Percorrer por autor "Sikonja, Jaka"
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- DLCN-PED – A New Proposal For Clinical Diagnosis Of Children And Young People With FHPublication . Miranda, Beatriz; Kafol, Jan; Humphries, Steve E.; Freiberger, Tomas; Medeiros, Ana Margarida; Sikonja, Jaka; Alves, Ana Catarina; Groselj, Urh; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, and premature cardiovascular disease (CVD). The most used clinical diagnostic criteria to identify FH are the Dutch Lipid Clinic Network-(DLCN) and Simon Broome-(SB), being SB the only with specific criteria for children. This work aims to propose an adaptation of DLCN criteria, for children and young people (DLCN-PED) and assess the performance of this adaptation in the Portuguese and Slovenian FH registries. DLCN-PED includes data on clinical examinations, lipid profile, familial history of CVD and hypercholesterolemia. We propose that those with a DLCN-PED score3 should be referred for genetic testing. Index cases included were studied with an NGS panel including at least the three FH-causing genes prior to evaluation with DLCN-PED This work includes 1696 patients (Portugal=340, Slovenia=1356): 29% FH-positives (presenting likely pathogenic/pathogenic variants in FH genes), 71% FH-negatives (no detection of pathogenic variants). Individuals with variants of uncertain significance were not included. Scores had a range between 0-17, 58% presenting a score between 2-4. Across DLCN-PED scores, we observe a distribution overlap for both FH groups: FH-negatives from 0-8 and FH-positives from 0-17. Overall, DLCN-PED3 presents higher sensitivity compared to SB (93% vs 81%) and slightly lower specificity (55% vs 79%). DLCN-PED6 presents lower sensitivity compared to SB (67% vs 81%) but an enhanced specificity (91% vs 79%). The different analysis suggests that score cutoffs should be adapted according to the screening approach intended (sensitivity and specificity trade-off). Compared to DLCN, the DLCN-PED shows an improved performance (p-value=0.024). Given the crucial role of clinical diagnosis in FH identification, we have shown that the proposed DLCN-PED performs better than the general DLCN and is similar to SB with the advantage that is possible to personalize the cut offs and so it could improve FH assessment worldwide.
- Proposal of a Familial Hypercholesterolemia Pediatric Diagnostic Score (FH-PeDS)Publication . Kafol, Jan; Miranda, Beatriz; Sikonja, Rok; Sikonja, Jaka; Wiegman, Albert; Medeiros, Ana Margarida; Alves, Ana Catarina; Freiberger, Tomas; Hutten, Barbara A.; Mlinaric, Matej; Battelino, Tadej; Humphries, Steve E.; Bourbon, Mafalda; Groselj, UrhBackground and aims: Familial hypercholesterolemia (FH) significantly increases cardiovascular risk from childhood yet remains widely underdiagnosed. This cross-sectional study aimed to evaluate existing pediatric FH diagnostic criteria in real-world cohorts and to develop two novel diagnostic tools: a semi-quantitative scoring system (FH-PeDS) and a machine learning model (ML-FH-PeDS) to enhance early FH detection. Methods: Five established FH diagnostic criteria were assesed (Dutch Lipid Clinics Network [DLCN], Simon Broome, EAS, Simplified Canadian, and Japanese Atherosclerosis Society) in Slovenian (N=1,360) and Portuguese (N=340) pediatric hypercholesterolemia cohorts, using FH-causing variants as the reference standard. FH-PeDS was developed from the Slovenian cohort, and ML-FH-PeDS was trained and tested using a 60%/40% split before external validation in the Portuguese cohort. Results: Only 47.4% of genetically confirmed FH cases were identified by all established criteria, while 10.9% were missed entirely. FH-PeDS outperformed DLCN in the combined cohort (AUC 0.897 vs. 0.857; p<0.01). ML-FH-PeDS showed superior predictive power (AUC 0.932 in training, 0.904 in testing vs. 0.852 for DLCN; p<0.01) and performed best as a confirmatory test in the testing subgroup (39.7% sensitivity, 87.7% PPV at 98% specificity). In the Portuguese cohort, ML-FH-PeDS maintained strong predictive performance (AUC 0.867 vs. 0.815 for DLCN; p<0.01) despite population differences. Conclusions: Current FH diagnostic criteria perform suboptimally in children. FH-PeDS and ML-FH-PeDS provide tools to improve FH detection, particularly where genetic testing is limited. They also help guide genetic testing decisions for hypercholesterolemic children. By enabling earlier diagnosis and intervention, these tools may reduce long-term cardiovascular risk and improve outcomes.