| Title: | TUDOR, an ascertainment-aware model for LDLR genetic-testing triage in specialist lipid clinics: development, validation, and UK Biobank transport |
| Journal: | Journal of Clinical Lipidology |
| Published: | 1 Jul 2026 |
| DOI: | https://doi.org/10.1016/j.jacl.2026.06.030 |
Publication 20683
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Abstract
Background Familial hypercholesterolaemia remains under-identified despite a clear causal pathway, effective treatment and efficient cascade testing after genetic confirmation. Contemporary lipid clinics increasingly evaluate treated patients, cascade-screened relatives and people with mixed metabolic dyslipidaemia, in whom the recorded LDL-C phenotype may no longer resemble the untreated proband phenotype assumed by conventional criteria. TUDOR was developed as an ascertainment-aware model for prioritising confirmatory LDLR genetic testing in specialist lipid clinics. Methods TUDOR is an eleven-feature elastic-net logistic model estimating genetically confirmed LDLR carrier status from routine lipid-clinic variables. It reconstructs untreated LDL-C, separates receptor-mediated LDL signal from mixed metabolic dyslipidaemia using triglycerides, non-HDL cholesterol and a type-2-diabetes-by-LDL interaction, and encodes index-referral versus cascade-relative ascertainment. Validation used bidirectional geographic internal-external validation in Wales, a complete-case head-to-head comparison against eDLCN, FAMCAT, Simon Broome and MEDPED, UKB lipid-clinic-eligible frozen transport, local coefficient updating, whole-UKB stress testing, LDL-C reconstruction validation and subgroup analyses. Results In the Welsh complete-case head-to-head cohort (n=1,274; 311 carriers), TUDOR reached AUC 0.760 compared with eDLCN 0.652, FAMCAT 0.600, Simon Broome 0.569 and MEDPED 0.524. Geographic internal-external validation yielded AUC 0.732 (95% CI 0.707-0.757) and 0.770 (95% CI 0.739-0.797), with pooled frozen Welsh AUC 0.746 (95% CI 0.726-0.764). Frozen transport to the UKB lipid-clinic-eligible cohort gave AUC 0.669 (95% CI 0.650-0.687); local coefficient updating gave apparent AUC 0.756 (95% CI 0.734-0.777). Whole-UKB stress testing retained signal at AUC 0.631 (95% CI 0.622-0.641). Back-calculation was validated in 649 Welsh patients with measured pre-treatment LDL-C (MAE 1.20 mmol/L, 95% CI 1.13-1.28). Conclusions TUDOR improved rank-ordering for genetically confirmed LDLR carrier status in Welsh specialist lipid-clinic validation and retained external signal when transported frozen to a UKB lipid-clinic-eligible cohort. Local coefficient updating recovered Welsh-range apparent discrimination, supporting transportability of the feature architecture but not universal portability of the frozen Welsh equation. TUDOR is a triage aid for confirmatory genetic testing, not a diagnostic replacement or population screener; prospective deployment requires local calibration, threshold-specific carrier yield, decision-curve analysis and safety monitoring.</p>
6 Authors
- Nader Genedy
- Kate Haralambos
- Zaheer Yousef
- Duncan Cole
- Dev Datta
- Soha Zouwail
1 Application
| Application ID | Title |
|---|---|
| 1002450 | Development and External Validation of the DRABackground: HeterozygouGON Risk Score: A Novel 10-Year Cardiovascular Risk Prediction Model for Patients with Heterozygous Familial Hypercholesterolemia |
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