Identification of early interventions to reduce/eliminate asthma - the most common chronic disease among children - could significantly reduce burden on the healthcare system. Large-scale asthma Exposome-Wide Association Studies (ExWAS) could identify potential interventions, however integration of diverse data is required to address association confounders. The CHILD Cohort Study has followed 3,454 healthy Canadian children and their families from early pregnancy, collecting exceptionally diverse data including 27,006 variables from participant questionnaires, clinical data, household and neighbourhood-level exposures, and sample-derived chemical analytic/omic datasets. Here, we report integration of these datasets into the CHILDdb database platform, and use these data to perform ExWAS and machine learning analyses, identifying and further characterizing associations between childhood asthma and 2,954 diverse early exposures (pregnancy-age 5). Significant asthma associations include antibiotic use, human milk components, DEHP-phthalate, and mother's prenatal cleaning product/disinfectant exposure. Subsequent analysis revealed epigenetic changes in the cord blood at birth, after prenatal cleaner exposure, and different microbiome and/or inflammatory cytokine changes associated with different asthma-associated exposures in the child. Collective results support asthma as a heterogeneous condition involving multiple etiologies, with associated endotypes, including significant prenatal exposures with potential transgenerational effects, and suggest targets for early interventions. ### Competing Interest Statement TE reports to have acted or acts as local PI for company-sponsored trials by DBV Therapeutics, Greer Stallergens, Novartis, and sub-investigator ALK-Abelló. He is Co-Investigator or scientific lead in three investigator-initiated oral immunotherapy trials supported by the SickKids Food Allergy and Anaphylaxis Program and serves as an associate editor for Allergy. He/his lab received unconditional/in-kind contributions from Macro Array Diagnostics and an unrestricted grant from ALK-Abelló. He holds scientific advisory board roles for ALK-Abelló, VAMED, Nutricia/Danone, Hipp, Sanofi, Greer-Stallergens, Allergy Therapeutics and Aimmune. TE reports lecture fees from Novartis, ThermoFisher, Nutricia/Danone, Aimmune, Sanofi, Schwalbe, MADX, ALK-Abelló. ### Funding Statement Key support for this work was provided by the Schroeder Allergy and Immunology Research Institute, Genome Canada, Genome BC, and CIHR, with additional support by Simon Fraser University and the Digital Research Alliance of Canada. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for the CHILD Cohort Study, including the oversight of the CHILD biological samples and the CHILD database (CHILDdb), was obtained from the local Research Ethics Board of each study site: the University of British Columbia, the University of Alberta, the University of Manitoba, the Hospital for Sick Children, and McMaster University. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data described in the manuscript are available by registration to the CHILD database https://childstudy.ca/childdb/ and the submission of a formal request. More information about data access for the CHILD Cohort Study can be found at https://childstudy.ca/for-researchers/dataaccess/. Researchers interested in accessing CHILD Cohort Study data for their research should contact child{at}mcmaster.ca.

BACKGROUND:Childhood asthma is characterized by altered lung function and airway inflammation that is thought to result from complex gene-environment interactions, especially with allergens. However, previous studies have shown inconsistent associations between allergen exposure and asthma. OBJECTIVES:We aimed to examine the longitudinal relationship between indoor allergen exposure during infancy with subsequent asthma and spirometry and the potential effect modification by genetic factors. METHODS:Data from a subcohort of the CHILD (Canadian Healthy Infant Longitudinal Development) study with analyzed dust samples (including Canis familiaris 1 [dog], Felinus domesticus 1 [cat], and endotoxin) and physician-diagnosed asthma or spirometry data were used to examine the relationships between allergen levels in dust analytes at age 3 months and asthma and, separately, spirometry data at age 5 years, including potential effect modification by genetic factors obtained by using lung function polygenic scores (PGSs). RESULTS:Of 1050 children with dust samples, 6.6% developed asthma by age 5 years. In an adjusted multivariable model, higher Can f 1 level significantly decreased the risk of asthma (odds ratio = 0.52 [95% CI = 0.25-0.98]). Independently, children exposed to high levels of Can f 1 had significantly higher FEV1z scores (β = 0.23 [95% CI = 0.06-0.40]), regardless of asthma status. In the gene-environment analyses, there were significant effects of gene-environment interactions in the relationship between Can f 1 and PGS on lung function, independent of asthma status. CONCLUSIONS:In a general population birth cohort, early-life exposure to high levels of Can f 1 was associated with improved lung function and protection against asthma at age 5 years. Furthermore, exposure to high levels of Can f 1 may modulate lung function in individuals with low PGSs.

BACKGROUND:Disentangling preschool wheezing heterogeneity in terms of clinical traits, temporal patterns, and collective health care burden is critical for precise and effective interventions. OBJECTIVE:We aimed to collectively define contributions and distinct characteristics of respiratory phenotypes based on longitudinal wheeze and atopic sensitization patterns in the first 5 years of life. METHODS:Group-based trajectory analysis was performed in the CHILD Cohort Study to identify distinct wheeze and allergic sensitization trajectories. Trajectories were evaluated for associated risk factors, health care utilization, biologic determinants, and clinical outcomes. Stool samples for shotgun metagenomic sequencing profiles of infant microbiomes collected at ages 3 months and 1 year were assessed for phenotype-specific biomarkers. RESULTS:A total of 6 distinct respiratory phenotypes were identified on the basis of samples from 2902 children; the phenotypes differed by temporal wheeze and allergic sensitization patterns. Although allergic wheeze phenotypes (found in 11.6% of participants) carried the highest risk of asthma diagnosis, the more common nonallergic phenotypes (in 88.3% of participants) contributed to the majority of 5-year asthma diagnoses (61.4% of diagnoses). Most importantly, nonallergic phenotypes accounted for more than two-thirds of health care utilization in this age group. Phenotypes differed by lung function, blood eosinophil counts, allergic comorbidities, and weight-for-age z score. Moreover, microbiome profiles developed from 1439 infants revealed that largely nonoverlapping microbial signatures at age 1 year are associated with each phenotype. CONCLUSION:We identified novel early-childhood respiratory phenotypes to disentangle nonoverlapping paths to preschool wheezing. Our findings highlight the continued clinical relevance of nonatopic wheeze phenotypes, which remain undertreated despite accounting for a substantial proportion of health care utilization and asthma diagnoses.

The gut microbiome undergoes primary ecological succession over the course of early life before achieving ecosystem stability around 3 years of age. These maturational patterns have been well-characterized for bacteria, but limited descriptions exist for other microbiota members, such as fungi. Further, our current understanding of the prevalence of different patterns of bacterial and fungal microbiome maturation and how inter-kingdom dynamics influence early-life microbiome establishment is limited. We examined individual shifts in bacterial and fungal alpha diversity from 3 to 12 months of age in 100 infants from the CHILD Cohort Study. We identified divergent patterns of gut bacterial or fungal microbiome maturation in over 40

The CHILD Cohort Study is an active multi-center longitudinal, prospective, population pregnancy cohort study following Canadian infants from fetal life until adulthood. We hypothesized that early life physical and psychosocial environments interact with biological factors (e.g. immunologic, genetic, physiologic, and metabolic) influencing burdensome non-communicable disease outcomes, including asthma and allergic disorders, growth and development, cardio-metabolic health, and neurodevelopmental outcomes that manifest during the life-course. Detailed clinical and physiologic phenotyping at strategic intervals was complemented by environmental sampling, actigraphy and global positioning system measures, biological sampling including gut, breastmilk and nasal microbiome, nutritional studies, genetics, and epigenetic profiling. Of 3,454 families recruited from 2008 to 2012, study retention was 96.0% at 1-year, 93.2% at 5-years and 90.7% at 8-years. Data collection during the SARS-2 COVID-19 pandemic was partially completed via virtual visits. A sub-cohort was implemented, capturing detailed information on the prevalence and predictors of SARS-CoV-2 infection and the health and psychosocial impact of the pandemic on Canadian families. The 13-year clinical assessment launched in 2022 will be completed in 2025. Ultimately, the CHILD Cohort Study provides a data science platform designed to enable a deep understanding of early life factors associated with the development of chronic non-communicable diseases and multimorbidity.

Asthma and allergies are the leading chronic illnesses among children in Canada, causing a significant burden on healthcare systems and negatively impacting the quality of life of children and their families. Currently, the association between asthma, wheeze, and atopy development and early-life exposure to endotoxin is not fully understood. Data from the CHILD Cohort Study were analyzed using multivariate logistic regression modelling to determine whether an association exists between household early-life endotoxin exposure measured in house dust and asthma, wheeze, and allergy development at 3 years of age. The models were adjusted for covariates relating to the child’s home environment, demographics and socioeconomic status. Those with higher household endotoxin concentrations showed lower odds of allergic sensitization at 3 years of age (OR 0.49, p=0.07 and OR 0.54, p=0.11) than those with the lowest household exposure. Sex stratification found that this relationship was specific to boys. No relationship was found between endotoxin exposure and recurrent wheeze at 3 years of age. Girls in homes with the highest exposure had lower odds of developing asthma by age 3 (p=0.10). These findings suggest endotoxin exposure in early life may protect against allergy at age 3 in Canadian children, particularly boys. Endotoxin is a measure of gram-negative bacteria but may be associated with the presence of ‘good’ microbes in the home environment as well. These findings are consistent with the hygiene hypothesis and encourage more research on early-life microbiome abundance and diversity.

BackgroundEarly antibiotic exposure is linked to persistent disruption of the infant gut microbiome and subsequent elevated pediatric asthma risk. Breastfeeding acts as a primary modulator of the gut microbiome during early life, but its effect on asthma development has remained unclear.MethodsWe harnessed the CHILD cohort to interrogate the influence of breastfeeding on antibiotic-associated asthma risk in a subset of children (n = 2,521). We then profiled the infant microbiomes in a subset of these children (n = 1,338) using shotgun metagenomic sequencing and compared human milk oligosaccharide and fatty acid composition from paired maternal human milk samples for 561 of these infants.FindingsChildren who took antibiotics without breastfeeding had 3-fold higher asthma odds, whereas there was no such association in children who received antibiotics while breastfeeding. This benefit was associated with widespread “re-balancing” of taxonomic and functional components of the infant microbiome. Functional changes associated with asthma protection were linked to enriched Bifidobacterium longum subsp. infantis colonization. Network analysis identified a selection of fucosylated human milk oligosaccharides in paired maternal samples that were positively associated with B. infantis and these broader functional changes.ConclusionsOur data suggest that breastfeeding and antibiotics have opposing effects on the infant microbiome and that breastfeeding enrichment of B. infantis is associated with reduced antibiotic-associated asthma risk.FundingThis work was supported in part by the Canadian Institutes of Health Research; the Allergy, Genes and Environment Network of Centres of Excellence; Genome Canada; and Genome British Columbia.

Unlike the bacterial microbiome, the role of early-life gut fungi in host metabolism and childhood obesity development remains poorly characterized. To address this, we investigate the relationship between the gut mycobiome of 100 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study and body mass index Z scores (BMIz) in the first 5 years of life. An increase in fungal richness during the first year of life is linked to parental and infant BMI. The relationship between richness pattern and early-life BMIz is modified by maternal BMI, maternal diet, infant antibiotic exposure, and bacterial beta diversity. Further, the abundances of Saccharomyces, Rhodotorula, and Malassezia are differentially associated with early-life BMIz. Using structural equation modeling, we determine that the mycobiome's contribution to BMIz is likely mediated by the bacterial microbiome. This demonstrates that mycobiome maturation and infant growth trajectories are distinctly linked, advocating for inclusion of fungi in larger pediatric microbiome studies.

Allergic diseases affect millions of people worldwide. An increase in their prevalence has been associated with alterations in the gut microbiome, i.e., the microorganisms and their genes within the gastrointestinal tract. Maturation of the infant immune system and gut microbiota occur in parallel; thus, the conformation of the microbiome may determine if tolerant immune programming arises within the infant. Here we show, using deeply phenotyped participants in the CHILD birth cohort ( n = 1115), that there are early-life influences and microbiome features which are uniformly associated with four distinct allergic diagnoses at 5 years: atopic dermatitis (AD, n = 367), asthma (As, n = 165), food allergy (FA, n = 136), and allergic rhinitis (AR, n = 187). In a subset with shotgun metagenomic and metabolomic profiling ( n = 589), we discover that impaired 1-year microbiota maturation may be universal to pediatric allergies (AD p = 0.000014; As p = 0.0073; FA p = 0.00083; and AR p = 0.0021). Extending this, we find a core set of functional and metabolic imbalances characterized by compromised mucous integrity, elevated oxidative activity, decreased secondary fermentation, and elevated trace amines, to be a significant mediator between microbiota maturation at age 1 year and allergic diagnoses at age 5 years (β indirect = −2.28; p = 0.0020). Microbiota maturation thus provides a focal point to identify deviations from normative development to predict and prevent allergic disease.

The lung clearance index (LCI) is a measure of pulmonary function. Variable feasibility (50‐>80%) in preschool children has been reported. There are limited studies exploring its relationship to respiratory symptoms and how it predicts persistent wheeze. We aimed to assess the association with respiratory symptoms in preschool‐aged children with LCI and determine its utility in predicting persistent wheeze.

BACKGROUND/OBJECTIVE:The steep rise in childhood obesity has emerged as a worldwide public health problem. The first 4 years of life are a critical window where long-term developmental patterns of body mass index (BMI) are established and a critical period for microbiota maturation. Understanding how the early-life microbiota relate to preschool growth may be useful for identifying preventive interventions for childhood obesity. We aim to investigate whether longitudinal shifts within the bacterial community between 3 months and 1 year of life are associated with preschool BMI z-score trajectories. METHODS:BMI trajectories from birth to 5 years of age were identified using group-based trajectory modeling in 3059 children. Their association with familial and environmental factors were analyzed. Infant gut microbiota at 3 months and 1 year was defined by 16S RNA sequencing and changes in diversity and composition within each BMIz trajectory were analyzed. RESULTS:Four BMIz trajectories were identified: low stable, normative, high stable, and rapid growth. Infants in the rapid growth trajectory were less likely to have been breastfed, and gained less microbiota diversity in the first year of life. Relative abundance of Akkermansia increased with age in children with stable growth, but decreased in those with rapid growth, abundance of Ruminococcus and Clostridium at 1 year were elevated in children with rapid growth. Children who were breastfed at 6 months had increased levels of Sutterella, and decreased levels of Ruminococcus and Clostridium. CONCLUSION:This study provides new insights into the relationship between the gut microbiota in infancy and patterns of growth in a cohort of preschool Canadian children. We highlight that rapid growth since birth is associated with bacteria shown in animal models to have a causative role in weight gain. Our findings support a novel avenue of research targeted on tangible interventions to reduce childhood obesity.

Limited data exist on pharmaceutical product use by infants, although available data suggests higher prevalence of use among children under 12 months of age. We conducted a descriptive study of 3050 infants recruited in the CHILD Cohort Study, a prospective, multicenter, longitudinal cohort following children from pregnancy through childhood. Parents were surveyed for use of prescription and over-the-counter drugs, and natural health products (NHPs, including homeopathic products and vitamins) at 3, 6, and 12 months after delivery. By one year of age, 96.0% of children had taken at least one pharmaceutical product. Among 307 reported products, 32 were given to at least 1% of cohort infants. Vitamin D, acetaminophen, ibuprofen, topical hydrocortisone, amoxicillin, and nystatin were the most common medications and natural health products (NHPs) received, with 8/32 of the most frequently used products being NHPs. Overall, 14.7% of pharmaceutical products administered to children were off-label and 35.8% were NHPs or products without a Drug Identification Number (DIN). The use of over-the-counter medications and NHPs is common and off-label use of drugs is frequent, even in the first year of life. This study highlights the importance of conducting studies on medication use in infants, and of infant medication use monitoring by healthcare providers.

Background: The ‘old friends’ hypothesis posits that reduced exposure to previously ubiquitous microorganisms is one factor involved in the increased rates of allergic diseases. Cytomegalovirus (CMV) may be one of the “old friends” hypothesized to help prevent allergic diseases. We sought to elucidate whether early-life CMV infection is associated with childhood atopy via perturbations of the gut microbiota. Methods: Participants were recruited from a population-based birth cohort (CHILD study) and followed prospectively until age five years in four Canadian cities. A total of 928 participants provided stool microbiome data, urine for CMV testing, skin-prick tests, and questionnaires-based detailed environmental exposures. CMV infection was assessed in the first year of life while the main outcome was defined by persistent sensitization to any allergen at ages 1, 3, and 5 years. Results: Early CMV infection was associated with increased beta and decreased alpha diversity of the gut microbiota. Both changes in diversity measures and early CMV infection were associated with persistent allergic sensitization at age 5 years (aOR= 2.08; 95%CI: 1, 4.33). Mediation analysis demonstrated that perturbation of gut microbial composition explains 30% of the association. Conclusions: Early-life CMV infection is associated with an alteration in the intestinal microbiota, which mediates the effect of the infection on childhood atopy. This work indicates that preventing CMV infection would not put children at increased risk of developing atopy. Rather, a CMV vaccine, in addition to preventing CMV-associated morbidity and mortality, might reduce the risk of childhood allergic diseases.

Introduction:Decreased sleep duration and increased screen time as early as preschool age may contribute to overweight and obesity. The effects of bedtime together with nocturnal sleep duration remain unclear with a paucity of data evaluating these associations longitudinally. We aim to evaluate the independent and joint effects of sleep duration, sleep bedtime, and screen time at 3 years of age on BMI status, particularly overweight and obesity by age 5 years. Methods:Data from 2185 participants of the CHILD Cohort Study were analyzed longitudinally using generalized estimating equations (GEE). Models included changes in overweight/obesity status from 3 to 5 years of age as outcome, and nocturnal sleep duration, bedtime, and daily screen time at 3 years of age as explanatory variables. The joint effects of nocturnal sleep time and excess screen time, late bedtime on overweight/obesity were subsequently analyzed. Results:The median nocturnal sleep time at 3 and 5 years of age was 11.0 hours/night [IQR 10.5, 11.5]. A total of 14.5% children went to bed after 9PM at 3 years and 7.2% at 5 years. Median screen time was 1.0 hr/day [IQR 1.0, 2.0] at both ages. Longitudinal analyses showed that sleeping less than 10.5 hours at age 3 years was associated with 46% greater odds of overweight/obesity by age 5 years (OR 1.46, 95% CI 1.07, 2.00). The risk was higher when coupled with late bedtime after 9pm (OR 1.60, 95% CI 1.12, 2.31). Children with both short nocturnal sleep duration and excess screen time (>1hr/day) had twice the associated risk of overweight/obesity by age 5 years (OR 1.96, 95% CI 1.34, 2.88). Conclusion:Nocturnal sleep duration and screen time are modifiable risk factors in young children, which may have important implications for obesity prevention as early as infancy.

Existing literature on the relationship between early-life (first year of life) allergy sensitization and risk of childhood asthma is mixed.1, 2 This is in part due to the use of statistical analytic methods that ignore changes in both allergy sensitization status and asthma-related treatment exposure that may influence future asthma risk as a child grows older. Our recent disease transition models show that both childhood allergy sensitization and current asthma states (and plausibly related treatment) are time-varying, and the likelihood of a feedback loop cannot be ruled out3; this underscores the analytic challenges associated with evaluating to what extent early-life allergy sensitization may be causally related to childhood asthma development. Moreover, it is unclear if early-life allergen avoidance prevents or merely delays the onset of current asthma into adolescence or adulthood.4 In contrast to traditional discrete-time and longitudinal models (e.g., Generalized Estimating Equations—GEE) used in previous research,1, 2 Marginal Structural Models (MSM) can be used to adjust for time-varying confounding to produce consistent average causal effect estimands.5 Previous simulation studies have demonstrated the superiority of the MSM over traditional longitudinal statistical methodology.5 In this study, we hypothesize that among infants genetically predisposed to asthma, early-life allergy sensitization is associated with an increased risk of current asthma but this risk can be attenuated by allergen avoidance. We carried out a post hoc analysis using the MSM approach to estimate the average causal effect of early-life allergy sensitization and allergen avoidance on the risk of current asthma under the context of dynamic (changing) allergy sensitization-current asthma states in the Canadian Asthma Primary Prevention Study (CAPPS).6 CAPPS was a multifaceted intervention designed to decrease exposure in the first year of infancy to indoor aeroallergens such as house dust mites and pets and to encourage prolonged breastfeeding and delayed introduction of milk and solid foods.6 Current asthma and allergy sensitization were based on a pediatric allergist's clinical decision and skin prick test results, respectively, at age 1-, 2-, 7-, and 15-years. Briefly, MSMs are estimated using an inverse-probability-of-treatment (or exposure) weighted approach5 to remove the effects of time-varying confounders (i.e., post-baseline allergy sensitization and asthma-related treatment states) in the pathway between early-life sensitization and subsequent risk of current asthma (see Appendix S1 for details). The prevalence of current asthma and allergy sensitization varied during follow-up with and without CAPPS exposure (Figures 1, S1 and S2). The prevalence of current asthma did not differ between children sensitized to aeroallergens vs. food allergens in the first 2 years; however, during the 7th and 15th years, the odds of current asthma were six and four-fold higher among children sensitized (vs. un-sensitized) to food and aeroallergens, respectively (Figure S2). These results suggest different profiles of allergy sensitization (define by type and age) may differentially influence or modify the propensity of school-age asthma development. Our MSM model results (Table 1) showed that the odds of current asthma were higher among children with (vs. without) an early-life allergy sensitization (adjusted odds ratio [aOR]: 3.02; 95% CI: 1.51, 6.01) at age 7-years; however, no differences were observed at 15-years (aOR: 2.32; 95% CI: 0.78, 6.85). In contrast, the GEE model results overestimated the strength of this association by 49% at 7-years (aOR: 4.50; 95% CI: 2.53, 8.00) and incorrectly estimated its precision at 15-years (aOR: 2.03; 95% CI: 1.02, 4.04). Overall, the odds of current asthma were lower among children randomized to the CAPPS intervention (aOR: 0.69; 95% CI: 0.51, 0.93). Female children had 28% lower odds of current asthma than male children (aOR: 0.72; 95% CI: 0.53, 0.98). Our results suggest that early life is an etiologically critical window during which allergy sensitization may induce pathogenesis towards school-age asthma onset irrespective of whether the pattern of sensitization is transient or persistent. Conversely, allergen avoidance during this period may reduce the risk of current asthma. Discrepancies between our GEE and MSM results for these competing risk and protective effects on current asthma suggest that confounding due to time-varying allergy sensitization states and asthma-related treatment exposure may explain some of the null associations reported in previous research.1, 2 This underscores the need to adjust for time-varying confounders when investigating the association between current asthma and suspected risk and protective factors under dynamic risk contexts. Our findings (i.e., allergy sensitization—current asthma induction period and early-life as a critical etiologic window with intervention potential) may be generalizable to both developed and less developed countries; however, interpretation of similar analyses in these heterogenous populations should not preclude an examination of potential effect moderation/modification by environmental factors. In the absence of randomized baseline exposures (e.g., allergy sensitization), MSMs hold promise for the elucidation of childhood asthma causal mechanisms needed to inform the timing and strategies for preventive intervention. We thank the Canadian Asthma Primary Prevention Study families, Meghan B. Azad, study coordinators (Rishma Chooniedass, RN, BN, CAE, Department of Pediatrics and Child Health, University of Manitoba; Marilyn Lilley, RN, Department of Pediatrics and Child Health, University of Manitoba; and Roxanne Rousseau, BSc, CCRP, Department of Medicine, University of British Columbia), and the Canadian Asthma Primary Prevention Study research team, whose commitment and hard work have made this research possible. Open access funding enabled and organized by ProjektDEAL. All authors have no financial conflict of interest and nothing to disclose. Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

IMPORTANCE Despite advances in asthma therapeutics, the burden remains highest in preschool children; therefore, it is critical to identify primary care tools that distinguish preschool children at high risk for burdensome disease for further evaluation. Current asthma prediction tools, such as the modified Asthma Predictive Index (mAPI), require invasive tests, limiting their applicability in primary care and low-resource settings. OBJECTIVE To develop and evaluate the use of a symptom-based screening tool to detect children at high risk of asthma, persistent wheeze symptoms, and health care burden. DESIGN, SETTING, AND PARTICIPANTS The cohort for this diagnostic study included participants from the CHILD Study (n = 2511) from January 1, 2008, to December 31, 2012, the Raine Study from January 1, 1989, to December 31, 2012 (n = 2185), and the Canadian Asthma Primary Prevention Study (CAPPS)from January 1, 1989, to December 31, 1995 (n = 349), with active follow-up to date. Data analysis was performed from November 1, 2019, to May 31, 2022. EXPOSURES The CHILDhood Asthma Risk Tool (CHART) identified factors associated with asthma in patients at 3 years of age (timing and number of wheeze or cough episodes, use of asthma medications, and emergency department visits or hospitalizations for asthma or wheeze) to identify children with asthma or persistent symptoms at 5 years of age. MAIN OUTCOMES AND MEASURES Within the CHILD Study cohort, CHART was evaluated against specialist clinician diagnosis and the mAPI. External validation was performed in both a general population cohort (Raine Study [Australia]) and a high-risk cohort (CAPPS [Canada]). Predictive accuracy was measured by sensitivity, specificity, area under the receiver operating characteristic curve (AUROC), and positive and negative predicted values. RESULTS Among 2511 children (mean [SD] age at 3-year clinic visit, 3.08 [0.17] years; 1324 [52.7%] male; 1608 of 2476 [64.9%] White) with sufficient questionnaire data to apply CHART at 3 years of age, 2354(93.7%) had available outcome data at 5 years of age. CHART applied in the CHILD Study at 3 years of age outperformed physician assessments and the mAPI in predicting persistent wheeze (AUROC, 0.94; 95% CI, 0.90-0.97), asthma diagnosis (AUROC, 0.73; 95% CI, 0.69-0.77), and health care use (emergency department visits or hospitalization for wheeze or asthma) (AU ROC, 0.70; 95% CI, 0.61-0.78). CHART had a similar predictive performance for persistent wheeze in the Raine Study (N = 2185) in children at 5 years of age (AUROC, 0.82; 95% CI, 0.79-0.86) and CAPPS (N = 349) at 7 years of age (AUROC, 0.87; 95% CI, 0.80-0.94). CONCLUSIONS AND RELEVANCE In this diagnostic study, CHART was able to identify children at high risk of asthma at as early as 3 years of age. CHART could be easily incorporated as a routine screening tool in primary care to identify children who need monitoring, timely symptom control, and introduction of preventive therapies.