CoChat
Sign Up
Cited by 201Cancer Genomics and DiagnosticsSarcoma Diagnosis and TreatmentGenomic variations and chromosomal abnormalities

The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index.

Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden

Open access
Peneder, Peter, Stütz, Adrian M., Surdez, Didier, Krumbholz, Manuela, Semper, Sabine, Chicard, Mathieu, Sheffield, Nathan C., Pierron, Gaelle, Lapouble, Eve, Tötzl, Marcus, Ergüner, Bekir, Barreca, Daniele, Rendeiro, André F., Agaimy, Abbas, Boztug, Heidrun, Engstler, Gernot, Dworzak, Michael, Bernkopf, Marie, Taschner-Mandl, Sabine, Ambros, Inge M., Myklebost, Ola, Marec-Bérard, Perrine, Burchill, Susan Ann, Brennan, Bernadette, Strauss, Sandra J., Whelan, Jeremy, Schleiermacher, Gudrun, Schaefer, Christiane, Dirksen, Uta, Hutter, Caroline, Boye, Kjetil, Ambros, Peter F., Delattre, Olivier, Metzler, Markus, Bock, Christoph, Tomazou, Eleni M.·2021·Nature Communications
DOI 10.1038/s41467-021-23445-wPMC PMC8163828
Open this paper in CoChat — free accountOpen PDF

Abstract

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-021-23445-w

Cites

82 of 82 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 Whole-genome sequencing of cfDNA enables fragment-based liquid biopsy analysis in Ewing sarcoma. The top row of the figure describes the fragmentation and fragment-based analysis of cfDNA in cancer patients. The center row introduces the study cohort (center left) and illustrates the quantification of tumor-derived DNA based on genetic evidence, which is used as a reference in this study (center right). The bottom part of the figure outlines three complementary approaches to fragment-based cfDNA analyses: global fragment-size distribution; regional fragment-size distribution along the genome; and fragment coverage at regions-of-interest (bottom left). CNA profiles were used for comparing cfDNA to matched tumors biopsies and for time-resolved monitoring of tumor evolution. Fragment-based cfDNA metrics were combined for machine learning-based tumor detection and classification (bottom right). The main figures describing each of the analyses are indicated in brackets.
Fig. 1 Whole-genome sequencing of cfDNA enables fragment-based liquid biopsy analysis in Ewing sarcoma. The top row of the figure describes the fragmentation and fragment-based analysis of cfDNA in cancer patients. The center row introduces the study cohort (center left) and illustrates the quantification of tumor-derived DNA based on genetic evidence, which is used as a reference in this study (center right). The bottom part of the figure outlines three complementary approaches to fragment-based cfDNA analyses: global fragment-size distribution; regional fragment-size distribution along the genome; and fragment coverage at regions-of-interest (bottom left). CNA profiles were used for comparing cfDNA to matched tumors biopsies and for time-resolved monitoring of tumor evolution. Fragment-based cfDNA metrics were combined for machine learning-based tumor detection and classification (bottom right). The main figures describing each of the analyses are indicated in brackets.CC BY · PubMed Central
Fig. 2 Global fragment-size analysis detects highly fragmented EwS tumor DNA. a Histogram (top) showing the cfDNA fragment-size distribution for three representative samples with high (95%), low (2%), and undetectable (0%) tumor-derived DNA (ctDNA) content. The range of cfDNA fragment sizes in 22 healthy controls is shown in gray. Heatmap (bottom) showing the relative fragment-size distribution of 235 cfDNA samples subjected to whole-genome sequencing, each normalized against the median of 22 healthy controls. EwS samples are grouped by genetically inferred tumor-derived DNA content. The three samples shown in the histogram are marked by arrows. b Proportion of short cfDNA fragments (20-150 bp) for pediatric sarcomas and healthy controls (data from this study) and for adult cancers (published data49). Boxes correspond to interquartile ranges (IQR), black lines indicate the median, and the whiskers extend to the lowest or highest data points that are still within 1.5 IQR of the bottom or top quartile, respectively. Significance versus the 22 healthy controls was assessed using two-sided Mann–Whitney U tests.
Fig. 2 Global fragment-size analysis detects highly fragmented EwS tumor DNA. a Histogram (top) showing the cfDNA fragment-size distribution for three representative samples with high (95%), low (2%), and undetectable (0%) tumor-derived DNA (ctDNA) content. The range of cfDNA fragment sizes in 22 healthy controls is shown in gray. Heatmap (bottom) showing the relative fragment-size distribution of 235 cfDNA samples subjected to whole-genome sequencing, each normalized against the median of 22 healthy controls. EwS samples are grouped by genetically inferred tumor-derived DNA content. The three samples shown in the histogram are marked by arrows. b Proportion of short cfDNA fragments (20-150 bp) for pediatric sarcomas and healthy controls (data from this study) and for adult cancers (published data49). Boxes correspond to interquartile ranges (IQR), black lines indicate the median, and the whiskers extend to the lowest or highest data points that are still within 1.5 IQR of the bottom or top quartile, respectively. Significance versus the 22 healthy controls was assessed using two-sided Mann–Whitney U tests.CC BY · PubMed Central
Fig. 3 CNA profiles in liquid biopsies reflect tumor aberrations and allow monitoring of tumor evolution. a Comparison of CNAs detected in cfDNA versus matched tumor biopsies. Only sample pairs with tumor-derived DNA detected in cfDNA based on ichorCNA are shown (n = 29 sample pairs); four copy-number neutral sample pairs were omitted from the plot. Patients are grouped according to CNA state in cfDNA relative to the matched tumor biopsy. Gray represents CNAs detected in both cfDNA and matched tumor biopsy, orange indicates CNAs detected only in cfDNA, and turquoise represents CNAs detected only in the tumor biopsy. The CNAs detected in cfDNAs versus matched tumor biopsies are summarized in a bar plot (bottom). b CNA plot (ichorCNA) of an EwS cfDNA sample (EwS_90_1) before (middle) and after (bottom) in silico size selection to the range of 90–150 bp. A subclonal CNA on chromosome 16 (indicated by black arrows) that was clearly visible in the tumor biopsy (top) became detectable in the matched cfDNA sample only after in silico size selection. c CNA profiles (ichorCNA) of longitudinal cfDNA samples derived from the same patient (EwS_5) support the monitoring of somatic clonal evolution for individual patients. The filtered CNA profiles of samples collected at diagnosis and two subsequent relapses are shown. The day of sample collection relative to the day of diagnosis is indicated (left). Inferred chromosomal gains are shown in red, inferred deletions are shown in green, and CNA-neutral regions are shown in blue.
Fig. 3 CNA profiles in liquid biopsies reflect tumor aberrations and allow monitoring of tumor evolution. a Comparison of CNAs detected in cfDNA versus matched tumor biopsies. Only sample pairs with tumor-derived DNA detected in cfDNA based on ichorCNA are shown (n = 29 sample pairs); four copy-number neutral sample pairs were omitted from the plot. Patients are grouped according to CNA state in cfDNA relative to the matched tumor biopsy. Gray represents CNAs detected in both cfDNA and matched tumor biopsy, orange indicates CNAs detected only in cfDNA, and turquoise represents CNAs detected only in the tumor biopsy. The CNAs detected in cfDNAs versus matched tumor biopsies are summarized in a bar plot (bottom). b CNA plot (ichorCNA) of an EwS cfDNA sample (EwS_90_1) before (middle) and after (bottom) in silico size selection to the range of 90–150 bp. A subclonal CNA on chromosome 16 (indicated by black arrows) that was clearly visible in the tumor biopsy (top) became detectable in the matched cfDNA sample only after in silico size selection. c CNA profiles (ichorCNA) of longitudinal cfDNA samples derived from the same patient (EwS_5) support the monitoring of somatic clonal evolution for individual patients. The filtered CNA profiles of samples collected at diagnosis and two subsequent relapses are shown. The day of sample collection relative to the day of diagnosis is indicated (left). Inferred chromosomal gains are shown in red, inferred deletions are shown in green, and CNA-neutral regions are shown in blue.CC BY · PubMed Central
Fig. 4 Regional fragment-size analysis detects an EwS tumor-specific epigenetic signature in cfDNA samples. a Schematic illustration of the regional fragment-size analysis, measuring the ratio of short (S) versus long (L) cfDNA fragments in 100 kb bins along the genome. Genomic regions that overlap with CNAs are excluded in order to focus the analysis on epigenetic signatures reflected in the cfDNA fragmentation patterns. b Heatmap comparing the genome-wide fragmentation profiles of cfDNA samples from patients with pediatric sarcoma to those of healthy controls. In each 100 kb bin (n = 20,706 bins), the log2(S/L ratio) of each sarcoma sample was compared to the distribution of log2(S/L ratios) of healthy controls via z-scores. Both CNA-affected and CNA-neutral bins are shown. EwS samples are grouped by genetically inferred tumor-derived DNA content. c Regional cfDNA fragmentation in patients with pediatric sarcoma compared to healthy controls. Only chromosome arms that are recurrently affected by CNAs in EwS tumors are shown. Box plots illustrate z-scores for EwS samples with genetic tumor evidence and without detected CNAs on the chromosomal arm (red), non-EwS sarcomas with genetic tumor evidence and without detected CNAs on the chromosomal arm (black), EwS samples without genetic tumor evidence (yellow), and healthy controls (green). The significance of the first group versus each of the other three groups was assessed using the two-sided Mann–Whitney U test; Bonferroni-corrected p-values are shown. Boxes correspond to interquartile ranges (IQR), thick black lines indicate the median, and the whiskers extend to the lowest or highest data point that are still within 1.5 IQR of the bottom or top quartile, respectively. d Functional enrichment analysis for regions with significantly shorter/longer cfDNA fragment size compared to healthy controls based on the LOLA software54. A selection of enriched terms is shown, while the full list is provided in Supplementary Data 6. e EwS tumor-specific epigenome profiles for selected regions with significantly shorter cfDNA fragment size compared to healthy controls. The genome browser profiles show open chromatin-associated histone H3K27 acetylation (for regions with shorter fragments) based on ChIP-seq data for primary EwS tumors41. EwS-specific DHSs along the selected genomic region are also indicated.
Fig. 4 Regional fragment-size analysis detects an EwS tumor-specific epigenetic signature in cfDNA samples. a Schematic illustration of the regional fragment-size analysis, measuring the ratio of short (S) versus long (L) cfDNA fragments in 100 kb bins along the genome. Genomic regions that overlap with CNAs are excluded in order to focus the analysis on epigenetic signatures reflected in the cfDNA fragmentation patterns. b Heatmap comparing the genome-wide fragmentation profiles of cfDNA samples from patients with pediatric sarcoma to those of healthy controls. In each 100 kb bin (n = 20,706 bins), the log2(S/L ratio) of each sarcoma sample was compared to the distribution of log2(S/L ratios) of healthy controls via z-scores. Both CNA-affected and CNA-neutral bins are shown. EwS samples are grouped by genetically inferred tumor-derived DNA content. c Regional cfDNA fragmentation in patients with pediatric sarcoma compared to healthy controls. Only chromosome arms that are recurrently affected by CNAs in EwS tumors are shown. Box plots illustrate z-scores for EwS samples with genetic tumor evidence and without detected CNAs on the chromosomal arm (red), non-EwS sarcomas with genetic tumor evidence and without detected CNAs on the chromosomal arm (black), EwS samples without genetic tumor evidence (yellow), and healthy controls (green). The significance of the first group versus each of the other three groups was assessed using the two-sided Mann–Whitney U test; Bonferroni-corrected p-values are shown. Boxes correspond to interquartile ranges (IQR), thick black lines indicate the median, and the whiskers extend to the lowest or highest data point that are still within 1.5 IQR of the bottom or top quartile, respectively. d Functional enrichment analysis for regions with significantly shorter/longer cfDNA fragment size compared to healthy controls based on the LOLA software54. A selection of enriched terms is shown, while the full list is provided in Supplementary Data 6. e EwS tumor-specific epigenome profiles for selected regions with significantly shorter cfDNA fragment size compared to healthy controls. The genome browser profiles show open chromatin-associated histone H3K27 acetylation (for regions with shorter fragments) based on ChIP-seq data for primary EwS tumors41. EwS-specific DHSs along the selected genomic region are also indicated.CC BY · PubMed Central
Fig. 5 Fragment analysis for EwS-specific genomic regions quantifies tumor-derived cfDNA in EwS patients. a Conceptual outline of the LIQUORICE method and software for fragment analysis of cfDNA based on tumor-specific epigenetic alterations. b Aggregated, bias-corrected, and normalized coverage signals at selected genomic region sets shown for healthy controls, for non-EwS sarcomas, and for EwS cfDNA samples. EwS samples are grouped by genetically inferred tumor-derived DNA content and clinical tumor evidence. cfDNA samples with coverage signals significantly different (three standard deviations) from healthy controls are displayed in red; the total number of those samples and the direction of the deviation (arrow) are indicated. Total dip depth was used as the metric of choice for the sharp dips at hematopoietic-specific and universal DHSs; area over the curve (AOC) was used for the other region sets. c cfDNA-based coverage signal at EwS-specific DHSs (bottom, nEwS = 38) reflects the aggregate DNA methylation profiles at these regions in matched tumor biopsies (top, nEwS = 38). d Scatterplots showing the correlation of the coverage signal at EwS-specific DHSs with the genetically inferred tumor-derived DNA content of the cfDNA samples. Pearson correlation coefficients (r) and linear trend lines are shown. The x-axes are shown in a log scale from 1% onwards. e Same as d but showing the coverage signal at hematopoietic-specific DHSs. Blue arrows indicate samples with significant liver signature. f Aggregated, bias-corrected, and normalized coverage signal (AOC) at alveolar rhabdomyosarcoma (ARMS)-specific DHSs for cfDNA samples from healthy controls and patients with EwS, RMS, and other pediatric sarcomas (left; p-values were calculated using two-sided Mann–Whitney U tests without correction for multiple testing). For ARMS patients with at least 9% ctDNA (genetic-based evidence), a striking reduction of fragment coverage was observed (right). A cfDNA sample from a patient with embryonal rhabdomyosarcoma (ERMS) did not show any reduction of fragment coverage at ARMS-specific DHSs (bottom right).
Fig. 5 Fragment analysis for EwS-specific genomic regions quantifies tumor-derived cfDNA in EwS patients. a Conceptual outline of the LIQUORICE method and software for fragment analysis of cfDNA based on tumor-specific epigenetic alterations. b Aggregated, bias-corrected, and normalized coverage signals at selected genomic region sets shown for healthy controls, for non-EwS sarcomas, and for EwS cfDNA samples. EwS samples are grouped by genetically inferred tumor-derived DNA content and clinical tumor evidence. cfDNA samples with coverage signals significantly different (three standard deviations) from healthy controls are displayed in red; the total number of those samples and the direction of the deviation (arrow) are indicated. Total dip depth was used as the metric of choice for the sharp dips at hematopoietic-specific and universal DHSs; area over the curve (AOC) was used for the other region sets. c cfDNA-based coverage signal at EwS-specific DHSs (bottom, nEwS = 38) reflects the aggregate DNA methylation profiles at these regions in matched tumor biopsies (top, nEwS = 38). d Scatterplots showing the correlation of the coverage signal at EwS-specific DHSs with the genetically inferred tumor-derived DNA content of the cfDNA samples. Pearson correlation coefficients (r) and linear trend lines are shown. The x-axes are shown in a log scale from 1% onwards. e Same as d but showing the coverage signal at hematopoietic-specific DHSs. Blue arrows indicate samples with significant liver signature. f Aggregated, bias-corrected, and normalized coverage signal (AOC) at alveolar rhabdomyosarcoma (ARMS)-specific DHSs for cfDNA samples from healthy controls and patients with EwS, RMS, and other pediatric sarcomas (left; p-values were calculated using two-sided Mann–Whitney U tests without correction for multiple testing). For ARMS patients with at least 9% ctDNA (genetic-based evidence), a striking reduction of fragment coverage was observed (right). A cfDNA sample from a patient with embryonal rhabdomyosarcoma (ERMS) did not show any reduction of fragment coverage at ARMS-specific DHSs (bottom right).CC BY · PubMed Central
Fig. 6 Fragment-based analysis of cfDNA enables accurate tumor detection and classification. Prediction performance of machine learning classifiers trained to distinguish patients with EwS from healthy controls (a) and from patients with other pediatric sarcomas (b), based on the following sets of input features: global fragment-size distribution (blue); fragment coverage at EwS-specific DHSs (orange); read depth in 5 Mb bins (green); and regional fragmentation patterns (red). Results are also shown for a meta-learner combining the predictions of all individual classifiers into a weighted consensus prediction (purple). The performance of each model was evaluated by and averaged over 100 iterations of bootstrapping, separately for the different sequencing coverage levels (median of 12×, 1×, and 0.1×). CI is the 95% confidence interval obtained by bootstrapping. a ROC curves show, for each feature set, the performance for distinguishing between cfDNA samples from patients with clinical evidence for EwS (nsamples = 103) and healthy controls from three independent sets (22 controls sequenced in this study; 22 controls from Cristiano et al.32; and 24 controls from Ulz et al.34). Machine learning models were trained separately for each of the 3 control sets; the mean results over the 3*100 bootstrap iterations are shown. b ROC curves show the performance of each feature set for distinguishing between cfDNA samples from patients with EwS (nsamples = 98) and from patients with other pediatric sarcomas (nsamples = 18). For both sets of samples, we ensured the presence of tumor-derived cfDNA in the blood based on genetic evidence.
Fig. 6 Fragment-based analysis of cfDNA enables accurate tumor detection and classification. Prediction performance of machine learning classifiers trained to distinguish patients with EwS from healthy controls (a) and from patients with other pediatric sarcomas (b), based on the following sets of input features: global fragment-size distribution (blue); fragment coverage at EwS-specific DHSs (orange); read depth in 5 Mb bins (green); and regional fragmentation patterns (red). Results are also shown for a meta-learner combining the predictions of all individual classifiers into a weighted consensus prediction (purple). The performance of each model was evaluated by and averaged over 100 iterations of bootstrapping, separately for the different sequencing coverage levels (median of 12×, 1×, and 0.1×). CI is the 95% confidence interval obtained by bootstrapping. a ROC curves show, for each feature set, the performance for distinguishing between cfDNA samples from patients with clinical evidence for EwS (nsamples = 103) and healthy controls from three independent sets (22 controls sequenced in this study; 22 controls from Cristiano et al.32; and 24 controls from Ulz et al.34). Machine learning models were trained separately for each of the 3 control sets; the mean results over the 3*100 bootstrap iterations are shown. b ROC curves show the performance of each feature set for distinguishing between cfDNA samples from patients with EwS (nsamples = 98) and from patients with other pediatric sarcomas (nsamples = 18). For both sets of samples, we ensured the presence of tumor-derived cfDNA in the blood based on genetic evidence.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 82 references

Research works printed but not linked: 1

  1. Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. Preprint at https://arxiv.org/abs/1303.3997 (2013). · arXiv

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Peneder, P., Stütz, A. M., Surdez, D., Krumbholz, M., Semper, S., Chicard, M., Sheffield, N. C., Pierron, G., Lapouble, E., Tötzl, M., Ergüner, B., Barreca, D., Rendeiro, A. F., Agaimy, A., Boztug, H., Engstler, G., Dworzak, M., Bernkopf, M., Taschner-Mandl, S., Ambros, I. M., Myklebost, O., Marec-Bérard, P., Burchill, S. A., Brennan, B., Strauss, S. J., Whelan, J., Schleiermacher, G., Schaefer, C., Dirksen, U., Hutter, C., Boye, K., Ambros, P. F., Delattre, O., Metzler, M., Bock, C., & Tomazou, E. M.
Affiliations
  • St. Anna Children's Cancer Research Institute (AT)
  • Inserm (FR)
  • Universitätsklinikum Erlangen (DE)
  • University of Virginia (US)
  • Institut Curie (FR)
  • Austrian Academy of Sciences (AT)
  • St Anna Children's Hospital (AT)
  • Oslo University Hospital (NO)
  • St James's University Hospital (GB)
  • Royal Manchester Children's Hospital (GB)
  • University College Hospital (GB)
  • Essen University Hospital (DE)
Corresponding author
  • Bock, Christoph
  • Tomazou, Eleni M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-05-28
Volume
12
Issue
1
Pages
3230-3230
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-23445-w
PMC
PMC8163828
OpenAlex
W3165287952
Cited by
200
References
82
Citations by year
2026: 26 · 2025: 39 · 2024: 38 · 2023: 45 · 2022: 39 · 2021: 12
FWCI
13.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Kreftforeningen
  • European Commission (HORIZON2020, 602856)
  • Vienna Science and Technology Fund (LS18-049)
  • Austrian Science Fund (V 506, I 2798)
  • Oesterreichische Nationalbank (17876)
  • Ligue Contre le Cancer
  • Deutsche Krebshilfe (#108128, 70112018, DKH 108128, 70113419)
  • H2020 European Research Council (679146)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
liquid biopsy, cell-free DNA, childhood cancer, Ewing sarcoma, pediatric sarcoma, low mutational burden, cfDNA fragmentation, chromatin signatures, epigenetic dysregulation, prognostic factors, machine learning classifiers
MeSH terms
Whole Genome Sequencing, Liquid Biopsy, Circulating Tumor DNA, Adolescent, Adult, Bone Neoplasms, Child, Child, Preschool, DNA Mutational Analysis, Female, Humans, Infant, Male, Middle Aged, Mutation, Sarcoma, Ewing, Biomarkers, Tumor, Case-Control Studies, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review