Background Asthma has its origins in early childhood, but different patterns of childhood wheezing vary in their associations with subsequent asthma, atopy, and bronchial hyperresponsiveness (BHR). ...Novel wheezing phenotypes have been identified on the basis of analyses of longitudinal data from the Avon Longitudinal Study of Parents And Children (ALSPAC). It is unclear whether these phenotypes can be replicated in other birth cohorts. Objective To compare wheezing phenotypes identified in the first 8 years of life in the ALSPAC study and the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study. Methods We used longitudinal latent class analysis to identify phenotypes on the basis of repeated reports of wheezing from 0 to 8 years in 5760 children from the ALSPAC study and 2810 children from the PIAMA study. Phenotypes were compared between cohorts. Associations with asthma, atopy, BHR, and lung function were analyzed by using weighted regression analyses. Results The model with the best fit to PIAMA data in the first 8 years of life was a 5-class model. Phenotypes identified in the PIAMA study had wheezing patterns that were similar to those previously reported in ALSPAC, adding further evidence to the existence of an intermediate-onset phenotype with onset of wheeze after 2 years of age. Associations with asthma, atopy, BHR, and lung function were remarkably similar in the 2 cohorts. Conclusion Wheezing phenotypes identified by using longitudinal latent class analysis were comparable in 2 large birth cohorts. Study of genetic and environmental factors associated with different phenotypes may help elucidate the origins of asthma.
Background The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) risk score predicts the probability of having asthma at school age among preschool children with suggestive symptoms. ...Objective We sought to externally validate the PIAMA risk score at different ages and in ethnic and socioeconomic subgroups of children in addition to updating it. Methods We studied 2877 children with preschool asthma-like symptoms participating in the multiethnic, prospective, population-based cohort study Generation R. The PIAMA risk score was assessed at preschool age, and asthma was predicted at age 6 years. Discrimination (concordance index C-index) and calibration were calculated. The PIAMA risk score was updated, and its performance was similarly analyzed. Results At age 6 years, 6% (168/2877) of the children had asthma. The discriminative ability of the original PIAMA risk score to predict asthma in Generation R was similar compared with that in the PIAMA cohort (C-index = 0.74 vs 0.71). The predicted risks by using the original PIAMA risk score for having asthma at the age of 6 years tended to be slightly higher than the observed risks (8% vs 6%). No differences in discriminative ability were found at different ages or in ethnic and socioeconomic subgroups ( P > .05). The updated PIAMA risk score had a C-index of 0.75. Conclusions The PIAMA risk score showed good external validity. The discriminative ability was similar at different ages and in ethnic and socioeconomic subgroups of preschool children, which suggests good generalizability. Further studies are needed to reproduce the predictive performance of the updated PIAMA risk score in other populations and settings and to assess its clinical relevance.
Background Genome-wide association studies identified IL33 and IL-1 receptor–like 1 ( IL1RL1 )/ IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. ...Objective In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll–IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor–associated kinase 1, IL-1 receptor–associated kinase 4, and TNF receptor–associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. Methods Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. Results Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. Conclusions IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.
Background It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects ...genetically predisposed to COPD show their first symptoms or reduced lung function in childhood. Objective We investigated whether replicated genes for COPD associate with transient early wheeze (TEW) and lung function levels in 6- to 8-year-old children and whether cigarette smoke exposure in utero and after birth (environmental tobacco smoke ETS) modifies these effects. Methods The association of COPD-related genotypes of 20 single nucleotide polymorphisms in 15 genes with TEW, FEV1 , forced vital capacity (FVC), and FEV1 /FVC ratio was studied in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort (n = 1996) and replicated in the Child, parents and health: lifestyle and genetic constitution (KOALA) and Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts. Results AGER showed replicated association with FEV1 /FVC ratio. TNS1 associated with more TEW in PIAMA and lower FEV1 in ALSPAC. TNS1 interacted with ETS in PIAMA, showing lower FEV1 in exposed children. HHIP rs1828591 interacted with cigarette smoke exposure in utero in PIAMA and with ETS in ALSPAC, with lower lung function in nonexposed children. SERPINE2 , FAM13A , and MMP12 associated with higher FEV1 and FVC, and SERPINE2 , HHIP , and TGFB1 interacted with cigarette smoke exposure in utero in PIAMA only, showing adverse effects of exposure on FEV1 being limited to children with genotypes conferring the lowest risk of COPD. Conclusion Our findings indicate relevant involvement of at least 3 COPD genes in lung development and lung growth by demonstrating associations pointing toward reduced airway caliber in early childhood. Furthermore, our results suggest that COPD genes are involved in the infant's lung response to smoke exposure in utero and in early life.
Objective To examine the association between pubertal timing and cardiometabolic markers among adolescents. Study design We used data from Dutch adolescents participating in a birth cohort study. The ...study population for the current study consisted of 799 adolescents of whom data were available for at least 1 of the exposure variables (pubertal timing and/or age at menarche) and any of the cardiometabolic markers (waist circumference, cholesterol, blood pressure BP, glycated hemoglobin) measured at age 16 years. Adolescents self-reported pubertal development at ages 11, 14, and 16 years. We categorized participants with early (84 girls, 88 boys), intermediate (240 girls, 211 boys), or late pubertal timing (89 girls, 85 boys). We estimated differences in cardiometabolic markers using linear regression analysis. Results Girls with early pubertal timing had 1.54 cm larger waist circumference (95% CI .05; 3.03) and 3.98 mm Hg higher systolic BP (95% CI 1.69; 6.27) at age 16 years than girls with intermediate pubertal timing. The association with systolic BP remained after adjusting for childhood body mass index (BMI) (age 8 years) but attenuated after adjusting for BMI in adolescence (age 16 years). Boys with early pubertal timing had 0.79 mmol/mol lower glycated hemoglobin (95%CI −1.38; −0.20) than boys with intermediate pubertal timing. Conclusions Girls with early pubertal timing had unfavorable BP levels at age 16 years, independent of BMI in childhood. Girls and boys with late pubertal timing had a tendency for lower waist circumference, but no differences in other cardiometabolic markers. Late pubertal timing does not appear to be a risk factor for unfavorable cardiometabolic markers in adolescence.
Objectives To investigate whether children delivered by cesarean had a higher risk of being overweight from early until late childhood and whether they had a higher blood pressure in adolescence ...compared with children delivered vaginally. Study design We used data from a Dutch birth cohort study with prenatal inclusion in 1996 and 1997. Mode of delivery (cesarean or vaginal delivery) was ascertained at 3 months after birth by questionnaire. During clinical examinations, height and weight (at age 4, 8, 12, and 16 years) and blood pressure (at age 12 and 16 years) were measured. We used mixed model analysis to estimate associations of cesarean delivery with overweight and blood pressure z scores in 2641 children who participated in at least 1 of the 4 examinations. Results Children born by cesarean delivery (n = 236, 8.9%) had a 1.52 (95% CI 1.18, 1.96) higher odds of being overweight throughout childhood than children delivered vaginally. Children born by cesarean delivery had no higher systolic blood pressure z-score (0.11 SD, 95% CI −0.04, 0.26), nor a different diastolic blood pressure z-score (−0.00 SD, 95% CI −0.10, 0.09) in adolescence than children delivered vaginally. Conclusions Compared with children delivered vaginally, children delivered by cesarean had a 52% higher risk of being overweight throughout childhood, but this was not accompanied by a higher blood pressure in adolescence.
Background Clinicians have difficulty in diagnosing asthma in preschool children with suggestive symptoms. Objective We sought to develop a clinical asthma prediction score for preschool children who ...have asthma-like symptoms for the first time. Methods The Prevalence and Incidence of Asthma and Mite Allergy birth cohort followed 3,963 children for 8 years. Between 0 and 4 years of age, 2,171 (55%) children reported “wheezing,” “coughing at night without a cold,” or both. In these children possible predictor variables for asthma were assessed at the age respiratory symptoms were first reported. Asthma was defined as wheezing, inhaled steroid prescription, or a doctor's diagnosis of asthma at both age 7 and 8 years of age. Results Eleven percent of children with symptoms at 0 to 4 years of age had asthma at 7 to 8 years of age. Eight clinical parameters independently predicted asthma at 7 to 8 years of age: male sex, postterm delivery, parental education and inhaled medication, wheezing frequency, wheeze/dyspnea apart from colds, respiratory infections, and eczema. In 72% of the cases, the model accurately discriminated between asthmatic and nonasthmatic children. A clinical risk score was developed (range, 0-55 points). Symptomatic children with a score of less than 10 points had a 3% risk, whereas children with a score of 30 points or greater had a 42% risk of asthma. Conclusion A risk score based on 8 readily available clinical parameters at the time preschool children first reported asthma-like symptoms predicted the risk of asthma at 7 to 8 years of age.
Background IL-1 receptor–like 1 (IL1RL1) is a membrane receptor involved in TH 2 inflammatory responses and eosinophilia. Single nucleotide polymorphisms (SNPs) in IL1RL1 have been associated with ...blood eosinophil counts in a genome-wide association study and with asthma in family-based and case-control studies. Objective We assessed in the prospective birth cohort Prevention and Incidence of Asthma and Mite Allergy (PIAMA) whether IL1RL1 SNPs associate with levels of its soluble transcript IL1RL1 (IL1RL1-a) in serum, blood eosinophil counts, and asthma prevalence from birth to age 8 years, and whether IL1RL1-a serum levels associate with blood eosinophil counts. Methods Fifteen IL1RL1 SNPs were genotyped. Serum IL1RL1-a levels were measured in 2 independent subsets within PIAMA, at 4 and 8 years. Blood eosinophil counts were measured in 4-year-old children. Results In 2 independent subsets of children, 13 of 15 SNPs were associated with serum IL1RL1-a levels at ages 4 and 8 years with a consistent direction of effect for each allele. Rs11685480 allele A and rs1420102 allele A were significantly associated with lower numbers of blood eosinophils. In the total cohort, rs1041973 allele A was associated with a decreased risk of developing asthma (odds ratio, 0.70; 95% CI, 0.54-0.90). Rs1420101, recently identified in a genome-wide association study in the Icelandic population, was not associated with asthma in this study. IL1RL1-a levels were not associated with eosinophil counts. Conclusion We demonstrate that IL1RL1 polymorphisms are associated with serum IL1RL1-a, blood eosinophils, and asthma in childhood.
Allergic sensitization is often used to predict asthma.1 Previously, in the German Multicenter Allergy Study, children sensitized to hen's egg at age 1 year were at an increased risk of allergic ...sensitization at the age of 3 years.2 Egg sensitization was previously associated with asthma in prospective studies.3-5 In a Dutch cohort of children with more repeated measurements and additional outcome measures, our study aimed to investigate whether sensitization to hen's egg allergen at age 1 year is more strongly associated with asthma development than is sensitization to other allergens. BHR was defined as a decrease of 20% or more in FEV1 at a cumulative dose of 0.61 mg or less of methacholine bromide.7 The associations between sensitization to hen's egg and cow's milk allergen and atopy, respectively, at age 1 year and asthma in the next 10 years were assessed by using generalized estimating equations.
Abstract Objective To test how attribute framing in a discrete choice experiment (DCE) affects respondents’ decision-making behavior and their preferences. Methods Two versions of a DCE questionnaire ...containing nine choice tasks were distributed among a representative sample of the Dutch population aged 55 to 65 years. The DCE consisted of four attributes related to the decision regarding participation in genetic screening for colorectal cancer (CRC). The risk attribute included was framed positively as the probability of surviving CRC and negatively as the probability of dying from CRC. Panel mixed-logit models were used to estimate the relative importance of the attributes. The data of the positively and negatively framed DCE were compared on the basis of direct attribute ranking, dominant decision-making behavior, preferences, and importance scores. Results The majority (56%) of the respondents ranked survival as the most important attribute in the positively framed DCE, whereas only a minority (8%) of the respondents ranked mortality as the most important attribute in the negatively framed DCE. Respondents made dominant choices based on survival significantly more often than based on mortality. The framing of the risk attribute significantly influenced all attribute-level estimates and resulted in different preference structures among respondents in the positively and negatively framed data set. Conclusions Risk framing affects how respondents value the presented risk. Positive risk framing led to increased dominant decision-making behavior, whereas negative risk framing led to risk-seeking behavior. Attribute framing should have a prominent part in the expert and focus group interviews, and different types of framing should be used in the pilot version of DCEs as well as in actual DCEs to estimate the magnitude of the effect of choosing different types of framing.
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