Gene-based association tests in family samples using GWAS summary statistics.

Genome-wide association studies (GWAS) have led to rapid growth in detecting genetic variants associated with various phenotypes. Owing to a great number of publicly accessible GWAS summary statistics, and the difficulty in obtaining individual-level genotype data, many existing gene-based association tests have been adapted to require only GWAS summary statistics rather than individual-level data. However, these association tests are restricted to unrelated individuals and thus do not apply to family samples directly. Moreover, due to its flexibility and effectiveness, the linear mixed model has been increasingly utilized in GWAS to handle correlated data, such as family samples. However, it remains unknown how to perform gene-based association tests in family samples using the GWAS summary statistics estimated from the linear mixed model. In this study, we show that, when family size is negligible compared to the total sample size, the diagonal block structure of the kinship matrix makes it possible to approximate the correlation matrix of marginal Z scores by linkage disequilibrium matrix. Based on this result, current methods utilizing summary statistics for unrelated individuals can be directly applied to family data without any modifications. Our simulation results demonstrate that this proposed strategy controls the type 1 error rate well in various situations. Finally, we exemplify the usefulness of the proposed approach with a dental caries GWAS data set.

Malachite green: a long-buried water-soluble AIEgen with near-infrared fluorescence for living cell nucleus staining.

Fluorescent imaging probes are crucial for exploring nucleus-related cellular events in live cells. Ideal probes should be photostable, small-sized, highly contrasted, and low in background. Here, we discovered that malachite green is a water-soluble near-infrared luminogen with aggregation-induced emission properties. Importantly, it can be used for living cell nucleus staining in a wash-free manner.

Contaminant Organism Growth in Febrile Infants at Low Risk for Invasive Bacterial Infection.

In this multicenter, cross-sectional, secondary analysis of 4042 low-risk febrile infants, nearly 10% had a contaminated culture obtained during their evaluation (4.9% of blood cultures, 5.0% of urine cultures, and 1.8% of cerebrospinal fluid cultures). Our findings have important implications for improving sterile technique and reducing unnecessary cultures.

Race, Ethnicity, Language, and the Treatment of Low-Risk Febrile Infants.

Importance: Febrile infants at low risk of invasive bacterial infections are unlikely to benefit from lumbar puncture, antibiotics, or hospitalization, yet these are commonly performed. It is not known if there are differences in management by race, ethnicity, or language. Objective: To investigate associations between race, ethnicity, and language and additional interventions (lumbar puncture, empirical antibiotics, and hospitalization) in well-appearing febrile infants at low risk of invasive bacterial infection. Design, Setting, and Participants: This was a multicenter retrospective cross-sectional analysis of infants receiving emergency department care between January 1, 2018, and December 31, 2019. Data were analyzed from December 2022 to July 2023. Pediatric emergency departments were determined through the Pediatric Emergency Medicine Collaborative Research Committee. Well-appearing febrile infants aged 29 to 60 days at low risk of invasive bacterial infection based on blood and urine testing were included. Data were available for 9847 infants, and 4042 were included following exclusions for ill appearance, medical history, and diagnosis of a focal infectious source. Exposures: Infant race and ethnicity (non-Hispanic Black, Hispanic, non-Hispanic White, and other race or ethnicity) and language used for medical care (English and language other than English). Main Outcomes and Measures: The primary outcome was receipt of at least 1 of lumbar puncture, empirical antibiotics, or hospitalization. We performed bivariate and multivariable logistic regression with sum contrasts for comparisons. Individual components were assessed as secondary outcomes. Results: Across 34 sites, 4042 infants (median [IQR] age, 45 [38-53] days; 1561 [44.4% of the 3516 without missing sex] female; 612 [15.1%] non-Hispanic Black, 1054 [26.1%] Hispanic, 1741 [43.1%] non-Hispanic White, and 352 [9.1%] other race or ethnicity; 3555 [88.0%] English and 463 [12.0%] language other than English) met inclusion criteria. The primary outcome occurred in 969 infants (24%). Race and ethnicity were not associated with the primary composite outcome. Compared to the grand mean, infants of families that use a language other than English had higher odds of the primary outcome (adjusted odds ratio [aOR]; 1.16; 95% CI, 1.01-1.33). In secondary analyses, Hispanic infants, compared to the grand mean, had lower odds of hospital admission (aOR, 0.76; 95% CI, 0.63-0.93). Compared to the grand mean, infants of families that use a language other than English had higher odds of hospital admission (aOR, 1.08; 95% CI, 1.08-1.46). Conclusions and Relevance: Among low-risk febrile infants, language used for medical care was associated with the use of at least 1 nonindicated intervention, but race and ethnicity were not. Secondary analyses highlight the complex intersectionality of race, ethnicity, language, and health inequity. As inequitable care may be influenced by communication barriers, new guidelines that emphasize patient-centered communication may create disparities if not implemented with specific attention to equity.

Racial and Ethnic Differences in Initiation of Menthol Tobacco Smoking and Subsequent Tobacco Use in the Population Assessment of Tobacco and Health Study, Waves 1-4 (2013-2018).

INTRODUCTION: Certain subpopulations in the United States are highly vulnerable to tobacco initiation and addiction, and elimination of disparities among those groups is crucial to reducing the burden of tobacco use. AIMS AND METHODS: This study evaluated the racial and ethnic differences in smoking initiation of menthol flavored cigarettes and cigars among never-users, and in subsequent tobacco use among new users of menthol-flavored products, using longitudinal data from waves 1-4 of the Population Assessment of Tobacco and Health Study. The outcomes of interest were new use of menthol-flavored products, and subsequent past 30-day and past 12-month cigarette and cigar smoking, irrespective of flavors, after initiation. RESULTS: The percentages of new users of menthol-flavored cigarettes and cigars at waves 2-4 were disproportionately higher in non-Hispanic black and Hispanic than in non-Hispanic white people. Adjusting for age and sex, black people who first used any menthol cigars had higher risk of past 30-day use of the same cigar category at the subsequent wave (adjusted risk ratio, aRR 1.48; 95% confidence interval [CI] 1.11 to 1.96) and past 12 months (aRR 1.74; 95% CI 1.55 to 2.63) compared to non-Hispanic white smokers. Black people who first used menthol-flavored cigarettes had marginally higher risk of subsequent past 30-day cigarette use (aRR 1.44; 95% CI 0.99 to 2.10) compared with their non-Hispanic white counterparts. CONCLUSIONS: This study shows that racial and ethnic differences exist in both initiation of menthol-flavored tobacco products and product-specific subsequent use after first using menthol-flavored products; black and Hispanic people have higher rates of initiation; black people also have higher rates of subsequent use. IMPLICATIONS: Use of menthol flavors in tobacco products is confirmed to be a contributor to large disparities in tobacco use; black and Hispanic people are more likely to maintain smoking through use of mentholated products than non-Hispanic white people. The findings suggest educational and regulatory actions on menthol-flavored tobacco products including restricting the selective marketing to vulnerable communities and banning characterizing flavors in cigarettes and cigars may reduce tobacco-related disparities and inform the Food And Drug Administration's evidence-based rulemaking process.

Impact of Institutional Universal Microsatellite-Instability (MSI) Reflex Testing on Molecular Profiling Differences Between Younger and Older Patients with Colorectal Cancer.

INTRODUCTION: DNA mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC) is found in about 15% of early-stage diseases and 5% of metastatic diseases. We reviewed a large, single-institutional database after implementation of universal reflex dMMR/MSI-H testing in CRC to compare profiles of younger (≤50) and older (>50) patients. PATIENTS AND METHODS: Between 2009 and 2017, all patients diagnosed with CRC at the University of Florida underwent reflex somatic tumor testing for dMMR by immunohistochemistry (MLH1, PMS2, MSH2, MSH6), MSI by PCR, and Next-Generation Sequencing. Statistical analysis was conducted with 2-sample comparison tests and logistic regression models. RESULTS: There were 375 patients included in the final analysis. Patients were grouped as younger (ages ≤50 years-old; n = 80) or older (>50 years-old; n = 295). Compared to tumors from older patients, tumors from younger patients were less likely to be dMMR/MSI-H (12.5% vs. 21.4%, P = .013) and less likely to have a BRAF mutation (1.5% vs. 16.1%, P = .002). BRAF mutation status was highly associated with MMR status; BRAF-mutated tumors were 29.7 times more likely than BRAF-WT tumors to be dMMR/MSI-H (P = < .001, 95% CI 11.3-78.3). CONCLUSIONS: Tumors of younger patients were less likely than tumors of older patients to have a dMMR/MSI-H or BRAF mutation. Universal MMR/MSI testing in our dataset identified a relatively large population of older patients with sporadic CRC who were eligible for immunotherapy.

Effective Removal of Boron from Aqueous Solutions by Inorganic Adsorbents: A Review.

Increasing levels of boron in water exceeding acceptable thresholds have triggered concerns regarding environmental pollution and adverse health effects. In response, significant efforts are being made to develop new adsorbents for the removal of boron from contaminated water. Among the various materials proposed, inorganic adsorbents have emerged as promising materials due to their chemical, thermal, and mechanical stability. This review aims to comprehensively examine recent advances made in the development of inorganic adsorbents for the efficient removal of boron from water. Firstly, the adsorption performance of the most used adsorbents, such as magnesium, iron, aluminum, and individual and mixed oxides, are summarized. Subsequently, diverse functionalization methods aimed at enhancing boron adsorption capacity and selectivity are carefully analyzed. Lastly, challenges and future perspectives in this field are highlighted to guide the development of innovative high-performance adsorbents and adsorption systems, ultimately leading to a reduction in boron pollution.

Decoupling the adsorption mechanisms of arsenate at molecular level on modified cube-shaped sponge loaded superparamagnetic iron oxide nanoparticles.

In this study, a commercial cube-shaped open-celled cellulose sponge adsorbent was modified by in-situ co-precipitation of superparamagnetic iron oxide nanoparticles (SPION) and used to remove As(V) from aqueous solutions. Fe K-edge X-ray absorption spectroscopy (XAS) and TEM identified maghemite as the main iron phase of the SPION nanoparticles with an average size 13 nm. Batch adsorption experiments at 800 mg/L showed a 63% increase of adsorption capacity when loading 2.6 wt.% mass fraction of SPION in the cube-sponge. Experimental determination of the adsorption thermodynamic parameters indicated that the As(V) adsorption on the composite material is a spontaneous and exothermic process. As K-edge XAS results confirmed that the adsorption enhancement on the composite can be attributed to the nanoparticles loaded. In addition, adsorbed As(V) did not get reduced to more toxic As(III) and formed a binuclear corner-sharing complex with SPION. The advantageous cube-shape of the sponge-loaded SPION composite together with its high affinity and good adsorption capacity for As(V), good regeneration capability and the enhanced-diffusion attributed to its open-celled structure make this adsorbent a good candidate for industrial applications.

A genome-wide association study of obstructive heart defects among participants in the National Birth Defects Prevention Study.

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (Ndiscovery  = 3978; Nreplication  = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (Ndiscovery_TDT  = 440; Nreplication_TDT  = 275) and case-control analyses separately in infants (Ndiscovery_CCI  = 1635; Nreplication_CCI  = 990) and mothers (case status defined by infant; Ndiscovery_CCM  = 1703; Nreplication_CCM  = 1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (pdiscovery  = 4.08 × 10-9 ; preplication  = 2.44 × 10-4 ). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (pdiscovery  = 1.61 × 10-7 ; preplication  = 0.0016). Two other SNPs were suggestively associated (p < 1 × 10-6 ) with OHD in only the discovery sample. In the case-control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds ( × discovery < 1 × 10-5 and preplication < 0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (pdiscovery  = 1.42 × 10-6 ; preplication  = 0.04). Additional SNPs with pdiscovery < 1 × 10-5 were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings.

Wireless Rehabilitation Training Sensor Arrays Made with Hot Screen-Imprinted Conductive Hydrogels with a Low Percolation Threshold.

Herein, we propose a highly sensitive wireless rehabilitation training ball with a piezoresistive sensor array for patients with Parkinson's disease (PD). The piezoresistive material is a low percolation threshold conductive hydrogel which is formed with polypyrrole (PPy) nanofibers (NFs) as a conductive filler derived from a polydopamine (PDA) template. The proton acid doping effect and molecular template of PDA are essential for endowing PPy NFs with a high aspect ratio, leading to a low percolation threshold (∼0.78 vol %) and a low Young's 004Dodulus of 37.69 kPa and hence easy deformation. The piezoresistive sensor exhibited a static and dynamic stability of 10,000 s and 15,000 cycle times, respectively. This stability could be attributed to the increased hydrophilicity of conductive fillers, enhancing the interfacial strength between the conductive filler and the matrix. The interaction between the PDA-PPy NFs and the hydrogel matrix endows the hydrogel with toughness and ensures the stability of the device. Additionally, the microdome structure of the conductive hydrogel, produced by hot screen-imprinting, dramatically improves the sensitivity of the piezoresistive sensor (∼856.14 kPa-1). The microdome conductive hydrogel can distinguish a subtle pressure of 15.40 Pa compared to the control hydrogel without a microstructure. The highly sensitive piezoresistive sensor has the potential to monitor the hand-grip force, which is not well controlled by patients with PD. The rehabilitation training ball assembled with a sensor array on the surface and a wireless chip for communication inside is built and used to monitor the pressure in real time through the WeChat applet. Thus, this work has significantly broadened the application of hydrogel-based flexible piezoresistive sensors for human activity monitoring, which provides a promising strategy to realize next-generation electronics.

Enhanced arsenite removal by superparamagnetic iron oxide nanoparticles in-situ synthesized on a commercial cube-shape sponge: adsorption-oxidation mechanism.

HYPOTHESIS: The easy aggregation of superparamagnetic iron oxide nanoparticles (SPION) greatly reduces their adsorption performance for removing arsenic (As) from polluted water. We propose to exploit the porosity and good diffusion properties of a cube-shaped cellulose sponge for loading SPION to reduce the aggregation and to develop a composite adsorbent in the cm-scale that could be used for industrial applications. EXPERIMENTS: SPION were in-situ synthesized by co-precipitation using a commercial cube-shaped sponge (MetalZorb®) as support. The morphology, iron-oxide phase, adsorption performance and thermodynamic parameters of the composite adsorbent were determined to better understand the adsorption process. X-ray absorption spectroscopy (XAS) was used to investigate the chemical state of the adsorbed As(III). FINDINGS: The adsorption of the supported SPION outperforms the unsupported SPION (ca. 14 times higher adsorption capacity). The modelling of the adsorption isotherms and the kinetic curves indicated that chemisorption is controlling the adsorption process. The thermodynamic analysis shows that the adsorption retains the spontaneous and endothermic character of the unsupported SPION. The XAS results revealed an adsorption-oxidation mechanism in which the adsorbed As(III) was partially oxidized to less toxic As(V) by the hydroxyl free radical (•OH) generated from Fe(III) species and by the hydroxyl groups.

Associations of five obesity metrics with epigenetic age acceleration: Evidence from 2,474 Taiwan Biobank participants.

OBJECTIVE: Obesity is associated with epigenetic age acceleration (EAA), resulting in an increased risk of many age-related disorders. However, most studies have focused on the relationship of EAA with BMI. Whether any other obesity metric is more relevant to EAA remains unknown. METHODS: Here, the methylation ages of 2,474 Taiwan Biobank (TWB) participants were calculated according to Levine's phenotypic age (PhenoAge) and Lu's GrimAge. Residuals from regressing methylation age on chronological age were used to quantify PhenoEAA and GrimEAA. Five obesity metrics were evaluated, namely BMI, body fat percentage, waist circumference, hip circumference, and waist-hip ratio. Sex-stratified EAA was regressed on each of the five obesity metrics. RESULTS: For male individuals, an increase of one SD in waist-hip ratio (0.06) was associated with a 0.602-year PhenoEAA (p = 6.3E-6) and a 0.481-year GrimEAA (p = 1.2E-8). For female individuals, every SD increase in BMI (3.7 kg/m2 ) was associated with a 0.600-year PhenoEAA (p = 3.3E-5) and a 0.305-year GrimEAA (p = 3.1E-5). CONCLUSIONS: "Abdominal obesity" and "general obesity" are significantly associated with male and female EAA, respectively. The prevention of abdominal obesity and general obesity is associated with a lower risk of EAA in men and women, respectively.

Innovative approach to identify multigenomic and environmental interactions associated with birth defects in family-based hybrid designs.

Genes, including those with transgenerational effects, work in concert with behavioral, environmental, and social factors via complex biological networks to determine human health. Understanding complex relationships between causal factors underlying human health is an essential step towards deciphering biological mechanisms. We propose a new analytical framework to investigate the interactions between maternal and offspring genetic variants or their surrogate single nucleotide polymorphisms (SNPs) and environmental factors using family-based hybrid study design. The proposed approach can analyze diverse genetic and environmental factors and accommodate samples from a variety of family units, including case/control-parental triads, and case/control-parental dyads, while minimizing potential bias introduced by population admixture. Comprehensive simulations demonstrated that our innovative approach outperformed the log-linear approach, the best available method for case-control family data. The proposed approach had greater statistical power and was capable to unbiasedly estimate the maternal and child genetic effects and the effects of environmental factors, while controlling the Type I error rate against population stratification. Using our newly developed approach, we analyzed the associations between maternal and fetal SNPs and obstructive and conotruncal heart defects, with adjustment for demographic and lifestyle factors and dietary supplements. Fourteen and 11 fetal SNPs were associated with obstructive and conotruncal heart defects, respectively. Twenty-seven and 17 maternal SNPs were associated with obstructive and conotruncal heart defects, respectively. In addition, maternal body mass index was a significant risk factor for obstructive defects. The proposed approach is a powerful tool for interrogating the etiological mechanism underlying complex traits.

Conditional and unconditional genome-wide association study reveal complicate genetic architecture of human body weight and impacts of smoking.

To reveal the impacts of smoking on genetic architecture of human body weight, we conducted a genome-wide association study on 5,336 subjects in four ethnic populations from MESA (The Multi-Ethnic Study of Atherosclerosis) data. A full genetic model was applied to association mapping for analyzing genetic effects of additive, dominance, epistasis, and their ethnicity-specific effects. Both the unconditional model (base) and conditional model including smoking as a cofactor were investigated. There were 10 SNPs involved in 96 significant genetic effects detected by the base model, which accounted for a high heritability (61.78%). Gene ontology analysis revealed that a number of genetic factors are related to the metabolic pathway of benzopyrene, a main compound in cigarettes. Smoking may play important roles in genetic effects of dominance, dominance-related epistasis, and gene-ethnicity interactions on human body weight. Gene effect prediction shows that the genetic effects of smoking cessation on body weight vary from different populations.

Soluble CD14 Subtype in Peripheral Blood is a Biomarker for Early Diagnosis of Sepsis.

OBJECTIVE: To study the value of serum soluble CD14 subtype (sCD14-ST) in early diagnosis of sepsis. METHODS: Seventy-two patients were diagnosed with systemic inflammatory response syndrome, sepsis, or septic shock. Peripheral blood was collected at 0, 12, 24, and 48 hours after admission to the hospital. Levels of sCD14-ST, procalcitonin (PCT), hypersensitive C-reactive protein (CRP), and white blood cells (WBC) were determined. RESULTS: Levels of sCD14-ST in the patients with septic shock were higher than those in the other patients (P < .01) and peaked at 48 h. PCT and CRP levels were similar in the patients at admission but increased by 5 times to 10 times in the next 48 h, especially in the patients with septic shock. WBC levels remained high and did not change dramatically. Receiver operating characteristic analysis revealed that the area under the curve, sensitivity, and specificity values of sCD14-ST to diagnose sepsis were much higher than those of the other markers. CONCLUSION: Compared with PCT, CRP, and WBC, sCD14-ST is a better biomarker for the early diagnosis of sepsis.

Separation and Recycling of Concentrated Heavy Metal Wastewater by Tube Membrane Distillation Integrated with Crystallization.

Tube membrane distillation (MD) integrated with a crystallization method is used in this study for the concurrent productions of pure water and salt crystals from concentrated single and mixed system solutions. The effects of concentrated Zn2+ and Ni2+ on performance in terms of membrane flux, permeate conductivity, crystal recovery rates, and crystal grades are investigated. Preferred crystallization and co-crystallization determinations were performed for mixed solutions. The results revealed that membrane fluxes remained at 2.61 kg·m-2·h-1 and showed a sharp decline until the saturation increased to 1.38. Water yield conductivity was below 10 µs·cm-1. High concentrated zinc and nickel did not have a particular effect on the rejection of the membrane process. For the mixed solutions, membrane flux showed a sharp decrease due to the high saturation, while the conductivity of permeate remained below 10 µs·cm-1 during the whole process. Co-crystallization has been proven to be a better method due to the existence of the SO42- common-ion effect. Membrane fouling studies have suggested that the membrane has excellent resistance to fouling from highly concentrated solutions. The MD integrated with crystallization proves to be a promising technology for treating highly concentrated heavy metal solutions.

Effects of growth hormone therapy in pediatric patients with growth hormone deficiency and Chiari I malformation: a retrospective study.

PURPOSE: The safety and efficacy of growth hormone replacement therapy (GHRT) on pediatric patients with growth hormone deficiency (GHD) and Chiari I malformation (CIM) are not well investigated within the current body of literature. With no clear indication of the effects of GHRT on CIM disease progression, we sought to determine the effect of GHRT on tonsillar herniation and progression of CIM symptomatology. METHODS: From a previously established database of 465 patients with radiologically confirmed CIM defined as > 5 mm of tonsillar descent on head magnetic resonance imaging (MRI), we identified 20 patients who also had GHD. Using the imaging analysis software package, ANALYZE, the degree of change in tonsillar herniation was documented between initial and final MRI measurements. The radiologic and clinical changes over time were examined via a proportional odds model, Student's t test, Mann-Whitney test, or a mixed model corresponding to the outcomes measured either on an ordinal scale or on a quantitative scale. RESULTS: Incidence of GHD in our CIM population was 4.3%. There was no significant effect of GHRT on the degree of tonsillar herniation in patients with GHD and CIM. No patient became symptomatic, developed syringomyelia, or required surgical intervention for CIM. CONCLUSION: Based on our findings with a larger sample size, along with recent reports, the incidence of patients with CIM and GHD we reported (0.86-5%) is likely more indicative of the actual incidence of GHD and CIM than the prior findings within the literature (9.1-20%). We also suggest that GHRT does not significantly affect CIM morphology or symptomatology. Therefore, neurosurgeons should have no hesitation clearing these patients for GHRT.

Correction to: Urinary metabolites of polycyclic aromatic hydrocarbons in pregnant women and their association with a biomarker of oxidative stress.

The correct name of the 1st Author is shown in this paper.

Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data.

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.