Publications
687 results found
Kasper SS, Custovic A, 2023, Does antipsychotic therapy prevent the development of chronic psychotic disorders in people addicted to ilegal psychoactive substances, Publisher: CAMBRIDGE UNIV PRESS, Pages: S676-S676, ISSN: 0924-9338
Custovic A, Fontanella S, 2023, Evolution of lung function within individuals: clinical insights and data-driven methods, American Journal of Respiratory and Critical Care Medicine, Vol: 207, Pages: 379-381, ISSN: 1073-449X
Tutino M, Granell R, Curtin JA, et al., 2023, Dog ownership in infancy is protective for persistent wheeze in 17q21 asthma-risk carriers, Journal of Allergy and Clinical Immunology, Vol: 151, Pages: 423-430, ISSN: 0091-6749
BackgroundAsthma-associated single nucleotide polymorphisms from large genome-wide association studies only explain a fraction of genetic heritability. Likely causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results.ObjectivesWe sought to study the GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze.MethodsWheezing classes derived from 5 UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. A total of 9149 children had both pet ownership and genotype data available. Summary statistics from individual analyses were meta-analyzed.Resultsrs2305480 G allele was associated with increased risk of persistent wheeze (additive model odds ratio, 1.37; 95% CI, 1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. We found significant evidence of a GxE interaction between rs2305480 and dog ownership (P = 8.3 × 10−4) on persistent wheeze; among dog owners, the G allele was no longer associated with an increased risk of persistent wheeze (additive model odds ratio, 0.95; 95% CI, 0.73-1.24). For those without pets, G allele was associated with increased risk of persistent wheeze (odds ratio, 1.61; 95% CI, 1.40-1.86). Among cat owners, no such dampening of the genetic effect was observed.ConclusionsAmong dog owners, rs2305480 G was no longer associated with an increased risk of persistent wheeze (or asthma). Early-life environmental exposures may therefore attenuate likelihood of asthma in those carrying 17q12-21 risk alleles.
Custovic A, de Moira AP, Murray CSS, et al., 2023, Environmental influences on childhood asthma: Allergens, Pediatric Allergy and Immunology, Vol: 34, Pages: 1-19, ISSN: 0905-6157
Allergen exposure is associated with the development of allergen-specific sensitization, but their relationship is influenced by other contemporaneous exposures (such as microbial exposure) and the genetic predisposition of the host. Clinical outcomes of the primary prevention studies that tested the effectiveness of allergen avoidance in pregnancy and early life on the subsequent development of sensitization and asthma published to date are inconsistent. Therefore, we cannot provide any evidence-based advice on the use of allergen avoidance for the primary prevention of these conditions. The evidence about the impact of allergen exposure among and among sensitized children with asthma is more consistent, and the combination of sensitization and high exposure to sensitizing allergen increases airway inflammation, triggers symptoms, adversely impacts upon disease control, and is associated with poorer lung function in preschool age. However, there are differing opinions about the role of inhalant allergen avoidance in asthma management, and recommendations differ in different guidelines. Evidence from more recent high-quality trials suggests that mite allergen-impermeable bed encasings reduce hospital attendance with asthma attacks and that multifaceted targeted environmental control improves asthma control in children. We therefore suggest a pragmatic approach to allergen avoidance in the management of childhood asthma for clinical practice, including the recommendations to: (1) tailor the intervention to the patient's sensitization and exposure status by using titer of allergen-specific IgE antibodies and/or the size of the skin test as indicators of potential response; (2) use a multifaceted allergen control regime to reduce exposure as much as possible; and (3) start intervention as early as possible upon diagnosis.
McCready C, Haider S, Little F, et al., 2023, Early childhood wheezing phenotypes and determinants in a South African birth cohort: longitudinal analysis of the Drakenstein Child Health Study, The Lancet Child & Adolescent Health, Vol: 7, Pages: 127-135, ISSN: 2352-4642
BACKGROUND: Developmental trajectories of childhood wheezing in low-income and middle-income countries (LMICs) have not been well described. We aimed to derive longitudinal wheeze phenotypes from birth to 5 years in a South African birth cohort and compare those with phenotypes derived from a UK cohort. METHODS: We used data from the Drakenstein Child Health Study (DCHS), a longitudinal birth cohort study in a peri-urban area outside Cape Town, South Africa. Pregnant women (aged ≥18 years) were enrolled during their second trimester at two public health clinics. We followed up children from birth to 5 years to derive six multidimensional indicators of wheezing (including duration, temporal sequencing, persistence, and recurrence) and applied Partition Around Medoids clustering to derive wheeze phenotypes. We compared phenotypes with a UK cohort (the Avon Longitudinal Study of Parents and Children [ALSPAC]). We investigated associations of phenotypes with early-life exposures, including all-cause lower respiratory tract infection (LRTI) and virus-specific LRTI (respiratory syncytial virus, rhinovirus, adenovirus, influenza, and parainfluenza virus) up to age 5 years. We investigated the association of phenotypes with lung function at 6 weeks and 5 years. FINDINGS: Between March 5, 2012, and March 31, 2015, we enrolled 1137 mothers and there were 1143 livebirths. Four wheeze phenotypes were identified among 950 children with complete data: never (480 children [50%]), early transient (215 children [23%]), late onset (104 children [11%]), and recurrent (151 children [16%]). Multivariate adjusted analysis indicated that LRTI and respiratory syncytial virus-LRTI, but not other respiratory viruses, were associated with increased risk of recurrent wheeze (odds ratio [OR] 2·79 [95% CI 2·05-3·81] for all LTRIs; OR 2·59 [1·30-5·15] for respiratory syncytial virus-LRTIs). Maternal smoking (1·88 [1·12-3·02]), high
Rijavec M, Maver A, Turner PJJ, et al., 2022, Integrative transcriptomic analysis in human and mouse model of anaphylaxis identifies gene signatures associated with cell movement, migration and neuroinflammatory signalling, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224
Background: Anaphylaxis is an acute life-threatening allergic reaction and a concern at a global level; therefore, further progress in understanding the underlying mechanisms and more effective strategies for diagnosis, prevention and management are needed.Objective: We sought to identify the global architecture of blood transcriptomic features of anaphylaxis by integrating expression data from human patients and mouse model of anaphylaxis.Methods: Bulk RNA-sequencings of peripheral whole blood were performed in: i) 14 emergency department (ED) patients with acute anaphylaxis, predominantly to Hymenoptera venom, ii) 11 patients with peanut allergy undergoing double-blind, placebo-controlled food challenge (DBPCFC) to peanut, iii) murine model of IgE-mediated anaphylaxis. Integrative characterisation of differential gene expression, immune cell-type-specific gene expression profiles, and functional and pathway analysis was undertaken.Results: 1023 genes were commonly and significantly dysregulated during anaphylaxis in ED and DBPCFC patients; of those genes, 29 were also dysregulated in the mouse model. Cell-type-specific gene expression profiles showed a rapid downregulation of blood basophil and upregulation of neutrophil signature in ED and DBPCFC patients and the mouse model, but no consistent and/or significant differences were found for other blood cells. Functional and pathway analysis demonstrated that human and mouse blood transcriptomic signatures of anaphylaxis follow trajectories of upregulation of cell movement, migration and neuroinflammatory signalling, and downregulation of lipid activating nuclear receptors signalling.Conclusion: Our study highlights the matched and extensive blood transcriptomic changes and suggests the involvement of discrete cellular components and upregulation of migration and neuroinflammatory pathways during anaphylaxis.
Duverdier A, Hurault G, Custovic A, et al., 2022, Recency bias in weekly POEM recording and its effects on POEM prediction, 51st Annual Meeting of the European-Society-for-Dermatological-Research (ESDR), Publisher: ELSEVIER SCIENCE INC, Pages: S198-S198, ISSN: 0022-202X
Haider S, Fontanella S, Ullah A, et al., 2022, Evolution of eczema, wheeze and rhinitis from infancy to early adulthood: four birth cohort studies, American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 950-960, ISSN: 1073-449X
BACKGROUND: The relationship between eczema, wheeze/asthma and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. OBJECTIVE: To investigate within-individual patterns of morbidity of eczema, wheeze and rhinitis from birth to adolescence/early adulthood. METHODS: We investigated onset/progression/resolution of eczema, wheeze and rhinitis using descriptive statistics, sequence mining and Latent Markov modelling (LMM) in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin mutations and 17q21 variants), increase the risk of multimorbidity. RESULTS: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema+wheeze+rhinitis was rare, but significantly over-represented (3-6 times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2-3-fold, rs7216389 risk variant by 1.4-1.7-fold). LMM revealed 5 latent states (No disease/low risk; Mainly eczema; Mainly Wheeze; Mainly rhinitis; Multimorbidity). The most likely transition to Multimorbidity was from Eczema state (0.21). However, although this was one of the highest transition probabilities, only 1/5 of those with eczema transitioned to multimorbidity. CONCLUSIONS: Atopic diseases fit a multimorbidity framework, with no evidence for sequential "atopic march" progression. The highest transition to multimorbidity was from eczema, but most children with eczema (>three quarters) had no comorbidities.
Papadopoulos N, Mathioudakis A, Custovic A, et al., 2022, Childhood asthma monitoring frequency and duration, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Farne H, Lin L, Jackson D, et al., 2022, In vivo bronchial epithelial interferon responses are augmented in asthma on day 4 following experimental rhinovirus infection, Thorax, Vol: 77, Pages: 929-932, ISSN: 0040-6376
Despite good evidence of impaired innate antiviral responses in asthma, trials of inhaled interferon-β given during exacerbations showed only modest benefits in moderate/severe asthma. Using human experimental rhinovirus infection, we observe robust in vivo induction of bronchial epithelial interferon response genes four days after virus inoculation in 25 subjects with asthma but not 11 control subjects. This signature correlated with virus loads and lower respiratory symptoms. Our data indicate that the in vivo innate antiviral response is dysregulated in asthma and open up the potential that prophylactic rather than therapeutic interferon therapy may have greater clinical benefit.
Lin L, Curtin JA, Regis E, et al., 2022, A systems immunology approach to investigate cytokine responses to viruses and bacteria and their association with disease, Scientific Reports, Vol: 12, Pages: 1-14, ISSN: 2045-2322
Patterns of human immune responses to viruses and bacteria and how this impacts risk of infections or onset/exacerbation of chronic respiratory diseases are poorly understood. In a population-based birth cohort, we measured peripheral blood mononuclear cell responses (28 cytokines) to respiratory viruses and bacteria, Toll-like receptor ligands and phytohemagglutinin, in 307 children. Cytokine responses were highly variable with > 1000-fold differences between children. Machine learning revealed clear distinction between virus-associated and bacteria-associated stimuli. Cytokines clustered into three functional groups (anti-viral, pro-inflammatory and T-cell derived). To investigate mechanisms potentially explaining such variable responses, we investigated cytokine Quantitative Trait Loci (cQTLs) of IL-6 responses to bacteria and identified nine (eight novel) loci. Our integrative approach describing stimuli, cytokines and children as variables revealed robust immunologically and microbiologically plausible clustering, providing a framework for a greater understanding of host-responses to infection, including novel genetic associations with respiratory disease.
Pepys J, Ullah A, Murray C, et al., 2022, Exposure to endotoxin modifies the risk of asthma in children with risk variants in 17q21 locus, Publisher: WILEY, Pages: 1053-1054, ISSN: 0954-7894
Granell R, Haider S, Deliu M, et al., 2022, Trajectories of restrictive pattern of lung function FEV<sub>1</sub>/FVC to physiological peak and their relationship with early life risk-factors and cardiac markers, Joint Conference of the British-Society-for-Allergy-and-Immunology (BSACI) and World-Allergy-Organization (WAO), Publisher: WILEY, Pages: 1041-1042, ISSN: 0954-7894
Stolting H, Baillon L, Frise R, et al., 2022, Distinct airway epithelial immune responses after infection with SARS-CoV-2 compared to H1N1, Mucosal Immunology, Vol: 15, Pages: 952-963, ISSN: 1933-0219
Children are less likely than adults to suffer severe symptoms when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), while influenza A H1N1 severity is comparable across ages except for the very young or elderly. Airway epithelial cells play a vital role in the early defence against viruses via their barrier and immune functions. We investigated viral replication and immune responses in SARS-CoV-2-infected bronchial epithelial cells from healthy paediatric (n = 6; 2.5–5.6 years old) and adult (n = 4; 47–63 years old) subjects and compared cellular responses following infection with SARS-CoV-2 or Influenza A H1N1. While infection with either virus triggered robust transcriptional interferon responses, including induction of type I (IFNB1) and type III (IFNL1) interferons, markedly lower levels of interferons and inflammatory proteins (IL-6, IL-8) were released following SARS-CoV-2 compared to H1N1 infection. Only H1N1 infection caused disruption of the epithelial layer. Interestingly, H1N1 infection resulted in sustained upregulation of SARS-CoV-2 entry factors FURIN and NRP1. We did not find any differences in the epithelial response to SARS-CoV-2 infection between paediatric and adult cells. Overall, SARS-CoV-2 had diminished potential to replicate, affect morphology and evoke immune responses in bronchial epithelial cells compared to H1N1.
Wang R, Fowler SJ, Turner SW, et al., 2022, Defining the normal range of fractional exhaled nitric oxide in children: one size does not fit all, ERJ OPEN RESEARCH, Vol: 8
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Duverdier A, Custovic A, Tanaka R, 2022, Data-driven research on eczema: systematic characterization of the field and recommendations for the future, Clinical and Translational Allergy, Vol: 12, Pages: 1-10, ISSN: 2045-7022
BackgroundThe past decade has seen a substantial rise in the employment of modern data-driven methods to study atopic dermatitis (AD)/eczema. The objective of this study is to summarise the past and future of data-driven AD research, and identify areas in the field that would benefit from the application of these methods.MethodsWe retrieved the publications that applied multivariate statistics (MS), artificial intelligence (AI, including machine learning-ML), and Bayesian statistics (BS) to AD and eczema research from the SCOPUS database over the last 50 years. We conducted a bibliometric analysis to highlight the publication trends and conceptual knowledge structure of the field, and applied topic modelling to retrieve the key topics in the literature.ResultsFive key themes of data-driven research on AD and eczema were identified: (1) allergic co-morbidities, (2) image analysis and classification, (3) disaggregation, (4) quality of life and treatment response, and (5) risk factors and prevalence. ML&AI methods mapped to studies investigating quality of life, prevalence, risk factors, allergic co-morbidities and disaggregation of AD/eczema, but seldom in studies of therapies. MS was employed evenly between the topics, particularly in studies on risk factors and prevalence. BS was focused on three key topics: treatment, risk factors and allergy. The use of AD or eczema terms was not uniform, with studies applying ML&AI methods using the term eczema more often. Within MS, papers using cluster and factor analysis were often only identified with the term AD. In contrast, those using logistic regression and latent class/transition models were “eczema” papers.ConclusionsResearch areas that could benefit from the application of data-driven methods include the study of the pathogenesis of the condition and related risk factors, its disaggregation into validated subtypes, and personalised severity management and prognosis. We highlight BS as a new and pro
Custovic A, Fontanella S, 2022, Machine Learning in Asthma Research and Clinical Practice, Publisher: WILEY, Pages: S10-S11, ISSN: 8755-6863
Custovic A, Fontanella S, 2022, Update on Diagnostic Tests in Pediatric Allergy, Publisher: WILEY, Pages: S85-S87, ISSN: 8755-6863
Zuberbier T, Doerr T, Aberer W, et al., 2022, Proposal of 0.5 mg of protein/100 g of processed food as threshold for voluntary declaration of food allergen traces in processed food-A first step in an initiative to better inform patients and avoid fatal allergic reactions: A GA<SUP>2</SUP>LEN position paper, ALLERGY, Vol: 77, Pages: 1736-1750, ISSN: 0105-4538
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- Citations: 11
Saglani S, Cohen RT, Chiel LE, et al., 2022, WITHDRAWN: Update in Asthma 2021., Am J Respir Crit Care Med
Ahead of Print article withdrawn by publisher.
Rouadi PW, Idriss SA, Bousquet J, et al., 2022, WAO-ARIA consensus on chronic cough - Part III: Management strategies in primary and cough-specialty care. <i>Updates in</i> COVID-19, WORLD ALLERGY ORGANIZATION JOURNAL, Vol: 15, ISSN: 1939-4551
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- Citations: 3
Kothalawala DM, Weiss VBN, Kadalayil L, et al., 2022, Nonlinear effects of environment on childhood asthma susceptibility, PEDIATRIC ALLERGY AND IMMUNOLOGY, Vol: 33, ISSN: 0905-6157
Turner P, Custovic A, 2022, Life-threatening anaphylaxis to peanut – impossible to predict?, Journal of Allergy and Clinical Immunology, Vol: 149, Pages: 1128-1129, ISSN: 0091-6749
Antunes KH, Stein RT, Franceschina C, et al., 2022, Short-chain fatty acid acetate triggers antiviral response mediated by RIG-I in cells from infants with respiratory syncytial virus bronchiolitis, EBIOMEDICINE, Vol: 77, ISSN: 2352-3964
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- Citations: 15
Pattaroni C, Macowan M, Chatzis R, et al., 2022, Early life inter-kingdom interactions shape the immunological environment of the airways, Microbiome, Vol: 10, ISSN: 2049-2618
Background: There is increasing evidence that the airway microbiome plays a key role in the establishment of respiratory health by interacting with the developing immune system early in life. While it has become clear that bacteria are involved in this process, there is a knowledge gap concerning the role of fungi. Moreover, the inter-kingdom interactions that influence immune development remain unknown. In this prospective exploratory human study, we aimed to determine early post-natal microbial and immunological features of the upper airways in 121 healthy newborns.Results: We found that the oropharynx and nasal cavity represent distinct ecological niches for bacteria and fungi. Breastfeeding correlated with changes in microbiota composition of oropharyngeal samples with the greatest impact upon the relative abundance of Streptococcus species and Candida. Host transcriptome profiling revealed that genes with the highest expression variation were immunological in nature. Multi-omics factor analysis of host and microbial data revealed unique co-variation patterns. Conclusion: These data provide evidence of a diverse multi-kingdom microbiota linked with local immunological characteristics in the first week of life that could represent distinct trajectories for future respiratory health.
Mkorombindo T, Balmes JR, Custovic A, et al., 2022, The air we breathe: respiratory impact of indoor air quality in chronic obstructive pulmonary disease, American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 378-380, ISSN: 1073-449X
Kotsapas C, Nicolaou N, Haider S, et al., 2022, Early-life predictors and risk factors of peanut allergy, and its association with asthma in later-life: Population-based birth cohort study, Clinical and Experimental Allergy, Vol: 52, Pages: 646-657, ISSN: 0954-7894
BackgroundUnderstanding risk factors for peanut allergy (PA) is essential to develop effective preventive measures.ObjectiveThe objective was to ascertain associates and predictors of PA, and the relationship between PA and asthma severity.MethodsIn a population-based birth cohort, we investigated the association between objectively confirmed PA with early-life environmental exposures, filaggrin (FLG)-loss-of-function mutations and other atopic disease. We then examined the association of PA with longitudinal trajectories of sensitization, wheeze and allergic comorbidities, which were previously derived using machine learning. Finally, we ascertained the relationship between PA and asthma severity.ResultsPA was confirmed in 30/959 participants with evaluable data. In the multivariate analysis, eczema in infancy (OR = 4.4, 95% CI 1.5–13.2, p = 0.007), egg sensitization at age 3 years (OR = 9.7, 95% CI 3.3–29.9, p < 0.001) and early-life cat ownership (OR = 3.0, 95% CI 1.1–8.4, p = 0.04) were independent associates of PA. In the stratified analysis among 700 participants with genetic information, in children with early-life eczema there was no difference in FLG mutations between children with and without PA (3/18 [16.7%] vs. 42/220 [19.1%], p = 1.00). In contrast, among children without eczema, those with PA were almost eight times more likely to have FLG mutations (2/6 [33.3%] vs. 27/456 [5.9%], p = 0.049). We observed associations between PA and multiple allergic sensitization profiles derived using machine learning, with ~60-fold increase in risk among individuals assigned to multiple early sensitization. PA was significantly associated with persistent wheeze (but not other wheeze phenotypes), and with trajectories of atopic disease characterized by co-morbid persistent eczema and wheeze (but not with transient phenotypes). Children with PA were more likely to have asthma, but among asthmatics we found no evidence of an association between PA a
Custovic A, Siddiqui S, Saglani S, 2022, Considering biomarkers in asthma disease severity, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 149, Pages: 480-487, ISSN: 0091-6749
Nakamura T, Haider S, Fontanella S, et al., 2022, Modelling trajectories of parentally reported and physician-confirmed atopic dermatitis in a birth cohort study., British Journal of Dermatology, Vol: 186, Pages: 274-284, ISSN: 0007-0963
BACKGROUND: In a population-based birth cohort, we aimed to identify longitudinal trajectories of atopic dermatitis (AD) during childhood using data from different sources (validated questionnaires and healthcare records), investigate impact of different AD definitions on such trajectories and their relationships with various risk factors. METHODS: Of the 1184 children born into the study, 1083 had information on current AD on at least three follow-ups from birth to age 11 years and were included in the analysis for parentally-reported AD (PRAD). Data were transcribed from healthcare records of 916/1184 children, for the analysis of doctor-diagnosed AD (DDAD). We also derived composite definition (CDAD; at least 2 of 3 features: PRAD, DDAD, current use of AD treatment). Using latent class analysis (LCA), we determined longitudinal profiles of AD using the three definitions (PRAD, DDAD CDAD). FLG genotype was available for 803 Caucasian participants. RESULTS: For PRAD, LCA identified four AD classes ("No AD", "Persistent", "Early-onset remitting"" and "Late-onset"). For DDAD and CDAD, the optimal number of phenotypes was three ("No AD", "Persistent" and "Early-onset remitting"). Although AD classes at population level appeared similar in different models, a considerable proportion of children (n=485, 45%) moved between classes. The association with FLG genotype, atopic diseases, and early-life risk factors were inconsistent across different definitions, but the association with oral food challenge-confirmed peanut allergy was similar, with a 9 to 11-fold increase amongst children in the Persistent AD class. In a CDAD model, compared to Early-onset remitting class, those with Persistent AD were significantly more likely to have (at age 3 years) moderate/severe AD (OR=11.6, [95% CI 1.7-80.2]), polysensitisation (5.2, [1.3-21.2]), and current wheeze (4.8, [1.4-16.6]), and were less likely to be b
Haider S, Granell R, Curtin J, et al., 2022, Modelling wheezing spells identifies phenotypes with different outcomes and genetic associates, American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 883-893, ISSN: 1073-449X
Background: Longitudinal modelling of current wheezing identified similar phenotypes, but their characteristics often differ between studies. We propose that more comprehensive description of wheeze may better describe trajectories than binary information on presence/absence of wheezing. Methods: We derived 6 multi-dimensional variables of wheezing spells from birth to adolescence (including duration, temporal sequencing, and the extent of persistence/recurrence). We applied Partition-Around-Medoids clustering on these variables to derive phenotypes in five birth cohorts. We investigated within- and between-phenotype differences compared to binary latent class analysis models (LCA-phenotypes), and ascertained associations of these phenotypes with asthma and lung function, and with polymorphisms in asthma loci 17q12-21 and CDHR3. Findings: Analysis among 7719 participants with complete data identified 5 spell-based wheeze phenotypes with high degree of certainty: Never (NWZ-54.1%), Early-transient (ETW-23.7%), Late-onset (LOW-6.9%), Persistent (PEW-8.3%), and a novel phenotype, Intermittent wheeze (INT-6.9%). FEV1/FVC was lower in PEW and INT compared to ETW and LOW, and declined from age 8 years to adulthood in INT. 17q12-21 and CDHR3 polymorphisms were associated with higher odds of PEW and INT, but not ETW or LOW. LCA- and spell-based-phenotypes appeared similar, but within-phenotype individual trajectories and phenotype allocation differed substantially. The spell-based approach was much more robust in dealing with missing data, and the derived clusters more stable and internally homogenous. Conclusions: Modelling of spell variables identified a novel intermittent wheeze phenotype associated with lung function decline to early adulthood. Using multi-dimensional spells variables may better capture wheeze development and provide a more robust input for phenotype derivation.
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