Abstract 4116714: Macrophage Colony Stimulating Factor as a Causal Metabolic Mediator of Cardiovascular Disease: An Observational and Mendelian Randomization Analysis
Bibliographic record
Abstract
Background: Macrophage biology plays a key role in the pathogenesis of atherosclerosis and circulating macrophage colony-stimulating factor (M-CSF) is a marker of macrophage activity. However, there is conflicting evidence regarding its role as a mediator of cardiovascular disease. Methods: We evaluated the association between plasma M-CSF concentration with myocardial infarction, stroke, heart failure and mortality in a large substudy involving 9992 participants drawn from 14 countries and followed for a median period of 9.8 years (Interquartile Range 8.9 years - 11.4 years) utilizing a nested case-cohort design in the Prospective Urban Rural Epidemiology (PURE) study. We then conducted a two-sample Mendelian randomization (MR) analysis to evaluate the upstream determinants (using genome wide association data from the PURE biobank and publicly available consortia) and downstream effects on clinical events.. Results: The strongest causal upstream determinant of M-CSF concentration was body mass index (BMI), which showed a positive association with plasma M-CSF concentration (Beta: 0.17 SD increase; 95% CI: 0.08 - 0.27). In a survival analysis, M-CSF was independently associated with increased incident myocardial infarction (HR: 1.25 per 1 SD M-CSF increase; 95% CI: 1.13-1.38), stroke (HR: 1.17; 95% CI:1.04-1.32), and heart failure (HR: 1.34; 95% CI: 1.15-1.56) and other cardiovascular disease risk factors. Circulating M-CSF concentration also showed a strong association with long-term risk of overall mortality (HR: 1.44; 95% CI: 1.39-1.60). Mendelian randomization analyses confirmed that increased M-CSF was associated with increased risk of MI, heart failure, and ischemic stroke (specifically large artery atherosclerotic and cardioembolic stroke). Conclusions: M-CSF is a strong causal driver of cardiovascular disease morbidity whose concentration is causally influenced by body mass index. Our analysis suggests a role for macrophage activity in mediating the relationship between body mass index and cardiovascular disease outcomes.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".