Polygenic Risk Scores and Longitudinal Lung Function Across the Adult Lifespan: Analysis of Two Population-based Studies
Bibliographic record
Abstract
Abstract Rationale: Lung function trajectories are associated with risk for cardiopulmonary diseases and mortality. While many genetic variants influencing lung function measured at a single time point have been identified, it remains unclear whether these variants are associated with lung function decline in adulthood. Methods: We selected participants aged ≥21 years from the Framingham Heart Study (FHS) and the Coronary Artery Risk Development in Young Adults (CARDIA) study, two population-based studies with longitudinal lung function measurements. Based on external GWAS data, we previously developed polygenic risk scores (PRS) for FEV1 (PRSFEV1) and FEV1/FVC (PRSratio), summarizing the cumulative effects of genetic variants across the genome, with higher scores indicating lower genetically predicted lung function. Associations between the PRSs and corresponding traits were tested using mixed-effects models to account for repeated measures. We tested an interaction between each PRS and age to estimate its effect on lung function decline and conducted stratified analyses by sex. We adjusted for height, smoking, and genetic ancestry. We tested the association between PRSratio and early-life airflow limitation (defined as FEV1/FVC < 0.7 before age of 40) using logistic regression, and compared the prediction performance between PRSratio and clinical risk factors (age, sex, and smoking pack-years) using the Area-Under-the-Receiver-Operating-Characteristic-Curve (AUC-ROC) metrics. Measurements and Main Results: We included 5,682 (mean baseline age 45.5 years; 47.5% male) FHS and 2,387 (mean baseline age 26.1 years; 43.0% male) CARDIA participants, with average follow-up duration of 12.0 and 15.0 years, respectively. A one-standard-deviation increase in the PRSFEV1 was associated with 153.6 ml and 148.4 ml lower FEV1 in FHS and CARDIA, respectively; however, no significant effect of PRSFEV1 on FEV1 decline was observed. We found a significant interaction between PRSratio and age on FEV1/FVC in FHS (β= -0.0093%, p=0.0013) but not in CARDIA (β= -0.0077%, p=0.087). In sex-stratified analyses, the interaction between PRSratio and age was significant in females in both FHS (β= -0.013%, p=0.0021) and CARDIA (β= -0.022%, p=0.0002), but not in males (β= -0.0066%, p=0.16 in FHS; β= 0.0073%, p=0.27 in CARDIA). For predicting early-life airflow limitation, the PRSratio outperformed clinical risk (AUC: 0.70 versus 0.58; p-value for AUC difference=0.0002) in FHS. Conclusions: The PRSFEV1 was associated with low FEV1 early in adulthood but not with its decline. The PRSratio was associated with FEV1/FVC decline in females and showed superior predictive performance for early-life airflow limitation than clinical risk factors.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.015 | 0.019 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.006 |
| Bibliometrics | 0.004 | 0.005 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".