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Supplementary Figure 2

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 MEIS1.Conclusions: 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.

Supplementary Tables S1-S8 and Supplementary Figure Legends.

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Supplementary Figure 3

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.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.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.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.

To more accurately estimate the 2012 maternal mortality ratio for Texas using an enhanced method for identifying maternal deaths.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).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.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.

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 MEIS1. Conclusions: 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.

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

ObjectiveThe study aimed to examine nutrition label use and dietary behaviours among ethnically diverse middle- and high-school students, in Texas, USA.DesignThe School Physical Activity and Nutrition (SPAN) survey is a cross-sectional statewide study using a self-administered questionnaire to assess nutrition and physical activity behaviours. Height and weight measurements were used to determine BMI. Multivariable logistic regression was used to determine associations between nutrition label use and dietary behaviours, with gender, grade, ethnicity, BMI, parent education, socio-economic status and nutrition knowledge as covariates.SettingParticipants from 283 schools, weighted to represent Texas youth.SubjectsSPAN 2009–2011 included 6716 8th and 11th graders (3465 girls and 3251 boys). The study population consisted of 39·83 % White/Other, 14·61 % African-American and 45·56 % Hispanic adolescents; with a mean age of 14·9 years, and 61·95 % at a healthy weight, 15·71 % having overweight and 22·34 % having obesity.ResultsAdolescents who did not use nutrition labels had 1·69 times greater odds of consuming ≥1 sugary beverages/d (PPPConclusionsNutrition label use is associated with healthier dietary behaviours in adolescents. Intervention strategies for youth should include efforts to teach adolescents to use labels to make healthy food choices.

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.

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.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.Three maternal single-nucleotide polymorphisms (SNPs) approached the study threshold for significance after correction for multiple testing (P1.0 × 10In 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.

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

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. Birth Defects Research (Part A) 2007. © 2006 Wiley-Liss, Inc.

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. 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

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.

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.

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.

Purpose The objective of this study was to examine the associations between paternal age and birth defects of unknown etiologies while carefully controlling for maternal age. Methods By using 1997 to 2004 data from the National Birth Defects Prevention Study, we fit logistic regression models with paternal and maternal age as continuous variables while adjusting for demographic and other factors. Results Elevated odds ratios (ORs) for each year increase in paternal age were found for cleft palate (OR. 1.02, 95% confidence interval [95% CI], 1.00–1.04), diaphragmatic hernia (OR, 1.04; 95% CI, 1.02–1.06), right ventricular outflow tract obstruction (OR, 1.03; 95% CI, 1.01–1.04), and pulmonary valve stenosis (OR, 1.02, 95% CI, 1.01–1.04). At younger paternal ages, each year increase in paternal age correlated with increased odds of having offspring with encephalocele, cataract, esophageal atresia, anomalous pulmonary venous return, and coarctation of the aorta, but these increased odds were not observed at older paternal ages. The effect of paternal age was modified by maternal age for gastroschisis, omphalocele, spina bifida, all orofacial clefts, and septal heart defects. Conclusions Our findings suggest that paternal age may be a risk factor for some multifactorial birth defects.

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.

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.