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pmid:33667236
Immune gene expression networks in sepsis: A network biology approach.
Kyung Soo Kim · Dong Wook Jekarl · Jaeeun Yoo · Seungok Lee · Myungshin Kim · Yonggoo Kim
PloS one · 2021 doi:10.1371/journal.pone.0247669
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Experiment
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Complete file
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From the Kyoto Encyclopedia of Genes and Genomes (KEGG) immune system pathways, 998 unique genes were selected, and genes were classified as follows based on gene annotation from KEGG, Gene Ontology, and Reactome: adaptive immunity, antigen presentation, cytokines and chemokines, complement, hematopoiesis, innate immunity, leukocyte migration, NK cell activity, platelet activity, and signaling. After correlation matrix formation, correlation coefficient of 0.8 was selected for network generation and network analysis. Total transcriptome was analyzed for differentially expressed genes (DEG), followed by gene set enrichment analysis. The network topological structure revealed that adaptive immunity tended to form a prominent and isolated cluster in sepsis. Common genes within the cluster from the 6 datasets included CD247, CD8A, ITK, LAT, and LCK. The clustering coefficient and modularity parameters were increased in 5/6 and 4/6 datasets in the sepsis group that seemed to be associated with functional aspect of the network. GSE95233 revealed that the nonsurvivor group showed a prominent and isolated adaptive immunity cluster, whereas the survivor group had isolated complement-coagulation and platelet-related clusters. T cell receptor signaling (TCR) pathway and antigen processing and presentation pathway were down-regulated in 5/6 and 4/6 datasets, respectively. Complement and coagulation, Fc gamma, epsilon related signaling pathways were up-regulated in 5/6 datasets. Altogether, network and gene set enrichment analysis showed that adaptive-immunity-related genes along with TCR pathway were down-regulated and isolated from immune the network that seemed to be associated with unfavorable prognosis. Prominence of platelet and complement-coagulation-related genes in the immune network was associated with survival in sepsis. Complement-coagulation pathway was up-regulated in the sepsis group that was associated with favorable prognosis. Network and gene set enrichment analysis supported elucidation of sepsis pathogenesis.", "claims": [{"id": "claim-method", "statement": "After a t-test using basic functions in R software, genes were selected based on false discovery rate of less than 0.01 (FDR < 0.01) [32].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33667236", "locator": "sections[6] \"Gene set enrichment for pathway analysis\" paragraph 2", "quote": "After a t-test using basic functions in R software, genes were selected based on false discovery rate of less than 0.01 (FDR < 0.01) [32]."}], "state": "complete"}, {"id": "claim-data-access", "statement": "All data generated or analyzed during this study are included in this published article (and supplementary material files). 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The GSE57065, GSE64456, GSE72829, and GSE95233 datasets were downloaded from the GEO website (https://www.ncbi.nlm.nih.gov/geo/). The GSE66099 and GSE54514 results published here are in whole or in part based on the publication at https://doi.org/10.1101/095489 and the data and results obtained from the synapse portal accessible at https://doi.org/10.7303/syn5612563.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "All data generated or analyzed during this study are included in this published article (and supplementary material files). The GSE57065, GSE64456, GSE72829, and GSE95233 datasets were downloaded from the GEO website (https://www.ncbi.nlm.nih.gov/geo/). The GSE66099 and GSE54514 results published here are in whole or in part based on the publication at https://doi.org/10.1101/095489 and the data and results obtained from the synapse portal accessible at https://doi.org/10.7303/syn5612563.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1617492", "GSM1617493", "GSM1617494", "GSM1617495", "GSM1617496", "GSM1617497", "GSM1617498", "GSM1617499", "GSM1617500", "GSM1617501", "GSM1617502", "GSM1617503", "GSM1617504", "GSM1617505", "GSM1617506", "GSM1617507", "GSM1617508", "GSM1617509", "GSM1617510", "GSM1617511", "GSM1617512", "GSM1617513", "GSM1617514", "GSM1617515", "GSM1617516", "GSM1617517", "GSM1617518", "GSM1617519", "GSM1617520", "GSM1617521", "GSM1617522", "GSM1617523", "GSM1617524", "GSM1617525", "GSM1617526", "GSM1617527", "GSM1617528", "GSM1617529", "GSM1617530", "GSM1617531", "GSM1617532", "GSM1617533", "GSM1617534", "GSM1617535", "GSM1617536", "GSM1617537", "GSM1617538", "GSM1617539", 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The GSE57065, GSE64456, GSE72829, and GSE95233 datasets were downloaded from the GEO website (https://www.ncbi.nlm.nih.gov/geo/). The GSE66099 and GSE54514 results published here are in whole or in part based on the publication at https://doi.org/10.1101/095489 and the data and results obtained from the synapse portal accessible at https://doi.org/10.7303/syn5612563.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "All data generated or analyzed during this study are included in this published article (and supplementary material files). The GSE57065, GSE64456, GSE72829, and GSE95233 datasets were downloaded from the GEO website (https://www.ncbi.nlm.nih.gov/geo/). The GSE66099 and GSE54514 results published here are in whole or in part based on the publication at https://doi.org/10.1101/095489 and the data and results obtained from the synapse portal accessible at https://doi.org/10.7303/syn5612563.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1872417", "GSM1872418", "GSM1872419", "GSM1872420", "GSM1872421", "GSM1872422", "GSM1872423", "GSM1872424", "GSM1872425", "GSM1872426", "GSM1872427", "GSM1872428", "GSM1872429", "GSM1872430", "GSM1872431", "GSM1872432", "GSM1872433", "GSM1872434", "GSM1872435", "GSM1872436", "GSM1872437", "GSM1872438", "GSM1872439", "GSM1872440", "GSM1872441", "GSM1872442", "GSM1872443", "GSM1872444", "GSM1872445", "GSM1872446", "GSM1872447", "GSM1872448", "GSM1872449", "GSM1872450", "GSM1872451", "GSM1872452", "GSM1872453", "GSM1872454", "GSM1872455", "GSM1872456", "GSM1872457", "GSM1872458", "GSM1872459", "GSM1872460", "GSM1872461", "GSM1872462", "GSM1872463", "GSM1872464", 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"16", "33", "15"], ["Up regulated immune pathway", "", "C, Fc, RIG", "C, Fc", "C, Fc, NK, K, TLR", "APC, C, CXC & etc, Fc, IgA,", "BCR, C, Fc, CXC & etc, LK, NK, TLR"], ["Down regulated immune pathway", "", "APC, TCR, H, K", "APC, BCR, CXC & etc, IgA, TCR", "APC, IgA, TCR", "H, TCR", "APC, IgA, TCR"]], "row_count": 9, "column_count": 7, "numeric_cells": 36, "header_rows": 2, "locator": "section[10]/table-wrap[1]#pone.0247669.t002"}}, {"id": "asset:table:pmid:33667236:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:6108450417c20ec9088dc796f11f2ebb87d3004ab813e8ecc6368093524aa3ba", "bytes": 2131, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#pone.0247669.t003", "version": null, "note": "Network topological parameters from gene expression data from GEO dataset for adult and paediatric patient.", "structure": {"pmcid": "PMC7935325", "section_index": 12, "section_title": "Network parameter analysis", "row_count": 15, "column_count": 15}, "table": {"label": "Table 3", "caption": "Network topological parameters from gene expression data from GEO dataset for adult and paediatric patient.", "rows": [["", "GSE54514", "GSE57065", "GSE95233", "GSE95233-1", "GSE64456", "GSE66099", "GSE72829"], ["Patient type", "Adult", "Adult", "Adult", "Adult", "Pediatric", "Pediatric", "Pediatric"], ["Disease type", "Control", "septic shock", "control", "septic shock", "control", "septic shock", "survivor", "non survivor", "Control", "sepsis", "Control", "sepsis", "Control", "sepsis"], ["Clustering coefficient", "0.319", "0.323", "0.328", "0.280", "0.328", "0.367", "0.390", "0.337", "0.367", "0.390", "0.337", "0.388", "0.381", "0.435"], ["Network density", "0.013", "0.016", "0.012", "0.010", "0.012", "0.039", "0.026", "0.014", "0.039", "0.026", "0.014", "0.012", "0.030", "0.034"], ["Network heterogeneity", "1.039", "1.142", "1.151", "1.172", "1.151", "1.504", "1.358", "1.193", "1.504", "1.358", "1.193", "1.091", "1.249", "1.129"], ["Connected components", "27", "30", "42", "61", "42", "34", "33", "47", "34", "33", "47", "32", "16", "25"], ["Network diameter", "19", "17", "14", "15", "14", "12", "19", "11", "12", "19", "11", "14", "13", "9"], ["Network centralization", "0.059", "0.079", "0.103", "0.048", "0.103", "0.196", "0.113", "0.075", "0.196", "0.113", "0.075", "0.078", "0.148", "0.121"], ["Shortest path", "160514", "80598", "59638", "17222", "59638", "142640", "121152", "11730", "142640", "121152", "11730", "36902", "38092", "22532"], ["Characteristic path length", "7.418", "5.267", "5.276", "5.088", "5.276", "3.862", "7.211", "3.482", "3.862", "7.211", "3.482", "4.705", "3.92", "2.824"], ["Average degree, <k>", "5.93", "7.42", "5.30", "3.64", "5.30", "17.87", "11.71", "4.04", "17.87", "11.71", "4.04", "4.50", "8.43", "10.27"], ["Number of nodes, N", "464", "453", "426", "367", "426", "457", "448", "297", "457", "448", "297", "380", "284", "299"], ["Degree correlation, μ", "0.489", "0.508", "0.422", "0.810", "0.422", "0.403", "0.715", "0.546", "0.403", "0.715", "0.546", "0.210", "0.475", "0.346"], ["Modularity, Mc", "0.743", "0.662", "0.644", "0.806", "0.644", "0.198", "0.581", "0.694", "0.198", "0.581", "0.694", "0.745", "0.434", "0.603"]], "row_count": 15, "column_count": 15, "numeric_cells": 175, "header_rows": 3, "locator": "section[12]/table-wrap[1]#pone.0247669.t003"}}], "gaps": ["asset:data:geo:GSE54514 not downloaded", "asset:data:geo:GSE54514 licence not read", "asset:data:geo:GSE57065 not downloaded", "asset:data:geo:GSE57065 licence not read", "asset:data:geo:GSE64456 not downloaded", "asset:data:geo:GSE64456 licence not read", "asset:data:geo:GSE66099 not downloaded", "asset:data:geo:GSE66099 licence not read", "asset:data:geo:GSE72829 not downloaded", "asset:data:geo:GSE72829 licence not read", "asset:data:geo:GSE95233 not downloaded", "asset:data:geo:GSE95233 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{"state": "blocked", "tier": "R4", "blocking_axis": "method", "blocked_on": "method:not_determinable", "axes": {"method": {"tier": "R4", "expressible": false, "required_operations": [], "missing_operations": [], "basis": "The reader quoted the method the paper names (t-test), but the corpus's method extractor could not map it onto a DSL operation, so the method is published but not expressible."}, "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": ["GSE54514", "GSE57065", "GSE64456", "GSE66099", "GSE72829", "GSE95233"], "resolved_accessions": ["GSE54514", "GSE57065", "GSE64456", "GSE66099", "GSE72829", "GSE95233"], "statements": ["All data generated or analyzed during this study are included in this published article (and supplementary material files). The GSE57065, GSE64456, GSE72829, and GSE95233 datasets were downloaded from the GEO website (https://www.ncbi.nlm.nih.gov/geo/). The GSE66099 and GSE54514 results published here are in whole or in part based on the publication at https://doi.org/10.1101/095489 and the data and results obtained from the synapse portal accessible at https://doi.org/10.7303/syn5612563."], "basis": "The paper names GSE54514, GSE57065, GSE64456, GSE66099, GSE72829, GSE95233 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": [], "assets": ["source:pmid:33667236", "data:geo:GSE54514", "asset:table:pmid:33667236:1", "asset:table:pmid:33667236:2", "asset:table:pmid:33667236:3", "asset:table:pmid:33667236:4"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE54514"]}, "gaps": ["method:not_determinable"]}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:27:31Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 34434, "completion_tokens": 1891, "cached_tokens": 11762}}, "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:33667236", "type": "paper", "label": "pmid:33667236"}, {"id": "source:pmid:33667236", "type": "manuscript", "label": "PMID 33667236 full text"}, {"id": "data:geo:GSE54514", "type": "dataset", "label": "GEO GSE54514"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:33667236", "type": "paper", "label": "pmid:33667236"}, {"id": "source:pmid:33667236", "type": "manuscript", "label": "PMID 33667236 full text"}, {"id": "data:geo:GSE54514", "type": "dataset", "label": "GEO GSE54514"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-33667236", "type": "extraction", "used": ["source:pmid:33667236"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE54514", "type": "accession_resolution", "used": ["data:geo:GSE54514"], "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:33667236", "parent_hash": "sha256:1daf2650a0fd88d52bfd4b3f014521f4a1a2134586f4c27b22dcb81d2e2c28de", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE54514 licence not read", "asset:data:geo:GSE54514 not downloaded", "asset:data:geo:GSE57065 licence not read", "asset:data:geo:GSE57065 not downloaded", "asset:data:geo:GSE64456 licence not read", "asset:data:geo:GSE64456 not downloaded", "asset:data:geo:GSE66099 licence not read", "asset:data:geo:GSE66099 not downloaded", "asset:data:geo:GSE72829 licence not read", "asset:data:geo:GSE72829 not downloaded", "asset:data:geo:GSE95233 licence not read", "asset:data:geo:GSE95233 not downloaded", "execution.not_run", "method.reader_named_unmapped", "review.human_critique", "review.independent_reader", "review.machine_critique"]}