuver and immediately after surfactant administration, in HFOV + VG vs. HFOV ventilated infants.ResultsThere were no significant differences in the two groups at starting ventilation with or without VG. The mean applied VThf per kg was 1.7 ± 0.3 ml/kg in the HFOV group and 1.7 ± 0.1 ml/kg in the HFOV + VG group. Thirty minutes after surfactant administration, HFOV group had a significant higher VThf/Kg than HFOV + VG (2.1 ± 0.3 vs. 1.6 ± 0.1 ml/kg, p < 0.0001) with significantly lower pCO2 levels (43.1 ± 3.8 vs. 46.8 ± 1.5 mmHg, p = 0.01), 54.4% of patients having pCO2 below 45 mmHg. Measured post-surfactant ΔP values were higher in HFOV group (17 ± 3 cmH2O) than in HFOV + VG group (13 ± 3 cmH2O, p = 0.01).ConclusionHFOV + VG maintains pCO2 levels within target range and reduces VThf delivered variations more consistently than HFOV alone after surfactant administration.

Extreme prematurity: Risk and resiliency

Individuals born extremely preterm (before 28 weeks of gestation) comprise only about 0.7% of births in the United States and an even lower proportion in other high resource countries. However, these individuals account for a disproportionate number of children with cerebral palsy, intellectual deficit, autism spectrum disorder, attention deficit hyperactivity disorder, and epilepsy. This review describes two large multiple center cohorts comprised of individuals born extremely preterm: the EPICURE cohort, recruited 1995 in the United Kingdom and the Republic of Ireland, and the Extremely Low Gestational Age Newborn (ELGAN), recruited 2002-2004 in five states in the United States. The primary focus of these studies has been neurodevelopmental disorders, but also of interest are growth, respiratory illness, and parent- and self-reported global health and well-being. Both of these studies indicate that among individuals born extremely preterm the risks of most neurodevelopmental disorders are increased. Early life factors that contribute to this risk include perinatal brain damage, some of which can be identified using neonatal head ultrasound, bronchopulmonary dysplasia, and neonatal systemic inflammation. Prenatal factors, particularly the family's socioeconomic position, also appear to contribute to risk. For most adverse outcomes, the risk is higher in males. Young adults born extremely preterm who have neurodevelopmental impairment, as compared to those without such impairment, rate their quality of life lower. However, young adults born extremely preterm who do not have neurodevelopmental impairments rate their quality of life as being similar to that of young adults born at term. Finally, we summarize the current state of interventions designed to improve the life course of extremely premature infants, with particular focus on efforts to prevent premature birth and on postnatal efforts to prevent adverse neurodevelopmental outcomes.

Urine Proteomics for Noninvasive Monitoring of Biomarkers in Bronchopulmonary Dysplasia

Introduction: Current techniques to diagnose and/or monitor critically ill neonates with bronchopulmonary dysplasia (BPD) require invasive sampling of body fluids, which is suboptimal in these frail neonates. We tested our hypothesis that it is feasible to use noninvasively collected urine samples for proteomics from extremely low gestational age newborns (ELGANs) at risk for BPD to confirm previously identified proteins and biomarkers associated with BPD. Methods: We developed a robust high-throughput urine proteomics methodology that requires only 50 μL of urine. We utilized the methodology with a proof-of-concept study validating proteins previously identified in invasively collected sample types such as blood and/or tracheal aspirates on urine collected within 72 h of birth from ELGANs (gestational age [26 ± 1.2] weeks) who were admitted to a single Neonatal Intensive Care Unit (NICU), half of whom eventually developed BPD (n = 21), while the other half served as controls (n = 21). Results: Our high-throughput urine proteomics approach clearly identified several BPD-associated changes in the urine proteome recapitulating expected blood proteome changes, and several urinary proteins predicted BPD risk. Interestingly, 16 of the identified urinary proteins are known targets of drugs approved by the Food and Drug Administration. Conclusion: In addition to validating numerous proteins, previously found in invasively collected blood, tracheal aspirate, and bronchoalveolar lavage, that have been implicated in BPD pathophysiology, urine proteomics also suggested novel potential therapeutic targets. Ease of access to urine could allow for sequential proteomic evaluations for longitudinal monitoring of disease progression and impact of therapeutic intervention in future studies.

Pulmonary function tests in extremely low gestational age infants at one year of age.

Identifying neonatal and post-discharge exposures among extremely low gestational age newborns (ELGANs) that drive increased pulmonary morbidity and abnormal lung function at 1 year of age proves challenging. The NIH-sponsored Prematurity and Respiratory Outcomes Program (PROP), evaluated infant pulmonary function tests (iPFTs) at 1 year corrected age to determine which demographic and clinical factors are associated with abnormal lung function. iPFTs were performed on a PROP subcohort of 135 participants following Institutional Review Board (IRB)-approved written consent. Demographic data, Neonatal Intensive Care Unit (NICU) clinical care, and post-NICU exposures were analyzed for association with iPFTs. A significant decrease in forced expiratory volume at 0.5 s (FEV0.5 ) and/or forced expiratory flows at 75% of forced vital capacity (FEF75 ), were associated with male sex and African American race. Clinical factors including longer duration of ventilatory support, exposure to systemic steroids, and weight less than the 10th percentile at 36 weeks postmenstrual age were also associated with airflow obstruction, whereas supplemental oxygen requirement and bronchopulmonary dysplasia were not. Additionally, the need for respiratory medications, technology, or hospitalizations during the first year, ascertained by a quarterly survey, were the only post-NICU factors associated with decreased FEV0.5 and FEF75 . Only 7% of infants had reversible airflow obstruction. Neonatal demographic factors, respiratory support in the NICU, and a history of greater post-NICU medical utilization for respiratory disease had the strongest association with lower lung function at 1 year in ELGANs.

Aberrant Hematopoiesis and Morbidity in Extremely Preterm Infants With Intrauterine Growth Restriction.

Background and Objective: Intrauterine growth restriction (IUGR) poses additional challenges in extremely low gestational age newborns (ELGANs). We assessed disturbed hematopoiesis and morbidities associated with this disorder.Methods: This single-center retrospective case–control study compared perinatal hematological profiles, major morbidities, and mortality of 49 infants (gestational age <28 weeks, birth weight ≤ 3rd percentile, and compromised placental function) and 98 infants (birth weight >10th percentile) matched for gestational age, year, and sex.Results: IUGR-ELGANs had significantly elevated nucleated red blood cells and lower neutrophil and platelet counts at birth and on the third day of life. During the first week of life, IUGR-ELGANs received more red blood cell, platelet, and plasma transfusions and were more intensively treated with antibiotics. Rates of infections acquired during the first week (59.2 vs. 17.3%, p < 0.001), severe bronchopulmonary dysplasia or death (42.9 vs. 17.3%, p < 0.01), and mortality (36.7 vs. 7.1%, p < 0.001) were markedly elevated in IUGR-ELGANs, but not of hemorrhages or other morbidities.Conclusions: IUGR-ELGANs have high rates of acquired infections during the first week of life and display severe pulmonary morbidity leading to bronchopulmonary dysplasia or death. The high rate of transfusions observed in these infants warrants further scrutiny.

Prospective Randomized Observational Pilot Trial Evaluating the Effect of Information of Early Childhood Intervention on Stress Levels of Parents of Extremely Low Gestational Age Infants at the NICU.

It is not known to what extent early information on early childhood intervention (ECI) by ECI professionals reduces or increases stress levels of parents having an extremely preterm infant at the neonatal intensive care unit (NICU). Using an observational pilot study, we gave information on ECI in a randomized matter to parents of an extremely low gestational age newborn (ELGAN) at the chronological age of 3–4 weeks (cases) or not (controls). After informed consent, parents judged the infants at the age of 5–7 weeks with the Parental Stressor Scales: Neonatal Intensive Care Unit [PSS: NICU test has three subscales = “Sights and Sounds” (five items), “Parental Role Alteration” (14 items), and “Look and Behave” (seven items)]. Total scales score and subscales scores were comparable between 13 cases and 13 controls over a study period of 1.5 years. Total scores were 9.32 ± 0.72 in the cases compared to 10.02 ± 0.76 in the controls, (95% CI −6.93 to 4.93). Overall, the cases scored lower in most of the items. Early information on ECI at the NICU was provided to parents with an ELGAN did not result in higher stress levels measured with the PSS: NICU. Whether early information on ECI is a strategy, which might be able to reduce parental stress levels, has to be proven in larger studies.

Prenatal Exposure to Toxic Metal Mixtures and Risk of Bacterial Sepsis in Extremely Low Gestational Age Newborns

BACKGROUND AND AIM: Prenatal exposures to toxic metals (and metalloids) have been linked to altered immune function in animal studies, but few epidemiologic studies have investigated immunological effects in humans. We evaluated the risk of bacterial sepsis – an extreme immune response to bacterial infection – in relation to prenatal toxic metal exposures, individually and jointly, among a US-based cohort of infants born extremely preterm. METHODS: We analyzed 237 participants enrolled in the ELGAN cohort, which recruited infants delivered before 28 weeks gestation from 14 hospitals during 2002-2004. The infants were followed from birth to postnatal day 28 with bacterial culture results reported weekly. Arsenic, cadmium, lead, and mercury concentrations were measured in umbilical cord tissue samples using inductively coupled plasma tandem mass spectrometry. We fit discrete-time hazard models to estimate associations between the sepsis incidence and individual metal quartiles, as well as a weighted quantile sum regression model for metal mixtures. RESULTS:Seventy (32%) of the extremely preterm infants developed sepsis during the follow-up period (median follow-up time: 2 weeks). After adjustment for maternal age, educational attainment, public health insurance status (a proxy for income), and smoking during pregnancy, only cadmium was individually associated with sepsis risk. Comparing the highest to lowest quartile, the hazard ratio (HR) for cadmium was 1.97 (95% CI: 1.00-3.99). The weighted quantile sum index was also associated with a higher incidence of sepsis (HR=1.36, 95% CI: 1.06-1.74); consistent with analyses of individual metals, the metal that was most highly weighted in the index was cadmium. CONCLUSIONS:Prenatal exposures to toxic metals, particularly cadmium, were prospectively associated with an increased risk of bacterial sepsis among infants born extremely preterm. Future research should examine whether increasing intakes of essential trace elements (e.g., zinc) during pregnancy or after delivery could counteract the apparent immunotoxicity of prenatal toxic metal exposures. KEYWORDS: Mixtures, Heavy metals, Infectious diseases, Birth outcomes, Environmental epidemiology

A Consideration of Racism in Pediatric Epidemiologic Studies

A Consideration of Racism in Pediatric Epidemiologic Studies

Extremely Preterm Birth and Its Consequences—The ELGAN Study

Over the last decades, improvement in perinatal and neonatal care has led to vastly increased survival rates for extremely low gestational age newborns (ELGAN). Among the most relevant prospective longitudinal studies in the field, the ELGAN Study contributed and continues to contribute to this dynamic by providing crucial knowledge on the mechanisms that lead to preterm birth, its consequences, and the causes and pathophysiology of brain damage which represents the major disabling morbidity in survivors.

Comparing the Predictivity of Human Placental Gene, microRNA, and CpG Methylation Signatures in Relation to Perinatal Outcomes.

Molecular signatures are being increasingly integrated into predictive biology applications. However, there are limited studies comparing the overall predictivity of transcriptomic versus epigenomic signatures in relation to perinatal outcomes. This study set out to evaluate mRNA and microRNA (miRNA) expression and cytosine-guanine dinucleotide (CpG) methylation signatures in human placental tissues and relate these to perinatal outcomes known to influence maternal/fetal health; namely, birth weight, placenta weight, placental damage, and placental inflammation. The following hypotheses were tested: (1) different molecular signatures will demonstrate varying levels of predictivity towards perinatal outcomes, and (2) these signatures will show disruptions from an example exposure (ie, cadmium) known to elicit perinatal toxicity. Multi-omic placental profiles from 390 infants in the Extremely Low Gestational Age Newborns cohort were used to develop molecular signatures that predict each perinatal outcome. Epigenomic signatures (ie, miRNA and CpG methylation) consistently demonstrated the highest levels of predictivity, with model performance metrics including R2 (predicted vs observed) values of 0.36-0.57 for continuous outcomes and balanced accuracy values of 0.49-0.77 for categorical outcomes. Top-ranking predictors included miRNAs involved in injury and inflammation. To demonstrate the utility of these predictive signatures in screening of potentially harmful exogenous insults, top-ranking miRNA predictors were analyzed in a separate pregnancy cohort and related to cadmium. Key predictive miRNAs demonstrated altered expression in association with cadmium exposure, including miR-210, known to impact placental cell growth, blood vessel development, and fetal weight. These findings inform future predictive biology applications, where additional benefit will be gained by including epigenetic markers.

Development of the genomic inflammatory index (GII) to assess key maternal antecedents associated with placental inflammation

IntroductionPlacental inflammation is associated with a variety of adverse health outcomes, including poor pregnancy outcomes as well as later in life health. The current clinical methodologies for evaluating placental histology for inflammation are limited in their sensitivity. The objective of this study was to develop a genomic inflammatory index (GII) that can be utilized as a biomarker to effectively quantify and evaluate placental inflammation. MethodsRNA-sequencing of n = 386 placentas from the Extremely Low Gestational Age Newborn (ELGAN) cohort was conducted. Transcriptional data for a biologically-targeted set of 14 genes, selected for their established role in pro-inflammatory signaling pathways, were aggregated to construct the GII. Multiple linear regression models were used to examine relationships between 47 perinatal factors and the GII. ResultsThe GII demonstrated a nine-fold difference across subjects and displayed positive trends with other indicators of placental inflammation. Significant differences in the GII were observed for race where women who self-identified as Black displayed higher levels of placental inflammation than those who self-identified as White women (p < 0.001). Additionally, married Black women showed reduced placental inflammation compared to those who were unmarried (beta value: 0.828, p-value: 0.032). Placentas from women who were treated with steroids during the delivery of the infant displayed higher GII levels than those who were not (p = 0.023). DiscussionOverall, the GII demonstrated an association between various perinatal factors and placental inflammation. It is anticipated that the GII will provide a novel genomics tool for quantifying placental inflammation, allowing for further investigation of causes, and ultimately the prevention, of inflammation in the placenta.

Noninvasive ventilation for respiratory distress syndrome is apotential risk factor for retinopathy of prematurity : Single Slovenian tertiary center study.

Retinopathy of prematurity (nROP) among extremely low gestational age newborns (ELGAN) in Slovenia has increased in recent years. At the same time mortality has further decreased and less invasive approaches for treatment of respiratory distress syndrome have been established. With the aim to study the possible association between the incidence of ROP and the duration of noninvasive ventilation, this retrospective study comprised ELGANs born during the first period (2010/2011), when invasive respiratory support was the prevalent method and in the second period (2015/2016), when noninvasive respiratory support was adopted. The results showed that the duration of noninvasive ventilation is apotential risk factor for ROP. Controlling for known risk factors for ROP and then adjusting for gestational age, number of transfusions and fraction of inspired oxygen (FiO2), the odds of ROP were 1.22 times greater (95% confidence interval, CI 1.01-1.48) with every additional week of noninvasive ventilation (p = 0.03).

Fetal hemoglobin levels in premature newborns. Should we reconsider transfusion of adult donor blood?

PurposeThe aim of this study was to assess the percent decrease in fetal hemoglobin (HbF) after transfusion of adult-derived donor packed red blood cell (pRBC) units in extremely low gestational age newborns (ELGANs). MethodsControl percent fetal hemoglobin (%HbF) levels were measured in newborn cord blood or peripheral blood samples in non-transfused patients prior to elective surgery. ELGANs were followed prospectively and %HbF was measured on residual post-test complete blood count (CBC) specimens. ELGAN %HbF values were compared to the control population and transfusions were recorded. ResultsInitial mean %HbF in ELGANs (n=16) was 92.2±1.3% (range 90.2-95.1%), which is similar to the control group (n=25). Mean levels dropped to 61.1±11.1% (range 34.2-73.2%) after a single pRBC transfusion (n=9) and to a mean of 35.6±6.3% after an additional transfusion (n=5). %HbF levels trended upwards if no additional transfusions were given, but levels still remained lower than expected for gestational age through discharge (n=85 samples). ConclusionsPercent fetal hemoglobin concentrations in ELGANs decrease precipitously after transfusion with adult donor pRBCs. Further studies are needed to evaluate the benefit of maintaining higher fetal hemoglobin concentrations in these patients and whether administration of HbF rather than adult donor pRBCs would improve patient outcomes.

Prenatal tobacco smoke exposure and neurological impairment at 10years of age among children born extremely preterm: a prospective cohort.

To determine the association between prenatal tobacco smoke exposure and neurological impairment at 10years of age among children born extremely preterm (<28weeks of gestation). The Extremely Low Gestational Age Newborn (ELGAN) Study, a prospective cohort. Ten-year follow-up of extremely preterm infants born at 14 US hospitals between 2002 and 2004. Prenatal tobacco smoke exposure was defined as a mother's report at enrolment of active (i.e. maternal) and passive smoking during pregnancy. Poisson regression with generalized estimating equations was used. Models adjusted for mother's age, race/ethnicity, education, insurance, pre-pregnancy body mass index, US region, multiple gestation and infant's sex; and in sensitivity analysis, gestational age at delivery and clinical subtype of preterm birth, given their classification as intermediate and non-confounding variables. Neurological impairment at 10years, epilepsy, cerebral palsy and cognitive impairment. Of 1200 ELGAN study survivors, 856 were assessed at 10years of age with neurological outcomes, of whom 14% (118/856) had active tobacco exposure during pregnancy and 24% (207/852) had passive tobacco exposure. Compared with children who were not exposed prenatally to tobacco, children exposed to active tobacco use during pregnancy had a higher risk of epilepsy (14% versus 5%; adjusted relative risk: 1.68, 95% CI 1.45-1.92). This risk remained after adjustment for gestational age at delivery and clinical subtype of preterm birth. Prenatal tobacco smoke exposure was not associated with other assessed neurological outcomes, including cerebral palsy and multiple measures of cognitive impairment. Among children born extremely preterm, prenatal active tobacco smoke exposure was associated with an increased risk of epilepsy at 10years of life. Among infants born before 28weeks of gestation, prenatal active tobacco smoke exposure was associated with an increased risk of epilepsy at 10years of life.

Micro-premature infants in New Jersey show improved mortality and morbidity from 2000-2018.

BACKGROUND:Micro-premature newborns, gestational age (GA) ≤ 25 weeks, have high rates of mortality and morbidity. Literature has shown improving outcomes for extremely low gestational age newborns (ELGANs) GA ≤ 29 weeks, but few studies have addressed outcomes of ELGANs ≤ 25 weeks.OBJECTIVE:To evaluate the trends in outcomes for ELGANs born in New Jersey, from 2000 to 2018 and to compare two subgroups: GA 23 to 25 weeks (E1) and GA 26 to 29 weeks (E2).METHODS:Thirteen NICUs in NJ submitted de-identified data. Outcomes for mortality and morbidity were calculated.RESULTS:Data from 12,707 infants represents the majority of ELGANs born in NJ from 2000 to 2018. There were 3,957 in the E1 group and 8,750 in the E2 group. Mortality decreased significantly in both groups; E1, 43.2% to 30.2% and E2, 7.6% to 4.5% over the 19 years. The decline in E1 was significantly greater than in E2. Most morbidities also showed significant improvement over time in both groups. Survival without morbidity increased from 14.5% to 30.7% in E1s and 47.2% to 69.9% in E2s. Similar findings held for 501–750 and 751–1000g birth weight strata.CONCLUSIONS:Significant declines in both mortality and morbidity have occurred in ELGANs over the last two decades. These rates of improvements for the more immature ELGANs of GA 230 to 256 weeks were greater than for the more mature group in several outcomes. While the rates of morbidity and mortality remain high, these results validate current efforts to support the micro-premature newborn.

360 Prenatal tobacco smoke and risk of neurological impairment at age 10 among extremely preterm infants

To determine the association between prenatal tobacco smoke exposure and neurological impairment at 10 years of age among children born extremely preterm (<28 weeks gestation). The multicenter, prospective Extremely Low Gestational Age Newborn (ELGAN) Study enrolled newborns at birth between 2002-2004. Prenatal tobacco smoke included self-reported maternal (i.e., active) and passive smoking during pregnancy at study enrollment. Neurological impairment at 10 years of age included: epilepsy, cerebral palsy, and cognitive impairment. Poisson regression with generalized estimating equations was used to estimate adjusted risk ratios (aRRs), adjusted for mother’s age, race/ethnicity, education, insurance, multiple gestation, and infant’s sex; and separately, we adjusted for gestational age at delivery in sensitivity analysis, given its classification as an intermediate and not confounding variable. Secondarily, we assessed whether 1) the primary association varied by infant sex (male vs. female) given sexual epigenetic dimorphism in the placenta; and 2) postnatal inflammation in the child within 2 weeks after birth. Of 1,200 ELGAN study survivors, 886 were assessed at 10 years of age, of whom 14% (120/867) had been exposed to maternal tobacco use during pregnancy and 24% (210/863) to passive tobacco smoke. Compared to children who were not exposed prenatally to tobacco, children exposed to maternal tobacco use during pregnancy had a higher risk of epilepsy at 10 years of age (14% vs. 5%; aRR: 1.6, 95% CI: 1.6 to 1.7). This risk remained after adjustment for gestational age at delivery. Prenatal tobacco smoke exposure was not associated with cerebral palsy and cognitive impairment. Secondarily, the primary association held for female but not male infants; and tobacco smoke exposure did not influence the contribution of postnatal inflammation to impaired neurodevelopment. Among extremely preterm infants born <28 weeks, active maternal tobacco smoke during pregnancy increases the risk of epilepsy in the offspring at 10 years of life.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm

BackgroundChildren born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes.MethodsWe examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS.ResultsGenes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case–control status.LimitationsThe ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited.ConclusionsAggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.

CUE: CpG impUtation ensemble for DNA methylation levels across the human methylation450 (HM450) and EPIC (HM850) BeadChip platforms

ABSTRACT DNA methylation at CpG dinucleotides is one of the most extensively studied epigenetic marks. With technological advancements, geneticists can profile DNA methylation with multiple reliable approaches. However, profiling platforms can differ substantially in the CpGs they assess, consequently hindering integrated analysis across platforms. Here, we present CpG impUtation Ensemble (CUE), which leverages multiple classical statistical and modern machine learning methods, to impute from the Illumina HumanMethylation450 (HM450) BeadChip to the Illumina HumanMethylationEPIC (HM850) BeadChip. Data were analysed from two population cohorts with methylation measured both by HM450 and HM850: the Extremely Low Gestational Age Newborns (ELGAN) study (n = 127, placenta) and the VA Boston Posttraumatic Stress Disorder (PTSD) genetics repository (n = 144, whole blood). Cross-validation results show that CUE achieves the lowest predicted root-mean-square error (RMSE) (0.026 in PTSD) and the highest accuracy (99.97% in PTSD) compared with five individual methods tested, including k-nearest-neighbours, logistic regression, penalized functional regression, random forest, and XGBoost. Finally, among all 339,033 HM850-only CpG sites shared between ELGAN and PTSD, CUE successfully imputed 289,604 (85.4%) sites, where success was defined as RMSE < 0.05 and accuracy >95% in PTSD. In summary, CUE is a valuable tool for imputing CpG methylation from the HM450 to HM850 platform.

A role for microRNAs in the epigenetic control of sexually dimorphic gene expression in the human placenta.

Aim: The contribution of miRNAs as epigenetic regulators of sexually dimorphic gene expression in the placenta is unknown. Materials & methods: 382 placentas from the extremely low gestational age newborns (ELGAN) cohort were evaluated for expression levels of 37,268 mRNAsand 2,102 miRNAs using genome-wide RNA-sequencing. Differential expression analysis was used to identify differences in the expression based on the sex of the fetus. Results: Sexually dimorphic expression was observed for 128 mRNAs and 59 miRNAs. A set of 25 miRNA master regulators was identified that likely contribute to the sexual dimorphic mRNA expression. Conclusion: These data highlight sex-dependent miRNA and mRNA patterning in the placenta and provide insight into a potential mechanism for observedsex differences in outcomes.