Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay.
The analytical validation is reported for a targeted methylation-based cell-free DNA multi-cancer early detection test designed to detect cancer and predict the cancer signal origin (tissue of origin). A machine-learning classifier was used to analyze the methylation patterns of >105 genomic targ...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0283001 |
| _version_ | 1797843273846358016 |
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| author | Gregory E Alexander Wendy Lin Fabian E Ortega Madhuvanthi Ramaiah Byoungsok Jung Lijuan Ji Ekaterina Revenkova Payal Shah Christian Croisetiere Jennifer R Berman Lane Eubank Gunjan Naik Jacqueline Brooks Andrea Mich Seyedmehdi Shojaee Neda Ronaghi Hemanshi Chawla Xinyi Hou Qinwen Liu Christopher-James A V Yakym Patriss Wais Moradi Meredith Halks-Miller Alexander M Aravanis Sonya Parpart-Li Nathan Hunkapiller |
| author_facet | Gregory E Alexander Wendy Lin Fabian E Ortega Madhuvanthi Ramaiah Byoungsok Jung Lijuan Ji Ekaterina Revenkova Payal Shah Christian Croisetiere Jennifer R Berman Lane Eubank Gunjan Naik Jacqueline Brooks Andrea Mich Seyedmehdi Shojaee Neda Ronaghi Hemanshi Chawla Xinyi Hou Qinwen Liu Christopher-James A V Yakym Patriss Wais Moradi Meredith Halks-Miller Alexander M Aravanis Sonya Parpart-Li Nathan Hunkapiller |
| author_sort | Gregory E Alexander |
| collection | DOAJ |
| description | The analytical validation is reported for a targeted methylation-based cell-free DNA multi-cancer early detection test designed to detect cancer and predict the cancer signal origin (tissue of origin). A machine-learning classifier was used to analyze the methylation patterns of >105 genomic targets covering >1 million methylation sites. Analytical sensitivity (limit of detection [95% probability]) was characterized with respect to tumor content by expected variant allele frequency and was determined to be 0.07%-0.17% across five tumor cases and 0.51% for the lymphoid neoplasm case. Test specificity was 99.3% (95% confidence interval, 98.6-99.7%). In the reproducibility and repeatability study, results were consistent in 31/34 (91.2%) pairs with cancer and 17/17 (100%) pairs without cancer; between runs, results were concordant for 129/133 (97.0%) cancer and 37/37 (100%) non-cancer sample pairs. Across 3- to 100-ng input levels of cell-free DNA, cancer was detected in 157/182 (86.3%) cancer samples but not in any of the 62 non-cancer samples. In input titration tests, cancer signal origin was correctly predicted in all tumor samples detected as cancer. No cross-contamination events were observed. No potential interferent (hemoglobin, bilirubin, triglycerides, genomic DNA) affected performance. The results of this analytical validation study support continued clinical development of a targeted methylation cell-free DNA multi-cancer early detection test. |
| first_indexed | 2024-04-09T17:02:30Z |
| format | Article |
| id | doaj.art-dd8363d94bd1437795386bee9e3165cc |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-09T17:02:30Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-dd8363d94bd1437795386bee9e3165cc2023-04-21T05:32:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01184e028300110.1371/journal.pone.0283001Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay.Gregory E AlexanderWendy LinFabian E OrtegaMadhuvanthi RamaiahByoungsok JungLijuan JiEkaterina RevenkovaPayal ShahChristian CroisetiereJennifer R BermanLane EubankGunjan NaikJacqueline BrooksAndrea MichSeyedmehdi ShojaeeNeda RonaghiHemanshi ChawlaXinyi HouQinwen LiuChristopher-James A V YakymPatriss Wais MoradiMeredith Halks-MillerAlexander M AravanisSonya Parpart-LiNathan HunkapillerThe analytical validation is reported for a targeted methylation-based cell-free DNA multi-cancer early detection test designed to detect cancer and predict the cancer signal origin (tissue of origin). A machine-learning classifier was used to analyze the methylation patterns of >105 genomic targets covering >1 million methylation sites. Analytical sensitivity (limit of detection [95% probability]) was characterized with respect to tumor content by expected variant allele frequency and was determined to be 0.07%-0.17% across five tumor cases and 0.51% for the lymphoid neoplasm case. Test specificity was 99.3% (95% confidence interval, 98.6-99.7%). In the reproducibility and repeatability study, results were consistent in 31/34 (91.2%) pairs with cancer and 17/17 (100%) pairs without cancer; between runs, results were concordant for 129/133 (97.0%) cancer and 37/37 (100%) non-cancer sample pairs. Across 3- to 100-ng input levels of cell-free DNA, cancer was detected in 157/182 (86.3%) cancer samples but not in any of the 62 non-cancer samples. In input titration tests, cancer signal origin was correctly predicted in all tumor samples detected as cancer. No cross-contamination events were observed. No potential interferent (hemoglobin, bilirubin, triglycerides, genomic DNA) affected performance. The results of this analytical validation study support continued clinical development of a targeted methylation cell-free DNA multi-cancer early detection test.https://doi.org/10.1371/journal.pone.0283001 |
| spellingShingle | Gregory E Alexander Wendy Lin Fabian E Ortega Madhuvanthi Ramaiah Byoungsok Jung Lijuan Ji Ekaterina Revenkova Payal Shah Christian Croisetiere Jennifer R Berman Lane Eubank Gunjan Naik Jacqueline Brooks Andrea Mich Seyedmehdi Shojaee Neda Ronaghi Hemanshi Chawla Xinyi Hou Qinwen Liu Christopher-James A V Yakym Patriss Wais Moradi Meredith Halks-Miller Alexander M Aravanis Sonya Parpart-Li Nathan Hunkapiller Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay. PLoS ONE |
| title | Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay. |
| title_full | Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay. |
| title_fullStr | Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay. |
| title_full_unstemmed | Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay. |
| title_short | Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay. |
| title_sort | analytical validation of a multi cancer early detection test with cancer signal origin using a cell free dna based targeted methylation assay |
| url | https://doi.org/10.1371/journal.pone.0283001 |
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