HBOCpred: An Ensemble Framework for Prioritisation of Germline Missense Variants in Hereditary Breast and Ovarian Cancer
- 1Department of Medical Genetics, Ankara Etlik City Hospital, 06170 Ankara, Türkiye
Abstract
HBOCpred was developed to support research prioritisation of unresolved germline missense variants in a defined 17-gene study panel. Four calibrated learners provide vote states (V0–V4) and a continuous modified adaptive classifier score (SMAC). The same directional descriptors apply to labelled and unresolved records: unanimous benign/likely benign-directed (V0), mixed (V1–V3), and unanimous likely pathogenic/pathogenic-directed (V4) votes. Development used 2160 anchors and five repeats of nested five-fold cross-validation, with preprocessing fitted within training partitions. The annotation-completeness rule permitted evaluation of 2046 anchors per repeat. Mean balanced accuracy for the secondary ≥3-of-4 endpoint was 0.9604; mean SMAC area under the receiver operating characteristic curve (AUROC) and Brier score were 0.9909 and 0.0294. In the first repeat, unanimity covered 1968/2160 anchors (91.11%), with source-label agreement in 1920/1968 unanimous outputs (97.56%). Leave-one-gene-out AUROC was 0.9812 among 2045 evaluable anchors, with substantial gene-specific variation. Among 43,679 unresolved records, V0, V1–V3, and V4 contained 33,414, 4491 and 5774 variants, respectively. HBOCpred makes learner agreement and disagreement available for expert review and functional follow-up. Independent validation is needed to assess its performance and utility in unresolved variants.
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BibTeX
@article{alay2026hbocpred,
title = {{HBOCpred: An Ensemble Framework for Prioritisation of Germline Missense Variants in Hereditary Breast and Ovarian Cancer}},
author = {Mustafa Tarık Alay and Haktan Bağış Erdem},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27198865},
url = {https://www.mdpi.com/1422-0067/27/19/8865},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HBOCpred: An Ensemble Framework for Prioritisation of Germline Missense Variants in Hereditary Breast and Ovarian Cancer
AU - Mustafa Tarık Alay
AU - Haktan Bağış Erdem
PY - 2026
DA - 2026/10/05
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27198865
UR - https://www.mdpi.com/1422-0067/27/19/8865
AB - HBOCpred was developed to support research prioritisation of unresolved germline missense variants in a defined 17-gene study panel. Four calibrated learners provide vote states (V0–V4) and a continuous modified adaptive classifier score (SMAC). The same directional descriptors apply to labelled and unresolved records: unanimous benign/likely benign-directed (V0), mixed (V1–V3), and unanimous likely pathogenic/pathogenic-directed (V4) votes. Development used 2160 anchors and five repeats of nested five-fold cross-validation, with preprocessing fitted within training partitions. The annotation-completeness rule permitted evaluation of 2046 anchors per repeat. Mean balanced accuracy for the secondary ≥3-of-4 endpoint was 0.9604; mean SMAC area under the receiver operating characteristic curve (AUROC) and Brier score were 0.9909 and 0.0294. In the first repeat, unanimity covered 1968/2160 anchors (91.11%), with source-label agreement in 1920/1968 unanimous outputs (97.56%). Leave-one-gene-out AUROC was 0.9812 among 2045 evaluable anchors, with substantial gene-specific variation. Among 43,679 unresolved records, V0, V1–V3, and V4 contained 33,414, 4491 and 5774 variants, respectively. HBOCpred makes learner agreement and disagreement available for expert review and functional follow-up. Independent validation is needed to assess its performance and utility in unresolved variants.
SN - 1422-0067
ER -