Newborn screening analytes and structural birth defects among 27,000 newborns.

BACKGROUND: Emerging evidence suggests newborn screening analytes may yield insights into the etiologies of birth defects, yet no effort has evaluated associations between a range of newborn screening analytes and birth defects. METHODS: This population-based study pooled statewide data on birth defects, birth certificates, and newborn screening analytes from Texas occurring between January 1, 2007 and December 31, 2009. Associations between a panel of thirty-six newborn screening analytes, collected by the statewide Texas Newborn Screening Program, and the presence of a birth defect, defined as at least one of 39 birth defects diagnoses recorded by the Texas Birth Defects Registry, were assessed using regression analysis. FINDINGS: Of the 27,643 births identified, 20,205 had at least one of the 39 birth defects of interest (cases) as identified by the Texas Birth Defects Registry, while 7,438 did not have a birth defect (controls). Among 1,404 analyte-birth defect associations evaluated, 377 were significant in replication analysis. Analytes most consistently associated with birth defects included the phenylalanine/tyrosine ratio (N = 29 birth defects), tyrosine (N = 28 birth defects), and thyroxine (N = 25 birth defects). Birth defects most frequently associated with a range of analytes included gastroschisis (N = 29 analytes), several cardiovascular defects (N = 26 analytes), and spina bifida (N = 23 analytes). CONCLUSIONS: Several significant and novel associations were observed between newborn screening analytes and birth defects. While some findings could be consequences of the defects themselves or to the care provided to infants with these defects, these findings could help to elucidate mechanisms underlying the etiology of some birth defects.

Factors associated with infant sex and preterm birth status for selected birth defects from the National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Birth defects and preterm birth co-occur, with some overlapping risk factors. Many birth defects and preterm births tend to have a male preponderance. We explored potential risk factors impacting sex and preterm (<37 weeks of gestation) birth differences among infants with selected birth defects delivered from 1997 to 2011 using data from the National Birth Defects Prevention Study (NBDPS). METHODS: The NBDPS was a large multisite, population-based case-control study. Using random forests, we identified important predictors of male preterm, female preterm, and male term, each compared with female term births for each birth defect. Using logistic regression, we estimated odds ratios for associations between important predictors and sex-preterm birth status by birth defect. RESULTS: We examined 11,379 infants with nine specific birth defects. The top 10 most important predictors of sex-preterm birth status from the random forests varied greatly across the birth defects and sex-preterm comparisons within a given defect group, with several being novel factors. However, one consistency was that short interpregnancy interval was associated with sex-preterm birth status for many of the studied birth defects. Although obesity has been identified as a risk factor for preterm birth and birth defects in other research, it was not associated with sex-preterm birth status for any of the examined defects. CONCLUSIONS: We confirmed expected associations for sex-preterm birth status differences and found new potential risk factors for further exploration among the studied birth defects.

The Effect of Postpartum Depressive Symptoms (PDS) on Maternal Health Practices After Childbirth, Texas Pregnancy Risk Assessment Monitoring System, 2012-2015.

OBJECTIVES: This study examined the contribution of postpartum depressive symptoms (PDS) on select maternal health practices among Texas women, using 2012-2015 survey data from the Pregnancy Risk Assessment Monitoring System. METHODS: Multiple logistic regression was used to assess the effect of PDS on postpartum checkups, postpartum dental visits, and use of postpartum birth control. Covariates included maternal age, race/ethnicity, marital status, education, and depression before birth. RESULTS: Data from 4679 respondents were used in analyses, and the prevalence of women reporting PDS was 13.8 percent. Women without PDS were more likely to attend a postpartum checkup (adjusted OR = 1.5; 95% CI 1.1-2.1) or have a postpartum dental visit (adjusted OR = 1.4, 95% CI 1.0-1.8) than women with PDS. There was insufficient evidence to conclude any association between PDS and use of postpartum birth control. CONCLUSIONS: These findings highlight adverse effects of PDS on maternal health practices not previously studied. Results stress the importance of healthcare professionals monitoring the moods and actions of women of childbearing age to provide early interventions for women experiencing PDS, and of emphasizing positive maternal health practices after childbirth.

Identifying Maternal Deaths in Texas Using an Enhanced Method, 2012.

OBJECTIVE: To more accurately estimate the 2012 maternal mortality ratio for Texas using an enhanced method for identifying maternal deaths. METHODS: This population-based descriptive study used both data matching and record review to verify pregnancy or delivery within 42 days for 147 deaths with obstetric cause-of-death codes, and used data matching alone to identify additional maternal deaths within the same timeframe. Crude maternal mortality ratios were calculated for confirmed maternal deaths overall, by race and ethnicity, and by age. These maternal mortality ratios were compared with maternal mortality ratios computed using obstetric cause-of-death codes alone (standard method). RESULTS: Fifty-six maternal deaths were confirmed to have occurred during pregnancy or within 42 days postpartum. Using our enhanced method, the 2012 maternal mortality ratio for Texas was 14.6 maternal deaths per 100,000 live births, less than half that obtained using the standard method (n=147). Approximately half (50.3%) of obstetric-coded deaths showed no evidence of pregnancy within 42 days, and a large majority of these incorrectly indicated pregnancy at the time of death. Insufficient information was available to determine pregnancy for 15 obstetric-coded deaths, which were excluded from the 2012 maternal mortality ratio estimate; however, had these deaths been included, the resulting maternal mortality ratio would still be significantly lower than that reported using the standard method. CONCLUSION: Relying solely on obstetric codes for identifying maternal deaths appears to be insufficient and can lead to inaccurate maternal mortality ratios. A method enhanced with data matching and record review yields more accurate ratios. Results likely have national implications, because miscoding of obstetric deaths with the standard method may affect the accuracy of other states' maternal mortality ratios.

Family-based exome-wide association study of childhood acute lymphoblastic leukemia among Hispanics confirms role of ARID5B in susceptibility.

We conducted an exome-wide association study of childhood acute lymphoblastic leukemia (ALL) among Hispanics to confirm and identify novel variants associated with disease risk in this population. We used a case-parent trio study design; unlike more commonly used case-control studies, this study design is ideal for avoiding issues with population stratification bias among this at-risk ethnic group. Using 710 individuals from 323 Guatemalan and US Hispanic families, two inherited SNPs in ARID5B reached genome-wide level significance: rs10821936, RR = 2.31, 95% CI = 1.70-3.14, p = 1.7×10-8 and rs7089424, RR = 2.22, 95% CI = 1.64-3.01, p = 5.2×10-8. Similar results were observed when restricting our analyses to those with the B-ALL subtype: ARID5B rs10821936 RR = 2.22, 95% CI = 1.63-3.02, p = 9.63×10-8 and ARID5B rs7089424 RR = 2.13, 95% CI = 1.57-2.88, p = 2.81×10-7. Notably, effect sizes observed for rs7089424 and rs10821936 in our study were >20% higher than those reported among non-Hispanic white populations in previous genetic association studies. Our results confirmed the role of ARID5B in childhood ALL susceptibility among Hispanics; however, our assessment did not reveal any strong novel inherited genetic risks for acute lymphoblastic leukemia among this ethnic group.

Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case-Control and Family-Based Studies in Multiethnic Populations.

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, suggesting that germline variants influence ALL risk. Although multiple genome-wide association (GWA) studies have identified variants predisposing children to ALL, it remains unclear whether genetic heterogeneity affects ALL susceptibility and how interactions within and among genes containing ALL-associated variants influence ALL risk.Methods: Here, we jointly analyzed two published datasets of case-control GWA summary statistics along with germline data from ALL case-parent trios. We used the gene-level association method PEGASUS to identify genes with multiple variants associated with ALL. We then used PEGASUS gene scores as input to the network analysis algorithm HotNet2 to characterize the genomic architecture of ALL.Results: Using PEGASUS, we confirmed associations previously observed at genes such as ARID5B, IKZF1, CDKN2A/2B, and PIP4K2A, and we identified novel candidate gene associations. Using HotNet2, we uncovered significant gene subnetworks that may underlie inherited ALL risk: a subnetwork involved in B-cell differentiation containing the ALL-associated gene CEBPE, and a subnetwork of homeobox genes, including MEIS1Conclusions: Gene and network analysis uncovered loci associated with ALL that are missed by GWA studies, such as MEIS1 Furthermore, ALL-associated loci do not appear to interact directly with each other to influence ALL risk, and instead appear to influence leukemogenesis through multiple, complex pathways.Impact: We present a new pipeline for post hoc analysis of association studies that yields new insight into the etiology of ALL and can be applied in future studies to shed light on the genomic underpinnings of cancer. Cancer Epidemiol Biomarkers Prev; 26(10); 1531-9. ©2017 AACR.

Maternal Mortality in Texas.

A commentary on maternal mortality in Texas is provided in response to a 2016 article in Obstetrics & Gynecology by MacDorman et al. While the Texas Department of State Health Services and the Texas Maternal Mortality and Morbidity Task Force agree that maternal mortality increased sharply from 2010 to 2011, the percentage change or the magnitude of the increase in the maternal mortality rate in Texas differs depending on the statistical methods used to compute and display it. Methodologic challenges in identifying maternal death are also discussed, as well as risk factors and causes of maternal death in Texas. Finally, several state efforts currently underway to address maternal mortality in Texas are described.

Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in hispanics.

BACKGROUND: Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) compared with other ethnic groups, but to the authors' knowledge, the genetic basis for these racial disparities remain incompletely understood. Genome-wide association studies of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of the maternal genotype on phenotype development in the offspring) also may play a role in ALL susceptibility. METHODS: The authors conducted a family-based exome-wide association study of maternal genetic effects among Hispanics with childhood B-cell ALL using the Illumina Infinium HumanExome BeadChip. A discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families were used. RESULTS: Three maternal single-nucleotide polymorphisms (SNPs) approached the study threshold for significance after correction for multiple testing (P<1.0 × 10-6 ): MTL5 rs12365708 (testis expressed metallothionein-like protein [tesmin]) (relative risk [RR], 2.62; 95% confidence interval [95% CI], 1.61-4.27 [P = 1.8 × 10-5 ]); ALKBH1 rs6494 (AlkB homolog 1, histone H2A dioxygenase) (RR, 3.77; 95% CI, 1.84-7.74 [P = 3.7 × 10-5 ]); and NEUROG3 rs4536103 (neurogenin 3) (RR, 1.75; 95% CI, 1.30-2.37 [P = 1.2 × 10-4 ]). Although effect sizes were similar, these SNPs were not nominally significant in the replication cohort in the current study. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not found to be statistically significant after correction for multiple comparisons (rs12365708: pooled RR, 2.27 [95% CI, 1.48-3.50], P = 1.99 × 10-4 ; rs6494: pooled RR, 2.31 [95% CI, 1.38-3.85], P = .001; and rs4536103: pooled RR, 1.67 [95% CI, 1.29-2.16] P = 9.23 × 10-5 ). CONCLUSIONS: In what to the authors' knowledge is the first family-based based exome-wide association study to investigate maternal genotype effects associated with childhood ALL, the results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, 3 maternal SNPs were identified that may play a modest role in susceptibility. Cancer 2016;122:3697-704. © 2016 American Cancer Society.

Fluoride exposure in public drinking water and childhood and adolescent osteosarcoma in Texas.

PURPOSE: The purpose of this study was to examine the association between fluoride levels in public drinking water and childhood and adolescent osteosarcoma in Texas; to date, studies examining this relationship have been equivocal. Using areas with high and low naturally occurring fluoride, as well as areas with optimal fluoridation, we examined a wide range of fluoride levels in public drinking water. METHODS: This was a population-based case-control study, with both cases and controls obtained from the Texas Cancer Registry. Eligible cases were Texas children and adolescents <20 years old diagnosed with osteosarcoma between 1996 and 2006. Controls were sampled from children and adolescents diagnosed with either central nervous system (CNS) tumors or leukemia during the same time frame. Using geocoded patient addresses at the time of diagnosis, we estimated patients' drinking water fluoride exposure levels based on the fluoride levels of their residence's public water system (PWS). Unconditional logistic regression models were used to assess the association between osteosarcoma and public drinking water fluoride level, adjusting for several demographic risk factors. RESULTS: Three hundred and eight osteosarcoma cases, 598 leukemia controls, and 604 CNS tumor controls met selection criteria and were assigned a corresponding PWS fluoride level. PWS fluoride level was not associated with osteosarcoma, either in a univariable analysis or after adjusting for age, sex, race, and poverty index. Stratified analyses by sex were conducted; no association between PWS fluoride level and osteosarcoma was observed among either males or females. CONCLUSIONS: No relationship was found between fluoride levels in public drinking water and childhood/adolescent osteosarcoma in Texas.

Relationship between vapor intrusion and human exposure to trichloroethylene.

Trichloroethylene (TCE) in groundwater has the potential to volatilize through soil into indoor air where it can be inhaled. The purpose of this study was to determine whether individuals living above TCE-contaminated groundwater are exposed to TCE through vapor intrusion. We examined associations between TCE concentrations in various environmental media and TCE concentrations in residents. For this assessment, indoor air, outdoor air, soil gas, and tap water samples were collected in and around 36 randomly selected homes; blood samples were collected from 63 residents of these homes. Additionally, a completed exposure survey was collected from each participant. Environmental and blood samples were analyzed for TCE. Mixed model multiple linear regression analyses were performed to determine associations between TCE in residents' blood and TCE in indoor air, outdoor air, and soil gas. Blood TCE concentrations were above the limit of quantitation (LOQ; ≥ 0.012 µg L(-1)) in 17.5% of the blood samples. Of the 36 homes, 54.3%, 47.2%, and >84% had detectable concentrations of TCE in indoor air, outdoor air, and soil gas, respectively. Both indoor air and soil gas concentrations were statistically significantly positively associated with participants' blood concentrations (P = 0.0002 and P = 0.04, respectively). Geometric mean blood concentrations of residents from homes with indoor air concentrations of >1.6 µg m(-3) were approximately 50 times higher than geometric mean blood TCE concentrations in participants from homes with no detectable TCE in indoor air (P < .0001; 95% CI 10.4-236.4). This study confirms the occurrence of vapor intrusion and demonstrates the magnitude of exposure from vapor intrusion of TCE in a residential setting.

Genetic, psychosocial, and demographic factors associated with social disinhibition in Mexican-origin youth.

INTRODUCTION: The genetic heritability for sensation-seeking tendencies ranges from 40 to 60%. Sensation-seeking behaviors typically manifest during adolescence and are associated with alcohol and cigarette experimentation in adolescents. Social disinhibition is an aspect of sensation-seeking that is closely tied to cigarette and alcohol experimentation. METHODS: We examined the contribution of candidate genes to social disinhibition among 1132 Mexican origin youth in Houston, Texas, adjusting for established demographic and psychosocial risk factors. Saliva samples were obtained at baseline in 2005-06, and social disinhibition and other psychosocial data were obtained in 2008-09. Participants were genotyped for 672 functional and tagging SNPs potentially related to sensation-seeking, risk-taking, smoking, and alcohol use. RESULTS: Six SNPs were significantly associated with social disinhibition scores, after controlling for false discovery and adjusting for population stratification and relevant demographic/psychosocial characteristics. Minor alleles for three of the SNPs (rs1998220 on OPRM1; rs9534511 on HTR2A; and rs4938056 on HTR3B) were associated with increased risk of social disinhibition, while minor alleles for the other three SNPs (rs1003921 on KCNC1; rs16116 downstream of NPY; and rs16870286 on LINC00518) exhibited a protective effect. Age, linguistic acculturation, thrill and adventure-seeking, and drug and alcohol-seeking were all significantly positively associated with increased risk of social disinhibition in a multivariable model (P < 0.001). CONCLUSIONS: These results add to our knowledge of genetic risk factors for social disinhibition. Additional research is needed to verify whether these SNPs are associated with social disinhibition among youth of different ethnicities and nationalities, and to elucidate whether and how these SNPs functionally contribute to social disinhibition.

Prevalence of amyotrophic lateral sclerosis in Texas, 1998-2003.

A prevalence study of amyotrophic lateral sclerosis (ALS) was conducted in 3 areas in Texas to enable the state health department to better respond to community concerns regarding the occurrence of ALS and to contribute to national prevalence estimates. The overall ALS point prevalence was lower than previously published US estimates. This study provides ALS prevalence estimates for Texas, including Hispanic populations.

Relationship between prenatal lead exposure and infant blood lead levels.

Recent literature has shown that analyzing newborn dried blood spots (DBS) may be effective in assessing some prenatal environmental exposures, such as exposure to lead. The purpose of this study was to evaluate the relationship between prenatal exposure to lead (as measured by newborn DBS results) and blood lead levels (BLLs) in infants 6 months of age or younger, using public health registry data for infants born in Texas from July 2002 through July 2006. The Texas Child Lead Registry (TCLR) was used to identify infants with documented elevated BLLs of 10 µg/dL or higher as well as infants with documented low BLLs. BLLs for these children were compared to their corresponding newborn DBS results using Pearson correlation coefficients and exact logistic regression models. Overall, a significant but weak positive correlation was found between infant BLLs and corresponding newborn DBS lead levels (r = 0.48). However, the odds of an infant with an elevated newborn DBS lead level having an elevated BLL at 6 months of age or younger were much greater than for an infant with a low newborn DBS lead level of <5 µg/dL (adjusted odds ratio 27.95, 95% CI: 5.52-277.28). Although an association was observed between newborn DBS lead levels and BLLs in infants tested between 0 to 6 months of age, our findings suggest that prenatal exposure may not be the only significant source of lead exposure for infants ≤6 months of age.

Updated prevalence estimates of multiple sclerosis in Texas, 1998 to 2003.

The Texas Department of State Health Services extended a prevalence study of multiple sclerosis (MS) in a 19-county area in North Texas to include 3 additional years of data and included a new geographic area with a predominantly Hispanic population (El Paso County). Patients in whom MS was diagnosed by a neurologist, who resided in the study areas, and who had an office visit between 1998 and 2003 were included in the study. The 6-year MS prevalence estimate for the North Texas counties was 71.5 per 100,000, and for El Paso County it was 49.4 per 100,000. In both areas, prevalence estimates were higher for females, age groups 40 to 49 and 50 to 59, and for non-Hispanic whites. These estimates provide valuable information about the epidemiology of MS in Texas and allow for a comparison with national estimates. The results also provide much needed prevalence data for the Hispanic population.

Association of paternal age with prevalence of selected birth defects.

BACKGROUND: Unlike maternal age, the effect of paternal age on birth defect prevalence has not been well examined. We used cases from the Texas birth defect registry, born during 1996-2002, to evaluate the association of paternal age with the prevalence of selected structural birth defects. METHODS: Poisson regression was used to calculate prevalence ratios (PRs) and 95% confidence intervals (CIs) associated with paternal age for each birth defect, adjusting for maternal age, race/ethnicity, and parity. RESULTS: Relative to fathers ages 25-29 years, fathers 20-24 years of age were more likely to have offspring with gastroschisis (PR 1.47, 95% CI: 1.12-1.94), and fathers 40+ years old were less likely to have offspring with trisomy 13 (PR 0.40, 95% CI: 0.16-0.96). No association was seen between paternal age and prevalence of anencephaly and encephalocele. A selection bias was observed for the other birth defects in which cases of younger fathers were more often excluded from study. CONCLUSIONS: In studies of birth defect risk and paternal age, the source of information may affect the validity of findings.

Linking teratogen information service and birth defects registry databases to improve knowledge of birth defect status.

BACKGROUND: Although teratogen information services (TISs) obtain maternal exposure information from their callers, such services often do not know if the pregnancies were affected by a birth defect. This study attempted to improve the completeness of this information for Texas Teratogen Information Service (TTIS) callers by linking their records with the Texas Birth Defects Registry (TBDR) and Texas birth certificates (TBCs). METHODS: A total of 344 expectant mothers called TTIS with expected dates of delivery between 1 January 2000 and 31 December 2001. These pregnancies were linked with TBDR and TBC data. The percentages of pregnancies with known birth defect information both before and after the linkage were compared. RESULTS: The TTIS originally collected birth defect status information for 101 of the 344 callers (29.4%) and 0.6% of all 344 callers or 2.0% of callers with birth defect status information had a pregnancy affected by a birth defect. Linking TTIS records with TBDR and TBC data helped to raise the percentage of callers with birth defect status information from 29.4% to 71.5%. Among those callers, the percentage known to have birth defects increased from 2.0% to 4.1%. The sensitivity of TTIS follow-up calls in identifying birth defects was 50%, and the specificity was 100%. CONCLUSIONS: Linking TTIS caller records with TBDR and TBC data significantly increased both the percentage of pregnancies with birth defect status information and the percentage of pregnancies identified as affected by birth defects. Such linkage may be a good approach by which TISs can increase the completeness of their birth defect status information.