Eliminating Medicaid dental benefits and early-stage oral cancer diagnoses.

BACKGROUND: Despite the importance of regular dental visits for detecting oral cancer, millions of low-income adults lack access to dental services. In July 2009, California eliminated adult Medicaid dental benefits. We tested if this impacted oral cancer detection for Medicaid enrollees. METHODS: We analyzed Surveillance, Epidemiology, and End Results-Medicaid data, which contains verified Medicaid enrollment status, to estimate a difference-in-differences model. Our design compares the change in early-stage (Stages 0-II) diagnoses before and after dropping dental benefits in California with the change in early-stage diagnoses among eight states that did not change Medicaid dental benefits. Patients were grouped by oropharyngeal cancer (OPC) and non-OPC (oral cavity cancer), type, and the length of Medicaid enrollment. We also assessed if the effect of dropping dental benefits varied by the number of dentists per capita. RESULTS: Dropping Medicaid dental benefits was associated with a 6.5%-point decline in early-stage diagnoses of non-OPC (95% CI = -14.5, -3.2, p = 0.008). This represented a 20% relative reduction from baseline rates. The effect was highest among beneficiaries with 3 months of continuous Medicaid enrollment prior to diagnosis who resided in counties with more dentists per capita. Specifically, dropping dental coverage was associated with a 1.25%-point decline in the probability of early-stage non-OPC diagnoses for every additional dentist per 5000 population (p = 0.006). CONCLUSIONS: Eliminating Medicaid dental benefits negatively impacted early detection of cancers of the oral cavity. Continued volatility of Medicaid dental coverage and provider shortages may be further delaying oral cancer diagnoses. Alternative approaches are needed to prevent advanced stage OPC.

Primary care physicians' participation in the Medicare shared savings program and preventive services delivery: Evidence from the first 7 years.

OBJECTIVE: To evaluate whether primary care physicians' participation in the Medicare Shared Savings Program (MSSP) is associated with changes in their preventive services delivery. DATA SOURCES: Medicare Provider Utilization and Payment Physician and Other Supplier Public Use File and MSSP Accountable Care Organizations (ACO) Provider-Level Research Identifiable File from 2012 to 2018. STUDY DESIGN: The design was a two-way fixed effects model estimating within-provider changes in preventive services delivery over time controlling for provider time-invariant characteristics, national time trends, and characteristics of served patients. The following preventive services were evaluated: influenza vaccination, pneumococcal vaccination, clinical depression screening, colorectal cancer screening, breast cancer screening, Body Mass Index (BMI) screening and follow-up, tobacco use assessment, and annual wellness visits. Both the likelihood of providing services and the volume of services delivered were evaluated. DATA COLLECTION/EXTRACTION METHODS: Secondary data linked at the provider level. PRINCIPAL FINDINGS: MSSP participation was associated with an increase in the likelihood of providing influenza vaccination (0.7 percentage-points), pneumococcal vaccination (2.0 percentage-points), clinical depression screening (2.1 percentage-points), tobacco use assessment (0.3 percentage-points), and annual wellness visits (4.1 percentage-points). A similar increase was found for the volume of services delivered per 100 patients for several preventive services: influenza vaccination (0.18), pneumococcal vaccination (0.56), clinical depression screening (0.46), and annual wellness visits (1.52). MSSP participation was associated with a decrease in the likelihood (-0.4 percentage-points) and the volume of colorectal cancer screening (-0.03). CONCLUSIONS: Primary care physicians' participation in MSSP was associated with an increase in the likelihood and the volume of several preventive services.

Genome-wide Interaction Study Implicates VGLL2 and Alcohol Exposure and PRL and Smoking in Orofacial Cleft Risk.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect, affecting approximately 1 in 700 births. NSCL/P has complex etiology including several known genes and environmental factors; however, known genetic risk variants only account for a small fraction of the heritability of NSCL/P. It is commonly suggested that gene-by-environment (G×E) interactions may help explain some of the "missing" heritability of NSCL/P. We conducted a genome-wide G×E interaction study in cases and controls of European ancestry with three common maternal exposures during pregnancy: alcohol, smoking, and vitamin use using a two-stage design. After selecting 127 loci with suggestive 2df tests for gene and G x E effects, 40 loci showed significant G x E effects after correcting for multiple tests. Notable interactions included SNPs of 6q22 near VGLL2 with alcohol and 6p22.3 near PRL with smoking. These interactions could provide new insights into the etiology of CL/P and new opportunities to modify risk through behavioral changes.

The effects of state facial surgery mandates on timeliness of primary cleft repair surgery in the United States.

OBJECTIVE: This study examines the effects of state facial surgery mandates on the timeliness of primary cleft repair surgery for privately insured children with oral clefts in the United States. MATERIALS AND METHODS: Using IBM Health MarketScan® Database from 2001 to 2017, we estimate regression models separately for age at cleft lip repair and cleft palate repair by having a mandate while considering child-level factors and other state differences. The sample includes 1,451 children who had primary cleft lip repair by age 12 months, and 1,402 children who had primary cleft palate repair by age 18 months. RESULTS: A mandate was associated with earlier cleft lip repair by 13 days (95% CI, -21.5 to -4.7 days) when controlling for state differences, regardless if the child had other birth defects. For children needing cleft palate repair, a mandate was associated with earlier surgery by 87 days (95% CI, -136.1 to -38.4 days) only when no other birth defects were present. CONCLUSIONS: State facial surgery mandates were associated with earlier cleft lip repair for children with or without other birth defects, and earlier cleft palate repair for children without other birth defects (besides oral clefts). Findings suggest benefits to privately insured children with oral clefts from state mandates to cover needed services.

State-Mandated Coverage of Cleft Lip and Cleft Palate Treatment.

OBJECTIVE: We conducted a comprehensive review of state laws and regulations that require private health insurance plans to cover the services needed by children born with cleft lip and/or cleft palate (CL/P). The goal is to better understand how states are reducing the barriers children with CL/P face when seeking recommended health care services. DESIGN: We identified all state laws and regulations mandating insurance coverage of services for children with CL/P by private insurance carriers from 1999 through 2017 using Westlaw legal database. We categorized laws and regulations into ten services: facial surgery (facial, corrective, reconstructive), oral surgery, orthodontics, dental care, habilitation/rehabilitation/speech therapy, prosthetic treatment, audiology, nutrition counseling, genetic testing, and psychological counseling. We also captured broad mandates indicating coverage for all necessary treatments. RESULTS: There was a trend toward increased coverage of services for CL/P over time. In 1999, 27 states and Washington, DC did not have relevant laws or regulations. By 2017, there were 19 states without laws or regulations mandating services. The most common mandated service was facial surgery followed by habilitation/rehabilitation/speech therapy, orthodontics, dental care, and oral surgery. Nutrition, audiology, genetic testing and psychological counseling were rarely included in mandated services. CONCLUSIONS: States vary widely in their requirements for coverage of services needed by children with CL/P in private health insurance plans. There has been an increase in mandates over the past two decades to cover services, although significant variation continues to exist across states.

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.

Effects of Contextual Economic Factors on Childhood Obesity.

OBJECTIVES: To examine the association between changes in contextual economic factors on childhood obesity in the US. METHODS: We combined data from 2003, 2007, and 2011/2012 National Surveys of Children's Health for 129,781 children aged 10-17 with 27 state-level variables capturing general economic conditions, labor supply, and the monetary or time costs of calorie intake, physical activity, and cigarette smoking. We employed regression models controlling for demographic factors and state and year fixed effects. We also examined heterogeneity in economic effects by household income. RESULTS: Obesity risk increased with workforce proportion in blue-collar occupations, urban sprawl, female labor force participation, and number of convenience stores but declined with median household income, smoking ban in restaurants, and full service restaurants per capita. Most effects were specific to low income households, except for density of supercenters/warehouse clubs which was significantly associated with higher overweight/obesity risk only in higher income households. CONCLUSIONS FOR PRACTICE: Changes in state-level economic factors related to labor supply and monetary or time cost of calorie intake may affect childhood obesity especially for children in low-income households. Policymakers should consider these effects when designing programs aimed at reducing childhood obesity.

The Impacts of the ACA Medicaid Expansions on Cancer Screening Use by Primary Care Provider Supply.

BACKGROUND: Recent studies of the impacts of the Affordable Care Act (ACA) Medicaid expansions on cancer screening use have mostly found insignificant effects. We posit that these findings mask meaningful heterogeneity in impacts depending on availability of primary care providers. OBJECTIVE: This study examined the impacts of the ACA Medicaid expansions on cancer screening use separately by state-level supply of primary care providers. RESEARCH DESIGN: We used data from the 2012 and 2016 Behavioral Risk Factor Surveillance System surveys to measure use of mammograms, Pap smear tests, blood stool tests, and sigmoidoscopy/colonoscopy for age groups recommended receiving these tests. The main analytical sample included 24,878-31,890 individuals with household income below 138% Federal Poverty Line. We used a difference-in-differences design comparing pre-post expansion changes in cancer screening use between expanding and nonexpanding states separately for 2 state groups defined by the median proportion of the state population residing in primary health professional shortage areas: low primary care provider supply (above median) and high supply (below median). RESULTS: Medicaid expansions were associated with significant increases in mammograms (11.4 percentage-points), Pap smear tests (6.9 percentage-points), and sigmoidoscopy/colonoscopy use (8.3 percentage-points) in states with high supply of primary care providers. In contrast, effects were small and insignificant in low supply states. CONCLUSIONS: ACA Medicaid expansions were associated with increased cancer screening use only in states with high supply of primary care providers. Improving access for Medicaid beneficiaries in provider shortage areas may require coupling coverage expansions with supply-side interventions to increase provider availability.

Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment.

The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10-8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.

Effects of Objective 3-Dimensional Measures of Facial Shape and Symmetry on Perceptions of Facial Attractiveness.

PURPOSE: Meeting patient desires for enhanced facial esthetics requires that providers have standardized and objective methods to measure esthetics. The authors evaluated the effects of objective 3-dimensional (3D) facial shape and asymmetry measurements derived from 3D facial images on perceptions of facial attractiveness. MATERIALS AND METHODS: The 3D facial images of 313 adults in Iowa were digitized with 32 landmarks, and objective 3D facial measurements capturing symmetric and asymmetric components of shape variation, centroid size, and fluctuating asymmetry were obtained from the 3D coordinate data using geo-morphometric analyses. Frontal and profile images of study participants were rated for facial attractiveness by 10 volunteers (5 women and 5 men) on a 5-point Likert scale and a visual analog scale. Multivariate regression was used to identify the effects of the objective 3D facial measurements on attractiveness ratings. RESULTS: Several objective 3D facial measurements had marked effects on attractiveness ratings. Shorter facial heights with protrusive chins, midface retrusion, faces with protrusive noses and thin lips, flat mandibular planes with deep labiomental folds, any cants of the lip commissures and floor of the nose, larger faces overall, and increased fluctuating asymmetry were rated as significantly (P < .001) less attractive. CONCLUSION: Perceptions of facial attractiveness can be explained by specific 3D measurements of facial shapes and fluctuating asymmetry, which have important implications for clinical practice and research.

Interaction between smoking and body mass index and risk of oral clefts.

PURPOSE: To examine maternal smoking and body mass index (BMI) interactions in contributing to risk of oral clefts. METHODS: We studied 4935 cases and 10,557 controls from six population-based studies and estimated a pooled logistic regression of individual-level data, controlling for study fixed effects and individual-level risk factors. RESULTS: We found a significant negative smoking-BMI interaction, with cleft risk with smoking generally declining with higher BMI. For all clefts combined, the odds ratio for smoking was 1.61 (95% confidence interval [CI]: 1.39-1.86) at BMI 17 (underweight), 1.47 (95% CI: 1.34-1.62) at BMI 22 (normal weight), 1.35 (95% CI: 1.22-1.48) at BMI 27 (overweight), 1.21 (95% CI: 1.04-1.41) at BMI 33 (obese), and 1.13 (95% CI: 0.92-1.38) at BMI 37 (very obese). A negative interaction was also observed for isolated clefts and across cleft types but was more pronounced for cleft lip only and cleft palate only. CONCLUSIONS: Our findings suggest that the risk of oral clefts associated with maternal smoking is largest among underweight mothers, although the smoking-BMI interaction is strongest for cleft lip only and cleft palate only. BMI was not protective for the effects of smoking; a clinically relevant increase in smoking-related cleft risk was still present among heavier women.

Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate.

Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 × 10-8). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 × 10-9). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.

Oral Clefts and Academic Performance in Adolescence: The Impact of Anesthesia-Related Neurotoxicity, Timing of Surgery, and Type of Oral Clefts.

OBJECTIVE: Early life exposure to anesthesia and surgery is suspected to associate with cognitive impairment later in life. We compared academic achievement among adolescents with cleft lip only (CL), cleft palate only (CP), and cleft lip and cleft palate (CLP) with a noncleft control group to investigate whether outcome depends on timing and number of operations during childhood and/or type of oral cleft. DESIGN: Nationwide register-based follow-up study. SETTING: Danish birth cohort 1986 to 1990. PARTICIPANTS: Five hundred fifty-eight children with isolated CL (n = 171), CLP (n = 222), or CP (n = 195), of which 509 children had been exposed to anesthesia and one or more cleft operation(s), and a 5% sample of the birth cohort (n = 14,677). MAIN OUTCOME MEASURE(S): Test score in the Danish standardized ninth-grade exam and proportion of nonattainment, defined as "results for ninth-grade exam unavailable." Data adjusted for sex, birth weight, parental age, and parental level of education. RESULTS: Compared to controls, children with CL achieved higher scores (mean difference 0.12, 95% CI -0.05; 0.29) and children with CLP presented with lower scores (mean difference -0.06, 95% CI -0.21; 0.09), albeit both statistically insignificant. Children with CP achieved significantly lower scores, mean difference -0.20 (95% CI -0.38; -0.03). Odds ratios for nonattainment at final exam were: CL 0.79 (95% CI 0.46; 1.35), CLP 1.07 (95% CI 0.71; 1.61), CP 2.59 (95% CI 1.78; 3.76). CONCLUSIONS: Oral cleft type rather than number and timing of anesthesia and operations associate to poorer academic performance. Although a potential neurotoxic effect due to anesthetic agents is not reflected in the data, it cannot be completely excluded.

A pilot study among older adults of the concordance between their self-reports to a health survey and spousal proxy reports on their behalf.

BACKGROUND: Proxy respondents are frequently used in health surveys, and the proxy is most often the spouse. Longstanding concerns linger, however, about the validity of using spousal proxies, especially for older adults. The purpose of this pilot study was to evaluate the concordance between self-reports and spousal proxy reports to a standard health survey in a small convenience sample of older married couples. METHODS: We used the Seniors Together in Aging Research (STAR) volunteer registry at the University of Iowa to identify and consent a cross-sectional, convenience sample of 28 married husband and wife couples. Private, personal interviews with each member of the married couple using a detailed health survey based on the 2012 Health and Retirement Study (HRS) instrument were conducted using computer assisted personal interviewing software. Within couples, each wife completed the health survey first for herself and then for her husband, and each husband completed the health survey first for himself and then for his wife. The health survey topics included health ratings, health conditions, mobility, instrumental activities of daily living (IADLs), health services use, and preventative services. Percent of agreement and prevalence and bias adjusted kappa statistics (PABAKs) were used to evaluate concordance. RESULTS: PABAK coefficients indicated moderate to excellent concordance (PABAKs >0.60) for most of the IADL, health condition, hospitalization, surgery, preventative service, and mobility questions, but only slight to fair concordance (PABAKs = -0.21 to 0.60) for health ratings, and physician and dental visits. CONCLUSIONS: These results do not allay longstanding concerns about the validity of routinely using spousal proxies in health surveys to obtain health ratings or the number of physician and dental visits among older adults. Further research is needed in a nationally representative sample of older couples in which each wife completes the health survey first for herself and then for her husband, each husband completes the health survey first for himself and then for his wife, and both spouses' Medicare claims are linked to their health survey responses to determine not just the concordance between spousal reports, but the concordance of those survey responses to the medical record.

A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13.

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.

Passive Smoke Exposure as a Risk Factor for Oral Clefts-A Large International Population-Based Study.

Maternal cigarette smoking is a well-established risk factor for oral clefts. Evidence is less clear for passive (secondhand) smoke exposure. We combined individual-level data from 4 population-based studies (the Norway Facial Clefts Study, 1996-2001; the Utah Child and Family Health Study, 1995-2004; the Norwegian Mother and Child Cohort Study, 1999-2009; and the National Birth Defects Prevention Study (United States), 1999-2007) to obtain 4,508 cleft cases and 9,626 controls. We categorized first-trimester passive and active smoke exposure. Multivariable logistic models adjusted for possible confounders (maternal alcohol consumption, use of folic acid supplements, age, body size, education, and employment, plus study fixed effects). Children whose mothers actively smoked had an increased risk of oral clefts (odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.11, 1.46). Children of passively exposed nonsmoking mothers also had an increased risk (OR = 1.14, 95% CI: 1.02, 1.27). Cleft risk was further elevated among babies of smoking mothers who were exposed to passive smoke (OR = 1.51, 95% CI: 1.35, 1.70). Using a large pooled data set, we found a modest association between first-trimester passive smoking and oral clefts that was consistent across populations, diverse study designs, and cleft subtypes. While this association may reflect subtle confounding or bias, we cannot rule out the possibility that passive smoke exposure during pregnancy is teratogenic.

Does the Relationship of the Proxy to the Target Person Affect the Concordance between Survey Reports and Medicare Claims Measures of Health Services Use?

OBJECTIVES: To compare concordance of survey reports of health service use versus claims data between self respondents and spousal and nonspousal relative proxies. DATA SOURCES: 1995-2010 data from the Survey on Assets and Health Dynamics among the Oldest Old and 1993-2010 Medicare claims for 3,229 individuals (13,488 person-years). STUDY DESIGN: Regression models with individual fixed effects were estimated for discordance of any hospitalizations and outpatient surgery and for the numbers of under- and over-reported physician visits. PRINCIPAL FINDINGS: Spousal proxies were similar to self respondents on discordance. Nonspousal proxies, particularly daughters/daughters-in-law and sons/sons-in-law, had less discordance, mainly due to reduced under-reporting. CONCLUSIONS: Survey reports of health services use from nonspousal relatives are more consistent with Medicare claims than spousal proxies and self respondents.

Federal Health Coverage Mandates and Health Care Utilization: The Case of the Women's Health and Cancer Rights Act and Use of Breast Reconstruction Surgery.

BACKGROUND: Utilization of breast reconstruction services remains low among women who underwent mastectomy despite the improvement in quality of life associated with this treatment. The objective of this study is to identify the effect of the Women's Health and Cancer Rights Act (WHCRA)-an understudied ongoing federal law that mandated insurance coverage of breast reconstruction following mastectomy beginning in 1999-on use of reconstructive surgery after mastectomy. METHODS: We use a difference-in-differences (DD) approach to identify the change in breast reconstruction utilization induced by WHCRA by comparing the pre- and post-policy changes in utilization between states that did not have existing laws mandating coverage before the WHCRA (treatment group) and those that had such state laws (control group). The data are from the Surveillance, Epidemiology, and End Results program. The main sample includes 15,737 female patients who were under the age of 64 and underwent mastectomy within 4 months of diagnosis of early stage breast cancer during 1998 and 2000. RESULTS: Based on the DD model, the odds of using reconstruction services in the states without preexisting laws increased after the WHCRA by 31% in 1999 and 36% in 2000 (compared with 1998 before the WHCRA). These effects are masked in a simple pre/post model for change in reconstruction across all states. Additional analyses through 2007 indicate that the WHCRA had long-term effects on utilization. Furthermore, analyses by state indicate that most states in the treatment group experienced a significance increase in utilization. CONCLUSIONS: The use of breast reconstruction after mastectomy significantly increased after the WHCRA. At a minimum, our estimates may be considered the lower bound of the real policy effect.

Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci.

Although genome-wide association studies (GWASs) for nonsyndromic orofacial clefts have identified multiple strongly associated regions, the causal variants are unknown. To address this, we selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out a series of statistical and functional analyses. Within a cluster of strongly associated common variants near NOG, we found that one, rs227727, disrupts enhancer activity. We furthermore identified significant clusters of non-coding rare variants near NTN1 and NOG and found several rare coding variants likely to affect protein function, including four nonsense variants in ARHGAP29. We confirmed 48 de novo mutations and, based on best biological evidence available, chose two of these for functional assays. One mutation in PAX7 disrupted the DNA binding of the encoded transcription factor in an in vitro assay. The second, a non-coding mutation, disrupted the activity of a neural crest enhancer downstream of FGFR2 both in vitro and in vivo. This targeted sequencing study provides strong functional evidence implicating several specific variants as primary contributory risk alleles for nonsyndromic clefting in humans.

Candidate gene study for smoking, alcohol use, and body weight in a sample of pregnant women.

OBJECTIVE: Prenatal smoking, alcohol use, and obesity have significant effects on maternal and fetal health. However, not much is known about the genetic contributions to these risk factors among pregnant women. We evaluate the associations between several candidate genes and smoking, alcohol use, pre-pregnancy body weight, and weight gain during pregnancy in a sample of pregnant women. METHODS: The study analyzes a sample of about 1900 mothers from the Danish National Birth Cohort. We test the association between 1450 SNPs in/near 117 genes/loci and various risk factor measures. RESULTS: Only a few SNPs in FTO were significantly associated with pre-pregnancy obesity and body mass index (4 and 2 SNPs, respectively) after SNP-level correction for multiple testing. A few loci were significantly related to various smoking measures (any smoking, quitting and cigarette number) with gene/locus-level correction for multiple testing, but not after SNP-level correction. Similarly, some loci were significant for the alcohol measures at the gene/locus-level but not at SNP-level correction. CONCLUSION: The study suggests that the majority of the evaluated candidate genes may not play an important role in influencing these risk factors among pregnant women, highlighting the importance of other genetic factors and non-genetic contributors to their etiology.