Systems biology and big data in asthma and allergy: recent discoveries and emerging challenges

Asthma is a common condition caused by immune and respiratory dysfunction, and it is often linked to allergy. A systems perspective may prove helpful in unravelling the complexity of asthma and allergy. Our aim is to give an overview of systems biology approaches used in allergy and asthma research. Specifically, we describe recent “omic”-level findings, and examine how these findings have been systematically integrated to generate further insight. Current research suggests that allergy is driven by genetic and epigenetic factors, in concert with environmental factors such as microbiome and diet, leading to early-life disturbance in immunological development and disruption of balance within key immuno-inflammatory pathways. Variation in inherited susceptibility and exposures causes heterogeneity in manifestations of asthma and other allergic diseases. Machine learning approaches are being used to explore this heterogeneity, and to probe the pathophysiological patterns or “endotypes” that correlate with subphenotypes of asthma and allergy. Mathematical models are being built based on genomic, transcriptomic, and proteomic data to predict or discriminate disease phenotypes, and to describe the biomolecular networks behind asthma. The use of systems biology in allergy and asthma research is rapidly growing, and has so far yielded fruitful results. However, the scale and multidisciplinary nature of this research means that it is accompanied by new challenges. Ultimately, it is hoped that systems medicine, with its integration of omics data into clinical practice, can pave the way to more precise, personalised and effective management of asthma.This work was supported by the National Health and Medical Research Council (NHMRC) of Australia via a postgraduate scholarship (ref. no. 1114753) to HHF Tang, research grant (1049539) to M Inouye and K Holt, and Fellowships (1061409) to K Holt and (1061435) to M Inouye. K Holt was further supported by a Senior Medical Research Fellowship from the Viertel Foundation of Australia

A meta-analysis of the relation between therapeutic alliance and treatment outcome in eating disorders.

The therapeutic alliance has demonstrated an association with favorable psychotherapeutic outcomes in the treatment of eating disorders (EDs). However, questions remain about the inter-relationships between early alliance, early symptom improvement, and treatment outcome. We conducted a meta-analysis on the relations among these constructs, and possible moderators of these relations, in psychosocial treatments for EDs. Twenty studies met inclusion criteria and supplied sufficient supplementary data. Results revealed small-to-moderate effect sizes, βs = 0.13 to 0.22 (p < .05), indicating that early symptom improvement was related to subsequent alliance quality and that alliance ratings also were related to subsequent symptom reduction. The relationship between early alliance and treatment outcome was partially accounted for by early symptom improvement. With regard to moderators, early alliance showed weaker associations with outcome in therapies with a strong behavioral component relative to nonbehavioral therapies. However, alliance showed stronger relations to outcome for younger (vs. older) patients, over and above the variance shared with early symptom improvement. In sum, early symptom reduction enhances therapeutic alliance and treatment outcome in EDs, but early alliance may require specific attention for younger patients and for those receiving nonbehaviorally oriented treatments

Airway Microbiota Dynamics Uncover a Critical Window for Interplay of Pathogenic Bacteria and Allergy in Childhood Respiratory Disease.

Repeated cycles of infection-associated lower airway inflammation drive the pathogenesis of persistent wheezing disease in children. In this study, the occurrence of acute respiratory tract illnesses (ARIs) and the nasopharyngeal microbiome (NPM) were characterized in 244 infants through their first five years of life. Through this analysis, we demonstrate that >80% of infectious events involve viral pathogens, but are accompanied by a shift in the NPM toward dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change frequently precedes the detection of viral pathogens and acute symptoms. Colonization of illness-associated bacteria coupled with early allergic sensitization is associated with persistent wheeze in school-aged children, which is the hallmark of the asthma phenotype. In contrast, these bacterial genera are associated with "transient wheeze" that resolves after age 3 years in non-sensitized children. Thus, to complement early allergic sensitization, monitoring NPM composition may enable early detection and intervention in high-risk children

Advance Access published March 30

Summary The modern environment is associated with an increasing burden of non-communicable diseases (NCDs). Mounting evidence implicates environmental exposures, experienced early in life (including in utero), in the aetiology of many NCDs, though the cellular/molecular mechanism(s) underlying this elevated risk across the life course remain unclear. Epigenetic variation has emerged as a candidate mediator of such effects. The Barwon Infant Study (BIS) is a population-derived birth cohort study (n ¼ 1074 infants) with antenatal recruitment, conducted in the south-east of Australia (Victoria). BIS has been designed to facilitate a detailed mechanistic investigation of development within an epidemiological framework. The broad objectives are to investigate the role of specific environmental factors, gut microbiota and epigenetic variation in early-life development, and subsequent immune, allergic, cardiovascular, respiratory and neurodevelopmental outcomes. Participants have been reviewed at birth and at 1, 6, 9 and 12 months, with 2-and 4-year reviews under way. Biological samples and measures include: maternal blood, faeces and urine during pregnancy; infant urine, faeces and blood at regular intervals during the first 4 years; lung function at 1 month and 4 years; cardiovascular assessment at 1 month and 4 years; skin-prick allergy testing and food challenge at 1 year; and neurodevelopmental assessment at 9 months, 2 and 4 years. Data access enquiries can be made at [www.barwoninfantstudy.org.au] or via [[email protected]]

Neonatal genetics of gene expression reveal potential origins of autoimmune and allergic disease risk

Abstract: Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4+ T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases

Tidal Volume Single Breath Washout of Two Tracer Gases - A Practical and Promising Lung Function Test

Small airway disease frequently occurs in chronic lung diseases and may cause ventilation inhomogeneity (VI), which can be assessed by washout tests of inert tracer gas. Using two tracer gases with unequal molar mass (MM) and diffusivity increases specificity for VI in different lung zones. Currently washout tests are underutilised due to the time and effort required for measurements. The aim of this study was to develop and validate a simple technique for a new tidal single breath washout test (SBW) of sulfur hexafluoride (SF(6)) and helium (He) using an ultrasonic flowmeter (USFM)

Trajectories of childhood immune development and respiratory health relevant to asthma and allergy.

Events in early life contribute to subsequent risk of asthma; however, the causes and trajectories of childhood wheeze are heterogeneous and do not always result in asthma. Similarly, not all atopic individuals develop wheeze, and vice versa. The reasons for these differences are unclear. Using unsupervised model-based cluster analysis, we identified latent clusters within a prospective birth cohort with deep immunological and respiratory phenotyping. We characterised each cluster in terms of immunological profile and disease risk, and replicated our results in external cohorts from the UK and USA. We discovered three distinct trajectories, one of which is a high-risk 'atopic' cluster with increased propensity for allergic diseases throughout childhood. Atopy contributes varyingly to later wheeze depending on cluster membership. Our findings demonstrate the utility of unsupervised analysis in elucidating heterogeneity in asthma pathogenesis and provide a foundation for improving management and prevention of childhood asthma

Airway smooth muscle as a target of asthma therapy: history and new directions

Ultimately, asthma is a disease characterized by constriction of airway smooth muscle (ASM). The earliest approach to the treatment of asthma comprised the use of xanthines and anti-cholinergics with the later introduction of anti-histamines and anti-leukotrienes. Agents directed at ion channels on the smooth muscle membrane (Ca(2+ )channel blockers, K(+ )channel openers) have been tried and found to be ineffective. Functional antagonists, which modulate intracellular signalling pathways within the smooth muscle (β-agonists and phosphodiesterase inhibitors), have been used for decades with success, but are not universally effective and patients continue to suffer with exacerbations of asthma using these drugs. During the past several decades, research energies have been directed into developing therapies to treat airway inflammation, but there have been no substantial advances in asthma therapies targeting the ASM. In this manuscript, excitation-contraction coupling in ASM is addressed, highlighting the current treatment of asthma while proposing several new directions that may prove helpful in the management of this disease

Fetal and infant origins of asthma

Previous studies have suggested that asthma, like other common diseases, has at least part of its origin early in life. Low birth weight has been shown to be associated with increased risks of asthma, chronic obstructive airway disease, and impaired lung function in adults, and increased risks of respiratory symptoms in early childhood. The developmental plasticity hypothesis suggests that the associations between low birth weight and diseases in later life are explained by adaptation mechanisms in fetal life and infancy in response to various adverse exposures. Various pathways leading from adverse fetal and infant exposures to growth adaptations and respiratory health outcomes have been studied, including fetal and early infant growth patterns, maternal smoking and diet, children’s diet, respiratory tract infections and acetaminophen use, and genetic susceptibility. Still, the specific adverse exposures in fetal and early postnatal life leading to respiratory disease in adult life are not yet fully understood. Current studies suggest that both environmental and genetic factors in various periods of life, and their epigenetic mechanisms may underlie the complex associations of low birth weight with respiratory disease in later life. New well-designed epidemiological studies are needed to identify the specific underlying mechanisms. This review is focused on specific adverse fetal and infant growth patterns and exposures, genetic susceptibility, possible respiratory adaptations and perspectives for new studies

Prenatal exposures and exposomics of asthma

This review examines the causal investigation of preclinical development of childhood asthma using exposomic tools. We examine the current state of knowledge regarding early-life exposure to non-biogenic indoor air pollution and the developmental modulation of the immune system. We examine how metabolomics technologies could aid not only in the biomarker identification of a particular asthma phenotype, but also the mechanisms underlying the immunopathologic process. Within such a framework, we propose alternate components of exposomic investigation of asthma in which, the exposome represents a reiterative investigative process of targeted biomarker identification, validation through computational systems biology and physical sampling of environmental medi