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Papers by John Dagle

Pediatric Research, Oct 1, 2020

Background:Identifying preterm infants at risk for mortality or major morbidity traditionally rel... more Background:Identifying preterm infants at risk for mortality or major morbidity traditionally relies on gestational age, birthweight, and other clinical characteristics that offer underwhelming utility. We sought to determine whether a newborn metabolic vulnerability profile at birth can be used to evaluate risk for neonatal mortality and major morbidity in preterm infants.Methods:This was a population-based retrospective cohort study of preterm infants born between 2005 and 2011 in California. We created a newborn metabolic vulnerability profile wherein maternal/infant characteristics along with routine newborn screening metabolites were evaluated for their association with neonatal mortality or major morbidity.Results:9,639 (9.2%) preterm infants experienced mortality or at least one complication. Six characteristics and 19 metabolites were included in the final metabolic vulnerability model. The model demonstrated exceptional performance for the composite outcome of mortality or any major morbidity (AUC 0.923 (95% CI: 0.917–0.929). Performance was maintained across mortality and morbidity subgroups (AUCs 0.893–0.979).Conclusion:Metabolites measured as part of routine newborn screening can be used to create a metabolic vulnerability profile. These findings lay the foundation for targeted clinical monitoring and further investigation of biological pathways that may increase the risk of neonatal death or major complications in infants born preterm.

Journal of Perinatology, Dec 5, 2018

Objective.-Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Pr... more Objective.-Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants. Study Design.-Preterm infants (n=1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables.

Pediatric Research, Jul 1, 2011

Intraventricular hemorrhage (IVH) is a significant morbidity seen in very LBW infants. Genes rela... more Intraventricular hemorrhage (IVH) is a significant morbidity seen in very LBW infants. Genes related to the inflammation, infection, complement, or coagulation pathways have been implicated as risk factors for IVH. We examined 10 candidate genes for associations with IVH in 271 preterm infants (64 with IVH grades I-IV and 207 without IVH) weighing Ͻ1500 g. The heterozygous genotype OR ϭ 8.1, CI ϭ 2.5-26.0, p ϭ 4 ϫ 10 Ϫ4) and the A allele (OR ϭ 7.3, CI ϭ 2.4-22.5, p ϭ 1 ϫ 10 Ϫ4) of the coagulation factor V (FV) Leiden mutation (rs6025) were associated with an increased risk of developing IVH grade I or II but not grade III or IV after correction for multiple testing with Bonferroni. Lack of association in the severe grades of IVH may be a result of lack of power to detect an effect given the small sample size (n ϭ 8). However, this result is consistent with previous research that demonstrates that the heterozygous genotype of the FV mutation is associated with increased risk for the development of IVH but a decreased risk for the progression or extension to more severe grades of IVH.

PLOS ONE, Jan 28, 2021

Background A growing amount of evidence indicates in utero and early life growth has profound, lo... more Background A growing amount of evidence indicates in utero and early life growth has profound, longterm consequences for an individual's health throughout the life course; however, there is limited data in preterm infants, a vulnerable population at risk for growth abnormalities. Objective To address the gap in knowledge concerning early growth and its determinants in preterm infants. Methods A retrospective cohort study was performed using a population of preterm (< 37 weeks gestation) infants obtained from an electronic medical record database. Weight z-scores were acquired from discharge until roughly two years corrected age. Linear mixed effects modeling, with random slopes and intercepts, was employed to estimate growth trajectories. Results Thirteen variables, including maternal race, hypertension during pregnancy, preeclampsia, first trimester body mass index, multiple status, gestational age, birth weight, birth length, head circumference, year of birth, length of birth hospitalization stay, total parenteral nutrition, and dextrose treatment, were significantly associated with growth rates of preterm infants in univariate analyses. A small percentage (1.32%-2.07%) of the variation in the growth of preterm infants can be explained in a joint model of these perinatal factors. In extremely preterm infants, additional variation in growth trajectories can be explained by conditions whose risk differs by degree of prematurity. Specifically, infants with periventricular leukomalacia or retinopathy of prematurity experienced decelerated rates of growth compared to infants without such conditions.

Cholesterol biosynthesis is a highly conserved metabolic process. However, genetic variability in... more Cholesterol biosynthesis is a highly conserved metabolic process. However, genetic variability in cholesterol metabolism contributes to both rare congenital disorders and common chronic conditions. In the post-lanosterol cholesterol biosynthesis pathway, ten enzymes are associated with rare disorders including Greenberg skeletal dysplasia, Pelger–Huet anomaly, CHILD syndrome, Conradi–Hunermann syndrome, lathosterolosis, Smith–Lemli–Opitz syndrome, and desmosterolosis. In addition to these profound dominant and recessive congenital disorders, common genetic variability, in particular, single nucleotide polymorphisms (SNPs), in the genes encoding these enzymes is associated with common chronic diseases such as cancer, diabetes, blood pressure, hepatitis C progression, and Alzheimer’s disease. We will discuss the genetic causes of rare disorders in the post-squalene cholesterol biosynthesis pathway and the chronic disease effects of common genetic variability in this pathway.

BMC Medical Genetics, Jul 26, 2013

Background: Preterm birth (PTB) is a complex disorder associated with significant neonatal mortal... more Background: Preterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known. Methods: To identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance. Results: Maternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case-control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors. Conclusions: Our study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302 and rs237902 may have gestational age-dependent effects on prematurity. Most of the OXTR rare variants identified do not appear to significantly contribute to the risk of PTB, but those shown to affect receptor function in our in vitro study warrant further investigation. Future studies with larger sample sizes are needed to confirm the findings of this study.

Journal of Perinatology, May 3, 2023

Pediatric Research, Dec 18, 2014

Articles Clinical Investigation nature publishing group Background: In recent years, increasing n... more Articles Clinical Investigation nature publishing group Background: In recent years, increasing numbers of preterm infants have been exposed to inhaled nitric oxide (iNO). This population has decreased methemoglobin (MetHb) reductase activity in their erythrocytes, which may increase the risk of MetHb toxicity. We sought to determine if genetic factors are associated with the observed variance in MetHb levels. Methods: A population of 127 preterm infants was genotyped for five single-nucleotide polymorphisms (SNPs) in the CYB5A and CYB5R3 genes. iNO dose and levels of MetHb were obtained by chart abstraction. ANOVA was performed to identify genetic associations with MetHb levels. results: An association was found between the heterozygous genotype (GA) of rs916321 in the CYB5R3 gene and the mean of the first recorded MetHb levels in Caucasian infants (P = 0.01). This result remained significant after adjustment for the iNO dose (P = 0.009), gender (P = 0.03), multiple gestation (P = 0.03), birth weight (P = 0.02), and gestational age (P = 0.02). No significant associations were found with the other SNPs. conclusion: We demonstrate a novel genetic association with neonatal MetHb levels. Identification of genetic risk factors may be useful in determining which preterm infants are most at risk of developing MetHb toxicity with the use of iNO.

Pharmacogenomics, Aug 1, 2019

Aims:To identify clinical andgenetic factors associated with indomethacin treatment failure in pr... more Aims:To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA).Patients & Methods:This is a multicenter cohort study of 144 preterm infants (22–32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention.Results:In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60–0.96), surfactant use (AOR 9.77, 95% CI 1.15–83.26), and CYP2C9*2 (AOR 3.74; 95% CI 1.34–10.44) were each associated with indomethacin failure.Conclusion:Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.

Pediatric Research, Oct 4, 2017

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated ... more BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance. Endogenous nitric oxide is critical for regulation of pulmonary vascular resistance. Nitric oxide is generated from L-arginine, supplied by the urea cycle (UC). We hypothesized that polymorphisms in UC enzyme genes and low concentrations of UC intermediates are associated with PPHN. METHODS: We performed a family-based candidate gene analysis to study 48 single-nucleotide polymorphisms (SNPs) in six UC enzyme genes. Genotyping was carried out in 94 infants with PPHN and their parents. We also performed a case-control analysis of 32 cases with PPHN and 64 controls to identify an association between amino-acid levels on initial newborn screening and PPHN. RESULTS: Three SNPs (rs41272673, rs4399666, and rs2287599) in carbamoyl phosphate synthase 1 gene (CPS1) showed a significant association with PPHN (P = 0.02). Tyrosine levels were significantly lower (P = 0.003) and phenylalanine levels were significantly higher (P = 0.01) in cases with PPHN. There was no difference in the arginine or citrulline levels between the two groups. CONCLUSIONS: This study suggests an association (Po0.05) between SNPs in CPS1 and PPHN. These findings warrant further replication in larger cohorts of patients.

Journal of Perinatology, 2022

Objective: Our study sought to determine whether metabolites from a retrospective collection of b... more Objective: Our study sought to determine whether metabolites from a retrospective collection of banked cord blood specimens could accurately estimate gestational age and to validate these findings in cord blood samples from Busia, Uganda. Study Design: Forty-seven metabolites were measured by tandem mass spectrometry or enzymatic assays from 942 banked cord blood samples. Multiple linear regression was performed, and the best model was used to predict gestational age, in weeks, for 150 newborns from Busia, Uganda. Results: The model including metabolites and birthweight, predicted the gestational ages within 2 weeks for 76.7% of the Ugandan cohort. Importantly, this model estimated the prevalence of preterm birth <34 weeks closer to the actual prevalence (4.67% and 4.00%, respectively) than a model with only birthweight which overestimates the prevalence by 283%. Conclusion: Models that include cord blood metabolites and birth weight appear to offer improvement in gestational age estimation over birth weight alone.

Journal of Global Health, 2021

Background Limited ultrasound capacity in low-resource settings makes correct gestational age (GA... more Background Limited ultrasound capacity in low-resource settings makes correct gestational age (GA) dating difficult. Previous work demonstrated that newborn metabolic profiles can accurately determine gestational age, but this relationship has not been evaluated in low-income countries. The objective of this study was to validate and adapt a metabolic GA dating model developed using newborn blood spots for use in a low-resource setting in rural Uganda. Methods A cohort of pregnant women was followed prospectively and heel stick blood spots were collected from 666 newborns in Busia, Uganda at the time of delivery. They were dried, frozen, and shipped to the US where they were tested for 47 metabolites. Metabolic model performance was assessed using early ultrasound determined GA as the standard. Models tested included previously built multivariable models and models specifically adapted to the Busia population. Results The previously built model successfully dated 81.2% of newborns within two weeks of their ultrasound GA. Only 4.8% of GAs were off by greater than three weeks. In the model adapted to the local population, 89.2% of GAs matched their corresponding ultrasound to within two weeks. The model-derived preterm birth rate was 7.2% compared to 5.9% by ultrasound. Conclusions These results suggest that metabolic dating is a reliable method to determine GA in a low-income setting. Metabolic dating offers the potential to better elucidate preterm birth rates in low-resource settings, which is important for assessing population-level patterns, tailoring clinical care, and understanding the developmental trajectories of preterm infants.

The Journal of Maternal-Fetal & Neonatal Medicine, 2020

Objective: To determine the prevalence of virus in a previously uncharacterized matched maternal-... more Objective: To determine the prevalence of virus in a previously uncharacterized matched maternal-infant preterm cohort and test if viral presence or viral load correlate with histologic chorioamnionitis, spontaneous preterm labor or pre-eclampsia. Study Design: Using qRT-PCR/qPCR we tested plasma or whole blood samples from 56 matched maternal and premature infant dyads for: adenovirus, anellovirus (alphatorquevirus and betatorquevirus), cytomegalovirus (CMV), Epstein-Barr virus (EBV), enterovirus, human herpesvirus 6 (HHV6), parechovirus, and parvovirus B19. Result: Viral detection was more common in maternal samples 29/56 (52%) than in cord blood from their infants (4/56 (7%)) (p .0001). No significant difference in viral load or viral prevalence was identified between pregnancies with and without histologic chorioamnionitis, spontaneous preterm labor or pre-eclampsia. Conclusion: Despite frequent detection of virus in maternal samples, virus was less frequently detected in the infants. Additionally, there was no association of presence or quantity of virus in maternal blood with histologic chorioamnionitis, spontaneous preterm labor or pre-eclampsia in this small, but well-defined cohort. Future studies are necessary to further characterize the role of virus in placental inflammatory states and pregnancy outcomes.

Lipids, 2019

Maternal lipid profiles are associated with risk for preterm birth (PTB), although the lipid comp... more Maternal lipid profiles are associated with risk for preterm birth (PTB), although the lipid component and effect size are inconsistent between studies. It is also unclear whether these associations are the result of excessive changes in lipid metabolism during pregnancy or genetic variability in genes controlling basal lipid metabolism. This study investigates the association between genetic risk scores (GRS) for four lipid components (high‐density lipoprotein [HDL‐C], low‐density lipoprotein [LDL‐C], triacylglycerols [TAG], and total cholesterol [TC]) with risk for PTB. Subjects included 954 pregnant women from California for whom second trimester serum samples were available, of which 479 gave birth preterm and 475 gave birth at term. We genotyped 96 single‐nucleotide polymorphisms, which were selected from genome‐wide association studies of lipid levels in adult populations. Lipid‐specific GRS were constructed for HDL‐C, LDL‐C, TAG, and TC. The associations between GRS and PTB w...

Pediatric Research, 2017

BACKGROUND: Patent ductus arteriosus (PDA) is a common complication seen in preterm infants. Indo... more BACKGROUND: Patent ductus arteriosus (PDA) is a common complication seen in preterm infants. Indomethacin is routinely used to treat PDA. Evidence suggests that the response of indomethacin is highly heritable. This study investigated the association between single-nucleotide polymorphisms (SNPs) in CYP2C9 and the closure of PDA in response to indomethacin. METHODS: Six SNPs in CYP2C9 were analyzed for association with indomethacin response. A case-control analysis was performed among neonates who responded to indomethacin (responders) and among those who required surgical ligation (non-responders). Independent transmission disequilibrium tests were performed among parent-child trios of responders and non-responders. RESULTS: The G allele of rs2153628 was associated with increased odds of response to indomethacin in the casecontrol analysis (odds ratios (OR): 1.918, 95% confidence interval (CI): 1.056, 3.483). Among indomethacin responders, the G allele of rs2153628 and the T allele of rs1799853 were overtransmitted from the parents to their child (OR: 2.667, 95% CI: 1.374, 5.177 and OR: 2.375, 95% CI: 1.040, 5.425, respectively), consistent with the case-control analysis. CONCLUSION: We identified an association between two SNPs in CYP2C9, rs2153628 and rs1799853, and indomethacin response for the treatment of PDA. These findings suggest that response to indomethacin in the closure of PDA may be influenced by polymorphisms associated with altered indomethacin metabolism.

The Journal of pediatrics, Jan 22, 2016

To identify single-nucleotide polymorphisms (SNPs) in specific candidate genes associated with pa... more To identify single-nucleotide polymorphisms (SNPs) in specific candidate genes associated with patent ductus arteriosus in term infants. We conducted an initial family-based, candidate gene study to analyze genotype data from DNA samples obtained from 171 term infants and their parents enrolled in the National Birth Defects Prevention Study (NBDPS). We performed transmission disequilibrium testing (TDT) using a panel of 55 SNPs in 17 genes. Replication of SNPs with P < .1 in the NBDPS trios was performed with a case-control strategy in an independent population. TDT analysis of the NBDPS trios resulted in 6 SNPs reaching the predetermined cutoff (P < .1) to be included in the replication study. These 6 SNPs were genotyped in the independent case-control population. A SNP in TGFBR2 was found to be associated with term patent ductus arteriosus in both populations after we corrected for multiple comparisons. (rs934328, TDT P = 2 × 10(-4), case-control P = 6.6 × 10(-5)). These fin...

BMC pediatrics, Apr 29, 2016

The use of Electronic Health Records (EHR) has increased significantly in the past 15 years. This... more The use of Electronic Health Records (EHR) has increased significantly in the past 15 years. This study compares electronic vs. manual data abstractions from an EHR for accuracy. While the dataset is limited to preterm birth data, our work is generally applicable. We enumerate challenges to reliable extraction, and state guidelines to maximize reliability. An Epic™ EHR data extraction of structured data values from 1,772 neonatal records born between the years 2001-2011 was performed. The data were directly compared to a manually-abstracted database. Specific data values important to studies of perinatology were chosen to compare discrepancies between the two databases. Discrepancy rates between the EHR extraction and the manual database were calculated for gestational age in weeks (2.6 %), birthweight (9.7 %), first white blood cell count (3.2 %), initial hemoglobin (11.9 %), peak total and direct bilirubin (11.4 % and 4.9 %), and patent ductus arteriosus (PDA) diagnosis (12.8 %). ...

Pediatrics, 2016

Background-Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated p... more Background-Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance (PVR). Endogenous nitric oxide is critical for regulation of PVR. Nitric oxide is generated from L-arginine, supplied by the urea cycle (UC). We hypothesized that polymorphisms in UC enzyme genes and low concentrations of UC intermediates are associated with PPHN. Methods-Family based candidate gene analysis to study 48 single nucleotide polymorphisms in 6 UC enzyme genes. Genotyping was done on 94 infants with PPHN and their parents. We also performed a case-control analysis of 32 cases with PPHN and 64 controls to identify the association between amino acid levels on initial newborn screening and PPHN. Results-Three SNPs in carbamoyl phosphate synthetase 1 gene (CPS1) showed significant association with PPHN (p=0.02). Tyrosine levels were significantly lower (p=0.003) and phenylalanine levels were significantly higher (p=0.01) in cases with PPHN. There was no difference in the arginine or citrulline levels between the two groups. Conclusions-This study suggests a potential association between SNPs in the CPS1 and PPHN. Tyrosine level was significantly lower and phenylalanine level was significantly higher in cases with PPHN. These findings warrant further replication in larger cohorts of patients.

Pediatric research, May 13, 2016

Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. There is strong evidenc... more Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. There is strong evidence of genetic susceptibility. Objective of the study was to identify genetic variants contributing to PTB. Genotyping was performed for 24 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NR5A2, FSHR, FOXP3, SERPINH1). Genotyping was completed on 728 maternal triads (mother & maternal grandparents of a preterm infant). Data were analyzed with Family Based Association Test. For all maternal triads rs2737667 of NR5A2 showed significant association at P= 0.02. When stratifying by gestational age three SNPs in NR5A2 had p values <0.05 in the <32 weeks gestational age group (rs12131233, p=0.007; rs2737667, p=0.04; rs2816949, p=0.02). When preterm premature rupture of membranes (PPROM) cases were excluded rs2737667 of NR5A2 showed the strongest association with a p value <0.0002. This association remained significant after correction for multiple testing. This study suggest...

American Journal of Obstetrics and Gynecology, 2016

BACKGROUND: Accurate gestational age estimation is extremely important for clinical care decision... more BACKGROUND: Accurate gestational age estimation is extremely important for clinical care decisions of the newborn as well as for perinatal health research. Although prenatal ultrasound dating is one of the most accurate methods for estimating gestational age, it is not feasible in all settings. Identifying novel and accurate methods for gestational age estimation at birth is important, particularly for surveillance of preterm birth rates in areas without routine ultrasound dating. OBJECTIVE: We hypothesized that metabolic and endocrine markers captured by routine newborn screening could improve gestational age estimation in the absence of prenatal ultrasound technology. STUDY DESIGN: This is a retrospective analysis of 230,013 newborn metabolic screening records collected by the Iowa Newborn Screening Program between 2004 and 2009. The data were randomly split into a model-building dataset (n ¼ 153,342) and a model-testing dataset (n ¼ 76,671). We performed multiple linear regression modeling with gestational age, in weeks, as the outcome measure. We examined 44 metabolites, including biomarkers of amino acid and fatty acid metabolism, thyroid-stimulating hormone, and 17-hydroxyprogesterone. The coefficient of determination (R 2) and the root-mean-square error were used to evaluate models in the model-building dataset that were then tested in the model-testing dataset. RESULTS: The newborn metabolic regression model consisted of 88 parameters, including the intercept, 37 metabolite measures, 29 squared metabolite measures, and 21 cubed metabolite measures. This model explained 52.8% of the variation in gestational age in the model-testing dataset. Gestational age was predicted within 1 week for 78% of the individuals and within 2 weeks of gestation for 95% of the individuals. This model yielded an area under the curve of 0.899 (95% confidence interval 0.895À0.903) in differentiating those born preterm (<37 weeks) from those born term (!37 weeks). In the subset of infants born small-forgestational age, the average difference between gestational ages predicted by the newborn metabolic model and the recorded gestational age was 1.5 weeks. In contrast, the average difference between gestational ages predicted by the model including only newborn weight and the recorded gestational age was 1.9 weeks. The estimated prevalence of preterm birth <37 weeks' gestation in the subset of infants that were small for gestational age was 18.79% when the model including only newborn weight was used, over twice that of the actual prevalence of 9.20%. The newborn metabolic model underestimated the preterm birth prevalence at 6.94% but was closer to the prevalence based on the recorded gestational age than the model including only newborn weight. CONCLUSIONS: The newborn metabolic profile, as derived from routine newborn screening markers, is an accurate method for estimating gestational age. In small-for-gestational age neonates, the newborn metabolic model predicts gestational age to a better degree than newborn weight alone. Newborn metabolic screening is a potentially effective method for population surveillance of preterm birth in the absence of prenatal ultrasound measurements or newborn weight.