PO.BCS01.11 · 生物信息与计算
PlasmaCHORD- A machine learning method for identifying clonal hematopoiesis variants in liquid biopsies
作者与单位
摘要 Abstract
Introduction: Genomic profiling of circulating tumor DNA (ctDNA) through liquid biopsies has become an important diagnostic method in clinical oncology. However, detection of variants related to clonal hematopoiesis (CH) is a major confounder that impairs the clinical utility of liquid biopsies. Strategies that reduce biological noise from CH in plasma NGS include deep sequencing of matched WBC DNA and/or tumor tissue sequencing. While these methods effectively distinguish most CH variants, the need for extra biospecimens and sequencing raises costs and limits feasibility.
Methods: Using a training cohort of 426 variants identified in ctDNA NGS from 225 patients with stage I-IV solid tumors, we developed plasmaCHORD, a machine learning model (MLM) that includes fragmentomic, variant, and patient-level features to distinguish between tumor- and CH-origin for mutations detected by fixed gene panel hybrid capture NGS. Model performance was assessed by comparison to the reference origin of each plasma variant determined from matched WBC and tumor NGS. Following locking the model parameters, we applied plasmaCHORD to an independent validation cohort of 1,412 plasma variants detected in 114 patients with metastatic cancers, as well as to cfDNA NGS from patients enrolled in a prospective liquid biopsy-informed clinical trial (NCT05585684).
Results: PlasmaCHORD predicted tumor versus CH-origin in the training set with high accuracy (cross-validated AUC=0.94), outperforming individual features such as variant allele frequency and canonical CH genes. Model performance remained robust when restricted to mutant DNA fragments supported by 3-5 mutant reads (AUC = 0.84). plasmaCHORD was locked for evaluation using a score of 0.5 as cutoff for distinguishing tumor- versus CH-origin variants. In the independent validation cohort, the locked model maintained similar overall accuracy (AUC=0.9) with a sensitivity of 82%, specificity 80.3% and accuracy of 80.2%. Our approach was shown to be highly reliable in classifying variant origin in clinically actionable genes not canonically associated with CH, including AKT1, ATM, BRCA1, BRCA2, and EGFR, as well as adjudicating cellular origin for TP53 mutations that are encountered in both solid and hematologic malignancies. Performance was consistent across cancer types, sequencing platforms, mutation classes, and a wide range of allele fractions. When applied to clinically challenging cases in the context of a precision oncology clinical trial, plasmaCHORD precisely determined variant origin, preventing mismatches with genotype-targeted therapies.
Conclusions: plasmaCHORD, a multi-feature machine-learning classifier, can significantly enhance the ability to identify bona fide tumor variants in routine plasma-only NGS, addressing a critical need in implementing liquid biopsy-guided therapy by minimizing misinterpretation caused by CH.
利益披露 Disclosure
D. J. Rabizadeh, None.
J. V. Canzoniero,
Foundation Medicine ).
AstraZeneca ).
I. Ziakas, None..
J. Wehr, None..
A. Balan, None.
S. C. Scott,
AstraZeneca Independent Contractor, ).
Black Diamond Therapeutics ).
Janssen Independent Contractor, ).
Daiichi Sankyo Independent Contractor.
EMD Serono Independent Contractor.
Foundation Medicine Independent Contractor.
Genentech Independent Contractor.
Merus Independent Contractor.
Regeneron Independent Contractor.
Tempus Independent Contractor.
G. Pereira, None.
V. K. Lam,
Pfizer Independent Contractor.
Genentech/Roche Independent Contractor.
Iovance Biotherapeutics Independent Contractor.
Anheart Therapeutics Independent Contractor.
Takeda Independent Contractor.
Seattle Genetics Independent Contractor, ).
Bristol Myers Squibb Independent Contractor, ).
AstraZeneca Independent Contractor, ).
Guardant Health Independent Contractor.
GlaxoSmithKline ).
Merck ).
C. M. Lovly,
AbbVie Independent Contractor.
Amgen Independent Contractor.
AnHeart Independent Contractor.
Astra Zeneca Independent Contractor.
Black Diamond Independent Contractor.
BMS Independent Contractor.
Jazz Independent Contractor.
JNJ Independent Contractor.
Merck Independent Contractor.
Nuvalent Independent Contractor.
Nuvation Independent Contractor.
Onviv Independent Contractor.
Pfizer Independent Contractor.
Regeneron Independent Contractor.
Summit Independent Contractor.
Takeda Independent Contractor.
Taiho Independent Contractor.
Tempus Boehringer Ingelheim, Independent Contractor.
Boehringer Ingelheim, Travel.
Daiichi Sankyo Travel.
J. Tao, None.
P. M. Forde,
AstraZeneca Independent Contractor, ).
Bristol-Myers Squibb Independent Contractor, ).
Novartis ).
Corvus ).
Kyowa ).
Amgen Independent Contractor.
Daiichi Sankyo Independent Contractor.
Genentech Independent Contractor.
G1 Therapeutics Independent Contractor.
Iteos Independent Contractor.
Janssen Independent Contractor.
Merck Independent Contractor.
Surface Oncology Independent Contractor.
Mirati Independent Contractor.
Novartis Independent Contractor.
Sanofi Independent Contractor.
Polaris Other, DSMB member.
Flame Therapeutics Other, DSMB member.
J. C. Murray, None.
M. Sausen,
Labcorp Employment, Stock.
G. A. Meijer,
LabCorp ).
Delfi Diagnostics ).
G. Vink,
BMS ).
Merck ).
Servier ).
PGDx ).
Bayer ).
Sirtex ).
Pierre Fabre ).
Delfi Diagnostics ).
Natera ).
Nordic pharma ).
R. J. Fijneman,
Labcorp ).
Delfi Diagnostics ).
Solvias ).
Natera ).
V. E. Velculescu,
Delfi Diagnostics g., Board of Directors, non-salaried role), Independent Contractor, Stock.
LabCorp Other Intellectual Property.
Qiagen Other Intellectual Property.
Sysmex Other Intellectual Property.
Agios Other Intellectual Property.
Genzyme Other Intellectual Property.
Esoterix Other Intellectual Property.
Ventana Other Intellectual Property.
ManaT Bio Other Intellectual Property.
Danaher Independent Contractor.
Takeda Pharmaceutical Independent Contractor.
Viron Therapeutics Independent Contractor.
J. A. Phallen, None.
R. Scharpf,
Delfi Diagnostics Independent Contractor, Stock.
LabCorp Other Intellectual Property.
Qiagen Other Intellectual Property.
Sysmex Other Intellectual Property.
Agios Other Intellectual Property.
Genzyme Other Intellectual Property.
Esoterix Other Intellectual Property.
Ventana Other Intellectual Property.
ManaT Bio Other Intellectual Property.
V. Anagnostou,
AstraZeneca Independent Contractor, ).
Personal Genome Diagnostics/Labcorp ).
Bristol-Myers Squibb ).
Delfi Diagnostics ).
Guardant Health Independent Contractor, Other, honoraria.
Neogenomics Independent Contractor.
Foundation Medicine Other, honoraria.
Personal Genome Diagnostics Other, honoraria.
Roche Other, honoraria.