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pmid:32324791
Normal myeloid progenitor cell subset-associated gene signatures for acute myeloid leukaemia subtyping with prognostic impact.
Anna A Schönherz · Julie Støve Bødker · Alexander Schmitz · Rasmus Froberg Brøndum · Lasse Hjort Jakobsen · Anne Stidsholt Roug · Marianne T Severinsen · Tarec C El-Galaly · Paw Jensen · Hans Erik Johnsen · Martin Bøgsted · Karen Dybkær
PloS one · 2020 doi:10.1371/journal.pone.0229593
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Complete file
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Here, we propose a classification system based on normal myeloid progenitor cell subset-associated gene signatures (MAGS) for individual assignments of AML subtypes. We generated a MAGS classifier including the progenitor compartments CD34+/CD38- for haematopoietic stem cells (HSCs), CD34+/CD38+/CD45RA- for megakaryocyte-erythroid progenitors (MEPs), and CD34+/CD38+/CD45RA+ for granulocytic-monocytic progenitors (GMPs) using regularised multinomial regression with three discrete outcomes and an elastic net penalty. The regularisation parameters were chosen by cross-validation, and MAGS assignment accuracy was validated in an independent data set (N = 38; accuracy = 0.79) of sorted normal myeloid subpopulations. The prognostic value of MAGS assignment was studied in two clinical cohorts (TCGA: N = 171; GSE6891: N = 520) and had a significant prognostic impact. Furthermore, multivariate Cox regression analysis using the MAGS subtype, FAB subtype, cytogenetics, molecular genetics, and age as explanatory variables showed independent prognostic value. Molecular characterisation of subtypes by differential gene expression analysis, gene set enrichment analysis, and mutation patterns indicated reduced proliferation and overrepresentation of RUNX1 and IDH2 mutations in the HSC subtype; increased proliferation and overrepresentation of CEBPA mutations in the MEP subtype; and innate immune activation and overrepresentation of WT1 mutations in the GMP subtype. 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"asset:table:pmid:32324791:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:e9d46dab0d6bbf697c2de554520b4f2f9c8abfb03a57c9e8fa7dec7736a588de", "bytes": 871, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[10]/table-wrap[1]#pone.0229593.t001", "version": null, "note": "MAGS prediction accuracy assigning 100% (A) or 85% (B) of the samples to the defined MAGS subtypes HSC, GMP, MEP, and an additional UC subtype.", "structure": {"pmcid": "PMC7179860", "section_index": 10, "section_title": "Generation and validation of MAGS", "row_count": 10, "column_count": 6}, "table": {"label": "Table 1", "caption": "MAGS prediction accuracy assigning 100% (A) or 85% (B) of the samples to the defined MAGS subtypes HSC, GMP, MEP, and an additional UC subtype.", "rows": [["A)", "", "Predicted", "Invalid Prediction (%)"], ["Observed", "", "HSC (%)", "MEP (%)", "GMP (%)", "UC (%)"], ["HSC (N = 26)", "18 (69.2)", "4 (15.4)", "4 (15.4)", "-", "8 (30.8)"], ["MEP (N = 5)", "0 (0)", "5 (100)", "0 (0)", "-", "0 (0)"], ["GMP (N = 7)", "0 (0)", "0 (0)", "7 (100)", "-", "0 (0)"], ["B)", "", "Predicted", "Invalid Prediction (%)"], ["Observed", "", "HSC (%)", "MEP (%)", "GMP (%)", "UC (%)"], ["HSC (N = 26)", "17 (65.4)", "3 (11.5)", "0 (0)", "6 (23.1)", "9 (34.6)"], ["MEP (N = 5)", "0 (0)", "5 (100)", "0 (0)", "0 (0)", "0 (0)"], ["GMP (N = 7)", "0 (0)", "0 (0)", "7 (100)", "0 (0)", "0 (0)"]], "row_count": 10, "column_count": 6, "numeric_cells": 33, "header_rows": 0, "locator": "section[10]/table-wrap[1]#pone.0229593.t001"}}, {"id": "asset:table:pmid:32324791:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:41ae1ff84260f8a631edb61f04f046e5df3119baf943f0230b416270d02f7d09", "bytes": 610, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[11]/table-wrap[1]#pone.0229593.t002", "version": null, "note": "Distributions and frequencies of assigned MAGS subtypes across two clinical cohorts: TCGA (N = 182) and GSE6891 (N = 520).Two-sided Fishers exact tests were used to determine significantly different distributions across data sets (p = 0.99).", "structure": {"pmcid": "PMC7179860", "section_index": 11, "section_title": "MAGS assignment of clinical samples and prognostic impact", "row_count": 3, "column_count": 6}, "table": {"label": "Table 2", "caption": "Distributions and frequencies of assigned MAGS subtypes across two clinical cohorts: TCGA (N = 182) and GSE6891 (N = 520).Two-sided Fishers exact tests were used to determine significantly different distributions across data sets (p = 0.99).", "rows": [["Cohort", "HSC (%)", "MEP (%)", "GMP (%)", "UC (%)", "Total (%)"], ["TCGA", "50 (27.5)", "48 (26.4)", "56 (30.8)", "28 (15.4)", "182 (100)"], ["GSE6891", "146 (28.1)", "134 (25.8)", "162 (31.2)", "78 (15.0)", "520 (100)"]], "row_count": 3, "column_count": 6, "numeric_cells": 11, "header_rows": 1, "locator": "section[11]/table-wrap[1]#pone.0229593.t002"}}, {"id": "asset:table:pmid:32324791:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:e1435be04c29712a8ccb4c73782a04ff5a4a1c9775aa00f2df517802c4133e73", "bytes": 1403, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[11]/table-wrap[2]#pone.0229593.t003", "version": null, "note": "Univariate Cox regression analysis for MAGS-assigned clinical cohorts (GSE6891 cohort: N = 520; TCGA-cohort: N = 171) and the corresponding AML meta-cohort (N = 691) that included both clinical cohorts.Analyses were performed for overall survival. Samples with missing survival information (TCGA cohort: N = 11) were excluded. Table columns indicate the total sample size (N), the number of patients that died (Events) per MAGS subtype, the associated hazards ration (HR), the 95% lower and upper confidence intervals (CI), and the estimated p-value (P).", "structure": {"pmcid": "PMC7179860", "section_index": 11, "section_title": "MAGS assignment of clinical samples and prognostic impact", "row_count": 16, "column_count": 6}, "table": {"label": "Table 3", "caption": "Univariate Cox regression analysis for MAGS-assigned clinical cohorts (GSE6891 cohort: N = 520; TCGA-cohort: N = 171) and the corresponding AML meta-cohort (N = 691) that included both clinical cohorts.Analyses were performed for overall survival. Samples with missing survival information (TCGA cohort: N = 11) were excluded. Table columns indicate the total sample size (N), the number of patients that died (Events) per MAGS subtype, the associated hazards ration (HR), the 95% lower and upper confidence intervals (CI), and the estimated p-value (P).", "rows": [["", "N", "Events", "HR", "95% CI", "P"], ["TCGA cohort", "", "", "", "", ""], ["HSC", "48", "40", "1", "", ""], ["MEP", "44", "22", "0.44", "0.26–0.74", "1.90e-03**"], ["GMP", "52", "34", "0.68", "0.43–1.08", "0.1"], ["UC", "27", "14", "0.37", "0.20–0.69", "1.63e-03**"], ["GSE6891 cohort", "", "", "", "", ""], ["HSC", "146", "115", "1", "", ""], ["MEP", "134", "77", "0.53", "0.40–0.71", "2.13e-05***"], ["GMP", "162", "101", "0.63", "0.48–0.83", "7.86e-04***"], ["UC", "78", "52", "0.70", "0.51–0.98", "0.03"], ["Meta-cohorta", "", "", "", "", ""], ["HSC", "194", "155", "1", "", ""], ["MEP", "178", "99", "0.51", "0.40–0.65", "1.46e-07***"], ["GMP", "214", "135", "0.64", "0.51–0.81", "1.64e-04***"], ["UC", "105", "66", "0.60", "0.45–0.80", "5.32e-04***"]], "row_count": 16, "column_count": 6, "numeric_cells": 56, "header_rows": 1, "locator": "section[11]/table-wrap[2]#pone.0229593.t003"}}, {"id": "asset:table:pmid:32324791:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:d616118d0c6f505e19ab2e800a7ed0eff0b4edc69f33f7b696a02a58395ded1c", "bytes": 8121, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[11]/table-wrap[3]#pone.0229593.t004", "version": null, "note": "Cox regression analysis of potential confounding variables conducted for the TCGA (N = 122), GSE6891 (N = 439), and meta-cohort (N = 561).Cohorts were limited to samples with complete records for all explanatory variables investigated. Results are shown for the (A) univariate Cox regression analysis per explanatory variable and (B) associated multivariate Cox regression analyses limited to confounding variables tested significant in univariate Cox regression analyses. Table columns are as described in Table 3. Analyses were performed for overall survival.", "structure": {"pmcid": "PMC7179860", "section_index": 11, "section_title": "MAGS assignment of clinical samples and prognostic impact", "row_count": 69, "column_count": 17}, "table": {"label": "Table 4", "caption": "Cox regression analysis of potential confounding variables conducted for the TCGA (N = 122), GSE6891 (N = 439), and meta-cohort (N = 561).Cohorts were limited to samples with complete records for all explanatory variables investigated. Results are shown for the (A) univariate Cox regression analysis per explanatory variable and (B) associated multivariate Cox regression analyses limited to confounding variables tested significant in univariate Cox regression analyses. Table columns are as described in Table 3. Analyses were performed for overall survival.", "rows": [["A) Simple Cox Regression", "", ""], ["", "TCGA cohort (N = 122)", "GSE6891 cohort (N = 439)", "AML meta-cohort (N = 561)"], ["", "", "N", "Events", "HR", "95% CI", "P", "N", "Events", "HR", "95% CI", "P", "N", "Events", "HR", "95% CI", "P"], ["MAGS", "HSC", "37", "32", "1", "", "", "120", "93", "1", "", "", "157", "125", "1", "", ""], ["MEP", "26", "15", "0.523", "0.282–0.971", "0.040*", "108", "56", "0.491", "0.352–0.685", "2.75E-05***", "134", "71", "0.486", "0.363–0.650", "1.26E-06***"], ["GMP", "40", "26", "0.595", "0.353–1.005", "0.052", "147", "89", "0.632", "0.472–0.846", "0.002**", "187", "115", "0.622", "0.483–0.802", "2.50E-04***"], ["UC", "19", "9", "0.309", "0.146–0.652", "0.002**", "64", "40", "0.666", "0.460–0.965", "0.032*", "83", "49", "0.580", "0.417–0.807", "0.001**"], ["Cytogenetic riska", "GOOD", "24", "10", "1", "", "", "97", "40", "1", "", "", "NA", "NA", "NA", "NA", "NA"], ["INTER", "60", "42", "2.636", "1.319–5.268", "0.006**", "247", "160", "1.900", "1.341–2.690", "3.02E-04***", "NA", "NA", "NA", "NA", "NA"], ["POOR", "35", "27", "2.828", "1.362–5.872", "0.005**", "85", "69", "3.222", "2.173–4.778", "5.84E-09***", "NA", "NA", "NA", "NA", "NA"], ["UC", "3", "3", "8.159", "2.188–30.431", "0.002**", "10", "9", "3.801", "1.839–7.857", "3.14E-04***", "NA", "NA", "NA", "NA", "NA"], ["FABb", "M0", "13", "9", "1", "", "", "16", "13", "1", "", "", "29", "22", "1", "", ""], ["M1", "28", "21", "1.773", "0.805–3.904", "0.155", "94", "60", "0.646", "0.355–1.177", "0.153", "122", "81", "0.772", "0.481–1.236", "0.281"], ["M2", "27", "17", "1.156", "0.520–2.659", "0.697", "104", "64", "0.629", "0.346–1.142", "0.128", "131", "81", "0.698", "0.435–1.119", "0.135"], ["M3", "6", "3", "0.542", "0.146–2.013", "0.360", "24", "11", "0.469", "0.210–1.048", "0.065", "30", "14", "0.492", "0.251–0.962", "0.038*"], ["M4", "27", "16", "0.861", "0.379–1.955", "0.720", "79", "48", "0.635", "0.344–1.173", "0.147", "106", "64", "0.683", "0.420–1.108", "0.123"], ["M4E", "NA", "NA", "NA", "NA", "NA", "5", "2", "0.325", "0.073–1.444", "0.140", "5", "2", "0.330", "0.077–1.403", "0.133"], ["M5", "14", "10", "1.957", "0.785–4.879", "0.150", "103", "72", "0.780", "0.432–1.407", "0.408", "117", "82", "0.846", "0.528–1.356", "0.488"], ["M6", "3", "3", "2.452", "0.649–9.272", "0.186", "6", "3", "0.415", "0.118–1.456", "0.170", "9", "6", "0.702", "0.284–1.731", "0.442"], ["M7", "3", "3", "2.311", "0.615–8.679", "0.215", "0", "0", "NA", "NA", "NA", "3", "3", "1.920", "0.573–6.429", "0.290"], ["UC", "1", "0", "2.751", "NA", "0.996", "8", "5", "0.869", "0.310–2.438", "0.790", "9", "5", "0.865", "0.328–2.286", "0.771"], ["CEBPA", "NEG", "119", "80", "1", "", "", "406", "262", "1", "", "", "525", "342", "1", "", ""], ["POS", "3", "2", "1.184", "0.289–4.851", "0.815", "29", "13", "0.555", "0.318–0.968", "0.038*", "32", "15", "0.556", "0.332–0.933", "0.026*"], ["FLT3-ITD", "NEG", "121", "81", "1", "", "", "315", "187", "1", "", "", "436", "268", "1", "", ""], ["POS", "1", "1", "5.724", "0.766–42.766", "0.089", "124", "91", "1.665", "1.294–2.141", "7.18E-05***", "125", "92", "1.428", "1.127–1.811", "0.003**"], ["FLT3-TKD", "NEG", "107", "71", "1", "", "", "390", "254", "1", "", "", "497", "325", "1", "", ""], ["POS", "15", "11", "1.478", "0.778–2.810", "0.233", "48", "24", "0.699", "0.460–1.062", "0.093", "63", "35", "0.820", "0.579–1.163", "0.265"], ["IDH1", "NEG", "116", "78", "1", "", "", "405", "256", "1", "", "", "521", "334", "1", "", ""], ["POS", "6", "4", "0.772", "0.282–2.114", "0.614", "31", "19", "0.901", "0.565–1.436", "0.661", "37", "23", "0.863", "0.565–1.316", "0.493"], ["IDH2", "NEG", "113", "78", "1", "", "", "400", "254", "1", "", "", "513", "332", "1", "", ""], ["POS", "9", "4", "0.509", "0.186–1.394", "0.189", "36", "21", "0.849", "0.544–1.324", "0.470", "45", "25", "0.765", "0.509–1.148", "0.196"], ["KRAS", "NEG", "116", "78", "1", "", "", "436", "276", "1", "", "", "552", "354", "1", "", ""], ["POS", "6", "4", "0.669", "0.244–1.836", "0.435", "3", "2", "1.028", "0.256–4.132", "0.970", "9", "6", "1.031", "0.460–2.311", "0.941"], ["NMP1", "NEG", "109", "73", "1", "", "", "303", "198", "1", "", "", "412", "271", "1", "", ""], ["POS", "13", "9", "1.739", "0.864–3.501", "0.121", "136", "80", "0.874", "0.674–1.133", "0.310", "149", "89", "0.845", "0.665–1.074", "0.169"], ["NRAS", "NEG", "115", "77", "1", "", "", "396", "253", "1", "", "", "511", "330", "1", "", ""], ["POS", "7", "5", "1.435", "0.578–3.563", "0.436", "42", "25", "0.826", "0.548–1.246", "0.362", "49", "30", "0.843", "0.580–1.225", "0.370"], ["WBC", "WBC", "122", "82", "1.002", "0.998–1.006", "0.402", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA"], ["Age", "Age", "122", "82", "1.041", "1.022–1.060", "1.44E-05***", "439", "278", "1.015", "1.005–1.026", "0.003**", "561", "360", "1.025", "1.017–1.033", "2.64E-09***"], ["Cohort", "TCGA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "122", "82", "1", "", ""], ["GSE6891", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "439", "278", "0.579", "0.451–0.744", "1.99E-05***"], ["B) Multivariate Cox Regression", "", ""], ["", "", "TCGA cohort (N = 122)", "GSE6891 cohort (N = 439)", "AML meta-cohort (N = 561)"], ["", "", "N", "Events", "HR", "95% CI", "P", "N", "Events", "HR", "95% CI", "P", "N", "Events", "HR", "95% CI", "P"], ["MAGS", "HSC", "37", "32", "1", "", "", "120", "93", "1", "", "", "157", "125", "1", "", ""], ["MEP", "26", "15", "0.781", "0.404–1.511", "0.464", "108", "56", "0.600", "0.419–0.862", "0.006**", "134", "71", "0.524", "0.374–0.734", "1.69E-04***"], ["GMP", "40", "26", "0.780", "0.445–1.365", "0.383", "147", "89", "0.723", "0.537–0.973", "0.032*", "187", "115", "0.593", "0.443–0.793", "4.32E-04***"], ["UC", "19", "9", "0.467", "0.213–1.025", "0.058*", "64", "40", "0.742", "0.508–1.084", "0.123", "83", "49", "0.561", "0.398–0.791", "9.55E-04***"], ["Cytogenetic riska", "GOOD", "24", "10", "1", "", "", "97", "40", "1", "", "", "-", "-", "-", "-", "-"], ["INTER", "60", "42", "1.996", "0.964–4.129", "0.063", "247", "160", "1.529", "1.045–2.239", "0.029", "-", "-", "-", "-", "-"], ["POOR", "35", "27", "1.911", "0.870–4.195", "0.107", "85", "69", "2.751", "1.825–4.147", "1.36E-06***", "-", "-", "-", "-", "-"], ["UC", "3", "3", "7.440", "1.928–28,712", "0.004**", "10", "9", "3.036", "1.445–6.379", "0.003**", "-", "-", "-", "-", "-"], ["FABb", "M0", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "29", "22", "1", "", ""], ["M1", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "122", "81", "1.267", "0.769–2.087", "0.353"], ["M2", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "131", "81", "1.266", "0.766–2.094", "0.358"], ["M3", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "30", "14", "1.089", "0.531–2.233", "0.816"], ["M4", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "106", "64", "1.143", "0.684–1.911", "0.610"], ["M4E", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "5", "2", "0.861", "0.196–3.790", "0.844"], ["M5", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "117", "82", "1.595", "0.934–2.723", "0.087"], ["M6", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "9", "6", "1.140", "0.418–3.112", "0.798"], ["M7", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "3", "3", "2.006", "0.573–7.021", "0.276"], ["UC", "-", "-", "-", "-", "-", "-", "-", "-", "-", "-", "9", "5", "1.186", "0.442–3.181", "0.735"], ["CEBPA", "NEG", "-", "-", "-", "-", "-", "406", "262", "1", "", "", "525", "342", "1", "", ""], ["POS", "-", "-", "-", "-", "-", "29", "13", "0.703", "0.386–1.283", "0.251", "32", "15", "0.759", "0.433–1.331", "0.336"], ["FLT3-ITD", "NEG", "-", "-", "-", "-", "-", "315", "187", "1", "", "", "436", "268", "1", "", ""], ["POS", "-", "-", "-", "-", "-", "124", "91", "1.621", "1.230–2.135", "6.04E-04***", "125", "92", "1.542", "1.193–1.994", "9.52E-04***"], ["Age", "Age", "122", "82", "1.035", "1.017–1.054", "1.71E-04***", "435", "275", "1.011", "1.001–1.022", "0.036*", "557", "357", "1.021", "1.012–1.030", "4.56E-06***"], ["Cohort", "TCGA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "122", "82", "1", "", ""], ["GSE6891", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "NA", "439", "278", "0.640", "0.472–0.869", "0.005**"]], "row_count": 69, "column_count": 17, "numeric_cells": 652, "header_rows": 0, "locator": "section[11]/table-wrap[3]#pone.0229593.t004"}}, {"id": "asset:table:pmid:32324791:5", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:d728a681f3957405306352a241379871e30665639209dff220b9db24770e2d5d", "bytes": 1382, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#pone.0229593.t005", "version": null, "note": "Overview of enrichment patterns detected using gene set enrichment analysis (GSEA) in the reduced assignment probability meta-cohort (N = 573: NGSE6891 = 423, NTCGA = 150), investigating the Hallmark, the C2-CP, and the C3-TFT gene set collections retrieved from the MSigDB.GSEA analysis was conducted for three comparisons: (A) HSC vs. Rest, (B) MEP vs. Rest, and (C) GMP vs. Rest. The total number of enriched gene sets (Total) with p-value ≤ 0.01 and FDR ≤ 0.25, and the numbers of enriched gene sets detected per group within each comparison are presented.", "structure": {"pmcid": "PMC7179860", "section_index": 12, "section_title": "DGE and functional annotation of enriched gene sets", "row_count": 15, "column_count": 4}, "table": {"label": "Table 5", "caption": "Overview of enrichment patterns detected using gene set enrichment analysis (GSEA) in the reduced assignment probability meta-cohort (N = 573: NGSE6891 = 423, NTCGA = 150), investigating the Hallmark, the C2-CP, and the C3-TFT gene set collections retrieved from the MSigDB.GSEA analysis was conducted for three comparisons: (A) HSC vs. Rest, (B) MEP vs. Rest, and (C) GMP vs. Rest. The total number of enriched gene sets (Total) with p-value ≤ 0.01 and FDR ≤ 0.25, and the numbers of enriched gene sets detected per group within each comparison are presented.", "rows": [["A) HSC vs. Rest"], ["MSigDB collection", "Total", "Enriched in HSC (%)", "Enriched in Rest (%)"], ["Hallmark", "31", "10 (32.3)", "21 (67.7)"], ["C2-CP", "256", "30 (11.7)", "226 (88.3)"], ["C3-TFT", "222", "173 (77.9)", "49 (22.1)"], ["B) MEP vs. Rest"], ["MSigDB collection", "Total", "Enriched in GMP (%)", "Enriched in Rest (%)"], ["Hallmark", "25", "11 (44.0)", "14 (56.0)"], ["C2-CP", "360", "59 (16.4)", "301 (83.6)"], ["C3-TFT", "101", "32 (31.7)", "69 (68.3)"], ["C) GMP vs. Rest"], ["MsigDB collection", "Total", "Enriched in MEP (%)", "Enriched in Rest (%)"], ["Hallmark", "21", "20 (95.2)", "1 (4.8)"], ["C2-CP", "254", "252 (99.2)", "301 (0.8)"], ["C3-TFT", "22", "9 (40.9)", "69 (59.1)"]], "row_count": 15, "column_count": 4, "numeric_cells": 27, "header_rows": 0, "locator": "section[12]/table-wrap[1]#pone.0229593.t005"}}], "gaps": ["asset:data:geo:GSE17054 not downloaded", "asset:data:geo:GSE17054 licence not read", "asset:data:geo:GSE19429 not downloaded", "asset:data:geo:GSE19429 licence not read", "asset:data:geo:GSE19599 not downloaded", "asset:data:geo:GSE19599 licence not read", "asset:data:geo:GSE42519 not downloaded", "asset:data:geo:GSE42519 licence not read", "asset:data:geo:GSE63270 not downloaded", "asset:data:geo:GSE63270 licence not read", "asset:data:geo:GSE6891 not downloaded", "asset:data:geo:GSE6891 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "survival_analysis", "specific": "kaplan_meier", "label": "Survival analysis", "dsl_operations": ["survival_km"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "Kaplan-Meier"}}, {"id": "method-2", "family": "survival_analysis", "specific": "cox_proportional_hazards", "label": "Survival analysis", "dsl_operations": ["cox_ph"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.7, "band": "medium", "quote": "Cox regression"}}, {"id": "method-3", "family": "survival_analysis", "specific": "log_rank_test", "label": "Survival analysis", "dsl_operations": ["logrank_test"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "log-rank"}}, {"id": "method-4", "family": "contingency_analysis", "specific": "fisher_exact", "label": "Categorical (contingency table) analysis", "dsl_operations": ["contingency_table", "chi_square_test"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["categorical_cross_tabulation"], "evidence": {"score": 0.8, "band": "high", "quote": "Fishers exact"}}, {"id": "method-5", "family": null, "specific": null, "label": "Regularised multinomial regression with an elastic net penalty", "dsl_operations": [], "missing_operations": [], "expressible": null, "parameters": {}, "data_shapes": [], "evidence": {"score": 1.0, "band": "verbatim", "quote": "The MAGS classifier for the HSC, MEP, and GMP subsets was obtained from regularised multinomial regression with the cell type as the discrete outcome and the median-centred GEP of the training cohort as the explanatory variable. The model was fitted with an elastic net penalty."}}], "targets": [], "gaps": ["method.reader_named_unmapped"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["survival_km"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: kaplan_meier."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE63270", "GSE42519", "GSE19599", "GSE17054", "GSE19429", "GSE6891"], "resolved_accessions": ["GSE63270", "GSE42519", "GSE19599", "GSE17054", "GSE19429", "GSE6891"], "statements": ["All relevant data are within the manuscript and its Supporting Information files."], "basis": "The paper names GSE63270, GSE42519, GSE19599, GSE17054, GSE19429, GSE6891 in Gene Expression Omnibus Database (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["survival_km"], "assets": ["source:pmid:32324791", "data:geo:GSE17054", "asset:table:pmid:32324791:1", "asset:table:pmid:32324791:2", "asset:table:pmid:32324791:3", "asset:table:pmid:32324791:4", "asset:table:pmid:32324791:5"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE17054"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:19:28Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 44779, "completion_tokens": 2029, "cached_tokens": 784}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:32324791", "type": "paper", "label": "pmid:32324791"}, {"id": "source:pmid:32324791", "type": "manuscript", "label": "PMID 32324791 full text"}, {"id": "data:geo:GSE17054", "type": "dataset", "label": "GEO GSE17054"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:32324791", "type": "paper", "label": "pmid:32324791"}, {"id": "source:pmid:32324791", "type": "manuscript", "label": "PMID 32324791 full text"}, {"id": "data:geo:GSE17054", "type": "dataset", "label": "GEO GSE17054"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-32324791", "type": "extraction", "used": ["source:pmid:32324791"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE17054", "type": "accession_resolution", "used": ["data:geo:GSE17054"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:32324791", "parent_hash": "sha256:78a9748bbab7fa64b43ac994dc8d67bb5a6f0dee308ecdf1c93a299f90cb699a", "fork_of": null, "generation": 6}, "gaps": ["asset:data:geo:GSE17054 licence not read", "asset:data:geo:GSE17054 not downloaded", "asset:data:geo:GSE19429 licence not read", "asset:data:geo:GSE19429 not downloaded", "asset:data:geo:GSE19599 licence not read", "asset:data:geo:GSE19599 not downloaded", "asset:data:geo:GSE42519 licence not read", "asset:data:geo:GSE42519 not downloaded", "asset:data:geo:GSE63270 licence not read", "asset:data:geo:GSE63270 not downloaded", "asset:data:geo:GSE6891 licence not read", "asset:data:geo:GSE6891 not downloaded", "execution.not_run", "method.reader_named_unmapped", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["level using a Brainarray custom CDF for the Affymetrix Human Genome U133 Plus 2.0 GeneChip (version"], "order_basis": "paper_text_order:2561", "id": "assay:1"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["survival_km"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.8, "evidence": ["Kaplan-Meier"], "order_basis": "consumes_earlier_output", "id": "assay:2"}]}