phenomenon · claim-type · cross-domain-transfer · mechanism · claim-relation · replication-status · limitation — grounded in the full text| phenomenon | a measurement that returns a non-zero score for cell types that are not in the sample, and scores that look like proportions without being them— “Finally, many of the cell types we estimate are not expected to be in a given mixture; however, the pipeline we described will often produce non-zero scores. In the 18 test simulated mixtures, 56.4% of the scores for cell types that are not part of the mixture were non-negligible (> 0.001).” | |
| claim-type | method— “The procedure was performed for each data source where the corresponding cell type was available, except the data source from which the signature was learned. Thus, a signature was only chosen if it is reliable in a data source it was not trained upon.” | |
| method — evidence | — “We then fit a power function to the scores corresponding to abundances of 0.8 to 25.6%. We used this range because we are mostly interested in identifying cell types with low abundance, and above that the function exponential increase may interfere with precise fitting.” | |
| object of study — evidence | — “At least seven major issues raise concerns that the in silico methods could be prone to errors and cannot reliably portray the cellular heterogeneity of the tumor microenvironment. First, current techniques depend on the expression profiles of purified cell types to identify reference genes and therefore rely heavily on the data source from… | |
| research question — evidence | — “However, because of this independence, it is many times hard to differentiate between closely related cell types. In addition, gene signature-based methods only provide enrichment scores and thus do not allow comparison across cell types and cannot provide insights into the abundance of cell types in the mixture.” | |
| contribution — evidence | — “The simulations also revealed another limitation of the raw scores: closely related cell types tend to have correlating scores (Additional file 2: Figure S5). That is, scores may show enrichment for a cell type due to a “spillover effect” between closely related cell types. This problem mimics the spillover problem in flow cytometry, in which… | |
| transfer | from flow cytometry: spillover compensation, carried from flow cytometry - where fluorophore emission spectra overlap - into gene signature scoring, where marker genes overlap— “The simulations also revealed another limitation of the raw scores: closely related cell types tend to have correlating scores (Additional file 2: Figure S5). That is, scores may show enrichment for a cell type due to a “spillover effect” between closely related cell types. This problem mimics the spillover problem in flow cytometry, in which… | transfers[0] |
| transfer | from statistics: null-distribution fitting for a presence test, carried from statistical hypothesis testing to ask whether a cell type is in a mixture at all— “In five of the cell types the scores from the random mixtures consistently produced 0; thus, we define those distributions as constant 0.001 (Additional file 2: Figure S7).” | transfers[1] |
| mechanism | spectral overlap as a statistical analogy closely related cell types share marker genes, so a signature for one is partly satisfied by the other - formally the same problem as fluorophores whose emission spectra overlap, and correctable by the same device, a compensation matrix estimated from mixtures where the true answer is known— “The simulations also revealed another limitation of the raw scores: closely related cell types tend to have correlating scores (Additional file 2: Figure S5). That is, scores may show enrichment for a cell type due to a “spillover effect” between closely related cell types. This problem mimics the spillover problem in flow cytometry, in which… | mechanisms[0] |
| mechanism | compensation trading independence for separability before compensation each cell type's score is computed alone, so one wrong inference cannot contaminate the rest; the correction couples them, which is exactly the property that makes deconvolution fragile - the paper accepts a limited amount of it and says how limited— “It is important to note that, until this step, the cell type scores are independent of each other, and a false inference of one cell type will not harm all other cell types. However, the spillover correction adjustment removes this strict independence between cell type inferences, as in deconvolution methods. Yet, the compensation is very… | mechanisms[1] |
| mechanism | unbounded scores for absent cell types a signature returns a score for any input, so a cell type absent from the mixture still receives one; only a null distribution built from mixtures that exclude it can say whether the score means presence— “Finally, many of the cell types we estimate are not expected to be in a given mixture; however, the pipeline we described will often produce non-zero scores. In the 18 test simulated mixtures, 56.4% of the scores for cell types that are not part of the mixture were non-negligible (> 0.001).” | mechanisms[2] |
| mechanism | purified profiles differing from the same cells in a mixture signatures are learned from cells isolated and profiled alone, and applied to cells sitting in tissue; if marker expression differs between those two states the method is calibrated on a population it never meets— “However, other explanations for the lower success when inferring abundances in real samples are possible—it may well be possible that the expression patterns of marker genes in mixtures are different to those in purified cells. Recent technologies such as single-cell RNA-sequencing may be able to clarify how much this may perturb the… | mechanisms[3] |
| critiques | in-silico cell-type dissection methods generally, on seven named grounds including reliance on the reference source, narrow cell-type coverage, and validation on few cell types in few samples— “At least seven major issues raise concerns that the in silico methods could be prone to errors and cannot reliably portray the cellular heterogeneity of the tumor microenvironment. First, current techniques depend on the expression profiles of purified cell types to identify reference genes and therefore rely heavily on the data source from… | claim_relations[0] |
| qualifies | CIBERSORT and other deconvolution approaches, whose strict inter-cell-type dependencies make them fragile on tumour expression profiles and tied to their reference matrix— “A fifth challenge is that deconvolution approaches are prone to many different biases because of the strict dependencies among all cell types that are inferred. This could highly affect reliability when analyzing tumor samples, which are prone to form non-conventional expression profiles. A sixth problem comes with inferring an increasing… | claim_relations[1] |
| extends | gene set enrichment analysis, by calibrating its scores onto a common scale and compensating the correlation between related signatures— “However, because of this independence, it is many times hard to differentiate between closely related cell types. In addition, gene signature-based methods only provide enrichment scores and thus do not allow comparison across cell types and cannot provide insights into the abundance of cell types in… | claim_relations[2] |
| qualifies | its own results and every comparable method's - digital dissection findings must be validated by other technologies before they are believed | claim_relations[3] |
| sense | xCell's performance - IN SIMULATED MIXTURES: outperforms every compared method in the large majority of cell types, across data sources and platforms 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 | xCell's performance - IN REAL MIXTURES: significantly better than the alternatives and still, in the authors' words, far from perfect - and beaten outright on CD8+ T cells by using one 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. | senses[1] |
| sense | an xCell score - AS COMPUTED: a single-sample gene-set enrichment score, interpretable only against other samples 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 | an xCell score - AS CALIBRATED: deliberately transformed to resemble a proportion so cell types can be compared, and explicitly not usable as a proportion 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 | signatures selected only if they hold up in a data source they were NOT trained on — 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 overfitting to the source a signature was learned from as the explanation of its performance - the reliance on reference data that the paper names as the first of the field's seven problems 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 | simulated mixtures built from an independent data source never used in development (GSE60424), scored before and after spillover compensation — 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 the development data as the source of the improvement - a correction tuned on the training sources could otherwise be measuring itself 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 | comparison against 53 previously published signatures and against CIBERSORT, a deconvolution method, on the same mixtures — 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 the possibility that any signature set would score as well - the comparison is to named alternatives on identical inputs rather than to nothing 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 | validation against cytometry immunophenotyping in 165 individuals across two independent studies, rather than against simulations alone — 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 in-silico mixing as the reason the method works - arithmetic admixtures cannot test whether marker expression survives being in real tissue 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 | a null distribution per cell type, learned from random mixtures that EXCLUDE that cell type and its relatives, to test whether a score means presence at all — 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 a non-zero score as evidence of presence - without this the method reports something for every cell type in every sample 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 | the significance threshold set at 20% and the trade-off stated, rather than chosen silently — 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 a threshold tuned to flatter the result - the cost in true-positive power is reported alongside the gain in false-positive suppression 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 | in-silico cell-type dissection methods generally, on seven named grounds including reliance on the reference source, narrow cell-type coverage, and validation on few cell types in few samples — 0.95 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 | CIBERSORT and other deconvolution approaches, whose strict inter-cell-type dependencies make them fragile on tumour expression profiles and tied to their reference matrix — 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 | gene set enrichment analysis, by calibrating its scores onto a common scale and compensating the correlation between related signatures — 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[2] |
| weight | its own results and every comparable method's - digital dissection findings must be validated by other technologies before they are believed — 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[3] |
| differs in (stated by the tagger, no quotation) | enrichment scores —distinct-from→ proportions — whether the value can be read as a share of the mixture | concept_edges[0] |
| relation | enrichment scores —distinct-from→ proportions — the score is calibrated to resemble a fraction and cannot be used as 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. 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 | enrichment scores —distinct-from→ proportions — 0.95 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] |
| differs in (stated by the tagger, no quotation) | simulated mixtures —contrasted-with→ real mixtures — whether the cells were mixed by arithmetic or by biology | concept_edges[1] |
| relation | simulated mixtures —contrasted-with→ real mixtures — every method scores better on in-silico admixtures than on tissue 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 | simulated mixtures —contrasted-with→ real mixtures — 0.95 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 — 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[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 — 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[2] |
| 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[3] |
| 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[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 outputs are enrichment scores and cannot be interpreted as proportions, although they are calibrated to resemble them 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 | every method, this one included, performs significantly better on simulated mixtures than on real ones, and the real-data correlations are called far from perfect 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 | 56.4% of scores for cell types absent from a test mixture were non-negligible; the significance test brings that to 28.8% and costs 13.5 points of the true positives 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 | the spillover correction removes the independence between cell type inferences that was the signature approach's main protection - limited, and the authors say so 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 | on CD8+ T cells the method is beaten by using CD8A expression alone, with the caveat that the single gene may not be reliable in cancer 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 | for five cell types the null distribution degenerated to zero and was replaced by a hand-set constant of 0.001 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] |
| 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[4] |
| quantity | scores for cell types absent from the mixture that were nonetheless non-negligible 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 | the share of genes xCell requires that were actually present in one validation study 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 | the significance threshold, chosen as a stated trade-off 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] |
| variable | enrichment scores 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 | spillover effect 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 | enrichment scores 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] |
| concept | enrichment scores — not defined in this paper's own words; what a signature method produces - a per-sample, per-cell-type score that is not a fraction of the mixture and is calibrated here to look like 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. | concepts[0] |
| concept | proportions — not defined in this paper's own words; the quantity a reader wants and the paper says it cannot deliver, because ssGSEA's extremes do not translate into fractions 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 | spillover effect — not defined in this paper's own words; a cell type scoring high because a closely related one is present - named after, and corrected by an analogue of, the spectral overlap problem in flow cytometry 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 | deconvolution — not defined in this paper's own words; inferring the whole composition at once, so every cell type's estimate depends on every other's - powerful and, the paper argues, fragile on tumour samples 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 | gene signatures — not defined in this paper's own words; independent per-cell-type scores, rank-based and cross-platform, whose independence is both their protection and their inability to separate related cell types 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 | simulated mixtures — not defined in this paper's own words; in-silico admixtures of purified profiles - where every method performs better than it does on tissue 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 | real mixtures — not defined in this paper's own words; actual tissue with cytometry counts beside it - the harder test, and the one whose correlations the authors call far from perfect 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 | tumor microenvironment — not defined in this paper's own words; the non-malignant cells around a tumour; the object all these methods are trying to enumerate, and richer than the immune subsets most of them cover 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 | CD8A — not defined in this paper's own words; the single gene that beats the whole method on CD8+ T cells, and which the authors note may not be a reliable biomarker in cancer 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 | ssGSEA — not defined in this paper's own words; single-sample gene set enrichment analysis - the scoring step, and the reason the output cannot be read as a fraction 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] |
| ssGSEA | 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] |
| p value | 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] |
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