phenomenon · claim-type · cross-domain-transfer · mechanism · claim-relation · replication-status · limitation — grounded in the full text| phenomenon | a clinical category - high mutational burden - whose membership depends on an assay's size, a list of exclusions, and a threshold stated once in a figure caption— “Specimens with TMB low and called as MSI-Stable are shown in light grey, specimens with high TMB (mutations/Mb >20) are shown in blue, and specimens called as MSI-High are shown in dark grey.” | |
| claim-type | existence— “We found that microsatellite instability (MSI-High) generally occurred as a subset of high TMB (Fig. 3a). The vast majority of MSI-High samples also had high TMB (83%), and 97% had TMB ≥10 mutations/Mb. However, the converse was not true; only 16% of samples with high TMB were classified as MSI-High.” | |
| method — evidence | — “For the WES samples, tumor and normal tissue were each sequenced in order to distinguish germline polymorphisms from somatic mutations. For the targeted CGP samples, no matched normal material was sequenced; rather, genomic variants were stringently filtered to eliminate germline polymorphisms (see “Methods” for details).” | |
| object of study — evidence | — “An emerging biomarker for response to immunotherapy is the total number of mutations present in a tumor specimen. This is termed the mutation load or tumor mutational burden (TMB). It is hypothesized that highly mutated tumors are more likely to harbor neoantigens which make them targets of activated immune cells.” | |
| research question — evidence | — “We finally sought to determine the effects of sequencing different amounts of the genome and how that might affect our ability to accurately determine TMB. We sampled the number of mutations that we would expect to see at different TMB levels (100 mutations/Mb, 20 mutations/Mb, 10 mutations/Mb) and at different amounts of megabases sequenced… | |
| contribution — evidence | — “We found that, as expected, the percentage deviation is lower for high underlying TMB, meaning that specimens with high TMB can be effectively identified by targeted sequencing of several hundred genes. In contrast, for intermediate levels of TMB, the percentage deviation starts to increase, especially with less than 0.5 Mb sequenced (Fig.… | |
| transfer | from statistics: principal components analysis, carried from multivariate statistics to collapse 228 repeat-length measurements into a single MSI score that can be cut into categories— “To determine MSI status, 114 intronic homopolymer repeat loci with adequate coverage on the CGP panel were analyzed for length variability and compiled into an overall MSI score via principal components analysis. The 114 loci were selected from a total set of 1897 that have adequate coverage on the FMI FoundationOne bait set. Amongst the… | transfers[0] |
| transfer | from survey sampling: resampling simulation, carried from survey methodology to ask how small a genomic panel may be before the rate it estimates stops being the rate— “We finally sought to determine the effects of sequencing different amounts of the genome and how that might affect our ability to accurately determine TMB. We sampled the number of mutations that we would expect to see at different TMB levels (100 mutations/Mb, 20 mutations/Mb, 10 mutations/Mb) and at different amounts of megabases sequenced… | transfers[1] |
| mechanism | sampling variance rising as the panel shrinks TMB is a rate estimated from a sample of the genome, so the fewer megabases read the noisier the estimate; the effect is worst where the underlying rate is low, because the expected count in the sampled region approaches zero— “We found that, as expected, the percentage deviation is lower for high underlying TMB, meaning that specimens with high TMB can be effectively identified by targeted sequencing of several hundred genes. In contrast, for intermediate levels of TMB, the percentage deviation starts to increase, especially with less than 0.5 Mb sequenced (Fig.… | mechanisms[0] |
| mechanism | synonymous mutations as a process signal a synonymous change cannot itself create a neoantigen, but it is produced by the same mutational process that produced the nonsynonymous ones elsewhere, so counting it raises the sample size of the rate estimate without changing what the rate is about— “Synonymous mutations are counted in order to reduce sampling noise. While synonymous mutations are not likely to be directly involved in creating immunogenicity, their presence is a signal of mutational processes that will also have resulted in nonsynonymous mutations and neoantigens elsewhere in the genome.” | mechanisms[1] |
| mechanism | germline filtering without a matched normal with no normal tissue sequenced, inherited variants must be removed by matching against reference databases - so the filter's accuracy is the databases' coverage of the patient's ancestry— “We found that filtering out germline alterations and rare variants was important to obtaining accurate measurements of TMB, and this will especially be important in patients from ethnic backgrounds not well represented in sequencing datasets.” | mechanisms[2] |
| qualifies | PD-1/PD-L1 expression by immunohistochemistry as the companion diagnostic for checkpoint inhibitors— “Assays that measure PD-1/PD-L1 protein expression by immunohistochemistry (IHC) are approved as complementary or companion diagnostics for some of these drugs; however, measurement of PD-1/PD-L1 expression is technically challenging, can be difficult to interpret, and is not always an accurate predictor of response to immunotherapy.” | claim_relations[0] |
| extends | whole exome measurement of tumour mutational burden, by showing a 1.1 Mb targeted panel reproduces it— “We also analyzed whole-exome sequencing data from 35 studies, published as part of TCGA, examining a total of 8917 cancer specimens. We determined the number of mutations in total and compared that to the number of mutations in the 315 genes targeted by our assay. As expected, these… | claim_relations[1] |
| qualifies | neoantigen load as the predictor of immunotherapy response - correlated, but with no recurrent neoantigens found that predict response | claim_relations[2] |
| sense | "high TMB" - AS USED throughout the abstract, results, discussion and conclusions: an unquantified clinical category of patients who might benefit from immunotherapy Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | senses[0] |
| sense | "high TMB" - AS DEFINED: more than 20 mutations per megabase. The threshold appears once in the paper, in the caption of Fig. 3, and nowhere in the prose Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | senses[1] |
| sense | agreement of targeted CGP with whole exome - AS ACCURACY: R2 = 0.74, from 29 specimens where both measurements were made on the same biopsy Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | senses[2] |
| sense | agreement of targeted CGP with whole exome - AS PRECISION: R2 = 0.98, the assay against itself on 60 replicate pairs. The paper labels this one precision, and it is the number that looks like agreement without being it Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | senses[3] |
| control | the same biopsy specimens measured by both the targeted panel and whole exome sequencing, so the panel is checked against a different measurement rather than against itself — partial Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. — rules out the targeted panel's own gene selection as the explanation of the burden it reports - the same biopsy measured by a method that selects no genes gives a correlated answer Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[0] |
| control | 60 replicate pairs run through the same assay, separating precision from accuracy — held Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. — rules out assay noise as the explanation of the remaining disagreement with whole exome sequencing - the assay repeats itself at R2 0.98, so what is left is between methods and not within one Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[1] |
| control | simulating the measurement at smaller panel sizes to find where sampling variance makes the estimate unusable, rather than asserting that 1.1 Mb is enough — partial Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. — rules out sampling variance as a hidden contributor at the panel size actually used - the simulation measures it rather than assuming 1.1 Mb is enough, and names where it stops being enough Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[2] |
| control | an independent check on 8,917 TCGA exomes, comparing total mutations against those in the 315 assay genes — held Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. — rules out this laboratory's own cohort and pipeline as the source of the agreement - the same comparison on 8,917 independently generated exomes reproduces it Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[3] |
| control | cohort filtering declared in advance - duplicates removed, coverage floor, and a minimum of 50 specimens before a cancer type is analysed at all — held Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. — rules out duplicate specimens and under-covered samples as contributors to the reported distribution Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[4] |
| control | checking whether more than the first principal component of the MSI score was needed — held Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. — rules out further principal components as carriers of microsatellite signal the one-dimensional score discards - none of the others explains more than 4% of the variance Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[5] |
| weight | PD-1/PD-L1 expression by immunohistochemistry as the companion diagnostic for checkpoint inhibitors — 0.9 Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | claim_relations[0] |
| weight | whole exome measurement of tumour mutational burden, by showing a 1.1 Mb targeted panel reproduces it — 0.9 Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | claim_relations[1] |
| weight | neoantigen load as the predictor of immunotherapy response - correlated, but with no recurrent neoantigens found that predict response — 0.85 Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | claim_relations[2] |
| relation | MSI-High —part-of→ TMB — MSI-High samples are largely a subset of the high-TMB population, and not the reverse Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concept_edges[0] |
| weight | MSI-High —part-of→ TMB — 0.85 Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concept_edges[0] |
| relation | mutation load —same-as→ TMB — one quantity under two names, given in apposition at first use Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concept_edges[1] |
| weight | mutation load —same-as→ TMB — 0.9 Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concept_edges[1] |
| outcome | control — partial Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[0] |
| outcome | control — held Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[1] |
| outcome | control — partial Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[2] |
| outcome | control — held Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[3] |
| outcome | control — held Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[4] |
| outcome | control — held Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | controls[5] |
| limitation | the germline filter depends on reference databases, so it will be least accurate for patients from ethnic backgrounds not well represented in them - stated by the authors Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | limitations[0] |
| limitation | the MSI cut points were set by manual unsupervised clustering against a reference that was itself partly APPROXIMATED by the same pipeline's homopolymer indel counts Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | limitations[1] |
| limitation | the accuracy figure rests on 29 specimens with matched whole exome sequencing; the two 0.98 correlations are the assay against itself and an in-silico subsetting Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | limitations[2] |
| limitation | known mismatch-repair and replication genes account for less than 10% of high-TMB cases, so the molecular basis of most of the phenomenon is unexplained Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | limitations[3] |
| limitation | the PMS2 promoter mutations are not shown to be causal, and the TOP2A association rests on eight cases Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | limitations[4] |
| limitation | targeted profiling measures the burden but cannot identify the neoantigens the mechanism depends on, since those may occur in any gene Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | limitations[5] |
finding · quantity · variable · definition · key-term — grounded in the full text| finding | Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.findings[0] |
| finding | Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.findings[1] |
| finding | Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.findings[2] |
| finding | Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.findings[3] |
| quantity | the panel size below which measurement variance increases significantly Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.quantities[0] |
| quantity | MSI-High samples that also had high TMB Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.quantities[1] |
| quantity | high-TMB samples classified as MSI-High - the converse, and much smaller Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.quantities[2] |
| quantity | the initial clinical cohort, filtered to 92,439 Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.quantities[3] |
| variable | percentage deviation Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.variables[0] |
| definition | TMB Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.definitions[0] |
| definition | high TMB Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.definitions[1] |
| definition | MSI score Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.definitions[2] |
| concept | TMB — not defined in this paper's own words; somatic, coding, base substitution and indel mutations per megabase of genome examined - a count defined mostly by its seven exclusions Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[0] |
| concept | mutation load — not defined in this paper's own words; the other name for TMB, given in apposition at first use and then not used again Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[1] |
| concept | biomarker — not defined in this paper's own words; a measurable stand-in for who will respond to immune checkpoint blockade; TMB is offered as one because the incumbent, PD-L1 by IHC, is not always an accurate predictor Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[2] |
| concept | Synonymous mutations — not defined in this paper's own words; counted although not themselves immunogenic, because their presence signals the mutational process that produced neoantigens elsewhere - an inclusion the authors stop to justify Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[3] |
| concept | MSI-High — not defined in this paper's own words; microsatellite instability high - a second marker of genomic instability, mostly a subset of high TMB but not the reverse Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[4] |
| concept | MSI score — not defined in this paper's own words; the first principal component of 114 homopolymer loci, cut into MSI-High / ambiguous / stable by manual unsupervised clustering Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[5] |
| concept | CGP — not defined in this paper's own words; comprehensive genomic profiling - the 315-gene, 1.1 Mb targeted assay, run without matched normal tissue and relying on filtering to remove germline variants Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[6] |
| concept | WES — not defined in this paper's own words; whole exome sequencing with matched tumour and normal tissue - the reference the targeted panel has to stand in for Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[7] |
| concept | neoantigens — not defined in this paper's own words; the mechanism by which mutation count is supposed to matter, and the thing TMB is a proxy for rather than a measurement of Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[8] |
| concept | percentage deviation — not defined in this paper's own words; how far a downsampled measurement lands from the whole-exome answer - the quantity that decides how small a panel may be Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[9] |
| concept | germline polymorphisms — not defined in this paper's own words; what must be removed without a matched normal sample, by filtering alone - and the filtering matters most for patients underrepresented in the reference databases Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[10] |
| concept | effect size — not defined in this paper's own words; the factor loading in the log-TMB model, cut at 0.5 - a chosen threshold equal to a 3.1-fold increase over wild-type Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | concepts[11] |
| R2 = 0.74 | Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.statistics[0] |
| R2 = 0.98 | Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.statistics[1] |
| principal components analysis | Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.statistics[2] |
| false discovery rate | Quotation withheld — this paper is not ours to reproduce, and the page has already quoted as much of it as the rights layer allows. The tag, its field and its confidence stand; the sentence is at the publisher. | content_tags.statistics[3] |
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