Date Published: November 13, 2018
Publisher: Public Library of Science
Author(s): Sara Fontanella, Clément Frainay, Clare S. Murray, Angela Simpson, Adnan Custovic, Thomas Platts-Mills
Abstract: BackgroundThe relationship between allergic sensitisation and asthma is complex; the data about the strength of this association are conflicting. We propose that the discrepancies arise in part because allergic sensitisation may not be a single entity (as considered conventionally) but a collection of several different classes of sensitisation. We hypothesise that pairings between immunoglobulin E (IgE) antibodies to individual allergenic molecules (components), rather than IgE responses to ‘informative’ molecules, are associated with increased risk of asthma.Methods and findingsIn a cross-sectional analysis among 461 children aged 11 years participating in a population-based birth cohort, we measured serum-specific IgE responses to 112 allergen components using a multiplex array (ImmunoCAP Immuno‑Solid phase Allergy Chip [ISAC]). We characterised sensitivity to 44 active components (specific immunoglobulin E [sIgE] > 0.30 units in at least 5% of children) among the 213 (46.2%) participants sensitised to at least one of these 44 components. We adopted several machine learning methodologies that offer a powerful framework to investigate the highly complex sIgE–asthma relationship. Firstly, we applied network analysis and hierarchical clustering (HC) to explore the connectivity structure of component-specific IgEs and identify clusters of component-specific sensitisation (‘component clusters’). Of the 44 components included in the model, 33 grouped in seven clusters (C.sIgE-1–7), and the remaining 11 formed singleton clusters. Cluster membership mapped closely to the structural homology of proteins and/or their biological source. Components in the pathogenesis-related (PR)-10 proteins cluster (C.sIgE-5) were central to the network and mediated connections between components from grass (C.sIgE-4), trees (C.sIgE-6), and profilin clusters (C.sIgE-7) with those in mite (C.sIgE-1), lipocalins (C.sIgE-3), and peanut clusters (C.sIgE-2). We then used HC to identify four common ‘sensitisation clusters’ among study participants: (1) multiple sensitisation (sIgE to multiple components across all seven component clusters and singleton components), (2) predominantly dust mite sensitisation (IgE responses mainly to components from C.sIgE-1), (3) predominantly grass and tree sensitisation (sIgE to multiple components across C.sIgE-4–7), and (4) lower-grade sensitisation. We used a bipartite network to explore the relationship between component clusters, sensitisation clusters, and asthma, and the joint density-based nonparametric differential interaction network analysis and classification (JDINAC) to test whether pairwise interactions of component-specific IgEs are associated with asthma. JDINAC with pairwise interactions provided a good balance between sensitivity (0.84) and specificity (0.87), and outperformed penalised logistic regression with individual sIgE components in predicting asthma, with an area under the curve (AUC) of 0.94, compared with 0.73. We then inferred the differential network of pairwise component-specific IgE interactions, which demonstrated that 18 pairs of components predicted asthma. These findings were confirmed in an independent sample of children aged 8 years who participated in the same birth cohort but did not have component-resolved diagnostics (CRD) data at age 11 years. The main limitation of our study was the exclusion of potentially important allergens caused by both the ISAC chip resolution as well as the filtering step. Clustering and the network analyses might have provided different solutions if additional components had been available.ConclusionsInteractions between pairs of sIgE components are associated with increased risk of asthma and may provide the basis for designing diagnostic tools for asthma.
Partial Text: Asthma is the most common noncommunicable disease in childhood. Over recent decades, a large body of evidence has demonstrated a close relationship between specific immunoglobulin E (sIgE) antibody responses and asthma [1, 2], but the data about the strength of this association are conflicting [2, 3]. Furthermore, in a clinical situation, confirmation of allergic sensitisation using standard diagnostic tests (skin prick tests [SPTs] and/or measurement of sIgE) does not necessarily indicate that patient’s symptoms are caused by an allergic reaction . We have previously proposed that these inconsistencies are in part consequent to ‘allergic sensitisation’ not being a single entity (as considered conventionally) but an umbrella term for a collection of several different classes of sensitisation that differ in their association with asthma and other allergic diseases. To test this, in a previous study we applied a machine learning approach with Bayesian inference to a comprehensive set of skin tests and sIgE data to whole allergen extracts collected from infancy to school age in a population-based birth cohort . Children clustered into four distinct sensitisation classes characterised by different patterns of responses to specific allergens and the time of onset of sensitisation . The risk of asthma was increased almost 30-fold amongst children belonging to one of these classes (assigned as ‘Multiple early sensitisation’, comprising less than one third of children diagnosed as sensitised using conventional definitions). We have replicated these findings in another birth cohort  and have shown that diminished lung function in adolescence and early adulthood is associated with ‘Multiple early’, but not other sensitisation classes [6, 7].
Our findings suggest that sIgE responses to multiple allergenic proteins are functionally coordinated and co-regulated, and that the patterns of interactions within this complex network may predict clinical phenotypes. In this study, we found that interactions between a limited set of component-specific sIgEs, rather than individual ‘informative’ components, are associated with increased risk of asthma and may provide the basis for designing diagnostic tools. We need to fundamentally rethink the way we interpret data obtained using CRD and move away from the focus on individual component-specific IgEs to a more holistic approach that takes into account the patterns of connectivity between IgEs.