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1.  Associations of Pet Ownership with Wheezing and Lung Function in Childhood: Findings from a UK Birth Cohort 
PLoS ONE  2015;10(6):e0127756.
Background
Asthma is a heterogeneous condition and differential effects of pet ownership on non-atopic versus atopic asthma have been reported. The aim of this study was to investigate whether pet ownership during pregnancy and early childhood was associated with wheezing from birth to age 7 years and with lung function at age 8 years in a UK population-based birth cohort.
Methods
Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used to investigate associations of pet ownership at six time-points from pregnancy to age 7 years with concurrent episodes of wheezing, wheezing trajectories (phenotypes) and lung function at age 8 years using logistic regression models adjusted for child’s sex, maternal history of asthma/atopy, maternal smoking during pregnancy, and family adversity.
Results
4,706 children had complete data on pet ownership and wheezing. From birth to age 7 years, cat ownership was associated with an overall 6% lower odds of wheezing (OR=0.94 (0.89-0.99)). Rabbit and rodent ownership was associated with 21% (OR=1.21 (1.12-1.31)) and 11% (OR=1.11 (1.02–1.21)) higher odds of wheezing, respectively, with strongest effects evident during infancy. Rabbit and rodent ownership was positively associated with a ‘persistent wheeze’ phenotype. Pet ownership was not associated with lung function at age 8 years, with the exception of positive associations of rodent and bird ownership with better lung function.
Conclusions
Cat ownership was associated with reduced risk, and rabbit and rodent ownership with increased risk, of wheezing during childhood. The mechanisms behind these differential effects warrant further investigation.
doi:10.1371/journal.pone.0127756
PMCID: PMC4465326  PMID: 26061067
2.  Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype 
Background
To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever.
Objective
We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases.
Methods
We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091).
Results
At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6).
Conclusion
By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.
doi:10.1016/j.jaci.2013.10.030
PMCID: PMC4280183  PMID: 24388013
Rhinitis; atopy; selection; genetic correlation; bivariate; single nucleotide polymorphism
3.  Influence of childhood growth on asthma and lung function in adolescence 
Background
Low birth weight and rapid infant growth in early infancy are associated with increased risk of childhood asthma, but little is known about the role of postinfancy growth in asthmatic children.
Objectives
We sought to examine the associations of children's growth patterns with asthma, bronchial responsiveness, and lung function until adolescence.
Methods
Individual growth trajectories from birth until 10 years of age were estimated by using linear spline multilevel models for 9723 children participating in a population-based prospective cohort study. Current asthma at 8, 14, and 17 years of age was based on questionnaires. Lung function and bronchial responsiveness or reversibility were measured during clinic visits at 8 and 15 years of age.
Results
Rapid weight growth between 0 and 3 months of age was most consistently associated with increased risks of current asthma at the ages of 8 and 17 years, bronchial responsiveness at age 8 years, and bronchial reversibility at age 15 years. Rapid weight growth was associated with lung function values, with the strongest associations for weight gain between 3 and 7 years of age and higher forced vital capacity (FVC) and FEV1 values at age 15 years (0.12 [95% CI, 0.08 to 0.17] and 0.11 [95% CI, 0.07 to 0.15], z score per SD, respectively) and weight growth between 0 and 3 months of age and lower FEV1/FVC ratios at age 8 and 15 years (−0.13 [95% CI, −0.16 to −0.10] and −0.04 [95% CI, −0.07 to −0.01], z score per SD, respectively). Rapid length growth was associated with lower FVC and FVC1 values at age 15 years.
Conclusion
Faster weight growth in early childhood is associated with asthma and bronchial hyperresponsiveness, and faster weight growth across childhood is associated with higher FVC and FEV1 values.
doi:10.1016/j.jaci.2014.10.046
PMCID: PMC4452091  PMID: 25577593
ALSPAC; asthma; cohort study; growth; lung function; ALSPAC, Avon Longitudinal Study of Parents and Children; FEF25-75, Forced expiratory flow between 25% and 75%; FVC, Forced vital capacity; OR, Odds ratio
4.  Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes 
Background
Genome-wide association studies have identified associations of genetic variants at 17q21 near ORMDL3 with childhood asthma.
Objectives
To find out whether associations in this region are specific to particular asthma phenotypes and specific to ORMDL3.
Methods
We examined associations between 244 independent single nucleotide polymorphisms (SNPs) plus 13 previously identified asthma-related SNPs in the region between 34 and 36 Mb on chromosome 17 and early wheezing phenotypes, doctor-diagnosed asthma and atopy at 7½ years, bronchial hyper-responsiveness and lung function at 8½ years in 7,045 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. With this, cis expression quantitative trait loci (eQTL) signals for the same SNPs were assessed in 875 samples across genes in the same region.
Results
The strongest evidence for phenotypic association was seen for persistent wheezing (rs8076131 near ORMDL3, relative risk ratio (RRR) 1.60 (95% CI 1.40, 1.84), p=1.4×10−11, rs2305480 near GSDML 1.60; 1.39-1.83, p=1.5×10−11 and rs9303277 near IKZF3 1.57; 1.37-1.79, p=4.4×10−11). Similar, but less precisely estimated effects were seen for intermediate-onset wheeze, but there was little evidence of associations with other wheezing phenotypes. There was some evidence of associations with bronchial hyper responsiveness. SNPs across the whole region show strong evidence of association with differential levels of expression at GSDML, IKZF3 and MED24, as well as ORMDL3.
Conclusions
Associations of SNPs in the 17q21 locus are specific to asthma and to specific wheezing phenotypes, and are not explained by associations with intermediate phenotypes, such as atopy or lung function.
doi:10.1016/j.jaci.2012.09.021
PMCID: PMC4427593  PMID: 23154084
ALSPAC; wheezing phenotypes; chromosome 17; ORMDL3; gene expression
7.  The Perception of Naturalness Correlates with Low-Level Visual Features of Environmental Scenes 
PLoS ONE  2014;9(12):e114572.
Previous research has shown that interacting with natural environments vs. more urban or built environments can have salubrious psychological effects, such as improvements in attention and memory. Even viewing pictures of nature vs. pictures of built environments can produce similar effects. A major question is: What is it about natural environments that produces these benefits? Problematically, there are many differing qualities between natural and urban environments, making it difficult to narrow down the dimensions of nature that may lead to these benefits. In this study, we set out to uncover visual features that related to individuals' perceptions of naturalness in images. We quantified naturalness in two ways: first, implicitly using a multidimensional scaling analysis and second, explicitly with direct naturalness ratings. Features that seemed most related to perceptions of naturalness were related to the density of contrast changes in the scene, the density of straight lines in the scene, the average color saturation in the scene and the average hue diversity in the scene. We then trained a machine-learning algorithm to predict whether a scene was perceived as being natural or not based on these low-level visual features and we could do so with 81% accuracy. As such we were able to reliably predict subjective perceptions of naturalness with objective low-level visual features. Our results can be used in future studies to determine if these features, which are related to naturalness, may also lead to the benefits attained from interacting with nature.
doi:10.1371/journal.pone.0114572
PMCID: PMC4273965  PMID: 25531411
8.  Developmental Profiles of Eczema, Wheeze, and Rhinitis: Two Population-Based Birth Cohort Studies 
PLoS Medicine  2014;11(10):e1001748.
Using data from two population-based birth cohorts, Danielle Belgrave and colleagues examine the evidence for atopic march in developmental profiles for allergic disorders.
Please see later in the article for the Editors' Summary
Background
The term “atopic march” has been used to imply a natural progression of a cascade of symptoms from eczema to asthma and rhinitis through childhood. We hypothesize that this expression does not adequately describe the natural history of eczema, wheeze, and rhinitis during childhood. We propose that this paradigm arose from cross-sectional analyses of longitudinal studies, and may reflect a population pattern that may not predominate at the individual level.
Methods and Findings
Data from 9,801 children in two population-based birth cohorts were used to determine individual profiles of eczema, wheeze, and rhinitis and whether the manifestations of these symptoms followed an atopic march pattern. Children were assessed at ages 1, 3, 5, 8, and 11 y. We used Bayesian machine learning methods to identify distinct latent classes based on individual profiles of eczema, wheeze, and rhinitis. This approach allowed us to identify groups of children with similar patterns of eczema, wheeze, and rhinitis over time.
Using a latent disease profile model, the data were best described by eight latent classes: no disease (51.3%), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%). When latent variable modelling was carried out separately for the two cohorts, similar results were obtained. Highly concordant patterns of sensitisation were associated with different profiles of eczema, rhinitis, and wheeze. The main limitation of this study was the difference in wording of the questions used to ascertain the presence of eczema, wheeze, and rhinitis in the two cohorts.
Conclusions
The developmental profiles of eczema, wheeze, and rhinitis are heterogeneous; only a small proportion of children (∼7% of those with symptoms) follow trajectory profiles resembling the atopic march.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Our immune system protects us from viruses, bacteria, and other pathogens by recognizing specific molecules on the invader's surface and initiating a sequence of events that culminates in the death of the pathogen. Sometimes, however, our immune system responds to harmless materials (allergens such as pollen) and triggers allergic, or atopic, symptoms. Common atopic symptoms include eczema (transient dry itchy patches on the skin), wheeze (high pitched whistling in the chest, a symptom of asthma), and rhinitis (sneezing or a runny nose in the absence of a cold or influenza). All these symptoms are very common during childhood, but recent epidemiological studies (examinations of the patterns and causes of diseases in a population) have revealed age-related changes in the proportions of children affected by each symptom. So, for example, eczema is more common in infants than in school-age children. These findings have led to the idea of “atopic march,” a natural progression of symptoms within individual children that starts with eczema, then progresses to wheeze and finally rhinitis.
Why Was This Study Done?
The concept of atopic march has led to the initiation of studies that aim to prevent the development of asthma in children who are thought to be at risk of asthma because they have eczema. Moreover, some guidelines recommend that clinicians tell parents that children with eczema may later develop asthma or rhinitis. However, because of the design of the epidemiological studies that support the concept of atopic march, children with eczema who later develop wheeze and rhinitis may actually belong to a distinct subgroup of children, rather than representing the typical progression of atopic diseases. It is important to know whether atopic march adequately describes the natural history of atopic diseases during childhood to avoid the imposition of unnecessary strategies on children with eczema to prevent asthma. Here, the researchers use machine learning techniques to model the developmental profiles of eczema, wheeze, and rhinitis during childhood in two large population-based birth cohorts by taking into account time-related (longitudinal) changes in symptoms within individuals. Machine learning is a data-driven approach that identifies structure within the data (for example, a typical progression of symptoms) using unsupervised learning of latent variables (variables that are not directly measured but are inferred from other observable characteristics).
What Did the Researchers Do and Find?
The researchers used data from two UK birth cohorts—the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Manchester Asthma and Allergy Study (MAAS)—for their study (9,801 children in total). Both studies enrolled children at birth and monitored their subsequent health at regular review clinics. At each review clinic, information about eczema, wheeze, and rhinitis was collected from the parents using validated questionnaires. The researchers then used these data and machine learning methods to identify groups of children with similar patterns of onset of eczema, wheeze, and rhinitis over the first 11 years of life. Using a type of statistical model called a latent disease profile model, the researchers found that the data were best described by eight latent classes—no disease (51.3% of the children), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%).
What Do These Findings Mean?
These findings show that, in two large UK birth cohorts, the developmental profiles of eczema, wheeze, and rhinitis were heterogeneous. Most notably, the progression of symptoms fitted the profile of atopic march in fewer than 7% of children with symptoms. The researchers acknowledge that their study has some limitations. For example, small differences in the wording of the questions used to gather information from parents about their children's symptoms in the two cohorts may have slightly affected the findings. However, based on their findings, the researchers propose that, because eczema, wheeze, and rhinitis are common, these symptoms often coexist in individuals, but as independent entities rather than as a linked progression of symptoms. Thus, using eczema as an indicator of subsequent asthma risk and assigning “preventative” measures to children with eczema is flawed. Importantly, clinicians need to understand the heterogeneity of patterns of atopic diseases in children and to communicate this variability to parents when advising them about the development and resolution of atopic symptoms in their children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001748.
The UK National Health Service Choices website provides information about eczema (including personal stories), asthma (including personal stories), and rhinitis
The US National Institute of Allergy and Infectious Diseases provides information about atopic diseases
The UK not-for-profit organization Allergy UK provides information about atopic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on eczema, wheezing, and rhinitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and asthma (in English and Spanish)
Information about ALSPAC and MAAS is available
Wikipedia has pages on machine learning and latent disease profile models (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001748
PMCID: PMC4204810  PMID: 25335105
9.  Child Allergic Symptoms and Mental Well-Being: The Role of Maternal Anxiety and Depression☆ 
The Journal of Pediatrics  2014;165(3):592-599.e5.
Objective
To determine whether maternal mental health mediates the relationship between eczema or asthma symptoms and mental well-being in children.
Study design
Analysis of 7250 children from the Avon Longitudinal Study of Parents and Children. Child mental well-being at 8 years was measured by the Strengths and Difficulties Questionnaire. Binary outcomes were high ‘internalizing’ (anxious/depressive) and ‘externalizing’ (oppositional/hyperactive) problems (high was >90th percentile). Child rash and wheeze categories were ‘none’; ‘early onset transient’ (infancy/preschool only); ‘persistent’ (infancy/preschool and at school age); and ‘late onset’ (school age only). Maternal anxiety and depression were reported during pregnancy and when child was 8 years old.
Results
Persistent wheezing symptoms were associated with high externalizing (OR 1.74, 95% CI, 1.41-2.15) and internalizing (1.67, 1.35-2.06) problems compared with never wheeze. Maternal anxiety and depression, and disrupted child sleep, attenuated these associations. Persistent rash (externalizing: 1.74, 1.40-2.15; internalizing: 1.42, 1.16-1.74) and late onset rash (externalizing: 1.62, 1.17-2.25; internalizing: 1.46, 1.07-1.99) symptoms were associated with poorer mental well-being compared with no rash at any age. Maternal anxiety and depression, particularly when child was aged 8 years rather than during pregnancy, accounted for the association with internalizing symptoms and partly for externalizing symptoms. Sleep disruption did not mediate the association.
Conclusions
Maternal anxiety and depression may mediate the association between child rash and wheeze and child mental well-being.
doi:10.1016/j.jpeds.2014.05.023
PMCID: PMC4148480  PMID: 24952709
ADHD, Attention deficit/hyperactivity disorder; ALSPAC, Avon Longitudinal Study of Parents and Children; SEP, Socioeconomic position; TDS, Total difficulties score
10.  Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study 
PLoS Medicine  2014;11(7):e1001669.
In this study, Granell and colleagues used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in the Avon Longitudinal Study of Parents and Children (ALSPAC) and found that higher BMI increases the risk of asthma in mid-childhood.
Please see later in the article for the Editors' Summary
Background
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.
Methods and Findings
We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.
Conclusions
Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma, a chronic (long-term) condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs), has been rising steadily over the past few decades. It is estimated that, nowadays, 200–300 million adults and children worldwide are affected by asthma. Although asthma can develop at any age, it is often diagnosed in childhood—asthma is the most common chronic disease in children. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke, becoming narrower so that less air can enter the lungs. Exercise, cold air, and infections can also trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
We cannot halt the ongoing rise in global asthma rates without understanding the causes of asthma. Some experts think obesity may be one cause of asthma. Obesity, like asthma, is increasingly common, and observational studies (investigations that ask whether individuals exposed to a suspected risk factor for a condition develop that condition more often than unexposed individuals) in children have reported that body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is positively associated with asthma. Observational studies cannot prove that obesity causes asthma because of “confounding.” Overweight children with asthma may share another unknown characteristic (confounder) that actually causes both obesity and asthma. Moreover, children with asthma may be less active than unaffected children, so they become overweight (reverse causality). Here, the researchers use “Mendelian randomization” to assess whether BMI has a causal effect on asthma. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if a higher BMI leads to asthma, genetic variants associated with increased BMI should be associated with an increased risk of asthma.
What Did the Researchers Do and Find?
The researchers investigated causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in 4,835 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC, a long-term health project that started in 1991). They calculated an allele score for each child based on 32 BMI-related genetic variants, and estimated associations between this score and BMI, fat mass and lean mass (both measured using a special type of X-ray scanner; in children BMI is not a good indicator of “fatness”), and asthma. They report that the allele score was strongly associated with BMI, fat mass, and lean mass, and with childhood asthma. The estimated causal relative risk (risk ratio) for the effect of BMI on asthma was 1.55 per kg/m2. That is, the relative risk of asthma increased by 55% for every extra unit of BMI. The estimated causal relative risks for the effects of fat mass and lean mass on asthma were 1.41 per 0.5 kg and 2.25 per kg, respectively.
What Do These Findings Mean?
These findings suggest that a higher BMI increases the risk of asthma in mid-childhood and that global increases in BMI toward the end of the 20th century may have contributed to the global increase in asthma that occurred at the same time. It is possible that the observed association between BMI and asthma reported in this study is underpinned by “genetic pleiotropy” (a potential limitation of all Mendelian randomization analyses). That is, some of the genetic variants included in the BMI allele score could conceivably also increase the risk of asthma. Nevertheless, these findings suggest that public health interventions designed to reduce obesity may also help to limit the global rise in asthma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001669.
The US Centers for Disease Control and Prevention provides information on asthma and on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on asthma and on obesity (in several languages)
The UK National Health Service Choices website provides information about asthma, about asthma in children, and about obesity (including real stories)
The Global Asthma Report 2011 is available
The Global Initiative for Asthma released its updated Global Strategy for Asthma Management and Prevention on World Asthma Day 2014
Information about the Avon Longitudinal Study of Parents and Children is available
MedlinePlus provides links to further information on obesity in children, on asthma, and on asthma in children (in English and Spanish
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001669
PMCID: PMC4077660  PMID: 24983943
11.  Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children 
Background
Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.
Objectives
We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).
Methods
First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes.
Results
Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27).
Conclusion
Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.
doi:10.1016/j.jaci.2013.12.1082
PMCID: PMC4024198  PMID: 24529685
Gestational age; low birth weight; infant growth; wheezing; asthma; children; cohort studies; epidemiology; BMI, Body mass index; ISAAC, International Study on Asthma and Allergy in Childhood; OR, Odds ratio; pOR, Pooled odds ratio; SDS, Standard deviation scores
12.  Validating childhood asthma in an epidemiological study using linked electronic patient records 
BMJ Open  2014;4(4):e005345.
Objective
To investigate the performance of parent-reported data in identifying physician-confirmed asthma.
Design and setting
Validation study using linkage between the Avon Longitudinal Study of Parents and Children (ALSPAC) and electronic patient records held within the General Practice Research Database (GPRD).
Participants
Participants were those eligible to participate in ALSPAC who also had a record in the GPRD; this included 765 individuals, just under 4% of ALSPAC-eligible participants. The analysis was based on 141 participants with complete parent-reported asthma data.
Primary and secondary outcome measures
The main GPRD outcome measure was whether a child had a diagnosis of asthma before they were nine. Parent-reported measures were doctor diagnosis of asthma (before mean age 7.5 years), various outcomes based on wheezing and breathlessness recorded longitudinally between 6 months and 8.5 years. Secondary outcomes were bronchial hyper-responsiveness (BHR), forced expiratory volume in 1 s/forced vital capacity ratio and skin prick test responses.
Results
Among the 141 participants with complete parent-reported data, 26 (18%) had an asthma diagnosis before age nine. Using general practitioner (GP)-recorded asthma as the gold standard, the question ‘Has a doctor ever diagnosed your child with asthma?’ was both sensitive (88.5%) and specific (95.7%). ‘Ever wheezed’ had the highest sensitivity (100%) but low specificity (60%). More specific definitions were obtained by restricting to those who had wheezed on more than one occasion, experienced frequent wheeze and/or wheezed after the age of 3, but these measures had low sensitivities. BHR only identified 50% of those with a GP-recorded diagnosis.
Conclusions
Parental reports of a doctor's diagnosis agree well with a GP-recorded diagnosis. High specificity for asthma can be achieved by using detailed wheezing questions, although these definitions are likely to exclude mild cases of asthma. Our study shows that linkage between observational studies and electronic patient records has the potential to enhance epidemiological research.
doi:10.1136/bmjopen-2014-005345
PMCID: PMC4010849  PMID: 24760357
Epidemiology; Primary Care
13.  Genome-wide association study of body mass index in 23,000 individuals with and without asthma 
Background
Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.
Objective
To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.
Methods
In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23,000 individuals with predominantly European descent, of whom 8,165 are asthmatics.
Results
We report associations between several DENND1B variants (p=2.2×10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2,691 asthmatic children (screening data). The top DENND1B SNPs were next evaluated in seven independent replication data sets comprising 2,014 asthmatics, and rs4915551 was nominally replicated (p<0.05) in two of the seven studies and of borderline significance in one (p=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, p=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 (p=0.01 for combined screening and replication data sets, N=4,705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.
Conclusions and Clinical Relevance
DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
doi:10.1111/cea.12054
PMCID: PMC3608930  PMID: 23517042
Association; Asthma; BMI; Genetics; Genome-wide; Obesity
15.  Prenatal alcohol exposure and childhood atopic disease: A Mendelian randomization approach☆ 
Background
Alcohol consumption in western pregnant women is not uncommon and could be a risk factor for childhood atopic disease. However, reported alcohol intake may be unreliable, and associations are likely to be confounded.
Objective
We aimed to study the relation between prenatal alcohol exposure and atopic phenotypes in a large population-based birth cohort with the use of a Mendelian randomization approach to minimize bias and confounding.
Methods
In white mothers and children in the Avon Longitudinal Study of Parents and Children (ALSPAC) we first analyzed associations between reported maternal alcohol consumption during pregnancy and atopic outcomes in the offspring measured at 7 years of age (asthma, wheezing, hay fever, eczema, atopy, and total IgE). We then analyzed the relation of maternal alcohol dehydrogenase (ADH)1B genotype (rs1229984) with these outcomes (the A allele is associated with faster metabolism and reduced alcohol consumption and, among drinkers, would be expected to reduce fetal exposure to ethanol).
Results
After controlling for confounders, reported maternal drinking in late pregnancy was negatively associated with childhood asthma and hay fever (adjusted odds ratio [OR] per category increase in intake: 0.91 [95% CI, 0.82-1.01] and 0.87 [95% CI, 0.78-0.98], respectively). However, maternal ADH1B genotype was not associated with asthma comparing carriers of A allele with persons homozygous for G allele (OR, 0.98 [95% CI, 0.66-1.47]) or hay fever (OR, 1.11 [95% CI, 0.71-1.72]), nor with any other atopic outcome.
Conclusion
We have found no evidence to suggest that prenatal alcohol exposure increases the risk of asthma or atopy in childhood.
doi:10.1016/j.jaci.2013.04.051
PMCID: PMC3884122  PMID: 23806636
Alcohol; ADH1B; Mendelian randomization; prenatal exposure; ALSPAC; pregnancy; birth cohort; asthma; atopy; ADH, Alcohol dehydrogenase; ALSPAC, Avon Longitudinal Study of Parents and Children (ALSPAC); GWAS, Genome Wide Association Study; PCA, Principal Components Analysis
16.  The neural substrates of natural reading: a comparison of normal and nonword text using eyetracking and fMRI 
Most previous studies investigating the neural correlates of reading have presented text using serial visual presentation (SVP), which may not fully reflect the underlying processes of natural reading. In the present study, eye movements and BOLD data were collected while subjects either read normal paragraphs naturally or moved their eyes through “paragraphs” of pseudo-text (pronounceable pseudowords or consonant letter strings) in two pseudo-reading conditions. Eye movement data established that subjects were reading and scanning the stimuli normally. A conjunction fMRI analysis across natural- and pseudo-reading showed that a common eye-movement network including frontal eye fields (FEF), supplementary eye fields (SEF), and intraparietal sulci was activated, consistent with previous studies using simpler eye movement tasks. In addition, natural reading versus pseudo-reading showed different patterns of brain activation: normal reading produced activation in a well-established language network that included superior temporal gyrus/sulcus, middle temporal gyrus (MTG), angular gyrus (AG), inferior frontal gyrus, and middle frontal gyrus, whereas pseudo-reading produced activation in an attentional network that included anterior/posterior cingulate and parietal cortex. These results are consistent with results found in previous single-saccade eye movement tasks and SVP reading studies, suggesting that component processes of eye-movement control and language processing observed in past fMRI research generalize to natural reading. The results also suggest that combining eyetracking and fMRI is a suitable method for investigating the component processes of natural reading in fMRI research.
doi:10.3389/fnhum.2014.01024
PMCID: PMC4274877  PMID: 25566039
reading; eye movements; fMRI; pseudo-reading; attention
17.  Do Grandmaternal Smoking Patterns Influence the Etiology of Childhood Asthma? 
Chest  2013;145(6):1213-1218.
Background:
Animal data suggest that tobacco smoke exposure of a mother when she is in utero influences DNA methylation patterns in her offspring and that there is an effect on the respiratory system, particularly airway responsiveness. The only study, to our knowledge, in humans suggests that there is a similar effect on asthma. The present study tests whether an association with respiratory problems can be confirmed in a large population study and aims to determine whether in utero exposure of the father has similar effects on his offspring.
Methods:
Information from the Avon Longitudinal Study of Parents and Children was used to compare the offspring of women and of men who had themselves been exposed to cigarette smoke in utero; separate analyses were performed for children of women smokers and nonsmokers. The outcome measures were trajectories of history of early wheezing, doctor-diagnosed asthma by age 7 years, and results of lung function and methacholine challenge tests at 8 years. A variety of social and environmental factors were taken into account; offspring sexes were examined separately.
Results:
There was no association with any outcome in relation to maternal prenatal exposure. There was some evidence of an increase in asthma risk with paternal prenatal exposure when the study mother was a nonsmoker (adjusted OR, 1.17; 95% CI, 0.97-1.41). This was particularly strong for girls (adjusted OR, 1.39; 95% CI, 1.04-1.86).
Conclusions:
We did not find that maternal prenatal exposure to her mother’s smoking had any effect on her children’s respiratory outcomes. There was suggestive evidence of paternal prenatal exposure being associated with asthma and persistent wheezing in the granddaughters.
doi:10.1378/chest.13-1371
PMCID: PMC4042509  PMID: 24158349
18.  Temporal oculomotor inhibition of return and spatial facilitation of return in a visual encoding task 
Oculomotor inhibition of return (O-IOR) is an increase in saccade latency prior to an eye movement to a recently fixated location compared to other locations. It has been proposed that this temporal O-IOR may have spatial consequences, facilitating foraging by inhibiting return to previously attended regions. In order to test this possibility, participants viewed arrays of objects and of words while their eye movements were recorded. Temporal O-IOR was observed, with equivalent effects for object and word arrays, indicating that temporal O-IOR is an oculomotor phenomenon independent of array content. There was no evidence for spatial inhibition of return (IOR). Instead, spatial facilitation of return was observed: participants were significantly more likely than chance to make return saccades and to re-fixate just-visited locations. Further, the likelihood of making a return saccade to an object or word was contingent on the amount of time spent viewing that object or word before leaving it. This suggests that, unlike temporal O-IOR, return probability is influenced by cognitive processing. Taken together, these results are inconsistent with the hypothesis that IOR functions as a foraging facilitator. The results also provide strong evidence for a different oculomotor bias that could serve as a foraging facilitator: saccadic momentum, a tendency to repeat the most recently executed saccade program. We suggest that models of visual attention could incorporate saccadic momentum in place of IOR.
doi:10.3389/fpsyg.2013.00400
PMCID: PMC3698447  PMID: 23847574
inhibition of return; facilitation of return; eye movement control; saccadic momentum; foraging facilitator
20.  Predicting Cognitive State from Eye Movements 
PLoS ONE  2013;8(5):e64937.
In human vision, acuity and color sensitivity are greatest at the center of fixation and fall off rapidly as visual eccentricity increases. Humans exploit the high resolution of central vision by actively moving their eyes three to four times each second. Here we demonstrate that it is possible to classify the task that a person is engaged in from their eye movements using multivariate pattern classification. The results have important theoretical implications for computational and neural models of eye movement control. They also have important practical implications for using passively recorded eye movements to infer the cognitive state of a viewer, information that can be used as input for intelligent human-computer interfaces and related applications.
doi:10.1371/journal.pone.0064937
PMCID: PMC3666973  PMID: 23734228
21.  A three-dimensional analysis of the effect of atopy on face shape 
SUMMARY
Three-dimensional (3D) imaging technology has been widely used to analyse facial morphology and has revealed an influence of some medical conditions on craniofacial growth and morphology.
The aim of the study is to investigate whether craniofacial morphology is different in atopic Caucasian children compared with controls.
Study design included observational longitudinal cohort study. Atopy was diagnosed via skin-prick tests performed at 7.5 years of age. The cohort was followed to 15 years of age as part of the Avon Longitudinal Study of Parents and Children (ALSPAC). A total of 734 atopic and 2829 controls were identified. 3D laser surface facial scans were obtained at 15 years of age. Twenty-one reproducible facial landmarks (x, y, z co-ordinates) were identified on each facial scan. Inter-landmark distances and average facial shells for atopic and non-atopic children were compared with explore differences in face shape between the groups.
Both total anterior face height (pg–g, pg–men) and mid-face height (Is–men, sn–men, n–sn) were longer (0.6 and 0.4mm respectively) in atopic children when compared with non-atopic children. No facial differences were detected in the transverse and antero-posterior relationships.
Small but statistically significant differences were detected in the total and mid-face height between atopic and non-atopic children. No differences were detected in the transverse and antero-posterior relationships.
doi:10.1093/ejo/cjs107
PMCID: PMC4174908  PMID: 25257926
22.  Co-registration of eye movements and event-related potentials in connected-text paragraph reading 
Eyetracking during reading has provided a critical source of on-line behavioral data informing basic theory in language processing. Similarly, event-related potentials (ERPs) have provided an important on-line measure of the neural correlates of language processing. Recently there has been strong interest in co-registering eyetracking and ERPs from simultaneous recording to capitalize on the strengths of both techniques, but a challenge has been devising approaches for controlling artifacts produced by eye movements in the EEG waveform. In this paper we describe our approach to correcting for eye movements in EEG and demonstrate its applicability to reading. The method is based on independent components analysis, and uses three criteria for identifying components tied to saccades: (1) component loadings on the surface of the head are consistent with eye movements; (2) source analysis localizes component activity to the eyes, and (3) the temporal activation of the component occurred at the time of the eye movement and differed for right and left eye movements. We demonstrate this method's applicability to reading by comparing ERPs time-locked to fixation onset in two reading conditions. In the text-reading condition, participants read paragraphs of text. In the pseudo-reading control condition, participants moved their eyes through spatially similar pseudo-text that preserved word locations, word shapes, and paragraph spatial structure, but eliminated meaning. The corrected EEG, time-locked to fixation onsets, showed effects of reading condition in early ERP components. The results indicate that co-registration of eyetracking and EEG in connected-text paragraph reading is possible, and has the potential to become an important tool for investigating the cognitive and neural bases of on-line language processing in reading.
doi:10.3389/fnsys.2013.00028
PMCID: PMC3706749  PMID: 23847477
eyetracking; event-related potentials (ERPs); reading; eye movements; coregistration; pseudo-reading
23.  Associations of Different Phenotypes of Wheezing Illness in Early Childhood with Environmental Variables Implicated in the Aetiology of Asthma 
PLoS ONE  2012;7(10):e48359.
Rationale
Asthma is a complex heterogeneous disease that has increased in prevalence in many industrialised countries. However, the causes of asthma inception remain elusive. Consideration of sub-phenotypes of wheezing may reveal important clues to aetiological risk factors.
Methods
Longitudinal phenotypes capturing population heterogeneity in wheezing reports from birth to 7 years were derived using latent class analysis in the Avon Longitudinal Study of Parents and Children (ALSPAC). Probability of class membership was used to examine the association between five wheezing phenotypes (transient early, prolonged early, intermediate-onset, late-onset, persistent) and early life risk factors for asthma.
Results
Phenotypes had similar patterns and strengths of associations with early environmental factors. Comparing transient early with prolonged early wheezing showed a similar pattern of association with most exposure variables considered in terms of the direction of the effect estimates but with prolonged early wheezing tending to have stronger associations than transient early wheezing except for parity and day care attendance.
Conclusions
Associations with early life risk factors suggested that prolonged early wheeze might be a severe form of transient early wheezing. Although differences were found in the associations of early life risk factors with individual phenotypes, these did not point to novel aetiological pathways. Persistent wheezing phenotype has features suggesting overlap of early and late-onset phenotypes.
doi:10.1371/journal.pone.0048359
PMCID: PMC3485223  PMID: 23118993
24.  The Association Between Irregular Menstruations and Acne With Asthma and Atopy Phenotypes 
American Journal of Epidemiology  2012;176(8):733-737.
Earlier menarche and irregular periods, among other markers of sex-hormone levels, have been associated with a higher risk of asthma and allergic diseases. This has suggested an etiologic role of sex hormones in the development of these conditions. The authors investigated the association of age at menarche, irregular periods, duration of menstruation, and acne with reported medical history of asthma and/or atopy (hay fever and/or eczema/urticaria) in a historical cohort of students born before the rise in asthma prevalence in the United Kingdom and attending university in 1948–1968. Finding consistent associations in a cohort that has experienced different life-course exposures and has different confounding structure can help to identify causal associations. In the Glasgow Alumni Cohort, irregular periods were associated with atopic asthma (multinomial odds ratio (MOR) = 2.79, 95% confidence interval (CI): 1.33, 5.83) and atopy alone (MOR = 1.40, 95% CI: 1.06, 1.84) but not with nonatopic asthma (MOR = 1.02, 95% CI: 0.45, 2.30), compared with students reporting no asthma and no atopy. The authors found no association with acne, a marker of high testosterone levels, that they hypothesized could point to polycystic ovary syndrome underpinning these associations. In summary, the authors found evidence for a potentially etiologic role of irregular menstruations with some specific asthma phenotypes, namely, atopic asthma and atopy, but not with nonatopic asthma.
doi:10.1093/aje/kws161
PMCID: PMC3472614  PMID: 23028012
acne; age at menarche; asthma; atopy; irregular menstruation
25.  META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IDENTIFIES THREE NEW RISK LOCI FOR ATOPIC DERMATITIS 
Paternoster, Lavinia | Standl, Marie | Chen, Chih-Mei | Ramasamy, Adaikalavan | Bønnelykke, Klaus | Duijts, Liesbeth | Ferreira, Manuel A | Alves, Alexessander Couto | Thyssen, Jacob P | Albrecht, Eva | Baurecht, Hansjörg | Feenstra, Bjarke | Sleiman, Patrick MA | Hysi, Pirro | Warrington, Nicole M | Curjuric, Ivan | Myhre, Ronny | Curtin, John A | Groen-Blokhuis, Maria M | Kerkhof, Marjan | Sääf, Annika | Franke, Andre | Ellinghaus, David | Fölster-Holst, Regina | Dermitzakis, Emmanouil | Montgomery, Stephen B | Prokisch, Holger | Heim, Katharina | Hartikainen, Anna-Liisa | Pouta, Anneli | Pekkanen, Juha | Blakemore, Alexandra IF | Buxton, Jessica L | Kaakinen, Marika | Duffy, David L | Madden, Pamela A | Heath, Andrew C | Montgomery, Grant W | Thompson, Philip J | Matheson, Melanie C | Le Souëf, Peter | Pourcain, Beate St | Smith, George Davey | Henderson, John | Kemp, John P | Timpson, Nicholas J | Deloukas, Panos | Ring, Susan M | Wichmann, H-Erich | Müller-Nurasyid, Martina | Novak, Natalija | Klopp, Norman | Rodríguez, Elke | McArdle, Wendy | Linneberg, Allan | Menné, Torkil | Nohr, Ellen A | Hofman, Albert | Uitterlinden, André G | van Duijn, Cornélia M | Rivadeneira, Fernando | de Jongste, Johan C | van der Valk, Ralf JP | Wjst, Matthias | Jogi, Rain | Geller, Frank | Boyd, Heather A | Murray, Jeffrey C | Kim, Cecilia | Mentch, Frank | March, Michael | Mangino, Massimo | Spector, Tim D | Bataille, Veronique | Pennell, Craig E | Holt, Patrick G | Sly, Peter | Tiesler, Carla MT | Thiering, Elisabeth | Illig, Thomas | Imboden, Medea | Nystad, Wenche | Simpson, Angela | Hottenga, Jouke-Jan | Postma, Dirkje | Koppelman, Gerard H | Smit, Henriette A | Söderhäll, Cilla | Chawes, Bo | Kreiner-Møller, Eskil | Bisgaard, Hans | Melén, Erik | Boomsma, Dorret I | Custovic, Adnan | Jacobsson, Bo | Probst-Hensch, Nicole M | Palmer, Lyle J | Glass, Daniel | Hakonarson, Hakon | Melbye, Mads | Jarvis, Deborah L | Jaddoe, Vincent WV | Gieger, Christian | Strachan, David P | Martin, Nicholas G | Jarvelin, Marjo-Riitta | Heinrich, Joachim | Evans, David M | Weidinger, Stephan
Nature genetics  2011;44(2):187-192.
Atopic dermatitis (AD) is a common chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing AD are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 cases and 20,565 controls from 16 population-based cohorts and followed up the ten most strongly associated novel markers in a further 5,419 cases and 19,833 controls from 14 studies. Three SNPs met genome-wide significance in the discovery and replication cohorts combined: rs479844 upstream of OVOL1 (OR=0.88, p=1.1×10−13) and rs2164983 near ACTL9 (OR=1.16, p=7.1×10−9), genes which have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster on 5q31.1 (OR=1.11, p=3.8×10−8). We also replicated the FLG locus and two recently identified association signals at 11q13.5 (rs7927894, p=0.008) and 20q13.3 (rs6010620, p=0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in AD pathogenesis.
doi:10.1038/ng.1017
PMCID: PMC3272375  PMID: 22197932

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