Gene Expression Dynamics of Lung Function Decline in COPD
Bibliographic record
Abstract
Abstract Rationale:Chronic obstructive pulmonary disease (COPD) is characterized by decline in lung function, assessed by forced expiratory volume in one second (FEV1). Understanding the genetic basis of FEV1 decline is crucial for unraveling the pathophysiology of COPD and developing effective therapies. We hypothesized that gene expression patterns in inflammatory pathways are associated with FEV1 decline. We investigated this hypothesis using whole blood RNA-sequencing data from the COPDGene Study. Methods:We employed linear regression models on data from 435 participants with available gene expression and FEV1 data to assess the association between gene expression and FEV1, adjusted for age, sex, race, smoking history, and white blood cell count and differential. Additional adjustments were made for height in cross-sectional analysis and baseline FEV1 in FEV1 change analysis, using three approaches: 1. Cross-sectional: We assessed associations between gene expression and FEV1 at the 5-year and 10-year follow-up visits independently. 2. FEV1 change: We assessed the association between gene expression at the 5-year follow up visit and changes in FEV1 observed between 5-year and 10-year follow up visits. 3. Longitudinal: We assessed the association between changes in gene expression and changes in FEV1 within individuals from the 5-year to 10-year follow up visits. We also performed pathway enrichment analysis using genes with P<0.05 generated from the longitudinal analysis to identify relevant biological pathways. Furthermore, we generated a gene signature from the 5-year follow up visit associated with change in FEV1 in three-time intervals: baseline to 5 years (N=3850), 5 years to 10 years (N=2043), and baseline to 10 years (N=2035) selecting participants based on the availability of gene expression data at the 5-year follow-up and FEV1 measurements across these intervals. Results:Distinct gene expression results were found for each approach (Cross-sectional: 2055; FEV1 Change: 101; Longitudinal: 322). Genes previously implicated in lung function, such as MMP9, IL1RL1, ALOX5AP, and OPTN, were identified in the longitudinal study. Pathway enrichment analysis revealed significant enrichment of oxidative stress and MAPK/ERK signaling pathways. The FEV1 change gene signature was associated with the 5-year visit outcomes of COPD progression, exacerbations, and chest CT scan measures of airway wall thickness and emphysema. We also validated the majority of the gene signature and phenotype associations in an independent sample of 673 subjects from the ECLIPSE study. Conclusions:These findings highlight key genes associated with FEV1 decline, offering new insights into the genetic underpinnings of COPD and potential therapeutic targets.
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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".