Clinical features and later prognosis of replicable early-life wheeze clusters from two birth cohorts 12 years apart.

BACKGROUND: Clustering techniques can define the heterogeneity of asthma and wheezing. Defining early-life wheezing clusters and associated asthma risk could potentially inform patient management strategies. Clustering models that yield replicable cluster groups will have greater validity and clinical utility. This study sought to identify early-life wheezing clusters that are translatable into clinical practice and assess their stability over time in two whole-population birth cohorts established a decade apart from the same geographical location. METHODS: Nonparametric K-means cluster analysis was performed separately on two birth cohorts from the Isle of Wight, UK; the Isle of Wight Birth Cohort (IOWBC) and Food Allergy and Intolerance Research Cohort (FAIR), using clinically defining variables in wheezing subjects in the first 3-4 years. Associations of resulting clusters with potential early-life risk factors and 10-year asthma outcomes were further assessed. RESULTS: Five clusters were identified in both cohorts: (1) infantile-onset-transient-non-atopic-wheeze, (2) infantile-onset-persistent-non-atopic-wheeze, (3) infantile-onset-atopic-wheeze, (4) early-childhood-onset-non-atopic-wheeze, and (5) early-childhood-onset-atopic-wheeze. Two atopic wheezing clusters (3 and 5) were associated with greatest early-life wheeze frequency, highest wheeze persistence, and asthma prevalence at 10 years. Cluster 1 was commonest but had lowest early-life wheeze frequency and asthma prevalence at 10 years. Cluster 2, characterized by limited atopy but recurrent infantile respiratory infections and ongoing early-life wheezing, had high 10-year asthma prevalence only in IOWBC. CONCLUSIONS: Early-life wheeze comprises several disease clusters (two more severe and three mild-moderate) with differing relationships to later childhood asthma, which can be replicated over time supporting their potential validity and clinical utility.

Modeling Wheezing Spells Identifies Phenotypes with Different Outcomes and Genetic Associates.

Rationale: Longitudinal modeling of current wheezing identified similar phenotypes, but their characteristics often differ between studies. Objectives: We propose that a more comprehensive description of wheeze may better describe trajectories than binary information on the presence/absence of wheezing. Methods: We derived six multidimensional 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 with binary latent class analysis models and ascertained associations of these phenotypes with asthma and lung function and with polymorphisms in asthma loci 17q12-21 and CDHR3 (cadherin-related family member 3). Measurements and Main Results: Analysis among 7,719 participants with complete data identified five spell-based wheeze phenotypes with a high degree of certainty: never (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 with 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. Latent class analysis- 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 were more stable and internally homogeneous. Conclusions: Modeling of spell variables identified a novel intermittent wheeze phenotype associated with lung function decline to early adulthood. Using multidimensional spell variables may better capture wheeze development and provide a more robust input for phenotype derivation.

Identifying wheezing phenotypes in a pediatric Turkish cohort.

OBJECTIVE: Characterization of wheezing phenotypes in children might help to identify the underlying mechanisms through which asthma occurs. In our study, we aimed to describe wheezing phenotypes in Turkish children and to identify risk factors according to phenotypes. METHODS: 651 wheezy children were evaluated and 5 wheezing phenotypes were described according to age of onset, atopy and persistence at 6 years of age and risk factors were identified. RESULTS: Distribution of wheezing phenotypes was transient early wheeze (TEW)(34.9%) non-atopic wheeze (NAW) (18%), atopic wheeze (AW) (22.3%), intermediate onset wheeze (IOW) (11.1%), late onset wheeze (LOW) (11.7%). LOW, AW, and IOW were associated with, father's, sibling's and family's atopy (p:0.001) whereas LOW and AW were associated with mother's asthma and atopy as well as family's asthma (p < 0.05). Atopic dermatitis and allergic rhinitis were common of patients with LOW, AW, and IOW (p < 0.05). Infection was the major trigger for TEW and NAW whereas multiple triggers were common of AW, LOW, and IOW. Allergens were mostly associated with AW, IOW and LOW. Aeroallergen-specific IgE positivity was mostly with AW, IOW, and LOW phenotype. Skin prick tests showed multiple allergen sensitivity in IOW, LOW groups and mostly single allergen in AW phenotype. Modified asthma predictive index (mAPI) positivity was high in all groups except TEW and NAW. CONCLUSIONS: With this study we classified five wheeze phenotypes and found that atopy and family's atopy history, maternal asthma were strongly associated with AW, LOW, and IOW phenotypes which were usually effected by allergens or multiple triggers.

Outcomes of Childhood Asthma and Wheezy Bronchitis. A 50-Year Cohort Study.

RATIONALE: Cohort studies suggest that airflow obstruction is established early in life, manifests as childhood asthma and wheezy bronchitis, and continues into early adulthood. Although an association between childhood asthma and chronic obstructive pulmonary disease (COPD) in later life has been demonstrated, it is unclear if childhood wheezy bronchitis is associated with COPD. OBJECTIVES: To investigate whether childhood wheezy bronchitis increases the risk of COPD in the seventh decade. METHODS: A cohort of children recruited in 1964 at age 10 to 15 years, which was followed up in 1989, 1995, and 2001, was followed up again in 2014 when at age 60 to 65 years. Discrete time-to-event and linear mixed effects models were used. MEASUREMENTS AND MAIN RESULTS: FEV1 and FVC were measured. COPD was defined as post-bronchodilator FEV1/FVC <0.7. Childhood wheezing phenotype was related to 1989, 1995, 2001, and 2014 spirometry data. Three hundred thirty subjects, mean age 61 years, were followed up: 38 with childhood asthma; 53 with childhood wheezy bronchitis; and 239 control subjects (of whom 57 developed adulthood-onset wheeze between ages 16 and 46 yr). In adjusted multivariate analyses, childhood asthma was associated with an increased risk of COPD (odds ratio, 6.37; 95% confidence interval, 3.73-10.94), as was childhood wheezy bronchitis (odd ratio 1.81; 95% confidence interval, 1.12-2.91). The COPD risk increased with childhood asthma, and wheezy bronchitis was associated with reduced FEV1 that was evident by the fifth decade and not an accelerated rate of FEV1 decline. In contrast, adulthood-onset wheeze was associated with accelerated FEV1 decline. CONCLUSIONS: Childhood wheezy bronchitis and asthma are associated with an increased risk of COPD and reduced ventilatory function.

Associations of wheezing phenotypes with late asthma outcomes in the Avon Longitudinal Study of Parents and Children: A population-based birth cohort.

BACKGROUND: Variable patterns of childhood wheezing might indicate differences in the cause and prognosis of respiratory illnesses. Better understanding of these patterns could facilitate identification of modifiable factors related to development of asthma. OBJECTIVES: We characterized childhood wheezing phenotypes from infancy to adolescence and their associations with asthma outcomes. METHODS: Latent class analysis was used to derive phenotypes based on patterns of wheezing recorded at up to 14 time points from birth to 16½ years among 12,303 participants from the Avon Longitudinal Study of Parents and Children. Measures of lung function (FEV1, forced vital capacity [FVC], and forced expiratory flow between 25% and 75% [FEF25-75]) and fraction of exhaled nitric oxide (Feno) were made at 14 to 15 years of age. RESULTS: Six wheezing phenotypes were identified: never/infrequent, preschool-onset remitting, midchildhood-onset remitting, school age-onset persisting, late childhood-onset persisting, and continuous wheeze. The 3 persistent phenotypes were associated with bronchodilator reversibility of 12% or greater (BDR) from baseline (odds ratio [OR] range, 2.14-3.34), a Feno value of 35 ppb or greater (OR range, 3.82-6.24), and lung function decrements (mean range of differences: -0.22 to -0.27 SD units (SDU) for FEV1/FVC ratio and -0.21 to -0.33 SDU for FEF25-75) compared with never/infrequent wheeze. Midchildhood-onset (4½ years) remitting wheeze was associated with BDR (OR, 1.77; 95% CI, 1.11-2.82), a Feno value of 35 ppb or greater (OR, 1.72; 95% CI, 1.14-2.59), FEV1/FVC ratio decrements (OR, -0.22 SDU; 95% CI, -0.36 to -0.08 SDU), and FEF25-75 decrements (OR, -0.16 SDU; 95% CI, -0.30 to -0.01 SDU). Preschool-onset (18 months) remitting wheeze was only associated with FEV1/FVC ratio decrements (OR, -0.15 SDU; 95% CI, -0.25 to -0.05 SDU) and FEF25-75 decrements (OR, -0.14 SDU; 95% CI, -0.24 to -0.04 SDU). The persisting phenotypes showed evidence of sex stratification during adolescence. CONCLUSIONS: Early childhood-onset wheezing that persists into adolescence represents the clearest target group for interventions to maximize lung function outcomes.

Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood.

BACKGROUND: Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. OBJECTIVE: In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor-associated kinase 1, IL-1 receptor-associated kinase 4, and TNF receptor-associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. METHODS: Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. RESULTS: Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. CONCLUSIONS: IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.

Age-specific influence of wheezing phenotypes on pre-adolescent and adolescent health-related quality of life.

INTRODUCTION: Asthma is associated with diminished health-related quality of life (HRQoL). Particularly in adolescence, asthma may be under-diagnosed and undertreated or poorly managed. Therefore, we aimed to determine the association between childhood wheezing phenotypes rather than asthma and adolescent HRQoL in children aged 10-17 yr. METHODS: We analyzed the data from two prospective population-based cohort studies (n = 604 and n = 1804) conducted in southern Germany with baseline assessments in 2000 and 2006 and follow-ups at frequent intervals. Parent-reported wheeze was categorized into never, early transient, persistent, and late-onset wheeze. We assessed child-reported HRQoL in seven scales using the validated KINDL-R. Multivariate linear regression models were computed. RESULTS: Participants with late-onset wheeze had significantly lower values in all HRQoL scales, but physical well-being compared to never wheezers. Early transient wheeze was negatively associated with three HRQoL scales only (family, school, and total). These effects were confined to the oldest age group (≥13.5 yr) in one study. Persistent wheeze was not associated with HRQoL. CONCLUSIONS: In teenagers, late-onset wheezers seem to be particularly vulnerable for impairments in psychosocial aspects of health-related quality of life. They may therefore require particular attention with regard to education about asthma management and potentially family-based psychosocial intervention.

Perinatal risk factors for wheezing phenotypes in the first 8 years of life.

BACKGROUND: A novel data-driven approach was used to identify wheezing phenotypes in pre-schoolchildren aged 0-8 years, in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort. Five phenotypes were identified: never/infrequent wheeze, transient early wheeze, intermediate onset wheeze, persistent wheeze and late onset wheeze. It is unknown which perinatal risk factors drive development of these phenotypes. OBJECTIVE: The objective of the study was to assess associations of perinatal factors with wheezing phenotypes and to identify possible targets for prevention. METHODS: In the PIAMA study (n = 3963), perinatal factors were collected at 3 months, and wheezing was assessed annually until the age of 8 years. Associations between perinatal risk factors and the five wheezing phenotypes were assessed using weighted multinomial logistic regression models. Odds ratios were adjusted for confounding variables and calculated with 'never/infrequent wheeze' as reference category. RESULTS: Complete data were available for 2728 children. Risk factors for transient early wheeze (n = 455) were male gender, maternal and paternal allergy, low maternal age, high maternal body mass index, short pregnancy duration, smoking during pregnancy, presence of older siblings and day-care attendance. Risk factors for persistent wheeze (n = 83) were male gender, maternal and paternal allergy, and not receiving breastfeeding for at least 12 weeks. Intermediate onset wheeze (n = 98) was associated with a lower birth weight and late onset wheeze (n = 45) with maternal allergy. CONCLUSION AND CLINICAL RELEVANCE: We identified different risk factors for specific childhood wheezing phenotypes. Some of these are modifiable, such as maternal age and body mass index, smoking, day-care attendance and breastfeeding, and may be important targets for prevention programmes.

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing.

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.

Three-quarters of children hospitalized for wheezing or asthma symptoms are preschool-aged. Some will continue to experience breathing difficulties through childhood and adulthood. Others will undergo a complete resolution of their symptoms by the time they reach elementary school. The varied trajectories of young children with wheezing suggest that it is not a single disease. There are likely different genetic or environmental causes. Despite these differences, wheezing treatments for young children are 'one size fits all.' Studying the genetic underpinnings of wheezing may lead to more customized treatment options. Granell et al. studied the genetic architecture of different patterns of wheezing from infancy to adolescence. To do so, they used machine learning technology to analyze the genomes of 9,568 individuals, who participated in five studies in the United Kingdom from birth to age 18. The experiments found a new genetic variation in the ANXA1 gene linked with persistent wheezing starting in early childhood. By comparing mice with and without this gene, Granell et al. showed that the protein encoded by ANXA1 controls inflammation in the lungs in response to allergens. Animals lacking the protein develop worse lung inflammation after exposure to dust mite allergens. Identifying a new gene linked to a specific subtype of wheezing might help scientists develop better strategies to diagnose, treat, and prevent asthma. More studies are needed on the role of the protein encoded by ANXA1 in reducing allergen-triggered lung inflammation to determine if this protein or therapies that boost its production may offer relief for chronic lung inflammation.

Distinguishing Wheezing Phenotypes from Infancy to Adolescence. A Pooled Analysis of Five Birth Cohorts.

Rationale: Pooling data from multiple cohorts and extending the time frame across childhood should minimize study-specific effects, enabling better characterization of childhood wheezing. Objectives: To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. Methods: We used latent class analysis to derive wheeze phenotypes among 7,719 participants from five birth cohorts with complete report of wheeze at five time periods. We tested the associations of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. Results: We identified five phenotypes: never/infrequent wheeze (52.1%), early onset preschool remitting (23.9%), early onset midchildhood remitting (9%), persistent (7.9%), and late-onset wheeze (7.1%). Compared with the never/infrequent wheeze, all phenotypes had higher odds of asthma and lower forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity in adolescence. The association with asthma was strongest for persistent wheeze (adjusted odds ratio, 56.54; 95% confidence interval, 43.75-73.06). We observed considerable within-class heterogeneity at the individual level, with 913 (12%) children having low membership probability (<0.60) of any phenotype. Class membership certainty was highest in persistent and never/infrequent, and lowest in late-onset wheeze (with 51% of participants having membership probabilities <0.80). Individual wheezing patterns were particularly heterogeneous in late-onset wheeze, whereas many children assigned to early onset preschool remitting class reported wheezing at later time points. Conclusions: All wheeze phenotypes had significantly diminished lung function in school-age children, suggesting that the notion that early life episodic wheeze has a benign prognosis may not be true for a proportion of transient wheezers. We observed considerable within-phenotype heterogeneity in individual wheezing patterns.

SERPINA1 gene polymorphisms in a population-based ALSPAC cohort.

BACKGROUND: There is an association between persistent preschool wheezing phenotypes and school-age asthma. These wheezing/asthma phenotypes likely represent clinical entities having specific genetic risk factors. The SERPINA1 gene encodes α 1 -antitrypsin (AAT), and mutations in the gene are important in the pathophysiology of pulmonary diseases. We hypothesized that there might be an association between SERPINA1 gene polymorphisms and the risk of developing wheezing/school age asthma. OBJECTIVE: To examine 10 single nucleotide polymorphisms (SNPs) of SERPINA1 (rs6647, rs11832, rs17580, rs709932, rs1243160, rs2854254, rs8004738, rs17751769, rs28929470, and rs28929474) and relate them to childhood wheezing phenotypes and doctor-diagnosed asthma in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. METHODS: Wheeze data, reports of physician-diagnosed asthma and data on the SERPINA1 gene SNPs, were available for 7964 children. Binary logistic regression was used to assess the associations between allele prevalence and wheezing and asthma phenotypes. P values were adjusted to account for multiple hypotheses using the Benjamini-Hochberg false discovery rate. RESULTS: Only within a subgroup of children with asthma who had no prior diagnosis of preschool wheeze was there a trend for association between rs28929474 (Glu342Lys, Pi*Z causing AAT deficiency; P = .0058, adjusted P = .058). No SNP was associated with wheezing and asthma in those with preschool wheeze. CONCLUSION: Analyzed SNPs in SERPINA1 are not associated with wheezing/asthma phenotypes. Only rs28929474, the most common pathologic SNP (Pi*Z) in the SERPINA1 gene, might be associated with a risk of developing school-age asthma without exhibiting preschool wheeze.

Asthmatic/wheezing phenotypes in preschool children: Influential factors, health care and urban-rural differences.

BACKGROUND: Different wheezing and asthmatic phenotypes turned out to indicate differences in etiology, risk factors and health care. We examined influential factors and urban-rural differences for different phenotypes. METHODS: Parents of 4732 children filled out a questionnaire concerning children's health and environmental factors administered within the Health Monitoring Units (GME) in a cross-sectional study in Bavaria, Germany (2014/2015). To classify respiratory symptoms, five phenotype groups were built: episodic, unremitting and frequent wheeze, ISAAC (International Study of Asthma and Allergies in Children) - asthma and physician-diagnosed asthma (neither of the groups are mutually exclusive). For each phenotype, health care variables were presented and stratified for residence. Urban-rural differences were tested by Pearson's chi-squared tests. Multivariable logistic regression was performed to analyze associations between influential factors and belonging to a phenotype group, and to compare groups with regard to health care variables as outcome. RESULTS: Risk factors for wheezing phenotypes were male gender (OR = 2.02, 95%-CI = [1.65-2.48]), having older siblings (OR = 1.24, 95%-CI = [1.02-1.51]), and preterm delivery (OR = 1.61, 95%-CI = [1.13-2.29]) (ORs for unremitting wheeze). 57% of children with ISAAC asthma and 74% with physician-diagnosed asthma had performed allergy tests. Medication intake among all groups was more frequent in rural areas, and physician's asthma diagnoses were more frequent in urban areas. CONCLUSIONS: In accordance with previous research this study confirms that male gender, older siblings and preterm delivery are associated with several wheezing phenotypes. Overall, low numbers of allergy tests among children with physician's diagnoses highlight a discrepancy between common practice and current knowledge and guidelines. Residential differences in health care might encourage further research and interventions strategies.

Optimum predictors of childhood asthma: persistent wheeze or the Asthma Predictive Index?

BACKGROUND: The Asthma Predictive Index (API) and persistent wheezing phenotypes are associated with childhood asthma, but previous studies have not assessed their ability to predict objectively confirmed asthma. OBJECTIVE: To determine whether the University of Cincinnati API Index (ucAPI) and/or persistent wheezing at age 3 can accurately predict objectively confirmed asthma at age 7. METHODS: Data from the Cincinnati Childhood Allergy and Air Pollution Study, a high-risk prospective birth cohort, was used. Asthma was defined as parent-reported or physician-diagnosed asthma objectively confirmed by a change in FEV1 of ≥12% after bronchodilator or a positive methacholine challenge (PC20 ≤ 4 mg/mL); or as prior treatment with daily asthma controller medication(s). Multivariate logistic regression was used to investigate the relationship between confirmed asthma at age 7 and a positive ucAPI (adapted and modified from prior published API definitions) and persistent wheezing at age 3. RESULTS: At age 7, 103 of 589 children (17.5%) satisfied the criteria for asthma. Confirmed asthma at age 7 was significantly associated with a positive ucAPI (adjusted odds ratio [aOR] 13.3 [95% CI, 7.0-25.2]; P < .01) and the persistent wheezing phenotype (aOR 9.8 [95% CI, 4.9-19.5]; P < .01) at age 3. Allergic persistent wheezing was associated with a significantly higher risk of asthma (aOR 10.4 [95% CI, 4.1-26.0]; P < .01) than nonallergic persistent wheezing (aOR 5.4 [95% CI, 2.04-14.06]; P < .01). CONCLUSION: Both a positive ucAPI and persistent wheeze at age 3 were associated with objectively confirmed asthma at age 7; however, the highest risk was associated with ucAPI. These results demonstrate the ucAPI as a clinically useful tool for predicting future asthma in school-age children.