The Prognostic Potential of Insulin-like Growth Factor-Binding Protein 1 for Cardiovascular Complications in Peripheral Artery Disease
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Bibliographic record
Abstract
Background/Objectives: Patients with peripheral artery disease (PAD) have a heightened risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and death. Despite this, limited progress has been made in identifying reliable biomarkers to prognosticate such outcomes. Circulating growth factors, known to influence endothelial function and the progression of atherosclerosis, may hold prognostic value in this context. The objective of this research was to evaluate a broad range of blood-based growth factors to investigate their potential as predictors of MACE in patients diagnosed with PAD. Methods: A total of 465 patients with PAD were enrolled in a prospective cohort study. Baseline plasma levels of five different growth factors were measured, and participants were monitored over a two-year period. The primary outcome was the occurrence of MACE within those two years. Comparative analysis of protein levels between patients who did and did not experience MACE was performed using the Mann–Whitney U test. To assess the individual prognostic significance of each protein for predicting MACE within two years, Cox proportional hazards regression was performed, adjusting for clinical and demographic factors including a history of coronary and cerebrovascular disease. Subgroup analysis was performed to assess the prognostic value of these proteins in females, who may be at higher risk of PAD-related adverse events. Net reclassification improvement (NRI), integrated discrimination improvement (IDI), and area under the receiver operating characteristic curve (AUROC) were calculated to assess the added value of significant biomarkers to model performance for predicting 2-year MACE when compared to using demographic/clinical features alone. Kaplan–Meier curves stratified by IGFBP-1 tertiles compared using log-rank tests and Cox proportional hazards analysis were used to assess 2-year MACE risk trajectory based on plasma protein levels. Results: The average participant age was 71 years (SD 10); 31.1% were female and 47.2% had diabetes. By the end of the two-year follow-up, 18.1% (n = 84) had experienced MACE. Of all proteins studied, only insulin-like growth factor-binding protein 1 (IGFBP-1) showed a significant elevation among patients who suffered MACE versus those who remained event-free (20.66 [SD 3.91] vs. 13.94 [SD 3.80] pg/mL; p = 0.012). IGFBP-1 remained a significant independent predictor of 2-year MACE occurrence in the multivariable Cox analysis (adjusted hazard ratio [HR] 1.57, 95% CI 1.21–1.97; p = 0.012). Subgroup analyses revealed that IGFBP-1 was significantly associated with 2-year MACE occurrence in both females (adjusted HR 1.52, 95% CI 1.16–1.97; p = 0.015) and males (adjusted HR 1.04, 95% CI 1.02–1.22; p = 0.045). Incorporating IGFBP-1 into the clinical risk prediction model significantly enhanced its predictive performance, with an increase in the AUROC from 0.73 (95% CI 0.71–0.75) to 0.79 (95% CI 0.77–0.81; p = 0.01), an NRI of 0.21 (95% CI 0.07–0.36; p = 0.014), and an IDI of 0.041 (95% CI 0.015–0.066; p = 0.008), highlighting the prognostic value of IGFBP-1. Kaplan–Meier analysis showed an increase in the cumulative incidence of 2-year MACE across IGFBP-1 tertiles. Patients in the highest IGFBP-1 tertile experienced a significantly higher event rate compared to those in the lowest tertile (log-rank p = 0.008). In the Cox proportional hazards analysis, the highest tertile of IGFBP-1 was associated with increased 2-year MACE risk compared to the lowest tertile (adjusted HR 1.81; 95% CI: 1.31–2.65; p = 0.001). Conclusions: Among the growth factors analyzed, IGFBP-1 emerged as the sole biomarker independently linked to the development of MACE over a two-year span in both female and male PAD patients. The addition of IGFBP-1 to clinical features significantly improved model predictive performance for 2-year MACE. Measuring IGFBP-1 levels may enhance risk stratification and guide the intensity of therapeutic interventions and referrals to cardiovascular specialists, ultimately supporting more personalized and effective management strategies for patients with PAD to reduce systemic vascular risk.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| 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 it