Monica M. Vasquez

Incidence and Remission of Sleep-Disordered Breathing and Related Symptoms in 6- to 17-Year Old Children—The Tucson Children's Assessment of Sleep Apnea Study

OBJECTIVE To determine the incidence and remission of sleep-disordered breathing in adolescent children. STUDY DESIGN A total of 319 children completed 2 home polysomnograms approximately 5 years apart. Sleep-disordered breathing (SDB) was determined to be present if a child had a respiratory disturbance index>or=1 event per hour associated with >or=3% oxygen desaturation. Subjective symptoms such as witnessed apnea, excessive daytime sleepiness, difficulty initiating and maintaining sleep, and habitual loud snoring were considered present if they occurred frequently or almost always. Body mass index percentiles were calculated with childhood growth charts from the Centers for Disease Control and Prevention adjusted for sex and age. RESULTS The mean age at assessment was 8.5 years at baseline and 13.7 years at follow-up, respectively. Incident SDB was more common in boys (odds ratio [OR]=3.93, P=.008, confidence interval [CI]=1.41-10.90). Children with prevalent SDB were more likely to be boys (OR=2.48, P=.006) and had a greater increase in body mass index percentile change (OR 1.01, P=.034). Children with prevalent SDB also had 3.41 greater odds for development of obesity from baseline to follow-up in comparison with children with prevalent NoSDB. CONCLUSIONS Adolescent boys are more likely to have persistent and incident SDB than girls. Children with prevalent SDB are more likely to have development of obesity. These risks are similar to those observed in adults.

Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study

BACKGROUND Low concentrations of the anti-inflammatory protein CC16 (approved symbol SCGB1A1) in serum have been associated with accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). We investigated whether low circulating CC16 concentrations precede lung function deficits and incidence of COPD in the general population. METHODS We assessed longitudinal data on CC16 concentrations in serum and associations with decline in FEV1 and incidence of airflow limitation for adults who were free from COPD at baseline in the population-based Tucson Epidemiological Study of Airway Obstructive Disease ([TESAOD] n=960, mean follow-up 14 years), European Community Respiratory Health Survey ([ECRHS-Sp] n=514, 11 years), and Swiss Cohort Study on Air Pollution and Lung Diseases in Adults ([SAPALDIA] n=167, 8 years) studies. Additionally, we measured circulating CC16 concentrations in samples from children aged 4-6 years in the Tucson Childrens Respiratory Study (n=427), UK Manchester Asthma and Allergy Study (n=481), and the Swedish Barn/children, Allergy, Milieu, Stockholm, Epidemiological survey (n=231) birth cohorts to assess whether low CC16 concentrations in childhood were predictive for subsequent lung function. FINDINGS After adjustment for sex, age, height, smoking status and intensity, pack-years, asthma, and FEV1 at baseline, we found an inverse association between CC16 concentration and decline in FEV1 in adults in TESAOD (4·4 mL/year additional FEV1 decline for each SD decrease in baseline CC16 concentration, p=0·0014) and ECRHS-Sp (2·4 mL/year, p=0·023); the effect in SAPALDIA was marginal (4·5 mL/year, p=0·052). Low CC16 concentration at baseline was also associated with increased risk of incident stage 2 airflow limitation (ratio of FEV1 to forced expiratory volume [FEV1/FVC] less than 70% plus FEV1 % predicted less than 80%) in TESAOD and ECRHS-Sp. In children, the lowest tertile of CC16 concentrations was associated with a subsequent FEV1 deficit of 68 mL up to age 16 years (p=0·0001), which was confirmed in children who had never smoked by age 16 years (-71 mL, p<0·0001). INTERPRETATION Low concentrations of CC16 in serum are associated with reduced lung function in childhood, accelerated lung function decline in adulthood, and development of moderate airflow limitation in the general adult population. FUNDING National Heart, Lung, and Blood Institute and European Union Seventh Framework Programme.

Effects of Sleep Patterns and Obesity on Increases in Blood Pressure in a 5-Year Period: Report from the Tucson Children's Assessment of Sleep Apnea Study

OBJECTIVES To determine associations between body mass index and sleep on blood pressure in a 5-year period from childhood to adolescence. STUDY DESIGN Study consisted of a longitudinal, community-based sample of 334 children recruited at ages 6 through 11 years. Each participant underwent in-home polysomnography initially and then 5 years later. Individual systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated at both points during wake periods and classified as hypertensive when SBP or DBP was ≥ 95th standardized percentiles for height and weight. RESULTS Hypertension was present in 3.6% of the sample at time one and increased to 4.2% 5 years later. Obesity prevalence increased from 15.0% to 19.5%. Normal changes in sleep architecture were observed in the sample. With random effects modeling, which controlled for age, sex, and ethnicity, change in obesity status and decrease in total sleep time were indicated to be associated with increases in SBP. Change in obesity status was also associated with increases in DBP in the 5-year period. A trend for sleep-disordered breathing to increase SBP was noted. CONCLUSIONS Increases in SBP and DBP were associated with increasing body mass index and decreased total sleep time in a 5-year period from childhood to adolescence.

The impact of CD14 polymorphisms on the development of soluble CD14 levels during infancy

CD14 is a receptor involved in the recognition of lipopolysaccharide and other bacterial wall components that may be involved in the balance between infectious and allergic disease and the early polarization towards TH1. Our group has shown an association between polymorphisms in the 5′ flanking region of the CD14 gene and plasma soluble CD14 (sCD14) levels at 11 years of age. However, whether this association is present at birth and in infancy remains to be determined. In this study, we measured sCD14 levels in plasma from the umbilical cord (n=387) and at 3 months (n=357) and 1 year (n=312) of age in non-selected healthy infants to assess their relationship with CD14 genotypes at −4190, −2838, −1720 and −260 (relative to translation start site). There was no relation of CD14 genotypes with sCD14 at birth. However, there was a significant association between CD14 genotypes and sCD14 as early as 3 months. Longitudinal analysis suggests that CD14 polymorphisms modulate sCD14 levels up to 1 year of age. This association early in life may have an impact on TH1 polarization and subsequent protection against allergic disease.

Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers.

Background The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. Objective We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. Methods We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell–derived IL‐1&bgr; levels were measured by means of ELISA. Results Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma‐associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL‐1&bgr;, an innate inflammatory mediator. Conclusions The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory. Graphical abstract Figure. No Caption available.

Asthma, airflow limitation and mortality risk in the general population

Asthma and chronic obstructive pulmonary disease co-exist in a significant proportion of patients. Whether asthma increases mortality risk among subjects with airflow limitation remains controversial. We used data from 2121 adult participants in the population-based Tucson Epidemiological Study of Airway Obstructive Disease cohort. At enrolment (1972–1973), participants completed questionnaires and lung function tests. Participants were categorised into four groups based on the combination of airflow limitation (AL; forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%) and physician-confirmed asthma at baseline. Vital status as of January 2011 was assessed through the National Death Index. Cox proportional hazards models were used to test differences in mortality risk across the four airflow limitation/asthma groups. In multivariate Cox models, the AL+/asthma+ group had a 114% increased mortality risk during follow-up compared with the AL-/asthma- group (adjusted HR 2.14; 95% CI 1.64–2.79). The corresponding hazard ratios were 1.09 (95% CI 0.89–1.34) and 1.34 (95% CI 1.14–1.57) for the AL-/asthma+ and AL+/asthma- groups, respectively. Among subjects with airflow limitation, asthma was associated with increased mortality risk (HR 1.58, 95% CI 1.17–2.12). However, this increased risk was substantially reduced and no longer significant after further adjustment for baseline FEV1 levels. Similar results were obtained when airflow limitation was defined as FEV1/FVC less than the lower limit of normal. In a population-based cohort, subjects with concomitant airflow limitation and asthma had an increased risk of dying, which was mainly related to their baseline lung function deficits. Asthma increases mortality risk in the general population, but only when associated with lung function deficits http://ow.ly/CckiC

Serum concentrations of club cell secretory protein (Clara) and cancer mortality in adults: a population-based, prospective cohort study

BACKGROUND Club cell secretory protein (Clara) (CC16) is produced mainly by bronchiolar club cells and has been shown to have protective effects against airway inflammation and oxidative stress from cigarette smoking and related carcinogens. The goal of this study was to establish whether serum CC16 concentrations predict all-cause and cancer-specific mortality in adults. METHODS We used data from the population-based Tucson Epidemiological Study of Airway Obstructive Diseases (TESAOD), a prospective cohort study of respiratory health initiated in Tucson, AZ, USA, in 1972, that recruited a multistage stratified cluster sample of non-Hispanic white households. We measured serum CC16 concentrations in cryopreserved serum samples and reviewed vital status up to Jan 1, 2011, through contact with next of kin, collection of death certificates, and searches of the National Death Index. Our primary analysis was the relation of baseline serum CC16 to all-cause mortality or cause-specific mortality risk, analysed by adjusted Cox proportional hazards models. FINDINGS 1086 TESAOD participants aged 21-70 years at enrolment were eligible for inclusion. Of these, 653 (60%) had died by 2011, and cause of death was ascertained for 649 (99%). When adjusted for sex, age, education, body-mass index, smoking and pack-years, and baseline levels of lung function, serum CC16 concentrations at baseline were inversely associated with mortality risk over the study follow-up. Mortality risk increased for each 1-SD decrease in CC16 (adjusted hazard ratio [HR] 1·16 [95% CI 1·06-1·26]; p=0·0007). For cause-specific mortality, each 1-SD decrease in serum CC16 was associated with an increased risk of dying of cancer (adjusted HR 1·41 [1·19-1·67]; p<0·0001). In the subset of smokers, the corresponding adjusted HR for mortality by lung cancer was 1·52 (1·14-2·03; p=0·004). INTERPRETATION Serum CC16 concentrations can predict mortality risk in the general adult population. The excess risk associated with lower CC16 concentrations is predominantly driven by cancer, particularly lung cancer. FUNDING National Heart, Lung, and Blood Institute.

Markers of Differential Response to Inhaled Corticosteroid Treatment Among Children with Mild Persistent Asthma

BACKGROUND Inhaled corticosteroids are recommended as first-line therapy for children with mild persistent asthma; however, specific patient characteristics may modify the treatment response. OBJECTIVE Identify demographic, clinical, and atopic characteristics that may modify the inhaled corticosteroid treatment response among children enrolled in the Treating Children to Prevent Exacerbations of Asthma trial. METHODS Children aged 6 to 18 years with mild persistent asthma were randomized to 44 weeks of combined, daily, rescue, or placebo treatment. Daily treatment consisted of 40 μg of beclomethasone twice daily. Rescue treatment consisted of 40 μg of beclomethasone accompanying each symptom-driven albuterol actuation. Combined treatment consisted of both. Outcomes included time to first exacerbation and proportion of asthma control days. Fourteen baseline characteristics were selected for interaction testing on the basis of their clinical relevance. RESULTS Two hundred eighty-eight children were randomized. Seventy-five percent were white, and 55% were male. As measured by time to first exacerbation, 4 characteristics identified children who received greater benefit from treatment: non-Hispanic ethnicity, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/μL or more, and history of oral corticosteroid use in the year before enrollment. As measured by asthma control days, 4 characteristics identified children who received greater benefit from treatment: male sex, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/μL or more, and incomplete run-in asthma control. CONCLUSIONS Children with mild persistent asthma who have markers of atopic asthma or who have greater asthma burden may obtain greater benefit from beclomethasone therapy. Additional study is needed to confirm whether these markers can guide individualized therapy.

Low Lung Function in Young Adult Life Is Associated with Early Mortality

Low levels of lung function are known to be a significant predictor of cardiopulmonary mortality in the adult general population (1–6). This association may be the consequence of an accelerated decline of lung function during adult life (e.g., in response to cigarette smoking), but it can also result from tracking of low levels of lung function achieved by early adulthood, possibly as a result of impaired lung growth during childhood and/or in utero. The goal of this study was to test the latter hypothesis by using TESAOD (Tucson Epidemiological Study of Airway Obstructive Disease) to determine the relation of levels of lung function achieved in young adulthood to subsequent mortality risk. Some of the results of this study have been previously reported in the form of an abstract (7). TESAOD is a population-based prospective cohort study of non-Hispanic white households initiated in Tucson, Arizona, in 1972 (8). At the initial survey and in 12 follow-up surveys completed approximately every 2 years up to 1996, participants completed a standardized respiratory questionnaire and, with the exception of survey 4, spirometric lung function tests (9). During the follow-up, newborns and spouses of participants were also recruited into the study. For this study, we defined as “baseline survey” the first survey at which participants were 21–35 years old and completed lung function tests. At the baseline survey, 1,412 participants also had available information for covariates and did not report having cystic fibrosis or having had any chest or lung surgery. Percentage predicted values for spirometric indices were computed using reference equations by Knudson and colleagues (10). For participants with available follow-up, 10-year within-subject slopes of FEV1 decline were also computed by regressing FEV1 values against age at each lung function test that was completed within 10 years of the baseline survey. Slopes of FVC and FEV1/FVC ratio were computed using similar methods. Vital status was updated during the study follow-up through direct contact with family and next of kin and collection of death certificates. In addition, a systematic review of mortality as of January 1, 2011, was completed through linkage with the National Death Index. Causes of death were determined on the basis of death certificates for events up to 1978 and on National Death Index records for events after 1978. For this study, we analyzed four causes of death: heart disease, chronic obstructive pulmonary disease (COPD), cancer, and external causes (mainly accidents, homicides, and suicides). Because of the small number of deaths resulting from COPD (n = 7), these events were combined with deaths resulting from heart disease into the category of cardiopulmonary mortality, as done previously (11). Cox proportional hazards models were used to estimate hazard ratios for all-cause mortality and cause-specific mortality while adjusting for covariates. Separate models were used to test the effects of baseline levels of FEV1, FVC, and FEV1/FVC ratio. FEV1 and FVC were tested both as percentage predicted and as crude values. Time to event was defined as the time from the baseline survey to the date of death for deceased participants and to January 1, 2011, for subjects who were still alive at that time. In secondary analyses, models were further adjusted for the decline of the specific lung function index of interest during the first 10 years after the baseline survey. As a consequence, for these models, follow-up for time to event began 10 years after the baseline survey. The 1,412 participants included in this study had a mean age of 26 years at baseline, with 52% females and 51% ever-smokers. Smokers had an average of 8.4 pack-years at baseline. The mean percentage predicted FEV1 at baseline was 100.5%. The mean follow-up period for the main mortality analyses was 32.56 6.7 years. By January 1, 2011, 122 participants (8.6%) had died (17 by heart disease, 7 by COPD, 42 by cancer, 24 by external causes, and 32 by other causes). Table 1 shows associations of lung function with all-cause and cause-specific mortality. Baseline FEV1, but not FVC, was associated with all-cause mortality. However, both FEV1 and FVC were associated with heart and cardiopulmonary mortality. In models adjusted for sex, age, body mass index, smoking status, and pack-years at baseline (Table 1), every 10% decrease in baseline FEV1 percentage predicted levels was associated with an increase in mortality risk of 15% (P = 0.052) for all causes, 72% (P = 0.002) for heart disease, and 67% (P = 0.002) for cardiopulmonary mortality. These associations were also confirmed when crude FEV1 levels were used (P = 0.02, 0.001, and ,0.001; respectively). Similarly, every 10% decrease in baseline FVC percentage predicted levels was associated with a 69% (P = 0.006) increase in heart disease and a 54% (P = 0.01) increase in cardiopulmonary mortality. Results were confirmed in Cox models that were further adjusted for the 10-year slope of lung function decline during the follow-up (Table 1). To rule out potential overadjustment in models on percentage predicted values, we also confirmed results for percentage predicted FEV1 and FVC after removing sex and age from covariates (data not shown). No significant associations were found between FEV1/FVC and mortality. No significant associations or trends were found with mortality by cancer or external causes for any of the lung function indices. Figure 1 shows the association of tertiles of FEV1 percentage predicted at baseline with cardiopulmonary mortality. Our findings demonstrate that individuals who achieve low levels of FEV1 and FVC by the beginning of adult life are at increased risk for early cardiopulmonary mortality. Associations appeared stronger for FEV1 than FVC, possibly because the former is able to capture deficits related to both obstructive and restrictive patterns. We observed consistent trends of association between low lung function and mortality for both heart disease and COPD, but the number of deaths with COPD as underlying cause was too small to test this disease separately. Interestingly, low levels of maximally achieved FEV1 in young adulthood have been shown to account for a significant proportion of incident COPD cases at This study was supported by awards HL107188 and HL095021 from the NHLBI, National Institutes of Health.

Least absolute shrinkage and selection operator type methods for the identification of serum biomarkers of overweight and obesity: simulation and application

BackgroundThe study of circulating biomarkers and their association with disease outcomes has become progressively complex due to advances in the measurement of these biomarkers through multiplex technologies. The Least Absolute Shrinkage and Selection Operator (LASSO) is a data analysis method that may be utilized for biomarker selection in these high dimensional data. However, it is unclear which LASSO-type method is preferable when considering data scenarios that may be present in serum biomarker research, such as high correlation between biomarkers, weak associations with the outcome, and sparse number of true signals. The goal of this study was to compare the LASSO to five LASSO-type methods given these scenarios.MethodsA simulation study was performed to compare the LASSO, Adaptive LASSO, Elastic Net, Iterated LASSO, Bootstrap-Enhanced LASSO, and Weighted Fusion for the binary logistic regression model. The simulation study was designed to reflect the data structure of the population-based Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD), specifically the sample size (N = 1000 for total population, 500 for sub-analyses), correlation of biomarkers (0.20, 0.50, 0.80), prevalence of overweight (40%) and obese (12%) outcomes, and the association of outcomes with standardized serum biomarker concentrations (log-odds ratio = 0.05–1.75). Each LASSO-type method was then applied to the TESAOD data of 306 overweight, 66 obese, and 463 normal-weight subjects with a panel of 86 serum biomarkers.ResultsBased on the simulation study, no method had an overall superior performance. The Weighted Fusion correctly identified more true signals, but incorrectly included more noise variables. The LASSO and Elastic Net correctly identified many true signals and excluded more noise variables. In the application study, biomarkers of overweight and obesity selected by all methods were Adiponectin, Apolipoprotein H, Calcitonin, CD14, Complement 3, C-reactive protein, Ferritin, Growth Hormone, Immunoglobulin M, Interleukin-18, Leptin, Monocyte Chemotactic Protein-1, Myoglobin, Sex Hormone Binding Globulin, Surfactant Protein D, and YKL-40.ConclusionsFor the data scenarios examined, choice of optimal LASSO-type method was data structure dependent and should be guided by the research objective. The LASSO-type methods identified biomarkers that have known associations with obesity and obesity related conditions.