Publications by authors named "Gary Shaw"

554 Publications

Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset.

Sci Transl Med 2021 May;13(592)

Department of Surgery, Stanford University School of Medicine, Palo Alto, CA 94305, USA.

Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [ = 0.85, 95% confidence interval (CI) [0.79 to 0.89], = 1.2 × 10, = 53, training set; = 0.81, 95% CI [0.61 to 0.91], = 3.9 × 10, = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abd9898DOI Listing
May 2021

Nitrate in Drinking Water during Pregnancy and Spontaneous Preterm Birth: A Retrospective Within-Mother Analysis in California.

Environ Health Perspect 2021 May 5;129(5):57001. Epub 2021 May 5.

Department of Pediatrics, Stanford University, Stanford, California, USA.

Background: Nitrate is a widespread groundwater contaminant and a leading cause of drinking water quality violations in California. Associations between nitrate exposure and select adverse birth outcomes have been suggested, but few studies have examined gestational exposures to nitrate and risk of preterm birth (before 37 wk gestation).

Objective: We investigated the association between elevated nitrate in drinking water and spontaneous preterm birth through a within-mother retrospective cohort study of births in California.

Methods: We acquired over 6 million birth certificate records linked with Office of Statewide Health Planning and Development hospital discharge data for California births from 2000-2011. We used public water system monitoring records to estimate nitrate concentrations in drinking water for each woman's residence during gestation. After exclusions, we constructed a sample of 1,443,318 consecutive sibling births in order to conduct a within-mother analysis. We used separate conditional logistic regression models to estimate the odds of preterm birth at 20-31 and 32-36 wk, respectively, among women whose nitrate exposure changed between consecutive pregnancies.

Results: Spontaneous preterm birth at 20-31 wk was increased in association with tap water nitrate concentrations during pregnancy of 5 to [odds ratio ; 95% confidence interval (CI): 1.29, 1.67] and (; 95% CI: 1.49, 4.26) compared with (as nitrogen). Corresponding estimates for spontaneous preterm birth at 32-36 wk were positive but close to the null for 5 to nitrate (; 95% CI: 1.02, 1.15) and for nitrate (; 95% CI: 0.85, 1.31) vs. nitrate. Our findings were similar in several secondary and sensitivity analyses, including in a conventional individual-level design.

Discussion: The results suggest that nitrate in drinking water is associated with increased odds of spontaneous preterm birth. Notably, we estimated modestly increased odds associated with tap water nitrate concentrations of 5 to (below the federal drinking water standard of ) relative to . https://doi.org/10.1289/EHP8205.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1289/EHP8205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098122PMC
May 2021

Measuring Variation in Interpregnancy Interval: Identifying Hotspots for Improvement Initiatives.

Am J Perinatol 2021 May 3. Epub 2021 May 3.

California Perinatal Quality Care Collaborative, Stanford University School of Medicine, Stanford, California.

Objective:  The study aimed to determine if single year birth certificate data can be used to identify regional and hospital variation in rates of short interpregnancy interval (IPI < 6 months).

Study Design:  IPI was estimated for multiparous women ages 15 to 44 years with singleton live births between 2015 and 2016. Perinatal outcomes, place of birth, maternal race, and data for IPI calculations were obtained by using birth certificates. IPI frequencies are presented as observed rates.

Results:  The cohort included 562,039 multiparous women. Short IPI rates were similar to those obtained with analyses by using linked longitudinal data and confirmed the association with preterm birth. Short IPI rates varied by race and Hispanic nativity. There was substantial hospital (0.8-9%) and regional (2.9-6.2%) variation in short IPI rates.

Conclusion:  IPI rates can be reliably obtained from current year birth certificate data. This can be a useful tool for quality improvement projects targeting interventions and rapidly assessing their progress to promote optimal birth spacing.

Key Points: · Near-real time regional and hospital IPI rates can be reliably obtained from current year birth certificate data.. · Substantial variations in rates of short IPI exist between hospital and perinatal regions.. · IPI rates from individual birth certificates can be a tool to target and assess interventions..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0041-1728819DOI Listing
May 2021

Trends in Spontaneous and Medically Indicated Preterm Birth in Twins versus Singletons: A California Cohort 2007 to 2011.

Am J Perinatol 2021 May 2. Epub 2021 May 2.

Department of Pediatrics, Stanford University, Stanford, California.

Objective:  The study aimed to describe preterm birth (PTB) rates, subtypes, and risk factors in twins compared with singletons to better understand reasons for the decline in PTB rate between 2007 and 2011.

Study Design:  This was a retrospective population-based analysis using the California linked birth certificates and maternal-infant hospital discharge records from 2007 to 2011. The main outcomes were overall, spontaneous (following spontaneous labor or preterm premature rupture of membranes), and medically indicated PTB at various gestational age categories: <37, <32, and 34 to 36 weeks in twins and singletons.

Results:  Among the 2,290,973 singletons and 28,937 twin live births pairs included, overall PTB <37 weeks decreased by 8.46% (6.77-6.20%) in singletons and 7.17% (55.31-51.35%) in twins during the study period. In singletons, this was primarily due to a 24.91% decrease in medically indicated PTB with almost no change in spontaneous PTB, whereas in twins indicated PTB declined 7.02% and spontaneous PTB by 7.39%.

Conclusion:  Recent declines in PTB in singletons appear to be largely due to declines in indicated PTB, whereas both spontaneous and indicated PTB declined in twins.

Key Points: · The declines in PTB noted between 2006 and 2014 occurred in both singleton and twins.. · Declines were mostly in medically indicated PTB.. · Interventions proposed as causing the declines in singletons would not apply to twins..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0041-1729161DOI Listing
May 2021

Corrigendum: Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation.

Front Pediatr 2021 12;9:680201. Epub 2021 Apr 12.

Departments of Bioengineering and Applied Physics, Stanford University, and Chan Zuckerberg Biohub, Stanford, CA, United States.

[This corrects the article DOI: 10.3389/fped.2020.605219.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2021.680201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065098PMC
April 2021

Understanding how biologic and social determinants affect disparities in preterm birth and outcomes of preterm infants in the NICU.

Semin Perinatol 2021 Mar 24:151408. Epub 2021 Mar 24.

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, 1265 Welch Rd, X157, Stanford, CA 94305-5415, USA.

To understand the disparities in spontaneous preterm birth (sPTB) and/or its outcomes, biologic and social determinants as well as healthcare practice (such as those in neonatal intensive care units) should be considered. They have been largely intractable and remain obscure in most cases, despite a myriad of identified risk factors for and causes of sPTB. We still do not know how they might actually affect and lead to the different outcomes at different gestational ages and if they are independent of NICU practices. Here we describe an integrated approach to study the interplay between the genome and exposome, which may drive biochemistry and physiology, with health disparities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semperi.2021.151408DOI Listing
March 2021

The relationship between air pollutants and maternal socioeconomic factors on preterm birth in California urban counties.

J Expo Sci Environ Epidemiol 2021 Apr 15. Epub 2021 Apr 15.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA.

Background: Preterm birth is the leading cause of perinatal morbidity and mortality in the U.S. and disparities among racial and ethnic groups persist. While etiologies of preterm birth have not been fully elucidated, it is probable that environmental and social factors play a role.

Objective: We hypothesized that there is an interactive association between exposure to fine particulate matter (PM) or ozone (O) and neighborhood socioeconomic factors that increase the risk of preterm birth.

Methods: We conducted a retrospective study using geocoded birth certificate data between 2007 and 2011, daily ambient air quality data on PM and O, and American Community Survey (2007-2011 5-year estimates) data to assess census tract-level socioeconomic factors in California urban counties.

Results: Our study found a small positive association between maternal exposures to PM and O and preterm birth that varied by gestational exposure period. In mixed-effects models, we found an increase in the risk of preterm birth for a one-unit change in PM averaged across the entire pregnancy (AOR = 1.02, 95% CI: 1.01, 1.02) and O during 3-months pre-pregnancy (AOR = 1.03, 95% CI: 1.02, 1.04). Interaction between census tract-level factors and air pollutants showed an increase in the risk of preterm birth among mothers living in higher socioeconomic areas, though, a fixed cohort bias sensitivity analysis showed these associations were not significant.

Significance: These findings substantiate previous studies that showed associations between air pollution and preterm birth, even as pollution levels have decreased. This study has important implications for policy decisions and may help inform research on potential mechanisms of preterm birth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41370-021-00323-7DOI Listing
April 2021

Acetylated Ubiquitin Modulates the Catalytic Activity of the E1 Enzyme Uba1.

Biochemistry 2021 Apr 13;60(16):1276-1285. Epub 2021 Apr 13.

Department of Biochemistry, Western University, London, Ontario N6A 5C1, Canada.

Ubiquitin (Ub) signaling requires the covalent passage of Ub among E1, E2, and E3 enzymes. The choice of E2 and E3 enzymes combined with multiple rounds of the cascade leads to the formation of polyubiquitin chains linked through any one of the seven lysines on Ub. The linkage type and length act as a signal to trigger important cellular processes such as protein degradation or the DNA damage response. Recently, proteomics studies have identified that Ub can be acetylated at six of its seven lysine residues under various cell stress conditions. To understand the potential differences in Ub signaling caused by acetylation, we synthesized all possible acetylated ubiquitin (acUb) variants and examined the E1-mediated formation of the corresponding E2∼acUb conjugates using kinetic methods. A Förster resonance energy transfer assay was optimized in which the Ub constructs were labeled with a CyPet fluorophore and the E2 UBE2D1 was labeled with a YPet fluorophore to monitor the formation of E2∼Ub conjugates. Our methods enable the detection of small differences that may otherwise be concealed in steady-state ubiquitination experiments. We determined that Ub, acetylated at K11, K27, K33, K48, or K63, has altered turnover numbers for E2∼Ub conjugate formation by the E1 enzyme Uba1. This work provides evidence that acetylation of Ub can alter the catalysis of ubiquitination early on in the pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biochem.1c00145DOI Listing
April 2021

African American Unemployment and the Disparity in Periviable Births.

J Racial Ethn Health Disparities 2021 Mar 30. Epub 2021 Mar 30.

Population, Family and Reproductive Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD, 21205, USA.

Periviable infants (i.e., born before 26 complete weeks of gestation) represent fewer than .5% of births in the US but account for 40% of infant mortality and 20% of billed hospital obstetric costs. African American women contribute about 14% of live births in the US, but these include nearly a third of the country's periviable births. Consistent with theory and with periviable births among other race/ethnicity groups, males predominate among African American periviable births in stressed populations. We test the hypothesis that the disparity in periviable male births among African American and non-Hispanic white populations responds to the African American unemployment rate because that indicator not only traces, but also contributes to, the prevalence of stress in the population. We use time-series methods that control for autocorrelation including secular trends, seasonality, and the tendency to remain elevated or depressed after high or low values. The racial disparity in male periviable birth increases by 4.45% for each percentage point increase in the unemployment rate of African Americans above its expected value. We infer that unemployment-a population stressor over which our institutions exercise considerable control-affects the disparity between African American and non-Hispanic white periviable births in the US.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40615-021-01022-7DOI Listing
March 2021

Association of Gestational Age with Postpartum Hemorrhage.

Anesthesiology 2021 Mar 23. Epub 2021 Mar 23.

Background: Risk factors for postpartum hemorrhage, such as chorioamnionitis and multiple gestation, have been identified in previous epidemiologic studies. However, existing data describing the association between gestational age at delivery and postpartum hemorrhage are conflicting. The aim of this study was to assess the association between gestational age at delivery and postpartum hemorrhage.

Methods: The authors conducted a population-based retrospective cohort study of women who underwent live birth delivery in Sweden between 2014 and 2017 and in California between 2011 and 2015. The primary exposure was gestational age at delivery. The primary outcome was postpartum hemorrhage, classified using International Classification of Diseases, Ninth Revision-Clinical Modification codes for California births and a blood loss greater than 1,000 ml for Swedish births. The authors accounted for demographic and obstetric factors as potential confounders in the analyses.

Results: The incidences of postpartum hemorrhage in Sweden (23,323/328,729; 7.1%) and in California (66,583/2,079,637; 3.2%) were not comparable. In Sweden and California, the incidence of postpartum hemorrhage was highest for deliveries between 41 and 42 weeks' gestation (7,186/75,539 [9.5%] and 8,921/160,267 [5.6%], respectively). Compared to deliveries between 37 and 38 weeks, deliveries between 41 and 42 weeks had the highest adjusted odds of postpartum hemorrhage (1.62 [95% CI, 1.56 to 1.69] in Sweden and 2.04 [95% CI, 1.98 to 2.09] in California). In both cohorts, the authors observed a nonlinear (J-shaped) association between gestational age and postpartum hemorrhage risk, with 39 weeks as the nadir. In the sensitivity analyses, similar findings were observed among cesarean deliveries only, when postpartum hemorrhage was classified only by International Classification of Diseases, Tenth Revision-Clinical Modification codes, and after excluding women with abnormal placentation disorders.

Conclusions: The postpartum hemorrhage incidence in Sweden and California was not comparable. When assessing a woman's risk for postpartum hemorrhage, clinicians should be aware of the heightened odds in women who deliver between 41 and 42 weeks' gestation.

Editor’s Perspective:
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ALN.0000000000003730DOI Listing
March 2021

A mechanistic review of Parkin activation.

Biochim Biophys Acta Gen Subj 2021 Jun 20;1865(6):129894. Epub 2021 Mar 20.

Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Electronic address:

Parkin and phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) constitute a feed-forward signalling pathway that mediates autophagic removal of damaged mitochondria (mitophagy). With over 130 mutations identified to date in over 1000 patients with early onset parkinsonism, Parkin is considered a hot spot of signalling pathways involved in PD aetiology. Parkin is an E3 ligase and how its activity is regulated has been extensively studied: inter-domain interactions exert a tight inhibition on Parkin activity; binding to phospho-ubiquitin relieves this auto-inhibition; and phosphorylation of Parkin shifts the equilibrium towards maximal Parkin activation. This review focusses on recent, structural findings on the regulation of Parkin activity. What follows is a mechanistic introduction to the family of E3 ligases that includes Parkin, followed by a brief description of structural elements unique to Parkin that lock the enzyme in an autoinhibited state, contrasted with emerging models that have shed light on possible mechanisms of Parkin activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagen.2021.129894DOI Listing
June 2021

Interdisciplinary data science to advance environmental health research and improve birth outcomes.

Environ Res 2021 Mar 15;197:111019. Epub 2021 Mar 15.

Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.

Rates of preterm birth and low birthweight continue to rise in the United States and pose a significant public health problem. Although a variety of environmental exposures are known to contribute to these and other adverse birth outcomes, there has been a limited success in developing policies to prevent these outcomes. A better characterization of the complexities between multiple exposures and their biological responses can provide the evidence needed to inform public health policy and strengthen preventative population-level interventions. In order to achieve this, we encourage the establishment of an interdisciplinary data science framework that integrates epidemiology, toxicology and bioinformatics with biomarker-based research to better define how population-level exposures contribute to these adverse birth outcomes. The proposed interdisciplinary research framework would 1) facilitate data-driven analyses using existing data from health registries and environmental monitoring programs; 2) develop novel algorithms with the ability to predict which exposures are driving, in this case, adverse birth outcomes in the context of simultaneous exposures; and 3) refine biomarker-based research, ultimately leading to new policies and interventions to reduce the incidence of adverse birth outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2021.111019DOI Listing
March 2021

Hematopoietic stem cell gene therapy targeting TGFβ enhances the efficacy of irradiation therapy in a preclinical glioblastoma model.

J Immunother Cancer 2021 Mar;9(3)

School of Medicine, University of Leeds, Leeds, UK

Patients with glioblastoma (GBM) have a poor prognosis, and inefficient delivery of drugs to tumors represents a major therapeutic hurdle. Hematopoietic stem cell (HSC)-derived myeloid cells efficiently home to GBM and constitute up to 50% of intratumoral cells, making them highly appropriate therapeutic delivery vehicles. Because myeloid cells are ubiquitously present in the body, we recently established a lentiviral vector containing matrix metalloproteinase 14 (MMP14) promoter, which is active specifically in tumor-infiltrating myeloid cells as opposed to myeloid cells in other tissues, and resulted in a specific delivery of transgenes to brain metastases in HSC gene therapy. Here, we used this novel approach to target transforming growth factor beta (TGFβ) as a key tumor-promoting factor in GBM. Transplantation of HSCs transduced with lentiviral vector expressing green fluorescent protein (GFP) into lethally irradiated recipient mice was followed by intracranial implantation of GBM cells. Tumor-infiltrating HSC progeny was characterized by flow cytometry. In therapy studies, mice were transplanted with HSCs transduced with lentiviral vector expressing soluble TGFβ receptor II-Fc fusion protein under MMP14 promoter. This TGFβ-blocking therapy was compared with the targeted tumor irradiation, the combination of the two therapies, and control. Tumor growth and survival were quantified (statistical significance determined by t-test and log-rank test). T cell memory response was probed through a repeated tumor challenge. Myeloid cells were the most abundant HSC-derived population infiltrating GBM. TGFβ-blocking HSC gene therapy in combination with irradiation significantly reduced tumor burden as compared with monotherapies and the control, and significantly prolonged survival as compared with the control and TGFβ-blocking monotherapy. Long-term protection from GBM was achieved only with the combination treatment (25% of the mice) and was accompanied by a significant increase in CD8+ T cells at the tumor implantation site following tumor rechallenge. We demonstrated a preclinical proof-of-principle for tumor myeloid cell-specific HSC gene therapy in GBM. In the clinic, HSC gene therapy is being successfully used in non-cancerous brain disorders and the feasibility of HSC gene therapy in patients with glioma has been demonstrated in the context of bone marrow protection. This indicates an opportunity for clinical translation of our therapeutic approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957127PMC
March 2021

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.

Acta Neuropathol 2021 05 10;141(5):725-754. Epub 2021 Mar 10.

Department of Neurobiology, Duke University, Durham, NC, USA.

The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (HO) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of HO. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, HO levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; HO levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering HO. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63 lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of HO, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson's-linked neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-021-02285-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043881PMC
May 2021

Genome-wide investigation identifies a rare copy-number variant burden associated with human spina bifida.

Genet Med 2021 Mar 8. Epub 2021 Mar 8.

Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.

Purpose: Next-generation sequencing has implicated some risk variants for human spina bifida (SB), but the genome-wide contribution of structural variation to this complex genetic disorder remains largely unknown. We examined copy-number variant (CNV) participation in the genetic architecture underlying SB risk.

Methods: A high-confidence ensemble approach to genome sequences (GS) was benchmarked and employed for systematic detection of common and rare CNVs in two separate ancestry-matched SB case-control cohorts.

Results: SB cases were enriched with exon disruptive rare CNVs, 44% of which were under 10 kb, in both ancestral populations (P = 6.75 × 10; P = 7.59 × 10). Genes containing these disruptive CNVs fall into molecular pathways, supporting a role for these genes in SB. Our results expand the catalog of variants and genes with potential contribution to genetic and gene-environment interactions that interfere with neurulation, useful for further functional characterization.

Conclusion: This study underscores the need for genome-wide investigation and extends our previous threshold model of exonic, single-nucleotide variation toward human SB risk to include structural variation. Since GS data afford detection of CNVs with greater resolution than microarray methods, our results have important implications toward a more comprehensive understanding of the genetic risk and mechanisms underlying neural tube defect pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01126-9DOI Listing
March 2021

Paternal genetic variants and risk of obstructive heart defects: A parent-of-origin approach.

PLoS Genet 2021 Mar 8;17(3):e1009413. Epub 2021 Mar 8.

Department of Epidemiology, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1009413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971842PMC
March 2021

Proteomic signatures predict preeclampsia in individual cohorts but not across cohorts - implications for clinical biomarker studies.

J Matern Fetal Neonatal Med 2021 Mar 2:1-8. Epub 2021 Mar 2.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Background: Early identification of pregnant women at risk for preeclampsia (PE) is important, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analyses of plasma proteins feature prominently among molecular approaches used for risk prediction. However, derivation of protein signatures of sufficient predictive power has been challenging. The recent availability of platforms simultaneously assessing over 1000 plasma proteins offers broad examinations of the plasma proteome, which may enable the extraction of proteomic signatures with improved prognostic performance in prenatal care.

Objective: The primary aim of this study was to examine the generalizability of proteomic signatures predictive of PE in two cohorts of pregnant women whose plasma proteome was interrogated with the same highly multiplexed platform. Establishing generalizability, or lack thereof, is critical to devise strategies facilitating the development of clinically useful predictive tests. A second aim was to examine the generalizability of protein signatures predictive of gestational age (GA) in uncomplicated pregnancies in the same cohorts to contrast physiological and pathological pregnancy outcomes.

Study Design: Serial blood samples were collected during the first, second, and third trimesters in 18 women who developed PE and 18 women with uncomplicated pregnancies (Stanford cohort). The second cohort (Detroit), used for comparative analysis, consisted of 76 women with PE and 90 women with uncomplicated pregnancies. Multivariate analyses were applied to infer predictive and cohort-specific proteomic models, which were then tested in the alternate cohort. Gene ontology (GO) analysis was performed to identify biological processes that were over-represented among top-ranked proteins associated with PE.

Results: The model derived in the Stanford cohort was highly significant ( = 3.9E-15) and predictive (AUC = 0.96), but failed validation in the Detroit cohort ( = 9.7E-01, AUC = 0.50). Similarly, the model derived in the Detroit cohort was highly significant ( = 1.0E-21, AUC = 0.73), but failed validation in the Stanford cohort ( = 7.3E-02, AUC = 0.60). By contrast, proteomic models predicting GA were readily validated across the Stanford ( = 1.1E-454,  = 0.92) and Detroit cohorts ( = 1.1.E-92,  = 0.92) indicating that the proteomic assay performed well enough to infer a generalizable model across studied cohorts, which makes it less likely that technical aspects of the assay, including batch effects, accounted for observed differences.

Conclusions: Results point to a broader issue relevant for proteomic and other omic discovery studies in patient cohorts suffering from a clinical syndrome, such as PE, driven by heterogeneous pathophysiologies. While novel technologies including highly multiplex proteomic arrays and adapted computational algorithms allow for novel discoveries for a particular study cohort, they may not readily generalize across cohorts. A likely reason is that the prevalence of pathophysiologic processes leading up to the "same" clinical syndrome can be distributed differently in different and smaller-sized cohorts. Signatures derived in individual cohorts may simply capture different facets of the spectrum of pathophysiologic processes driving a syndrome. Our findings have important implications for the design of omic studies of a syndrome like PE. They highlight the need for performing such studies in diverse and well-phenotyped patient populations that are large enough to characterize subsets of patients with shared pathophysiologies to then derive subset-specific signatures of sufficient predictive power.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14767058.2021.1888915DOI Listing
March 2021

Decreased Mortality Rate Among COVID-19 Patients Prescribed Statins: Data From Electronic Health Records in the US.

Front Med (Lausanne) 2021 3;8:639804. Epub 2021 Feb 3.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States.

The severe respiratory illness due to SARS-CoV-2, the virus responsible for coronavirus disease 2019 (COVID-19), is triggered by an intense pro-inflammatory host response. Statins, prescribed primarily for lipid reduction, are known to have anti-inflammatory and immunomodulatory properties and have been associated with a reduced mortality rate among COVID-19 patients taking statins as reported in two recent retrospective studies. However, a meta-analysis that included nine studies showed that statin use did not improve in-hospital outcomes of those with COVID-19. In addition, concerns regarding the use of statins and an increase in COVID-19 infections have been raised, as statins may increase the expression of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the SARS-CoV-2 virus. Our goal was to investigate the effect of statins in COVID-19 patients in a large, diverse patient population across the United States containing nearly 120,000 patients diagnosed with COVID-19. We used propensity score matching of demographics, comorbidities, and medication indication to compare statin-treated patients ( = 2,297) with matched controls ( = 4,594). We observed a small, but statistically significant, decrease in mortality among patients prescribed statins (16.1%) when compared with matched COVID-19-positive controls (18.0 to 20.6%). These results support previous evidence that statins do not increase COVID-19-related mortality and may, in fact, have a mitigating effect on severity of the disease reflected in a slight reduction in mortality. Mixed findings on effects of statins in COVID-19 patients reported in the literature should prompt prospective randomized controlled trials in order to define better who might be advantaged with respect to clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2021.639804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887302PMC
February 2021

Data-Driven Modeling of Pregnancy-Related Complications.

Trends Mol Med 2021 Feb 8. Epub 2021 Feb 8.

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

A healthy pregnancy depends on complex interrelated biological adaptations involving placentation, maternal immune responses, and hormonal homeostasis. Recent advances in high-throughput technologies have provided access to multiomics biological data that, combined with clinical and social data, can provide a deeper understanding of normal and abnormal pregnancies. Integration of these heterogeneous datasets using state-of-the-art machine-learning methods can enable the prediction of short- and long-term health trajectories for a mother and offspring and the development of treatments to prevent or minimize complications. We review advanced machine-learning methods that could: provide deeper biological insights into a pregnancy not yet unveiled by current methodologies; clarify the etiologies and heterogeneity of pathologies that affect a pregnancy; and suggest the best approaches to address disparities in outcomes affecting vulnerable populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmed.2021.01.007DOI Listing
February 2021

Gene-environment interactions between air pollution and biotransformation enzymes and risk of birth defects.

Birth Defects Res 2021 May 10;113(9):676-686. Epub 2021 Feb 10.

Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.

Genetic and environmental factors have been observed to influence risks for birth defects, though few studies have investigated gene-environment interactions. Our aim was to examine the interaction terms of gene variants in biotransformation enzyme pathways and air pollution exposures in relation to risk of several structural birth defects. We evaluated the role of ambient air pollutant exposure (nitrogen dioxide [NO ], nitrogen oxide, carbon monoxide, particulate matter <10 [PM ] and <2.5 [PM ] microns) during pregnancy and 104 gene variants of biotransformation enzymes from infant bloodspots or buccal cells in a California population-based case-control study in 1997-2006. Cases included cleft lip with or without cleft palate (N = 206), gastroschisis (N = 94), tetralogy of Fallot (N = 69), and dextro-transposition of the great arteries (d-TGA; N = 40) and were compared to 208 nonmalformed controls. Overall, the results were not consistent, though did highlight some associations for further investigation as indicated by Wald chi-square test p value <.1. Increased risk of cleft lip was associated with exposure to high PM and two CYP gene variants. High PM and the variant of SLCO1B1 was associated with increased risk of teratology of Fallot. Higher NO and two gene variants, CYP2A6 and SLC01B1, were associated with increased risk of d-TGA. Results for gastroschisis were inconsistent in direction and across pollutants. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of air pollution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdr2.1880DOI Listing
May 2021

Timing of Transfer and Mortality in Neonates with Hypoplastic Left Heart Syndrome in California.

Pediatr Cardiol 2021 Apr 3;42(4):906-917. Epub 2021 Feb 3.

Division of Neonatology and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, USA.

Maternal race/ethnicity is associated with mortality in neonates with hypoplastic left heart syndrome (HLHS). We investigated whether maternal race/ethnicity and other sociodemographic factors affect timing of transfer after birth and whether timing of transfer impacts mortality in infants with HLHS. We linked two statewide databases, the California Perinatal Quality Care Collaborative and records from the Office of Statewide Health Planning and Development, to identify cases of HLHS born between 1/1/06 and 12/31/11. Cases were divided into three groups: birth at destination hospital, transfer on day of life 0-1 ("early transfer"), or transfer on day of life ≥ 2 ("late transfer"). We used log-binomial regression models to estimate relative risks (RR) for timing of transfer and Cox proportional hazard models to estimate hazard ratios (HR) for mortality. We excluded infants who died within 60 days of life without intervention from the main analyses of timing of transfer, since intervention may not have been planned in these infants. Of 556 cases, 107 died without intervention (19%) and another 52 (9%) died within 28 days. Of the 449 included in analyses of timing of transfer, 28% were born at the destination hospital, 49% were transferred early, and 23% were transferred late. Late transfer was more likely for infants of low birthweight (RR 1.74) and infants born to US-born Hispanic (RR 1.69) and black (RR 2.45) mothers. Low birthweight (HR 1.50), low 5-min Apgar score (HR 4.69), and the presence of other major congenital anomalies (HR 3.41), but not timing of transfer, predicted neonatal mortality. Late transfer was more likely in neonates born to US-born Hispanic and black mothers but was not associated with higher mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00246-021-02561-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857096PMC
April 2021

Calcium binds and rigidifies the dysferlin C2A domain in a tightly coupled manner.

Biochem J 2021 01;478(1):197-215

Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1.

The membrane protein dysferlin (DYSF) is important for calcium-activated plasma membrane repair, especially in muscle fibre cells. Nearly 600 mutations in the DYSF gene have been identified that are causative for rare genetic forms of muscular dystrophy. The dysferlin protein consists of seven C2 domains (C2A-C2G, 13%-33% identity) used to recruit calcium ions and traffic accessory proteins and vesicles to injured membrane sites needed to reseal a wound. Amongst these, the C2A is the most prominent facilitating the calcium-sensitive interaction with membrane surfaces. In this work, we determined the calcium-free and calcium-bound structures of the dysferlin C2A domain using NMR spectroscopy and X-ray crystallography. We show that binding two calcium ions to this domain reduces the flexibility of the Ca2+-binding loops in the structure. Furthermore, calcium titration and mutagenesis experiments reveal the tight coupling of these calcium-binding sites whereby the elimination of one site abolishes calcium binding to its partner site. We propose that the electrostatic potential distributed by the flexible, negatively charged calcium-binding loops in the dysferlin C2A domain control first contact with calcium that promotes subsequent binding. Based on these results, we hypothesize that dysferlin uses a 'calcium-catching' mechanism to respond to calcium influx during membrane repair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BCJ20200773DOI Listing
January 2021

Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation.

Front Pediatr 2020 14;8:605219. Epub 2020 Dec 14.

Departments of Bioengineering and Applied Physics, Stanford University, and Chan Zuckerberg Biohub, Stanford, CA, United States.

In recent years, there have been major advances in the application of non-invasive techniques to predict pregnancy-related complications, for example by measuring cell-free RNA (cfRNA) in maternal blood. In contrast to cell-free DNA (cfDNA), which is already in clinical use to diagnose fetal aneuploidy, circulating RNA levels can correspond with tissue-specific gene expression and provide a snapshot of prenatal health across gestation. Here, we review the physiologic origins of cfRNA and its novel applications and corresponding challenges to monitor fetal and maternal health and predict pregnancy-related complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.605219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767905PMC
December 2020

Maternal Exposure to Disinfection By-Products and Risk of Hypospadias in the National Birth Defects Prevention Study (2000-2005).

Int J Environ Res Public Health 2020 12 21;17(24). Epub 2020 Dec 21.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

The purpose of this study was to estimate the association between 2nd and 3rd degree hypospadias and maternal exposure to disinfection by-products (DBPs) using data from a large case-control study in the United States. Concentration estimates for total trihalomethanes (TTHMs), the sum of the five most prevalent haloacetic acids (HAA5), and individual species of each were integrated with data on maternal behaviors related to water use from the National Birth Defects Prevention Study (NBDPS) to create three different exposure metrics: (1) household DBP concentrations; (2) estimates of DBP ingestion; (3) predicted uptake (i.e., internal dose) of trihalomethanes (THMs) via ingestion, showering, and bathing. The distribution of DBP exposure was categorized as follows: (Q1/referent) < 50%; (Q2) ≥ 50% to < 75%; and (Q3) ≥ 75%. Logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Generally, null associations were observed with increasing TTHM or HAA5 exposure. An increased risk was observed among women with household bromodichloromethane levels in the second quantile (aOR: 1.8; 95% CI: 1.2, 2.7); however, this association did not persist after the inclusion of individual-level water-use data. Findings from the present study do not support the hypothesis that maternal DBP exposures are related to the occurrence of hypospadias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph17249564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766973PMC
December 2020

Early prediction of preeclampsia via machine learning.

Am J Obstet Gynecol MFM 2020 05 14;2(2):100100. Epub 2020 Mar 14.

Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA.

Background: Early prediction of preeclampsia is challenging because of poorly understood causes, various risk factors, and likely multiple pathogenic phenotypes of preeclampsia. Statistical learning methods are well-equipped to deal with a large number of variables, such as patients' clinical and laboratory data, and to select the most informative features automatically.

Objective: Our objective was to use statistical learning methods to analyze all available clinical and laboratory data that were obtained during routine prenatal visits in early pregnancy and to use them to develop a prediction model for preeclampsia.

Study Design: This was a retrospective cohort study that used data from 16,370 births at Lucile Packard Children Hospital at Stanford, CA, from April 2014 to January 2018. Two statistical learning algorithms were used to build a predictive model: (1) elastic net and (2) gradient boosting algorithm. Models for all preeclampsia and early-onset preeclampsia (<34 weeks gestation) were fitted with the use of patient data that were available at <16 weeks gestational age. The 67 variables that were considered in the models included maternal characteristics, medical history, routine prenatal laboratory results, and medication intake. The area under the receiver operator curve, true-positive rate, and false-positive rate were assessed via cross-validation.

Results: Using the elastic net algorithm, we developed a prediction model that contained a subset of the most informative features from all variables. The obtained prediction model for preeclampsia yielded an area under the curve of 0.79 (95% confidence interval, 0.75-0.83), sensitivity of 45.2%, and false-positive rate of 8.1%. The prediction model for early-onset preeclampsia achieved an area under the curve of 0.89 (95% confidence interval, 0.84-0.95), true-positive rate of 72.3%, and false-positive rate of 8.8%.

Conclusion: Statistical learning methods in a retrospective cohort study automatically identified a set of significant features for prediction and yielded high prediction performance for preeclampsia risk from routine early pregnancy information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajogmf.2020.100100DOI Listing
May 2020

Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.

JAMA Netw Open 2020 12 1;3(12):e2029655. Epub 2020 Dec 1.

Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.

Importance: Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies.

Objective: To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB.

Design, Setting, And Participants: This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019.

Exposures: Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites.

Main Outcomes And Measures: The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation.

Results: Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways.

Conclusions And Relevance: This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.29655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749442PMC
December 2020

Association between preconception paternal health and pregnancy loss in the USA: an analysis of US claims data.

Hum Reprod 2021 Feb;36(3):785-793

Department of Urology, Stanford University School of Medicine, Stanford, CA 94305-5118, USA.

Study Question: Is preconception paternal health associated with pregnancy loss?

Summary Answer: Poor preconception paternal health is associated with a higher risk of pregnancy loss as confirmed in sensitivity analyses accounting for maternal age and health.

What Is Known Already: Preconception paternal health can negatively impact perinatal outcomes.

Study Design, Size, Duration: Retrospective cohort study of US insurance claims database from 2009 to 2016 covering 958 804 pregnancies.

Participants/materials, Setting, Methods: US insurance claims database including women, men and pregnancies within the USA between 2007 and 2016. Paternal preconception health status (e.g. metabolic syndrome diagnoses (MetS), Charlson comorbidity index (CCI) and individual chronic disease diagnoses) was examined in relation to pregnancy loss (e.g. ectopic pregnancy, miscarriage and stillbirth).

Main Results And The Role Of Chance: In all, 958 804 pregnancies were analyzed. The average paternal age was 35.3 years (SD 5.3) and maternal age was 33.1 years (SD 4.4). Twenty-two percent of all pregnancies ended in a loss. After adjusting for maternal factors, the risk of pregnancy loss increased with increasing paternal comorbidity. For example, compared to men with no components of MetS, the risk of pregnancy loss increased for men with one (relative risk (RR) 1.10, 95% CI 1.09-1.12), two (RR 1.15, 95% CI 1.13-1.17) or three or more (RR 1.19, 95% CI 1.14-1.24) components. Specifically, less healthy men had a higher risk of siring a pregnancy ending in spontaneous abortion, stillbirth and ectopic pregnancies. Similar patterns remained with other measures of paternal health (e.g. CCI, chronic diseases, etc.). When stratifying by maternal age as well as maternal health, a similar pattern of increasing pregnancy loss risk for men with 1, 2 or 3+ MetS was observed. A statistically significant but weak association between timing of pregnancy loss and paternal health was found.

Limitations, Reasons For Caution: Retrospective study design covering only employer insured individuals may limit generalizability.

Wider Implications Of The Findings: Optimization of a father's health may improve pregnancy outcomes.

Study Funding/competing Interests: National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085). M.L.E. is an advisor for Sandstone Diagnostics, Dadi, Hannah and Underdog. No other competing interests were declared.

Trial Registration Number: N/A.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/humrep/deaa332DOI Listing
February 2021

Residential proximity to green space and preeclampsia in California.

Environ Epidemiol 2020 Dec 21;4(6):e120. Epub 2020 Oct 21.

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, California.

Background: We investigated whether residing near more green space might reduce the risk of preeclampsia.

Methods: Participants were women who delivered a live, singleton birth between 1998 and 2011 in eight counties of the San Joaquin Valley in California. There were 7276 cases of preeclampsia divided into mild, severe, or superimposed on preexisting hypertension. Controls were 197,345 women who did not have a hypertensive disorder and delivered between 37 and 41 weeks. Green space was estimated from satellite data using Normalized Difference Vegetation Index (NDVI), an index calculated from surface reflectance at the visible and near-infrared wavelengths. Values closer to 1 denote a higher density of green vegetation. Average NDVI was calculated within a 50 m, 100 m, and 500 m buffer around each woman's residence. Odds ratios and 95% confidence intervals were estimated comparing the lowest and highest quartiles of mean NDVI to the interquartile range comparing each preeclampsia phenotype, divided into early (20-31 weeks) and late (32-36 weeks) preterm birth, to full-term controls.

Results: We observed an inverse association in the 500 m buffer for women in the top quartile of NDVI and a positive association for women in the lowest quartile of NDVI for women with superimposed preeclampsia. There were no associations in the 50 and 100 m buffers.

Conclusion: Within a 500 m buffer, more green space was inversely associated with superimposed preeclampsia. Future work should explore the mechanism by which green space may protect against preeclampsia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/EE9.0000000000000120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727466PMC
December 2020

Integration of mechanistic immunological knowledge into a machine learning pipeline improves predictions.

Nat Mach Intell 2020 Oct 12;2(10):619-628. Epub 2020 Oct 12.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.

The dense network of interconnected cellular signalling responses that are quantifiable in peripheral immune cells provides a wealth of actionable immunological insights. Although high-throughput single-cell profiling techniques, including polychromatic flow and mass cytometry, have matured to a point that enables detailed immune profiling of patients in numerous clinical settings, the limited cohort size and high dimensionality of data increase the possibility of false-positive discoveries and model overfitting. We introduce a generalizable machine learning platform, the immunological Elastic-Net (iEN), which incorporates immunological knowledge directly into the predictive models. Importantly, the algorithm maintains the exploratory nature of the high-dimensional dataset, allowing for the inclusion of immune features with strong predictive capabilities even if not consistent with prior knowledge. In three independent studies our method demonstrates improved predictions for clinically relevant outcomes from mass cytometry data generated from whole blood, as well as a large simulated dataset. The iEN is available under an open-source licence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42256-020-00232-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720904PMC
October 2020

Parental age and preterm birth: a population-based cohort of nearly 3 million California livebirths from 2007 to 2012.

J Perinatol 2020 Dec 8. Epub 2020 Dec 8.

Departments of Urology and Obstetrics/Gynecology, Stanford University School of Medicine, Stanford, CA, USA.

Purpose: To assess the relationships between parental ages and preterm birth subtypes.

Methods: A population-based cohort analysis of California livebirths 2007-2012. Associations between maternal and paternal age with spontaneous and medically indicated preterm birth were estimated from Cox proportional hazard models. Parental age was modeled with restricted cubic splines to account for nonlinear relationships.

Results: Young paternal age was associated with increased hazard ratios for spontaneous and medically indicated preterm birth. Older fathers showed elevated hazards for preterm birth in crude analysis but after adjustment the relationship was generally not observed. Aging mothers showed increased hazard ratios for both preterm birth phenotypes.

Conclusions: After adjusting for parental demographics, births to younger fathers and older mothers had the highest risks for spontaneous preterm birth. The paternal influence on preterm birth was observed to be independent of maternal factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41372-020-00894-7DOI Listing
December 2020