Joint modeling of parentally reported and physician-confirmed wheeze identifies children with persistent troublesome wheezing

Belgrave, Danielle; Simpson, Angela; Semiç-Jusufagiç, Aida; Murray, Clare; Buchan, Iain; Pickles, Andrew; Čustović, Adnan

doi:10.1016/j.jaci.2013.05.041

Cited by 87 publications

(134 citation statements)

References 35 publications

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“…Lung function was progressively worse with the increasing number of exacerbations and hospital admissions. This is consistent with the results of our recent study in which children with persistent troublesome wheeze (defined using latent class analysis on both parental and primary-care reports of wheeze, and characterized by frequent exacerbations) had significantly greater increase in sRaw over time compared with persistent wheezers with controlled disease (27). Similar to the findings on wheeze phenotypes, our data demonstrate that it is not just atopy, but a specific atopy phenotype that is associated with poor lung function (multiple early atopy, comprising approximately one-quarter of children conventionally defined as being atopic [30]).…”

Section: Discussionsupporting

confidence: 92%

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Trajectories of Lung Function during Childhood

Belgrave

Buchan

Bishop

et al. 2014

Am J Respir Crit Care Med

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163

140

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Rationale: Developmental patterns of lung function during childhood may have major implications for our understanding of the pathogenesis of respiratory disease throughout life.Objectives: To explore longitudinal trajectories of lung function during childhood and factors associated with lung function decline.Methods: In a population-based birth cohort, specific airway resistance (sRaw) was assessed at age 3 (n = 560), 5 (n = 829), 8 (n = 786), and 11 years (n = 644). Based on prospective data (questionnaires, skin tests, IgE), children were assigned to wheeze phenotypes (no wheezing, transient, late-onset, and persistent) and atopy phenotypes (no atopy, dust mite, non-dust mite, multiple early, and multiple late). We used longitudinal linear mixed models to determine predictors of change in sRaw over time.Measurements and Main Results: Contrary to the assumption that sRaw is independent of age and sex, boys had higher sRaw than girls (mean difference, 0.080; 95% confidence interval [CI], 0.049-0.111; P , 0.001) and a higher rate of increase over time. For girls, sRaw increased by 0.017 kPa $ s 21 per year (95% CI, 0.011-0.023). In boys this increase was significantly greater (P = 0.012; mean betweensex difference, 0.011 kPa $ s 21; 95% CI, 0.003-0.019). Children with persistent wheeze (but not other wheeze phenotypes) had a significantly greater rate of deterioration in sRaw over time compared with never wheezers (P = 0.009). Similarly, children with multiple early, but not other atopy phenotypes had significantly poorer lung function than those without atopy (mean difference, 0.116 kPa $ s 21 ; 95% CI, 0.065-0.168; P , 0.001). sRaw increased progressively with the increasing number of asthma exacerbations.Conclusions: Children with persistent wheeze, frequent asthma exacerbations, and multiple early atopy have diminished lung function throughout childhood, and are at risk of a progressive loss of lung function from age 3 to 11 years. These effects are more marked in boys.

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Section: Discussionsupporting

confidence: 92%

“…We extracted all data from primary care medical records, including wheeze episodes, prescriptions of asthma medications, oral corticosteroid prescriptions, emergency department admissions, and asthma-and wheeze-related hospitalizations (27).…”

Section: Data Sourcesmentioning

confidence: 99%

Trajectories of Lung Function during Childhood

Belgrave

Buchan

Bishop

et al. 2014

Am J Respir Crit Care Med

Self Cite

163

140

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“…The present study would suggest that asthma is secondary to atopy in these children. Other studies have also shown a strong association between atopy and asthma persistence, as reflected by the atopic asthma group in the present study [5,14]. Nonatopic asthma has resulted as a separate entity in some previous analyses [7,9,12].…”

supporting

confidence: 71%

“…wheeze", "early transient wheeze" or "late onset wheeze" [3][4][5][6]. Similarly we investigated symptoms of cough and wheeze at two time-points in the Leicestershire cohort studies and identified patterns such as "transient viral wheeze" and "atopic persistent wheeze" [7,8].…”

mentioning

confidence: 99%

Asthma phenotypes in childhood: conceptual thoughts on stability and transition

Spycher¹,

Kuehni²

2016

Eur Respir J

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“…Recent developments in machine learning (a data‐driven approach to identify structure within the data using unsupervised learning of latent variables) provide new ways to capture the heterogeneity in patterns of responses to multiple items. Machine learning is increasingly used to disaggregate complex phenotypes in respiratory medicine and allergy 8, 9, 10, 11, 12, 13, 14, 15, where conventional modelling techniques might not uncover the underlying complexity 16.…”

Section: Introductionmentioning

confidence: 99%

Relationship between cytokine expression patterns and clinical outcomes: two population‐based birth cohorts

Prosperi

Simpson

et al. 2015

Clin Experimental Allergy

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SummaryBackgroundModels that incorporate patterns of multiple cytokine responses to allergens, rather than individual cytokine production, may better predict sensitization and asthma.ObjectiveTo characterize the patterns of peripheral blood mononuclear cells’ (PBMCs) cytokine responses to house dust mite (HDM) allergens among children from two population‐based birth cohorts using machine learning techniques.Methods PBMCs collected at 8 years of age from the UK Manchester Asthma and Allergy Study (n = 268) and at 14 years of age from the Australian Raine Study (n = 1374) were cultured with HDM extract (10 μg/ml). Cytokine expression (IL‐13, IL‐5, IFN‐γ, and IL10) was measured in the supernatant. Cytokine patterns were identified using a Gaussian mixture model clustering, and classification stability was assessed by bootstrapping.ResultsA six‐class model indicated complex latent structure of cytokine expression. Based on the characteristics of each class, we designated them as follows: ‘Nonresponders’ (n = 905, 55%); ‘IL‐10 responders’ (n = 49, 3%); ‘IFN‐γ and IL‐13 medium responders’ (n = 56, 3.4%); ‘IL‐13 medium responders’ (n = 351, 21.4%); ‘IL‐5 and IL‐13 medium responders’ (n = 77, 4.7%); and ‘IL‐13 and IL‐5 high responders’ (n = 204, 12.4%). ‘IL‐13 and IL‐5 high responders’ were at much higher risk of HDM sensitization and asthma compared to all other classes, with 88% of children assigned to this class being sensitized and 28.5% having asthma.ConclusionUsing model‐based clustering, we identified several distinct patterns of cytokine response to HDM and observed interplay between cytokine expression level, cytokine patterns (especially IL‐13 and IL‐5), and clinical outcomes. ‘IL‐13 and IL‐5 high responders’ class was strongly associated with HDM sensitization. However, among HDM‐sensitized children, one‐third showed no PBMC response to HDM, and the majority of HDM‐sensitized children did not have asthma or wheeze. Our findings suggest that positive HDM ‘allergy tests’ and asthma are associated with a broad range of immunophenotypes, which may have important implications for the use of cytokine‐targeted treatment approaches.

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Joint modeling of parentally reported and physician-confirmed wheeze identifies children with persistent troublesome wheezing

Abstract: We identified a novel group of children with persistent troublesome wheezing, who have markedly different outcomes compared with persistent wheezers with controlled disease.

Cited by 87 publications

References 35 publications

Trajectories of Lung Function during Childhood

Trajectories of Lung Function during Childhood

Asthma phenotypes in childhood: conceptual thoughts on stability and transition

Relationship between cytokine expression patterns and clinical outcomes: two population‐based birth cohorts

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