Publications
62 results found
Custovic A, Custovic D, Fontanella S, 2024, Understanding the heterogeneity of childhood allergic sensitization and its relationship with asthma., Curr Opin Allergy Clin Immunol, Vol: 24, Pages: 79-87
PURPOSE OF REVIEW: To review the current state of knowledge on the relationship between allergic sensitization and asthma; to lay out a roadmap for the development of IgE biomarkers that differentiate, in individual sensitized patients, whether their sensitization is important for current or future asthma symptoms, or has little or no relevance to the disease. RECENT FINDINGS: The evidence on the relationship between sensitization and asthma suggests that some subtypes of allergic sensitization are not associated with asthma symptoms, whilst others are pathologic. Interaction patterns between IgE antibodies to individual allergenic molecules on component-resolved diagnostics (CRD) multiplex arrays might be hallmarks by which different sensitization subtypes relevant to asthma can be distinguished. These different subtypes of sensitization are associated amongst sensitized individuals at all ages, with different clinical presentations (no disease, asthma as a single disease, and allergic multimorbidity); amongst sensitized preschool children with and without lower airway symptoms, with different risk of subsequent asthma development; and amongst sensitized patients with asthma, with differing levels of asthma severity. SUMMARY: The use of machine learning-based methodologies on complex CRD data can help us to design better diagnostic tools to help practising physicians differentiate between benign and clinically important sensitization.
Regis E, Fontanella S, Curtin JA, et al., 2024, Association between polymorphisms on chromosome 17q12-q21 and rhinovirus-induced interferon responses., J Allergy Clin Immunol
BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes on chromosome 17q12-q21 are associated with childhood-onset asthma and rhinovirus-induced wheezing. There is little mechanistic data linking chromosome 17q12-q21 to wheezing illness. OBJECTIVE: To investigate whether 17q12-q21 risk alleles may be associated with impaired interferon (IFN) responses to rhinovirus. METHODS: In a population-based birth cohort of European ancestry, we stimulated peripheral blood mononuclear cells (PBMCs) with rhinovirus-A1 (RV-A1) and rhinovirus-A16 (RV-A16) and measured IFN and IFN-induced chemokine CXCL10/IP10 responses in supernatants. We investigated associations between virus-induced cytokines and six SNPs in 17q12-q21. Bayesian profile regression was applied to identify clusters of individuals with different immune response profiles and genetic variants. RESULTS: Five SNPs (in high linkage disequilibrium, r2≥0.8) were significantly associated with RV-A1-induced IFN-β (rs9303277: P=0.010; rs11557467: P=0.012; rs2290400: P=0.006; rs7216389: P=0.008; rs8079416: P=0.005). A reduction in RV-A1-induced IFN-β was observed among individuals carrying asthma risk alleles. There were no significant associations for RV-A1-induced IFN-α or CXCL10, or for any RV-A16-induced IFN/CXCL10. Bayesian profile regression analysis identified three clusters which differed in IFN-β induction to RV-A1 (low, medium and high). The typical genetic profile of the cluster associated with low RV-A1-induced IFN-β responses was characterised by a very high probability of being homozygous for the asthma risk allele for all SNPs. Children with persistent wheeze were almost 3-times more likely to be in clusters with reduced/average RV-A1-induced IFN- β responses than in the high immune response cluster. CONCLUSIONS: Polymorphisms on chromosome 17q12-q21 are associated with rhinovirus-induced IFN-β, suggesting a novel mechanism (impaired IFN-β induction) linking 17q1
Melén E, Faner R, Allinson JP, et al., 2024, Lung-function trajectories: relevance and implementation in clinical practice, The Lancet, ISSN: 0140-6736
Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.
Howard R, Fontanella S, Simpson A, et al., 2024, Component-specific clusters for diagnosis and prediction of allergic airway diseases., Clin Exp Allergy
BACKGROUND: Previous studies which applied machine learning on multiplex component-resolved diagnostics arrays identified clusters of allergen components which are biologically plausible and reflect the sources of allergenic proteins and their structural homogeneity. Sensitization to different clusters is associated with different clinical outcomes. OBJECTIVE: To investigate whether within different allergen component sensitization clusters, the internal within-cluster sensitization structure, including the number of c-sIgE responses and their distinct patterns, alters the risk of clinical expression of symptoms. METHODS: In a previous analysis in a population-based birth cohort, by clustering component-specific (c-s)IgEs, we derived allergen component clusters from infancy to adolescence. In the current analysis, we defined each subject's within-cluster sensitization structure which captured the total number of c-sIgE responses in each cluster and intra-cluster sensitization patterns. Associations between within-cluster sensitization patterns and clinical outcomes (asthma and rhinitis) in early-school age and adolescence were examined using logistic regression and binomial generalized additive models. RESULTS: Intra-cluster sensitization patterns revealed specific associations with asthma and rhinitis (both contemporaneously and longitudinally) that were previously unseen using binary sensitization to clusters. A more detailed description of the subjects' within-cluster c-sIgE responses in terms of the number of positive c-sIgEs and unique sensitization patterns added new information relevant to allergic diseases, both for diagnostic and prognostic purposes. For example, the increase in the number of within-cluster positive c-sIgEs at age 5 years was correlated with the increase in prevalence of asthma at ages 5 and 16 years, with the correlations being stronger in the prediction context (e.g. for the largest 'Broad' component cluster, contemporaneous
Efstathiou C, Liew F, Fontanella S, et al., 2024, Large scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease, Nature Immunology, ISSN: 1529-2908
Ullah A, Granell R, Haider S, et al., 2024, Obstructive and restrictive spirometry from school age to adulthood: three birth cohort studies, EClinicalMedicine, Vol: 67, ISSN: 2589-5370
Background:Spirometric obstruction and restriction are two patterns of impaired lung function which are predictive of poor health. We investigated the development of these phenotypes and their transitions through childhood to early adulthood.Methods:In this study, we analysed pooled data from three UK population−based birth cohorts established between 1989 and 1995. We applied descriptive statistics, regression modelling and data-driven modelling to data from three population−based birth cohorts with at least three spirometry measures from childhood to adulthood (mid-school: 8–10 years, n = 8404; adolescence: 15–18, n = 5764; and early adulthood: 20–26, n = 4680). Participants were assigned to normal, restrictive, and obstructive spirometry based on adjusted regression residuals. We considered two transitions: from 8–10 to 15–18 and from 15–18 to 20–26 years.Findings:Obstructive phenotype was observed in ∼10%, and restrictive in ∼9%. A substantial proportion of children with impaired lung function in school age (between one third in obstructive and a half in restricted phenotype) improved and achieved normal and stable lung function to early adulthood. Of those with normal lung function in school-age, <5% declined to adulthood. Underweight restrictive and obese obstructive participants were less likely to transit to normal. Maternal smoking during pregnancy and current asthma diagnosis increased the risk of persistent obstruction and worsening. Significant associate of worsening in restrictive phenotypes was lower BMI at the first lung function assessment. Data-driven methodologies identified similar risk factors for obstructive and restrictive clusters.Interpretation:The worsening and improvement in obstructive and restrictive spirometry were observed at all ages. Maintaining optimal weight during childhood and reducing maternal smoking during pregnancy may reduce spirometry obstruction and restrictio
Haider S, Granell R, Curtin JA, et al., 2024, Identification of eczema clusters and their association with filaggrin and atopic comorbidities: analysis of 5 birth cohorts, British Journal of Dermatology, Vol: 190, Pages: 45-54, ISSN: 0007-0963
Background: Longitudinal modelling of the presence/absence of current eczema through childhood has identified similar phenotypes, but their characteristics often differ between studies. Objectives: We propose that more comprehensive description of longitudinal pattern of symptoms may better describe trajectories than binary information on eczema presence. Methods: We derived 6 multi-dimensional variables of eczema spells from birth to age 18 years (including duration, temporal sequencing, and the extent of persistence/recurrence). Spells were defined as consecutive observations eczema separated by no-eczema across 5 epochs in five birth cohorts: infancy (first year); early childhood (age 2-3 years); pre-school/early school age (4-5 years); middle childhood (8-10 years); adolescence (14-18 years). We applied Partition-Around-Medoids clustering on these variables to derive clusters of the temporal patterns of eczema. We then investigated the stability of the clusters, within-cluster homogeneity, and associated risk factors, including filaggrin mutations.Results: Analysis among 7,464 participants with complete data identified five clusters: 1) No eczema (NOE) (51%); 2) Early transient (ETE) (21.6%); (3) Late-onset (LOE) (8.1%); 4) Intermittent (INT) (7.5%); and 5) Persistent (PE) (11.8%) eczema. There was a very high agreement between assignment of individual children into clusters when using complete or imputed (n=15,848) data (adjusted Rand index=0.99), i.e., the clusters were very stable. Within-individual symptom patterns across clusters confirmed within−cluster homogeneity, with consistent patterns of symptoms among participants within each cluster, and no overlap between the clusters. Clusters were characterised by differences in associations with risk factors (e.g., parental eczema was associated with all clusters apart from LOE; sensitisation to inhalant allergens was associated with all clusters, with highest risk of PE). All clusters apart from LOE we
Fontanella S, Cucco A, Custovic A, 2023, Breathing new life into asthma research: a review of machine learning and multi-omics approaches, Minerva Respiratory Medicine, Vol: 62, Pages: 163-176, ISSN: 2784-8477
INTRODUCTION: Asthma is a chronic respiratory disease that affects millions of people worldwide, and despite intensive study, the underlying molecular pathways are still unknown. Recent breakthroughs in machine learning and multi-omics technology provide new avenues for delving deeper into disease pathophysiology and identifying potential treatment targets. EVIDENCE ACQUISITION: We comprehensively reviewed the literature to explore the potential of machine learning and multi-omics approaches in asthma research. We searched the Scopus database using a combination of terms such as “asthma,” “machine learning”, and “multi-omics” and their synonyms. EVIDENCE SYNTHESIS: Our review revealed that machine learning and multi-omics approaches have been increasingly used to identify biomarkers, classify asthma subtypes, predict treatment outcomes, and understand the disease pathophysiology at the molecular level. CONCLUSIONS: Combining machine learning and multi-omics technologies holds tremendous potential for advancing our understanding of asthma pathogenesis and identifying novel therapeutic targets. Overall, this analysis demonstrates how these techniques have the potential to revitalize asthma research and improve patient outcomes. More study is needed, however, to confirm the utility of these approaches and understand how to build viable models that can be applied to clinical practice.
Custovic D, Fontanella S, Custovic A, 2023, Understanding progression from pre-school wheezing to school-age asthma: Can modern data approaches help?, Pediatr Allergy Immunol, Vol: 34
Preschool wheezing and childhood asthma create a heavy disease burden which is only exacerbated by the complexity of the conditions. Preschool wheezing exhibits both "curricular" and "aetiological" heterogeneity: that is, heterogeneity across patients both in the time-course of its development and in its underpinning pathological mechanisms. Since these are not fully understood, but clinical presentations across patients may nonetheless be similar, current diagnostic labels are imprecise-not mapping cleanly onto underlying disease mechanisms-and prognoses uncertain. These uncertainties also make a identifying new targets for therapeutic intervention difficult. In the past few decades, carefully designed birth cohort studies have collected "big data" on a large scale, incorporating not only a wealth of longitudinal clinical data, but also detailed information from modalities as varied as imaging, multiomics, and blood biomarkers. The profusion of big data has seen the proliferation of what we term "modern data approaches" (MDAs)-grouping together machine learning, artificial intelligence, and data science-to make sense and make use of this data. In this review, we survey applications of MDAs (with an emphasis on machine learning) in childhood wheeze and asthma, highlighting the extent of their successes in providing tools for prognosis, unpicking the curricular heterogeneity of these conditions, clarifying the limitations of current diagnostic criteria, and indicating directions of research for uncovering the etiology of the diseases underlying these conditions. Specifically, we focus on the trajectories of childhood wheeze phenotypes. Further, we provide an explainer of the nature and potential use of MDAs and emphasize the scope of what we can hope to achieve with them.
Pronello N, Ignaccolo R, Ippoliti L, et al., 2023, Penalized model-based clustering of complex functional data, STATISTICS AND COMPUTING, Vol: 33, ISSN: 0960-3174
van Breugel M, Fehrmann RSN, Bügel M, et al., 2023, Current state and prospects of artificial intelligence in allergy, Allergy, Vol: 78, Pages: 2623-2643, ISSN: 0105-4538
The field of medicine is witnessing an exponential growth of interest in artificial intelligence (AI), which enables new research questions and the analysis of larger and new types of data. Nevertheless, applications that go beyond proof of concepts and deliver clinical value remain rare, especially in the field of allergy. This narrative review provides a fundamental understanding of the core concepts of AI and critically discusses its limitations and open challenges, such as data availability and bias, along with potential directions to surmount them. We provide a conceptual framework to structure AI applications within this field and discuss forefront case examples. Most of these applications of AI and machine learning in allergy concern supervised learning and unsupervised clustering, with a strong emphasis on diagnosis and subtyping. A perspective is shared on guidelines for good AI practice to guide readers in applying it effectively and safely, along with prospects of field advancement and initiatives to increase clinical impact. We anticipate that AI can further deepen our knowledge of disease mechanisms and contribute to precision medicine in allergy.
Turner P, Patel N, Isaacs E, et al., 2023, Optimal dose of adrenaline auto-injector for children and young people at risk of anaphylaxis: a phase IV randomised controlled crossover study, Allergy, Vol: 78, Pages: 1997-2006, ISSN: 0105-4538
BackgroundGuidelines recommend intramuscular injection of 500 μg adrenaline (epinephrine) for anaphylaxis in teenagers and adults; however, most autoinjectors deliver a maximum 300 μg dose. We evaluated plasma adrenaline levels and cardiovascular parameters (including cardiac output) following self-injection with 300 μg or 500 μg adrenaline in teenagers at risk of anaphylaxis.MethodsSubjects were recruited to a randomized, single-blind two period crossover trial. Participants received all 3 injections (Emerade® 500 μg, Emerade® 300 μg, Epipen® 0.3 mg) on 2 separate visits (allocated in a randomized block design), at least 28 days apart. Intramuscular injection was confirmed by ultrasound, and heart rate/stroke volume assessed using continuous monitoring. The trial was registered at Clinicaltrials.gov (NCT03366298).ResultsTwelve participants (58% male, median 15.4 years) participated; all completed the study. 500 μg injection resulted in a higher and more prolonged peak concentration (p = 0.01) and greater Area-Under-Curve for plasma adrenaline (p < 0.05) compared to 300 μg, with no difference in adverse events. Adrenaline caused a significant increase in heart rate irrespective of dose and device. Unexpectedly, 300 μg adrenaline resulted in a significant increase in stroke volume when delivered with Emerade®, but a negative inotropic effect with Epipen® (p < 0.05).ConclusionsThese data support a 500 μg dose of adrenaline to treat anaphylaxis in individuals >40 kg in the community. The contrasting effects on stroke volume between Epipen® and Emerade®, despite similar peak plasma adrenaline levels, are unexpected. There is an urgent need to better understand differences in pharmacodynamics following adrenaline administration by autoinjector. In the meantime, we recommend adrenaline injection
Shamji MH, Ollert M, Adcock IM, et al., 2023, EAACI guidelines on environmental science in allergic diseases and asthma - Leveraging artificial intelligence and machine learning to develop a causality model in exposomics, Allergy, Vol: 78, Pages: 1742-1757, ISSN: 0105-4538
Allergic diseases and asthma are intrinsically linked to the environment we live in and to patterns of exposure. The integrated approach to understanding the effects of exposures on the immune system includes the ongoing collection of large-scale and complex data. This requires sophisticated methods to take full advantage of what this data can offer. Here we discuss the progress and further promise of applying artificial intelligence and machine-learning approaches to help unlock the power of complex environmental data sets toward providing causality models of exposure and intervention. We discuss a range of relevant machine-learning paradigms and models including the way such models are trained and validated together with examples of machine learning applied to allergic disease in the context of specific environmental exposures as well as attempts to tie these environmental data streams to the full representative exposome. We also discuss the promise of artificial intelligence in personalized medicine and the methodological approaches to healthcare with the final AI to improve public health.
Granell R, Curtin JA, Haider S, et al., 2023, A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing, eLife, Vol: 12, Pages: 1-57, ISSN: 2050-084X
BACKGROUND: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. METHODS: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. RESULTS: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. CONCLUSIONS: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. FUNDING: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study.
Custovic A, Fontanella S, Haider S, 2023, Reply to Beck et al. and to Owora, American Journal of Respiratory and Critical Care Medicine, Vol: 207, Pages: 634-636, ISSN: 1073-449X
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.
Pronello N, Ignaccolo R, Ippoliti L, et al., 2023, Penalized Model-Based Functional Clustering: A Regularization Approach via Shrinkage Methods, Pages: 313-321, ISSN: 1431-8814
With the advance of modern technology, and with data being recorded continuously, functional data analysis has gained a lot of popularity in recent years. Working in a mixture model-based framework, we develop a flexible functional clustering technique achieving dimensionality reduction schemes through a L1 penalization. The proposed procedure results in an integrated modelling approach where shrinkage techniques are applied to enable sparse solutions in both the means and the covariance matrices of the mixture components, while preserving the underlying clustering structure. This leads to an entirely data-driven methodology suitable for simultaneous dimensionality reduction and clustering. Preliminary experimental results, both from simulation and real data, show that the proposed methodology is worth considering within the framework of functional clustering.
Liew F, Talwar S, Cross A, et al., 2023, SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination, EBioMedicine, Vol: 87, Pages: 1-14, ISSN: 2352-3964
Background:Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.Methods:In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.Findings:Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination.Interpretation:The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.Funding:This
Liew F, Talwar S, Efstathiou C, et al., 2022, Vaccination after recovery from COVID-19 affects nasal antibody levels, 2022 ERS International Congress, Publisher: European Respiratory Society, ISSN: 0903-1936
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.
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
Custovic A, Fontanella S, 2022, Update on Diagnostic Tests in Pediatric Allergy, Publisher: WILEY, Pages: S85-S87, ISSN: 8755-6863
Custovic A, Fontanella S, 2022, Machine Learning in Asthma Research and Clinical Practice, Publisher: WILEY, Pages: S10-S11, ISSN: 8755-6863
Bucci A, Ippoliti L, Valentini P, et al., 2022, Clustering spatio-temporal series of confirmed COVID-19 deaths in Europe, SPATIAL STATISTICS, Vol: 49, ISSN: 2211-6753
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del Gobbo E, Fontanella L, Fontanella S, et al., 2022, Geographies of Twitter debates Detect public stances on Brexit at UK parliamentary constituencies' level, JOURNAL OF COMPUTATIONAL SOCIAL SCIENCE, Vol: 5, Pages: 647-663, ISSN: 2432-2717
Fairfield B, Padulo C, Mammarella N, et al., 2022, Dopamine-related polymorphisms and Affective Working Memory in aging, NEUROBIOLOGY OF LEARNING AND MEMORY, Vol: 191, ISSN: 1074-7427
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.
Regis E, Fontanella S, Lin L, et al., 2021, Sex differences in innate anti-viral immune responses to respiratory viruses and in their clinical outcomes in a birth cohort study, Scientific Reports, Vol: 11, Pages: 1-15, ISSN: 2045-2322
The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34–2.06-fold lower in males than females (P = 0.018 − < 0.001). IFN-β, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy (P = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.
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