Machine learning guided signal enrichment for ultrasensitive plasma tumor burden monitoring
Machine learning guided signal enrichment for ultrasensitive plasma tumor burden monitoring
ABSTRACT In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole genome sequencing (WGS). We now introduce MRD-EDGE, a composite machine learning-guided WGS ctDNA single nucleotide variant (SNV) and copy number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGE uses deep learning and a ctDNA-specific feature space to increase SNV signal to noise enrichment in WGS by 300X compared to our previous noise suppression platform MRDetect. MRD-EDGE also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1Gb to 200Mb, thereby expanding its applicability to a wider range of solid tumors. We harness the improved performance to track changes in tumor burden in response to neoadjuvant immunotherapy in non-small cell lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal to noise enrichment in MRD-EDGE enables de novo mutation calling in melanoma without matched tumor, yielding clinically informative TF monitoring for patients on immune checkpoint inhibition.
?gaard Nadia、Shah Minita、Khamnei Cole C.、Zhang Mingxuan、Halmos Daniel、Nors Jesper、Therkildsen Christina、Brand Ryan、Maher Colleen、Spain Lavinia、Krause Kate、Frederick Dennie T.、Marton Melissa、Boland Genevieve、Wolchok Jedd D.、Imielinski Marcin、Altorki Nasser K.、Landau Dan A.、Steinsnyder Zoe、Liao Will、Rasmussen Mads Heilskov、Jensen Sarah ?strup、Winterkorn Lara、Manaa Dina、Saxena Ashish、Sotelo Jesus、Callahan Margaret K.、Bass Jake、Turajlic Samra、Rajagopalan Srinivas、Berger Michael F.、Postow Michael A.、Andersen Claus Lindbjerg、Frydendahl Amanda、Shah Ronak H.、Widman Adam J.、Cheng Alexandre Pellan、Langanay Theophile、Malbari Murtaza S.、Deshpande Aditya、Robine Nicolas、Arora Anushri
Department of Molecular Medicine, Aarhus University Hospital||Department of Clinical Medicine, Aarhus UniversityNew York Genome CenterNew York Genome CenterWeill Cornell MedicineNew York Genome Center||Weill Cornell MedicineDepartment of Molecular Medicine, Aarhus University Hospital||Department of Clinical Medicine, Aarhus UniversityGastro Unit, Copenhagen University Hospital, Amager - Hvidovre HospitalNew York Genome CenterMemorial Sloan Kettering Cancer Center||Parker Institute for Cancer ImmunotherapyCancer Dynamics Laboratory, The Francis Crick Institute||Renal and Skin Unit, The Royal Marsden NHS Foundation TrustMass General Cancer Center, Massachusetts General HospitalMass General Cancer Center, Massachusetts General HospitalNew York Genome CenterMass General Cancer Center, Massachusetts General HospitalMemorial Sloan Kettering Cancer CenterNew York Genome Center||Weill Cornell MedicineWeill Cornell MedicineNew York Genome Center||Weill Cornell MedicineNew York Genome CenterNew York Genome CenterDepartment of Molecular Medicine, Aarhus University Hospital||Department of Clinical Medicine, Aarhus UniversityDepartment of Molecular Medicine, Aarhus University Hospital||Department of Clinical Medicine, Aarhus UniversityNew York Genome CenterNew York Genome CenterWeill Cornell MedicineWeill Cornell MedicineMemorial Sloan Kettering Cancer CenterNew York Genome CenterCancer Dynamics Laboratory, The Francis Crick Institute||Renal and Skin Unit, The Royal Marsden NHS Foundation TrustWeill Cornell MedicineMemorial Sloan Kettering Cancer CenterMemorial Sloan Kettering Cancer CenterDepartment of Molecular Medicine, Aarhus University Hospital||Department of Clinical Medicine, Aarhus UniversityDepartment of Clinical Medicine, Aarhus UniversityMemorial Sloan Kettering Cancer CenterNew York Genome Center||Memorial Sloan Kettering Cancer CenterNew York Genome Center||Weill Cornell MedicineNew York Genome Center||Weill Cornell MedicineWeill Cornell MedicineNew York Genome Center||Weill Cornell MedicineNew York Genome CenterNew York Genome Center
肿瘤学生物科学研究方法、生物科学研究技术生物科学理论、生物科学方法
?gaard Nadia,Shah Minita,Khamnei Cole C.,Zhang Mingxuan,Halmos Daniel,Nors Jesper,Therkildsen Christina,Brand Ryan,Maher Colleen,Spain Lavinia,Krause Kate,Frederick Dennie T.,Marton Melissa,Boland Genevieve,Wolchok Jedd D.,Imielinski Marcin,Altorki Nasser K.,Landau Dan A.,Steinsnyder Zoe,Liao Will,Rasmussen Mads Heilskov,Jensen Sarah ?strup,Winterkorn Lara,Manaa Dina,Saxena Ashish,Sotelo Jesus,Callahan Margaret K.,Bass Jake,Turajlic Samra,Rajagopalan Srinivas,Berger Michael F.,Postow Michael A.,Andersen Claus Lindbjerg,Frydendahl Amanda,Shah Ronak H.,Widman Adam J.,Cheng Alexandre Pellan,Langanay Theophile,Malbari Murtaza S.,Deshpande Aditya,Robine Nicolas,Arora Anushri.Machine learning guided signal enrichment for ultrasensitive plasma tumor burden monitoring[EB/OL].(2025-03-28)[2025-06-17].https://www.biorxiv.org/content/10.1101/2022.01.17.476508.点此复制
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