Gene Expression Profile of Change in Exacerbation Frequency in COPDGene
Bibliographic record
Abstract
Abstract Rationale: Acute exacerbations of COPD (AE-COPD) are associated with a significant disease burden. Furthermore, evidence supports the existence of an exacerbation-susceptible subtype which may represent an important target group for treatment. Here, we identify unique gene expression profiles associated with change in exacerbation frequency over a 5-year period specific to exacerbation susceptible and non-susceptible individuals. Methods: Blood RNA sequencing data (n=5,118) from the COPDGene (Genetic Epidemiology of COPD) Study was analyzed, and complete quality control passing data from 2,714 subjects was available for both phases 2 and 3 (5 and 10-year visits, respectively) and was included in longitudinal analysis. We tested for association between blood gene expression and change in AE-COPD frequency across phase 2 and phase 3 using Limma-Voom, and pathway analysis was performed using Sigora. Results: We found a significant decline in exacerbation frequency from phase 2 to phase 3 (frequency = 0.253 vs 0.202, p=0.002), but not proportion of severe exacerbations (number = 198 vs 205, p=0.48). Initial exacerbation status was an important predictor of five-year exacerbation trajectory. Most subjects (85.0%) in the cohort were nonexacerbators at Phase 2, and the majority of those subjects (93.0%) remained nonexacerbators at Phase 3. Subjects with this “stable nonexacerbator” trajectory had significantly (p<0.01 each) higher FEV1 and FEV1/FVC ratio, and decreased incidence of severe exacerbations when compared to all other exacerbator groups. We subdivided the subjects into five groups based on change in exacerbation status between phases: significant improvement (exacP3-exacP2 <= -2), mild improvement (exacP3-exacP2 = -1), no change (exacP3-exacP2 = 0), mild decline (exacP3-exacP2 = 1), significant decline (exacP3-exacP2 >= 2). We found that differential expression of 3989 genes, corresponding to 87 pathways was associated with improvement in exacerbation frequency, while 181 genes corresponding to 11 pathways were associated with mild decline. We next focused on genes specific to “improvers” by removing genes that are differentially expressed in subjects with frequent exacerbations compared to non-exacerbators in phase 2. We found 1167 differentially expressed genes and 26 pathways that were unique to these “improver” subjects, and 2822 genes and 61 pathways that were shared between exacerbation-susceptible and improver subjects. Conclusions: We identified a gene expression profile enriched for pathways involved in metabolism, which is unique to subjects whose exacerbation frequency improves between Phase 2 to 3, and a separate profile specific to exacerbation-susceptible subjects that improve over phases enriched for viral response pathways.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".