Time from insertion to expulsion of cervical ripening balloon in preterm versus term inductions of labor.

OBJECTIVE: Preterm induction of labor can be necessary for maternal and fetal wellbeing. Duration of cervical ripening balloon (CRB) use has been studied in only term inductions. Our study investigated duration of time in hours for CRB expulsion and vaginal delivery in preterm inductions of labor. METHODS: This was a single-institution retrospective cohort study of preterm (< 37 weeks) and term (≥ 37 weeks) inductions with CRB between 2010 and 2021. Cesarean deliveries were excluded. Primary outcome was insertion to expulsion time of CRB. Secondary outcomes included induction to delivery time, cervical dilation after expulsion, misoprostol, and Pitocin use. Institutional review board (IRB) approval was obtained prior to the study. RESULTS: Ninety-eight patients with vaginal delivery after preterm CRB use were identified and matched 1:1 on baseline characteristics (p > 0.05) to term patients with vaginal delivery after CRB use. Mean insertion to expulsion time was significantly shorter for term than preterm inductions (mean 7.2 ± 3.09 h versus 8.5 ± 3.38 h; p < 0.01). Mean induction to delivery time was significantly shorter for term than preterm inductions (18.4 ± 7.6 h versus 22.5 ± 9.01 h; p < 0.01). Increased use of misoprostol, Pitocin, and second CRB were noted among the preterm cohort. Among term patients, more CRB placement at start of induction and greater cervical dilation post-balloon were found in comparison to preterm patients. CONCLUSION: Among patients undergoing preterm induction, longer insertion to expulsion time of CRB, longer induction to delivery time, and increased interventions should be expected. Different standards for labor management should be considered for achieving vaginal delivery in preterm inductions.

Health Plans Struggle to Report on Depression Quality Measures That Require Clinical Data.

OBJECTIVE: Depression quality measures aligned with evidence-based practices require that health care organizations use standardized tools for tracking and monitoring patient-reported symptoms and functioning over time. This study describes challenges and opportunities for reporting 5 HEDIS measures which use electronic clinical data to assess adolescent and perinatal depression care quality. METHODS: Two learning collaboratives were convened with 10 health plans from 5 states to support reporting of the depression measures. We conducted content analysis of notes from collaborative meetings and individual calls with health plans to identify key challenges and strategies for reporting. RESULTS: Health plans used various strategies to collect the clinical data needed to report the measures, including setting up direct data exchange with providers and data aggregators and leveraging data captured in health information exchanges and case management records. Health plans noted several challenges to reporting and performance improvement: 1) lack of access to clinical data sources where the results of patient-reported tools were documented; 2) unavailability of the results of patient-reported tools in usable data fields; 3) lack of routine depression screening and ongoing assessment occurring in provider practices. CONCLUSIONS: Our findings demonstrate ongoing challenges in collecting and using patient-reported clinical data for health plan quality measurement. Systems to track and improve outcomes for individuals with depression will require significant investments and policy support at the point of care and across the healthcare system.

Harnessing electronic clinical data to report adult and prenatal immunization quality measures.

OBJECTIVE: To explore the use of health plan quality measures specified for electronic clinical data to monitor immunizations. MATERIALS AND METHODS: We analyzed 2018 data submitted by health plans reporting 2 new Healthcare Effectiveness Data and Information Set measures assessing receipt of clinically recommended vaccines among pregnant women and adults. We analyzed the number of plans reporting a valid performance rate and electronic data source used. We consulted expert panels and reviewed coverage rates from other sources to understand the results. RESULTS: We received 136 data submissions across commercial, Medicaid and Medicare plans and 87 submissions across commercial and Medicaid plans for the adult and prenatal immunization measures, respectively. These submissions represent approximately 15% of possible submissions. Plans used claims, registries and electronic health records. Mean performance rates for adult immunizations were 21.2 (commercial), 14.0 (Medicaid) and 19.5% (Medicare). Mean rates for prenatal immunizations were 33.1 (commercial) and 16.7% (Medicaid). DISCUSSION: Results from the first year of reporting 2 electronic clinical data measures suggest health plans can feasibly report these measures and are seeking electronic data to supplement claims. Comparison of rates to other national results showed lower than expected rates for the adult immunization measure. However, prenatal immunization rates were on par with those from a national survey, suggesting this measure is closer to use for quality improvement. CONCLUSION: Quality measure reporting that encourages connection to electronic data sources is a step forward in performance monitoring and improvement. The use of electronic sources may advance health information exchange for patient care.

Facilitators and Barriers to Implementing a Patient-Centered Oncology Care Model.

PURPOSE: Oncology practices often serve as the "medical home" for patients but may not have systems to support all aspects of patient-centered care. We piloted a new set of oncology medical home standards that call for accessible, continuous, coordinated, and team-based care. We examined how adoption of the standards varies across a variety of practices and compared practice self-report with external evaluation of implementation. METHODS: Five medical oncology practices in southeastern Pennsylvania implemented the standards from 2014 into 2016. Implementation support included training webinars and technical assistance. External reviewers evaluated practices' implementation of the standards. We conducted site visits to interview providers and patients. RESULTS: Between baseline and follow-up, practice self-assessments and independent audits showed practices increased implementation of the patient-centered oncology standards. The largest improvement was seen in continuous quality improvement (QI). Practices were less successful in implementing care coordination: achievement on two standards (access and evidence-based decision support) declined from baseline to follow-up. Qualitative analyses revealed that practices focused QI in five areas: goals of care, engaging patients in QI, financial counseling, symptom management, and care coordination. Interviewees talked about facilitators, such as leadership support and physician buy-in, and barriers to transformation, including inadequate resources and staffing. Health information technology both supported and limited implementation. CONCLUSION: Oncology practices showed some progress in their implementation of patient-centered care processes over the course of the pilot program. Systems for tracking and documenting improvement, training for staff and clinicians, leadership support, and alignment of financial incentives are critical to transformation.

Patient-centered oncology care: impact on utilization, patient experiences, and quality.

OBJECTIVES: To determine whether implementation of patient-centered oncology standards in 5 medical oncology practices improved patient experiences and quality and reduced emergency department (ED) and hospital use. STUDY DESIGN: Retrospective, pre-post study design with a concurrent nonrandomized control group. METHODS: We used insurance claims to calculate all-cause hospitalizations and ED visits and primary care and specialist office visits (n = 28,826 eligible patients during baseline and 30,843 during follow-up) and identify patients for a care experiences survey (n = 715 preintervention and 437 postintervention respondents). For utilization and patient experience outcomes, we compared pilot practices' performance with 18 comparison practices using difference-in-differences (DID) regression models accounting for practice-level clustering. We assessed pilot practice performance on 31 quality measures from the American Society of Clinical Oncology Quality Oncology Practice Initiative program. RESULTS: There were no statistically significant differences in hospital, ED, or primary care visits between the pilot and comparison groups over time, but there was a significant increase in specialty visits for the pilot group (adjusted DID of 0.07; 95% CI, 0.01-0.13; P = .03). For care experiences, pilot practices improved more on shared decision-making (4.03 DID composite score; P = .013), whereas the comparison group improved more on access (-6.36 DID composite score; P < .001) and exchanging information (-4.25 DID composite score; P = .013). On average, pilot practices improved performance on 65% of core quality measures from baseline to follow-up. CONCLUSIONS: This pilot of patient-centered oncology care showed improved quality but no impact on hospitalizations/ED use and mixed results for patient experiences. Findings are consistent with early evaluations of primary care patient-centered medical homes.

Assessing Cancer Patient Experience of Care in Outpatient Oncology Practices in the United States.

INTRODUCTION: Cancer patients' experience of care is an important component of quality that has not previously been used for comparing performance. We administered a new patient experience survey to cancer patients receiving outpatient chemotherapy treatment. We examined its measures for sensitivity to adjustment for case-mix and response tendency (level of general optimism/pessimism) and reliability for making performance comparisons between practices. METHODS: We surveyed 2304 cancer patients who received chemotherapy at 23 medical oncology practices in Southeastern Pennsylvania, receiving 715 responses (response rate 31%; 14 practices had 10 or more responses). We aggregated patient responses to calculate practice-level scores on 5 predefined composites: Affective Communication, Shared Decision-Making, Patient Self-Management, Exchanging Information, and Access. We then ranked the practices on each composite before and after adjustment for standard case-mix variables and supplemental adjustment for response tendency (measured via the Life Orientation Test-Revised). We calculated the reliability of practice scores on each composite using hierarchical linear models and calculated minimum sample sizes necessary to achieve reliabilities exceeding 0.7. RESULTS: After adjusting responses for case-mix and converting to a 0-100 scale, composite scores ranged from 77 for the Patient Self-Management composite to 92 for the Access composite. Adjustment for response tendency had an impact on practice rankings only for the Shared Decision-Making composite. The number of responses necessary to create reliable practice-level measurements ranged from 17 (Access composite) to 96 (Affective Communication composite). CONCLUSIONS: Patient experiences at oncology practices can be measured reliably using reasonable sample sizes. Standard case-mix adjustment is adequate for making comparisons on most composites.

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos.

BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

Supporting Human Papillomavirus Vaccination in Adolescents: Perspectives From Commercial and Medicaid Health Plans.

CONTEXT: An estimated 79 million Americans are infected with human papillomavirus (HPV). Vaccination can reduce the burden of infection and HPV-associated cancers; yet, vaccination rates remain low. Little is known about why some health plans achieve higher vaccination rates. OBJECTIVE: This study sought to identify strategies used by higher-performing health plans to support HPV vaccination. DESIGN: We used 2013 data from the Healthcare Effectiveness Data and Information Set (HEDIS) Human Papillomavirus Vaccine for Female Adolescents measure to identify high-performing plans. The measure examines the percentage of female adolescent plan members who received 3 doses of HPV vaccine by their 13th birthday. High performers were defined as the subset of commercial plans with the top 10 rates and the subset of Medicaid plans with the top 10 rates. An interview guide was developed to assess activities related to providing HPV vaccination. Interviews were conducted with selected plans and audio-recorded. Transcripts were reviewed independently by 2 interviewers and analyzed by hand to identify key themes. PARTICIPANTS: Staff members representing 10 plans agreed to be interviewed, representing a diversity of plan size (range, 5500 to >2.7 million members); plan type (about half were commercial, half were Medicaid plans); patient population, from predominantly white to predominantly nonwhite; and geographic region. RESULTS: Plans Participants highlighted multiple strategies that support HPV vaccination, particularly the "normalizing" of the vaccine. Plans' efforts highlighted patient and provider education, reminders, feedback loops, community collaborations, immunization registries, and use of medical home concepts-including team-driven efforts and coordination. IMPLICATIONS: There is an important need to improve the uptake of HPV vaccination. As health coverage expands to more organizations and individuals, it will be critical for health plans to consider the strategies implemented by higher-performing organizations. CONCLUSION: Although HPV immunization rates are low nationally, health plans can employ multiple efforts to encourage vaccination by implementing activities that involve the patient, the provider, and the community.

Human Papillomavirus Vaccination Coverage Among Female Adolescents in Managed Care Plans - United States, 2013.

Human papillomavirus (HPV) is the most common sexually transmitted infection, with a reported 79 million persons aged 15­59 years in the United States currently infected with HPV, and approximately 14 million new cases diagnosed each year. Although most HPV infections are asymptomatic, transient, and do not cause disease, persistent HPV infection can lead to cervical, vulvar, vaginal, anal, penile, and oropharyngeal cancer. In the United States, approximately 27,000 HPV-attributable cancers occur each year. HPV vaccination is an effective primary prevention strategy that can reduce many of the HPV infections that lead to cancer, and is routinely recommended for adolescents aged 11­12 years. To determine whether the recommended HPV vaccination series is currently being administered to adolescents with health insurance, CDC and the National Committee for Quality Assurance (NCQA) assessed 2013 data from the Healthcare Effectiveness Data and Information Set (HEDIS). The HEDIS HPV Vaccine for Female Adolescents performance measure evaluates the proportion of female adolescent members in commercial and Medicaid health plans who receive the recommended 3-dose HPV vaccination series by age 13 years. In 2013, in the United States, the median HPV vaccination coverage levels for female adolescents among commercial and Medicaid plans were 12% and 19%, respectively (ranges = 0%­34% for commercial plans; 5%­52% for Medicaid plans). Improving HPV vaccination coverage and understanding of what health plans might do to support HPV vaccination are needed, including understanding the barriers to, and facilitators for, vaccination coverage.

Lessons From Early Implementation of a Patient-Centered Care Model in Oncology.

PURPOSE: Oncology practices may serve as the primary health provider for patients with cancer and the so-called neighbor during periods of transition and survivorship. New standards for patient-centered oncology practice articulate expectations for the primary health provider and neighbor roles. We report the implementation experiences of five oncology practices participating in a pilot of these standards. METHODS: For each practice, auditors reviewed workflows and documentation supporting the progress of the practice in meeting the oncology medical home standards. We also observed clinical encounters and practice workflow and interviewed clinicians, staff, and patients. RESULTS: Referral coordination and care management were the most demonstrated functions. The least commonly demonstrated functions related to tracking and coordination of tests and medications, as well as quality measurement and improvement. Some opportunities for structural and process improvement included improving the use of health information technology, care coordination, quality improvement, telephone triage, symptom management, patient education, financial counseling, and care team communication. Making patient-centered care a priority and motivation to change were cited as facilitators for transformation. CONCLUSION: The pilot oncology practices had many structures and processes in common, many of which were established during the early intervention period of this pilot. However, there was little standardization within and across practices in the way these processes were established and documented. Establishing structures for care coordination, quality improvement, and quality measurement should be priorities for practices considering transformation to a patient-centered model of care.

Genetic ancestry influences asthma susceptibility and lung function among Latinos.

BACKGROUND: Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest. OBJECTIVE: To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children. METHODS: We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry. RESULTS: Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively). CONCLUSION: Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.

Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos.

BACKGROUND: IgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic disorders. OBJECTIVE: We sought to identify genetic variants associated with IgE levels in Latinos. METHODS: We performed a genome-wide association study and admixture mapping of total IgE levels in 3334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1564 European Americans, and 3187 African Americans from independent studies. RESULTS: We confirmed associations of 6 genes identified by means of previous genome-wide association studies and identified a novel genome-wide significant association of a polymorphism in the zinc finger protein 365 gene (ZNF365) with total IgE levels (rs200076616, P = 2.3 × 10(-8)). We next identified 4 admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) at which local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower IgE levels (P = 4.95 × 10(-8)). All but 22q13.1 were replicated in an independent sample of Latinos, and 2 of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified 6 genome-wide significant single nucleotide polymorphisms in Latinos, 2 of which replicated in European Americans. Another single nucleotide polymorphism was peak-wide significant within 14q23.2 in African Americans (rs1741099, P = 3.7 × 10(-6)) and replicated in non-African American samples (P = .011). CONCLUSION: We confirmed genetic associations at 6 genes and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse multiethnic populations to uncover novel loci associated with total IgE levels.

Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma.

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS.

Socioeconomic status and asthma control in African American youth in SAGE II.

OBJECTIVE: African Americans are disproportionately burdened by asthma. We assessed the individual and joint contribution of socioeconomic status (SES) on asthma morbidity among African American youth. METHODS: We examined 686 African Americans (8-21 years) with asthma. To account for the joint effects of SES, a composite index was derived from maternal educational attainment, household income, and insurance status. Ordinal logistic regression was used to estimate the individual and joint effect of SES on asthma control. Models were adjusted for age, sex, controller medication use, in utero smoke exposure, family history of asthma, family history of rhinitis, breastfeeding, daycare attendance, and mold exposure. RESULTS: Participants were classified as Poorly Controlled Asthma (40.8%), Partially Controlled Asthma (29.7%), or Controlled Asthma (30.2%). Of the individual SES indicators, low income was the strongest predictor of poor asthma control. Children with low income had worse asthma control than those with higher income (OR 1.39; 95% CI 0.92-2.12). The SES index ranged from 4-9. SES was associated with 17% increased odds of poor asthma control with each decrease in the index (95% CI 1.05-1.32). The SES index was associated with asthma-related symptoms, nocturnal awakenings, limited activity, and missed school days. CONCLUSIONS: The negative effects of SES were observed along the entire socioeconomic gradient, and the adverse asthma outcomes observed in African American youth were not limited to the very poor. We also found that the SES index may be a more consistent and useful predictor of poor asthma outcomes than each indicator alone.

Dissecting childhood asthma with nasal transcriptomics distinguishes subphenotypes of disease.

BACKGROUND: Bronchial airway expression profiling has identified inflammatory subphenotypes of asthma, but the invasiveness of this technique has limited its application to childhood asthma. OBJECTIVES: We sought to determine whether the nasal transcriptome can proxy expression changes in the lung airway transcriptome in asthmatic patients. We also sought to determine whether the nasal transcriptome can distinguish subphenotypes of asthma. METHODS: Whole-transcriptome RNA sequencing was performed on nasal airway brushings from 10 control subjects and 10 asthmatic subjects, which were compared with established bronchial and small-airway transcriptomes. Targeted RNA sequencing nasal expression analysis was used to profile 105 genes in 50 asthmatic subjects and 50 control subjects for differential expression and clustering analyses. RESULTS: We found 90.2% overlap in expressed genes and strong correlation in gene expression (ρ = .87) between the nasal and bronchial transcriptomes. Previously observed asthmatic bronchial differential expression was strongly correlated with asthmatic nasal differential expression (ρ = 0.77, P = 5.6 × 10(-9)). Clustering analysis identified TH2-high and TH2-low subjects differentiated by expression of 70 genes, including IL13, IL5, periostin (POSTN), calcium-activated chloride channel regulator 1 (CLCA1), and serpin peptidase inhibitor, clade B (SERPINB2). TH2-high subjects were more likely to have atopy (odds ratio, 10.3; P = 3.5 × 10(-6)), atopic asthma (odds ratio, 32.6; P = 6.9 × 10(-7)), high blood eosinophil counts (odds ratio, 9.1; P = 2.6 × 10(-6)), and rhinitis (odds ratio, 8.3; P = 4.1 × 10(-6)) compared with TH2-low subjects. Nasal IL13 expression levels were 3.9-fold higher in asthmatic participants who experienced an asthma exacerbation in the past year (P = .01). Several differentially expressed nasal genes were specific to asthma and independent of atopic status. CONCLUSION: Nasal airway gene expression profiles largely recapitulate expression profiles in the lung airways. Nasal expression profiling can be used to identify subjects with IL13-driven asthma and a TH2-skewed systemic immune response.

Genome-wide association study and admixture mapping identify different asthma-associated loci in Latinos: the Genes-environments & Admixture in Latino Americans study.

BACKGROUND: Asthma is a complex disease with both genetic and environmental causes. Genome-wide association studies of asthma have mostly involved European populations, and replication of positive associations has been inconsistent. OBJECTIVE: We sought to identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping. METHODS: Latino children with asthma (n = 1893) and healthy control subjects (n = 1881) were recruited from 5 sites in the United States: Puerto Rico, New York, Chicago, Houston, and the San Francisco Bay Area. Subjects were genotyped on an Affymetrix World Array IV chip. We performed genome-wide association and admixture mapping to identify asthma-associated loci. RESULTS: We identified a significant association between ancestry and asthma at 6p21 (lowest P value: rs2523924, P < 5 × 10(-6)). This association replicates in a meta-analysis of the EVE Asthma Consortium (P = .01). Fine mapping of the region in this study and the EVE Asthma Consortium suggests an association between PSORS1C1 and asthma. We confirmed the strong allelic association between SNPs in the 17q21 region and asthma in Latinos (IKZF3, lowest P value: rs90792, odds ratio, 0.67; 95% CI, 0.61-0.75; P = 6 × 10(-13)) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies. CONCLUSIONS: Admixture mapping and genome-wide association are complementary techniques that provide evidence for multiple asthma-associated loci in Latinos. Admixture mapping identifies a novel locus on 6p21 that replicates in a meta-analysis of several Latino populations, whereas genome-wide association confirms the previously identified locus on 17q21.

Genome-wide association study of lung function phenotypes in a founder population.

BACKGROUND: Lung function is a long-term predictor of mortality and morbidity. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. METHODS: We performed a genome-wide association study (GWAS) of FEV1, forced vital capacity (FVC), and FEV1/FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. RESULTS: Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7 × 10(-8) to 3.4 × 10(-9)). Nine SNPs at or near 4 additional loci had P < 10(-5) with FEV1/FVC. Only 2 SNPs were found with P < 10(-5) for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P < .05), including 3 clusters of ß-defensin genes, 2 chemokine genes (CCL18 and CXCL12), and TNFRSF13B. CONCLUSION: This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function.

A genome-wide association study of bronchodilator response in Latinos implicates rare variants.

BACKGROUND: The primary rescue medication to treat acute asthma exacerbation is the short-acting ß2-adrenergic receptor agonist; however, there is variation in how well a patient responds to treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR). OBJECTIVE: To identify genetic variation associated with bronchodilator drug response in Latino children with asthma. METHODS: We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity. RESULTS: We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10(-8)), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells. CONCLUSION: Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.

Socioeconomic status and childhood asthma in urban minority youths. The GALA II and SAGE II studies.

RATIONALE: The burden of asthma is highest among socioeconomically disadvantaged populations; however, its impact is differentially distributed among racial and ethnic groups. OBJECTIVES: To assess the collective effect of maternal educational attainment, annual household income, and insurance type on childhood asthma among minority, urban youth. METHODS: We included Mexican American (n = 485), other Latino (n = 217), and African American (n = 1,141) children (aged 8-21 yr) with and without asthma from the San Francisco Bay Area. An index was derived from maternal educational attainment, annual household income, and insurance type to assess the collective effect of socioeconomic status on predicting asthma. Logistic regression stratified by racial and ethnic group was used to estimate adjusted odds ratios (aOR) and their 95% confidence intervals (CI). We further examined whether acculturation explained the socioeconomic-asthma association in our Latino population. MEASUREMENTS AND MAIN RESULTS: In the adjusted analyses, African American children had 23% greater odds of asthma with each decrease in the socioeconomic index (aOR, 1.23; 95% CI, 1.09-1.38). Conversely, Mexican American children have 17% reduced odds of asthma with each decrease in the socioeconomic index (aOR, 0.83; 95% CI, 0.72-0.96) and this relationship was not fully explained by acculturation. This association was not observed in the other Latino group. CONCLUSIONS: Socioeconomic status plays an important role in predicting asthma, but has different effects depending on race and ethnicity. Further steps are necessary to better understand the risk factors through which socioeconomic status could operate in these populations to prevent asthma.