Title |
Integrated digital error suppression for improved detection of circulating tumor DNA
|
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Published in |
Nature Biotechnology, March 2016
|
DOI | 10.1038/nbt.3520 |
Pubmed ID | |
Authors |
Aaron M Newman, Alexander F Lovejoy, Daniel M Klass, David M Kurtz, Jacob J Chabon, Florian Scherer, Henning Stehr, Chih Long Liu, Scott V Bratman, Carmen Say, Li Zhou, Justin N Carter, Robert B West, George W Sledge Jr, Joseph B Shrager, Billy W Loo, Joel W Neal, Heather A Wakelee, Maximilian Diehn, Ash A Alizadeh |
Abstract |
High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 24 | 22% |
Spain | 8 | 7% |
United Kingdom | 5 | 5% |
Japan | 4 | 4% |
France | 3 | 3% |
Norway | 2 | 2% |
Canada | 2 | 2% |
Austria | 1 | <1% |
Belgium | 1 | <1% |
Other | 13 | 12% |
Unknown | 48 | 43% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 64 | 58% |
Scientists | 29 | 26% |
Practitioners (doctors, other healthcare professionals) | 13 | 12% |
Science communicators (journalists, bloggers, editors) | 5 | 5% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 5 | <1% |
Korea, Republic of | 2 | <1% |
United Kingdom | 2 | <1% |
China | 2 | <1% |
South Africa | 1 | <1% |
Israel | 1 | <1% |
Ireland | 1 | <1% |
Argentina | 1 | <1% |
Switzerland | 1 | <1% |
Other | 2 | <1% |
Unknown | 871 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 219 | 25% |
Student > Ph. D. Student | 141 | 16% |
Other | 62 | 7% |
Student > Master | 62 | 7% |
Student > Bachelor | 57 | 6% |
Other | 148 | 17% |
Unknown | 200 | 22% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 224 | 25% |
Agricultural and Biological Sciences | 184 | 21% |
Medicine and Dentistry | 130 | 15% |
Engineering | 27 | 3% |
Computer Science | 18 | 2% |
Other | 65 | 7% |
Unknown | 241 | 27% |