Genetic characterization of preschool wheeze phenotypes
Bibliographic record
Abstract
BACKGROUND: Preschool wheeze is a heterogenous and poorly understood clinical syndrome. As a result, current treatments are insufficient, and prevention is not possible. OBJECTIVE: We sought to increase understanding of the genetic susceptibility and underlying disease mechanisms of wheeze phenotypes in early childhood through large-scale genome-wide association study analyses. METHODS: We performed meta-analyses of genome-wide association study on early-onset wheeze, defined as recurrent wheeze or asthma in the first 3 years of life, and its subtypes, including early transient and persistent wheeze, defined by asthma/wheeze at age 3 and subsequent remission or persistence at age 6, respectively. The discovery analyses included data on more than 13,000 children from 15 cohorts; replication was sought through meta-analyses of data from 7 additional cohorts including up to 5000 children. Genetic variants associated with asthma-related traits in adulthood (adult asthma, atopy, eosinophils, and lung function) were used to quantify the degree to which genetic risk influencing asthma-related adult traits also influences genetic risk of preschool wheeze. RESULTS: Variants near the GSDMB gene in the 17q region showed genome-wide significant association with early-onset wheeze (rs2305480; odds ratio [95% confidence interval] = 1.26 [1.17-1.33], P = 2.30E-16) and persistent wheeze (rs11078926; 1.43 [1.30-1.578], P = 2.14E-11), but not with early transient wheeze (rs1054609; 1.08 [0.98-1.18], P = .094). Other known asthma loci were associated with early-onset wheeze, particularly CDHR3. Additionally, increased genetic risk to early-onset wheeze was associated with genetic risk for asthma at older ages, atopy, eosinophil count, and lower adult lung function. This was driven by persistent wheeze, whereas transient early wheeze was only associated with low lung function. CONCLUSIONS: Preschool wheeze phenotypes displayed distinct patterns of single nucleotide polymorphism associations and genetic enrichment with asthma-related traits. These results indicate distinct etiologies of wheeze phenotypes, which could inform studies in optimization of prevention and treatment strategies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".