Ridgely Fisk Green

Association of Paternal Age and Risk for Major Congenital Anomalies From the National Birth Defects Prevention Study, 1997 to 2004

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.

Association between maternal age and birth defects of unknown etiology: United States, 1997-2007.

BACKGROUND Birth defects affect 3% of babies born, and are one of the leading causes of infant mortality. Both younger and older maternal age may pose increased risks for certain birth defects. This study assessed the relationship between maternal age at the estimated delivery date and the risk for birth defects. METHODS Data were obtained from the National Birth Defects Prevention Study, a population-based case-control study including mothers across 10 states. Maternal age was stratified into six categories: <20, 20 to 24, 25 to 29, 30 to 34, 35 to 39, and ≥40 years, and also analyzed as a continuous variable. Logistic regression models adjusted formaternal race/ethnicity, education, body mass index (BMI), folic acid use, smoking, gravidity, and parental age difference were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS For maternal age <20 years, associations with total anomalous pulmonary venous return (aOR, 2.3; 95% CI, 1.3-4.0), amniotic band sequence (aOR, 2.4; 95% CI, 1.5-3.8), and gastroschisis (aOR, 6.1; 95% CI, 4.8-8.0) were observed. For the ≥40 year age group, associations with several cardiac defects, esophageal atresia (aOR, 2.9; 95% CI, 1.7-4.9), hypospadias (aOR, 2.0; 95% CI, 1.4-3.0), and craniosynostosis (aOR, 1.6; 95% CI, 1.1-2.4) were observed. Results using maternal age as a continuous variable were consistent with those that used categorized maternal age. CONCLUSION Elucidating risk factors specific to women ateither extreme of maternal age may offer prevention opportunities. All women should be made aware of prevention opportunities, such as folic acid supplementation, to reduce the occurrence of birth defects.

Folate-related gene variants in Irish families affected by neural tube defects

Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19 bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative (“risk genotypes”) and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p = 0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic mechanisms.

Genomics in Public Health: Perspective from the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC).

The national effort to use genomic knowledge to save lives is gaining momentum, as illustrated by the inclusion of genomics in key public health initiatives, including Healthy People 2020, and the recent launch of the precision medicine initiative. The Office of Public Health Genomics (OPHG) at the Centers for Disease Control and Prevention (CDC) partners with state public health departments and others to advance the translation of genome-based discoveries into disease prevention and population health. To do this, OPHG has adopted an “identify, inform, and integrate” model: identify evidence-based genomic applications ready for implementation, inform stakeholders about these applications, and integrate these applications into public health at the local, state, and national level. This paper addresses current and future work at OPHG for integrating genomics into public health programs.

From public health genomics to precision public health: a 20-year journey

In this paper, we review the evolution of the field of public health genomics in the United States in the past two decades. Public health genomics focuses on effective and responsible translation of genomic science into population health benefits. We discuss the relationship of the field to the core public health functions and essential services, review its evidentiary foundation, and provide examples of current US public health priorities and applications. We cite examples of publications to illustrate how Genetics in Medicine reflected the evolution of the field. We also reflect on how public-health genomics is contributing to the emergence of “precision public health” with near-term opportunities offered by the US Precision Medicine (AllofUs) Initiative.

BRCA Genetic Testing and Receipt of Preventive Interventions Among Women Aged 18–64 Years with Employer-Sponsored Health Insurance in Nonmetropolitan and Metropolitan Areas — United States, 2009–2014

Problem/Condition Genetic testing for breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations can identify women at increased risk for breast and ovarian cancer. These testing results can be used to select preventive interventions and guide treatment. Differences between nonmetropolitan and metropolitan populations in rates of BRCA testing and receipt of preventive interventions after testing have not previously been examined. Period Covered 2009–2014. Description of System Medical claims data from Truven Health Analytics MarketScan Commercial Claims and Encounters databases were used to estimate rates of BRCA testing and receipt of preventive interventions after BRCA testing among women aged 18–64 years with employer-sponsored health insurance in metropolitan and nonmetropolitan areas of the United States, both nationally and regionally. Results From 2009 to 2014, BRCA testing rates per 100,000 women aged 18–64 years with employer-sponsored health insurance increased 2.3 times (102.7 to 237.8) in metropolitan areas and 3.0 times (64.8 to 191.3) in nonmetropolitan areas. The relative difference in BRCA testing rates between metropolitan and nonmetropolitan areas decreased from 37% in 2009 (102.7 versus 64.8) to 20% in 2014 (237.8 versus 191.3). The relative difference in BRCA testing rates between metropolitan and nonmetropolitan areas decreased more over time in younger women than in older women and decreased in all regions except the West. Receipt of preventive services 90 days after BRCA testing in metropolitan versus nonmetropolitan areas throughout the period varied by service: the percentage of women who received a mastectomy was similar, the percentage of women who received magnetic resonance imaging of the breast was lower in nonmetropolitan areas (as low as 5.8% in 2014 to as high as 8.2% in 2011) than metropolitan areas (as low as 7.3% in 2014 to as high as 10.3% in 2011), and the percentage of women who received mammography was lower in nonmetropolitan areas in earlier years but was similar in later years. Interpretation Possible explanations for the 47% decrease in the relative difference in BRCA testing rates over the study period include increased access to genetic services in nonmetropolitan areas and increased demand nationally as a result of publicity. The relative differences in metropolitan and nonmetropolitan BRCA testing rates were smaller among women at younger ages compared with older ages. Public Health Action Improved data sources and surveillance tools are needed to gather comprehensive data on BRCA testing in the United States, monitor adherence to evidence-based guidelines for BRCA testing, and assess receipt of preventive interventions for women with BRCA mutations. Programs can build on the recent decrease in geographic disparities in receipt of BRCA testing while simultaneously educating the public and health care providers about U.S. Preventive Services Task Force recommendations and other clinical guidelines for BRCA testing and counseling.

Trends in utilization and costs of BRCA testing among women aged 18–64 years in the United States, 2003–2014

PurposeWe examined 12-year trends in BRCA testing rates and costs in the context of clinical guidelines, national policies, and other factors.MethodsWe estimated trends in BRCA testing rates and costs from 2003 to 2014 for women aged 18–64 years using private claims data and publicly reported revenues from the primary BRCA testing provider.ResultsThe percentage of women with zero out-of-pocket payments for BRCA testing increased during 2013–2014, after 7 years of general decline, coinciding with a clarification of Affordable Care Act coverage of BRCA genetic testing. Beginning in 2007, family history accounted for an increasing proportion of women with BRCA tests compared with personal history, coinciding with BRCA testing guidelines for primary care settings and direct-to-consumer advertising campaigns. During 2013–2014, BRCA testing rates based on claims grew at a faster rate than revenues, following 3 years of similar growth, consistent with increased marketplace competition. In 2013, BRCA testing rates based on claims increased 57%, compared with 11% average annual increases over the preceding 3 years, coinciding with celebrity publicity.ConclusionThe observed trends in BRCA testing rates and costs are consistent with possible effects of several factors, including the Affordable Care Act, clinical guidelines and celebrity publicity.

A knowledge base for tracking the impact of genomics on population health

Purpose:We created an online knowledge base (the Public Health Genomics Knowledge Base (PHGKB)) to provide systematically curated and updated information that bridges population-based research on genomics with clinical and public health applications.Methods:Weekly horizon scanning of a wide variety of online resources is used to retrieve relevant scientific publications, guidelines, and commentaries. After curation by domain experts, links are deposited into Web-based databases.Results:PHGKB currently consists of nine component databases. Users can search the entire knowledge base or search one or more component databases directly and choose options for customizing the display of their search results.Conclusion:PHGKB offers researchers, policy makers, practitioners, and the general public a way to find information they need to understand the complicated landscape of genomics and population health.Genet Med 18 12, 1312–1314.

Use of Family History Information for Neural Tube Defect Prevention: Integration into State-Based Recurrence Prevention Programs.

Abstract Background: A family history of neural tube defects (NTDs) can increase the risk of a pregnancy affected by an NTD. Periconceptional folic acid use decreases this risk. Purpose: Our objective was to determine whether seconddegree relatives of NTD-affected children showed differences in folic acid use compared with the general population and to provide them with folic acid education. Methods: Michigan and Colorado health workers contacted families with a previous pregnancy or child affected by an NTD, identified through NTD recurrence prevention programs. Families were interviewed to identify the number of second-degree relatives of child-bearing age. Families mailed surveys to these relatives, who returned them to the state health departments. The survey assessed folic acid use, views on having an affected child, and reproductive planning. Folic acid education materials were sent to relatives who provided contact information. Results: Folic acid supplement use among relatives was similar to that of the general population, despite elevated risk perceptions. Discussion: Both state health departments plan to increase efforts to contact affected families and their relatives through partnerships with family support groups. Translation to Health Education Practice: Including outreach to second-degree relatives in NTD recurrence prevention programs could increase the impact of these programs.

Maternal reports of family history from the National Birth Defects Prevention Study, 1997-2001

Purpose: To assess usefulness of family history information obtained in pediatric practice, we evaluated maternally reported family history data.Methods: We analyzed family history responses from the National Birth Defects Prevention Study using interview data from mothers of children with birth defects (n = 9,331) and of unaffected liveborn children (n = 3,390) with 1997–2001 estimated delivery dates. We examined the effects of demographic factors, case–control status, and type of defect on birth defect family history reports. Interview information was compared with occurrence of prenatal testing.Results: Among case mothers, 1,577 (17%) reported a first- or second-degree relative with a birth defect, compared with 327 (10%) control mothers (odds ratio = 1.91, 95% confidence interval = 1.68–2.16). Reports of affected relatives were also more frequent among mothers who were non-Hispanic white, were 25 years or older, had more than 12 years of education, had an annual household income greater than