The use of machine learning to understand the relationship between IgE to specific allergens and asthma

In a study recently published in PLOS Medicine, Custovic and colleagues report an elegant analysis of the results of specific Immunoglobulin E (IgE) assays on sera from a birth cohort that they have studied in detail over the last 15 years. The IgE assays used a microchip with >100 purified allergens, and their machine learning approach used a hypothesis-free statistical approach to group children with similar allergen sensitization profiles. The primary objective was to evaluate the relationship of the results to the diagnosis of current asthma. The goal of employing a “machine learning” approach is both as a form of data reduction to avoid spuriously identified associations resulting from multiple comparisons and to identify biologically relevant groupings that may not be recognized with conventional approaches. The use of “hypothesis free” clustering methods with individual allergen components in itself is not novel. However, the authors have employed a new network analysis method, which is improved over previous methods because it can capture nonlinear relationships and does not rely on assumption of a parametric probability. As the authors show, this approach can lead to improved sensitivity and specificity. With this model, they were able to show that pairings of allergens (e.g., the cat allergen Fel d 1 and the peanut allergen Ara h 1) were more predictive of the child having asthma than individual components, although we must be cautious in the generalizability of the specific patterns identified, in this single cohort in the United Kingdom, because the pairing may represent host susceptibility to making an IgE response or common co-exposures, which could be allergens or adjuvants. Still, the concept of complicated connections between individual allergenic proteins and allergic disease are likely to apply more broadly and are important to consider in future studies

High incidence and remission of reported food hypersensitivity in Swedish children followed from 8 to 12 years of age – a population based cohort study

Background: Few population-based cohort studies have examined reported food hypersensitivity longitudinally. We investigated prevalence, incidence and remission of perceived food hypersensitivity among schoolchildren from 8 to 12 years of age, and risk factors associated with incidence and remission. Methods: A population-based cohort including all 7–8 year-old children in three Swedish towns was recruited in 2006. A total of 2,585 (96% of invited) children participated in a parental questionnaire. The children in two of the towns, n = 1,700 (90% of invited) also participated in skin-prick-testing with airborne allergens. The cohort was followed using the same methods at 11–12 years of age. At study follow up, specific IgE to foods was analyzed in a randomized subset of children (n = 652). Results: The prevalence of perceived food hypersensitivity increased from 21% at 8 years to 26% at 12 years of age. During this four-year-period, the cumulative incidence of food hypersensitivity was high (15%), as was remission (33%). This pattern was particularly evident for hypersensitivity to cow´s milk, while the incidence of hypersensitivity to other foods was lower. Female sex, allergic heredity, current rhinitis and allergic sensitization were associated with the incidence of food hypersensitivity and allergic sensitization was negatively associated with remission. Risk-factor-patterns for both incidence and remission were different for hypersensitivity to milk compared with hypersensitivity to other foods. Generally, the agreement between reported food hypersensitivity and IgE-sensitization to the implicated food was poor. Conclusions: In this longitudinal, population-based cohort-study perceived food hypersensitivity was common among children between ages 8 and 12, often transient and not well correlated with food-specific IgE. While these findings suggest an overestimated prevalence of food hypersensitivity, the public-health-significance remains high as they reflect the perceived reality to which the children adapt their life and food intakes

Association of recent exposure to ambient metals on fractional exhaled nitric oxide in 9–11 year old inner-city children

Exposure to ambient metals in urban environments has been associated with wheeze, and emergency room visits and hospitalizations due to respiratory illness. However, the effect of ambient metals exposure on airway inflammation, and how these associations may be modified by seroatopy, has not been determined. Fractional exhaled nitric oxide (FENO) is a reliable proxy marker of airway inflammation. We hypothesized that recent ambient concentrations of Ni, V, Zn and Fe would be associated differentially with proximal and distal fractions of exhaled NO, and that these associations would be modified by seroatopy. As part of the Columbia Center for Children’s Environmental Health (CCCEH) birth cohort study, 9–11 year old children (n = 192) were evaluated. Ambient measures of Ni, V, Zn and Fe were obtained from a local central monitoring site and averaged over 9 days based on three 24 h measures every third day. Fractional exhaled nitric oxide (FENO) samples were obtained at constant flows of 50 (FENO50), 83 and 100 mL/s, and used to determine surrogate measures for proximal (JNO) and alveolar (Calv) inflammation. Seroatopy was determined by specific IgE at age 7. Data were analyzed using multivariable linear regression. Ambient V and Fe concentrations were associated positively with FENO50 (p = 0.018, p = 0.027). Ambient Fe was associated positively with JNO (p = 0.017). Ambient Ni and V concentrations were associated positively with Calv (p = 0.004, p = 0.018, respectively). A stronger association of Ni concentrations with Calv was observed among the children with seroatopy. These results suggest that ambient metals are associated differentially with different fractions of FENO production, and this relationship may be modified by seroatopy

Association of recent exposure to ambient metals on fractional exhaled nitric oxide in 9–11 year old inner-city children

Exposure to ambient metals in urban environments has been associated with wheeze, and emergency room visits and hospitalizations due to respiratory illness. However, the effect of ambient metals exposure on airway inflammation, and how these associations may be modified by seroatopy, has not been determined. Fractional exhaled nitric oxide (FENO) is a reliable proxy marker of airway inflammation. We hypothesized that recent ambient concentrations of Ni, V, Zn and Fe would be associated differentially with proximal and distal fractions of exhaled NO, and that these associations would be modified by seroatopy. As part of the Columbia Center for Children’s Environmental Health (CCCEH) birth cohort study, 9–11 year old children (n = 192) were evaluated. Ambient measures of Ni, V, Zn and Fe were obtained from a local central monitoring site and averaged over 9 days based on three 24 h measures every third day. Fractional exhaled nitric oxide (FENO) samples were obtained at constant flows of 50 (FENO50), 83 and 100 mL/s, and used to determine surrogate measures for proximal (JNO) and alveolar (Calv) inflammation. Seroatopy was determined by specific IgE at age 7. Data were analyzed using multivariable linear regression. Ambient V and Fe concentrations were associated positively with FENO50 (p = 0.018, p = 0.027). Ambient Fe was associated positively with JNO (p = 0.017). Ambient Ni and V concentrations were associated positively with Calv (p = 0.004, p = 0.018, respectively). A stronger association of Ni concentrations with Calv was observed among the children with seroatopy. These results suggest that ambient metals are associated differentially with different fractions of FENO production, and this relationship may be modified by seroatopy

Polycyclic aromatic hydrocarbon exposure, obesity and childhood asthma in an urban cohort

Background: Exposure to traffic-related air pollutants, including polycyclic aromatic hydrocarbons (PAHs) from traffic emissions and other combustion sources, and childhood obesity, have been implicated as risk factors for developing asthma. However, the interaction between these two on asthma among young urban children has not been studied previously. Methods: Exposure to early childhood PAHs was measured by two week residential indoor monitoring at age 5–6 years in the Columbia Center for Children's Environmental Health birth cohort (n=311). Semivolatile [e.g., methylphenanthrenes] and nonvolatile [e.g., benzo(a)pyrene] PAHs were monitored. Obesity at age 5 was defined as a body mass index (BMI) greater than or equal to the 95th percentile of the year 2000 age- and sex-specific growth charts (Center for Disease Control). Current asthma and recent wheeze at ages 5 and 7 were determined by validated questionnaires. Data were analyzed using a modified Poisson regression in generalized estimating equations (GEE) to estimate relative risks (RR), after adjusting for potential covariates. Results: Neither PAH concentrations or obesity had a main effect on asthma or recent wheeze. In models stratified by presence/absence of obesity, a significant positive association was observed between an interquartile range (IQR) increase in natural log-transformed 1-methylphenanthrene (RR [95% CI]: 2.62 [1.17–5.88] with IQRln=0.76), and 9-methylphenanthrene (2.92 [1.09–7.82] with IQRln=0.73) concentrations and asthma in obese children (n=63). No association in non-obese (n=248) children was observed at age 5 (Pinteraction<0.03). Similar associations were observed for 3-methylphenanthrene, 9-methylphenanthrene, and 3,6-dimethylphenanthrene at age 7. Conclusions: Obese young children may be more likely to develop asthma in association with greater exposure to PAHs, and methylphenanthrenes in particular, than non-obese children

Infant rhinitis and watery eyes predict school-age exercise-induced wheeze, emergency department visits and respiratory-related hospitalizations

Background: Rhinitis and conjunctivitis are often linked to asthma development through an allergic pathway. However, runny nose and watery eyes can result from nonallergic mechanisms. These mechanisms can also underlie exercise-induced wheeze (EIW), which has been associated with urgent medical visits for asthma, independent of other indicators of asthma severity or control. Objective: To test the hypothesis that rhinitis or watery eyes without cold symptoms (RWWC) in infancy predict development of EIW and urgent respiratory-related medical visits at school age, independent of seroatopy. Methods: Within a prospective birth cohort of low-income, urban children (n = 332), RWWC was queried during the first year of life. Relative risks (RRs) for EIW, emergency department (ED) visits, and hospitalizations for asthma and other breathing difficulties at 5 to 7 years of age were estimated with multivariable models. Seroatopy was determined at 7 years of age. Results: Infant RWWC was common (49% of children) and predicted school-age EIW (RR, 2.8; P < .001), ED visits (RR, 1.8; P = .001), and hospitalizations (RR, 9.8; P = .002). These associations were independent of infant wheeze. They were also independent of birth order, an indicator of increased risk of exposure to viruses in infancy, and infant ear infections, an indicator of sequelae of upper airway infections. The association between infant RWWC and ED visits at 5 to 7 years of age was attenuated (RR, 1.2; P = .23) when EIW at 5 to 7 years of age was included in the model, suggesting EIW mediates the association. Adjustment for seroatopy did not diminish the magnitudes of any of these associations. Conclusion: These findings suggest a nonallergic connection between infant nonwheeze symptoms and important consequences of urban respiratory health by school age through EI

Prenatal phthalate and early childhood bisphenol A exposures increase asthma risk in inner-city children

To the Editor: We previously reported that inner-city childhood asthma was independently associated with measures of early childhood exposure to bisphenol A (BPA)1 and prenatal, but not childhood, exposures to di-n-butyl phthalate and butylbenzyl phthalate (BBzP). 2 Here, we evaluate whether these 2 classes of endocrine-disrupting chemicals interact to increase the risk of asthma. We evaluated 292 inner-city women and their children aged 5 to 11 years from the Columbia Center for Children's Environmental Health birth cohort of pregnant women who delivered between 1998 and 2006. Enrollment, exclusion criteria, and a description of the cohort have been reported previously.3 Subjects were selected for the present study on the basis of the availability of (1) measurements of phthalates in spot urine collected from the mother during pregnancy (33.9 ± 3.1 weeks' gestation) and BPA in child urine at ages 3 (n = 237), 5 (259), and/or 7 (n = 161) years; (2) data on child asthma and wheeze-related outcomes; and (3) availability of model covariates. Demographic characteristics of Columbia Center for Children's Environmental Health subjects are provided in Table E1 in this article's Online Repository at www.jacionline.org. All participants gave written informed consent

Asthma in Inner-City Children at 5–11 Years of Age and Prenatal Exposure to Phthalates: The Columbia Center for Children’s Environmental Health Cohort

Background: Studies suggest that phthalate exposures may adversely affect child respiratory health. Objectives: We evaluated associations between asthma diagnosed in children between 5 and 11 years of age and prenatal exposures to butylbenzyl phthalate (BBzP), di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), and diethyl phthalate (DEP). Methods: Phthalate metabolites were measured in spot urine collected from 300 pregnant inner-city women. Children were examined by an allergist or pulmonologist based on the first parental report of wheeze, other respiratory symptoms, and/or use of asthma rescue/controller medication in the preceding 12 months on repeat follow-up questionnaires. Standardized diagnostic criteria were used to classify these children as either having or not having current asthma at the time of the physician examination. Children without any report of wheeze or the other asthma-like symptoms were classified as nonasthmatics at the time of the last negative questionnaire. Modified Poisson regression analyses were used to estimate relative risks (RR) controlling for specific gravity and potential confounders. Results: Of 300 children, 154 (51%) were examined by a physician because of reports of wheeze, other asthma-like symptoms, and/or medication use; 94 were diagnosed with current asthma and 60 without current asthma. The remaining 146 children were classified as nonasthmatic. Compared with levels in nonasthmatics, prenatal metabolites of BBzP and DnBP were associated with a history of asthma-like symptoms (p 70% higher among children with maternal prenatal BBzP and DnBP metabolite concentrations in the third versus the first tertile. Conclusion: Prenatal exposure to BBzP and DnBP may increase the risk of asthma among inner-city children. However, because this is the first such finding, results require replication. Citation: Whyatt RM, Perzanowski MS, Just AC, Rundle AG, Donohue KM, Calafat AM, Hoepner LA, Perera FP, Miller RL. 2014. Asthma in inner-city children at 5–11 years of age and prenatal exposure to phthalates: the Columbia Center for Children’s Environmental Health Cohort. Environ Health Perspect 122:1141–1146; http://dx.doi.org/10.1289/ehp.130767