Ferritin and transferrin predict common carotid intima-media thickness in females: a machine-learning informed individual participant data meta-analysis
Bibliographic record
Abstract
BACKGROUND: Iron overload promotes atherosclerosis in mice and causes vascular dysfunction in humans with Hemochromatosis. However, data are controversial on whether systemic iron availability within physiological limits affects the pathogenesis of atherosclerosis. We, therefore, performed an individual participant data (IPD) meta-analysis and studied the association between serum iron biomarkers with common carotid intima-media thickness (CC-IMT); in addition, since sex influences iron metabolism and vascular diseases, we studied if there are sex-specific differences. METHODS: We pooled the IPD and analysed the data on adults (age≥18y) by orthogonal approaches: machine learning (ML) and a single-stage meta-analysis. For ML, we tuned a gradient-boosted tree regression model (XGBoost) and subsequently, we interpreted the features using variable importance. For the single-stage metaanalysis, we examined the association between iron biomarkers and CC-IMT using spline-based linear mixed models, accounting for sex interactions and study-specific effects. To confirm robustness, we repeated analyses on imputed data using multivariable regression adjusted for key covariates identified through machine learning. Further, subgroup analyses were performed in children and adolescents (age<18y). In addition, to evaluate causality, we used UK Biobank data to examine associations between the hemochromatosis (HFE) genotypes (C282Y/H63D) and mean CC-IMT in ~ 42,500 participants with carotid ultrasound data, using sex-stratified linear regression (adjusted for age, assessment centre, and genetic principal components). RESULTS: We included IPD from 21 studies (N = 10,807). The application of the ML model showed moderate predictive performance and identified iron biomarkers (transferrin, ferritin, transferrin saturation, and iron) as key features for IMT prediction. Multivariable analyses showed non-linear sex-specific relationships for ferritin and transferrin with CC-IMT, both only among females at specific ranges. Ferritin showed a significant positive association [Ferritin > 233 ng/mL: β = 0.04, 95% CI (0.002, 0.08), p = 0.037], while transferrin showed negative associations at specific ranges [ Transferrrin 231–263 mg/dL: β=-0.21, 95% CI (-0.43, 0.003), p = 0.054; Transferrrin > 263 mg/dL: β=-0.73, 95% CI (-1.48, 0.01), p = 0.05]; No significant associations were found between CC-IMT in those with HFE genotypes in either sex in the UK Biobank. CONCLUSION: Our observational data show that iron biomarkers - ferritin and transferrin are non-linearly associated with CC-IMT specifically in females, while a significant causal association between the HFE genotype and CC-IMT could not be demonstrated in the UK Biobank data. We conclude that our observational findings may reflect residual confounding, reverse causation, or other non-causal mechanisms rather than a direct causal relationship. OTHER: No financial support was received for this meta-analysis. The protocol for this study is registered in the PROSPERO database ( CRD42020155429; https://www.crd.york.ac.uk/ ).
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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 | 0.016 | 0.028 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.008 | 0.031 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".