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pmid:28235076
Changes in plasma protein levels as an early indication of a bloodstream infection.
Pentti Kuusela · Mayank Saraswat · Sakari Joenväärä · Johanna Kaartinen · Asko Järvinen · Risto Renkonen
PloS one · 2017 doi:10.1371/journal.pone.0172987
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Experiment
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Complete file
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However, blood culture is slow and time consuming method to detect blood stream infections or separate septic and/or bacteremic patients from others with less serious febrile disease. Plasma proteomics, despite its challenges, remains an important source for early biomarkers for systemic diseases and might show changes before direct evidence from bacteria can be obtained. We have performed a plasma proteomic analysis, simultaneously at the time of blood culture sampling from ten blood culture positive and ten blood culture negative patients, and quantified 172 proteins with two or more unique peptides. Principal components analysis, Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) and ROC curve analysis were performed to select protein(s) features which can classify the two groups of samples. We propose a number of candidates which qualify as potential biomarkers to select the blood culture positive cases from negative ones. Pathway analysis by two methods revealed complement activation, phagocytosis pathway and alterations in lipid metabolism as enriched pathways which are relevant for the condition. Data are available via ProteomeXchange with identifier PXD005022.", "claims": [{"id": "claim-method", "statement": "Differences between controls and cases were evaluated with ANOVA on a protein-to-protein basis.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:28235076", "locator": "sections[8] \"2.4.2 Data analysis\" paragraph 4", "quote": "Differences between controls and cases were evaluated with ANOVA on a protein-to-protein basis."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The raw files were converted with MSConvert (ProteoWizard) to mzML-files. 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The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD005022.", "access_statement_kind": "data_availability_statement", "sample_accessions": [], "sample_count": null, "group_sizes": null, "group_sizes_basis": null, "platform": null, "taxon": null, "title": "Quantitative proteomics of bloodstream infection", "resolution_checked_at": "2026-10-31T18:35:55Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "asset:table:pmid:28235076:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:33038560d245c56cd72d66d4118617819939569e9c29be552ed73891664ad1ab", "bytes": 3231, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#pone.0172987.t001", "version": null, "note": "Top 10 up- and downregulated proteins in plasma of ten patients with a positive blood culture (cases) and ten with a negative blood culture (controls) at the time point of blood culture sampling.The top proteins are according to the fold change in case versus controls. Only the proteins having less than 0.05 ANOVA p values are shown. Peptide count is the total peptides found for corresponding proteins and unique peptides is the number of unique peptides found out of the total peptides. Confidence score, ANOVA p value, maximum fold change, condition of the highest and lowest mean and full name of the protein are given in separate columns.", "structure": {"pmcid": "PMC5325609", "section_index": 12, "section_title": "3.2 Proteomic dataset", "row_count": 21, "column_count": 9}, "table": {"label": "Table 1", "caption": "Top 10 up- and downregulated proteins in plasma of ten patients with a positive blood culture (cases) and ten with a negative blood culture (controls) at the time point of blood culture sampling.The top proteins are according to the fold change in case versus controls. Only the proteins having less than 0.05 ANOVA p values are shown. Peptide count is the total peptides found for corresponding proteins and unique peptides is the number of unique peptides found out of the total peptides. Confidence score, ANOVA p value, maximum fold change, condition of the highest and lowest mean and full name of the protein are given in separate columns.", "rows": [["Accession", "Peptide count", "Unique peptides", "Confidence score", "Anova (p)", "Max fold change", "Highest mean condition", "Lowest mean condition", "Description"], ["Q9H497", "2", "2", "10.7157", "0.001182", "8.844932", "Case", "Control", "Torsin-3A"], ["P07339;C9JH19", "2", "2", "11.8647", "0.003668", "2.631503", "Case", "Control", "Cathepsin D"], ["Q96SN7;C9J2H9;C9J5L2;C9JQR7;C9JUY6", "4", "3", "27.6575", "0.000649", "2.027496", "Case", "Control", "Protein orai-2"], ["Q9Y4B5;J3QLE1", "3", "2", "20.227", "0.010045", "1.870043", "Case", "Control", "Microtubule cross-linking factor 1"], ["Q08AH1;E5RFK0", "3", "3", "18.8377", "0.019465", "1.84317", "Case", "Control", "Acyl-coenzyme A synthetase ACSM1, mitochondrial"], ["A0A087WU16;B2REA4;O75626", "4", "4", "26.6581", "7.38E-07", "1.77715", "Case", "Control", "PR domain zinc finger protein 1"], ["Q16531", "2", "2", "7.7408", "0.034509", "1.750108", "Case", "Control", "DNA damage-binding protein 1"], ["P02750", "40", "37", "186.9309", "0.00229", "1.640414", "Case", "Control", "Leucine-rich alpha-2-glycoprotein"], ["A0A0A0MTD1;A0A0A0MTC4;A0A0A0MTC5;A0A0A0MTC6;E5RJN7;E7EPX0;E7EVJ4;E9PH62;F8VPI7;G5EA18;Q9NUL3", "5", "4", "22.6587", "0.013193", "1.61796", "Case", "Control", "Double-stranded RNA-binding protein Staufen homolog 2"], ["P04217;M0R009", "48", "41", "261.3448", "0.001136", "1.596944", "Case", "Control", "Alpha-1B-glycoprotein"], ["O94782;C9JC88;C9JWX4", "3", "2", "16.0733", "0.001325", "5.967845", "Control", "Case", "Ubiquitin carboxyl-terminal hydrolase 1"], ["G3V1N2;P69905", "3", "3", "31.698", "0.000981", "5.127688", "Control", "Case", "HCG1745306, isoform CRA_a"], ["A0A075B702", "2", "2", "17.6117", "1.07E-05", "4.41976", "Control", "Case", "Protein TRAJ41 (Fragment)"], ["E9PLW5;R4GN25", "2", "2", "10.7804", "0.003909", "4.260173", "Control", "Case", "Putative protein N-methyltransferase FAM86B1"], ["P38935", "2", "2", "9.2636", "0.001711", "3.612221", "Control", "Case", "DNA-binding protein SMUBP-2"], ["O60309", "4", "3", "18.0095", "0.000957", "3.304585", "Control", "Case", "Leucine-rich repeat-containing protein 37A3"], ["E9PPB4", "2", "2", "18.3488", "0.002286", "3.190066", "Control", "Case", "Peroxisomal biogenesis factor 19"], ["Q7Z3I0;A0A075B7G4;Q8IYB9", "3", "2", "22.3658", "0.000508", "3.14666", "Control", "Case", "Putative uncharacterized protein DKFZp313E1411"], ["H0YFH1", "9", "2", "78.0417", "0.005951", "2.729399", "Control", "Case", "Alpha-2-macroglobulin (Fragment)"], ["P01617;A0A0A0MTQ6", "4", "2", "37.2069", "6.15E-05", "2.570449", "Control", "Case", "Ig kappa chain V-II region TEW"]], "row_count": 21, "column_count": 9, "numeric_cells": 134, "header_rows": 1, "locator": "section[12]/table-wrap[1]#pone.0172987.t001"}}, {"id": "asset:table:pmid:28235076:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:e0c19a2527a7f2f4ca048356181c70c7076d5d75766e307971f6cc95d1aff731", "bytes": 3087, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[14]/table-wrap[1]#pone.0172987.t002", "version": null, "note": "Proteins significantly different in the S-Plot in cases versus controls are shown in the table.Uniprot accession or a group of accessions is given as primary Id. Peptides column represents the total number of peptides found for the said protein and unique peptides are number of unique peptides out of the total peptides for the given protein. Confidence score, ANOVA p value, highest and lowest mean condition, full name of the protein, covariance (p[1]) and correlation (p(corr)[1]) are given in various columns of the table.", "structure": {"pmcid": "PMC5325609", "section_index": 14, "section_title": "3.4 Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA)", "row_count": 15, "column_count": 11}, "table": {"label": "Table 2", "caption": "Proteins significantly different in the S-Plot in cases versus controls are shown in the table.Uniprot accession or a group of accessions is given as primary Id. Peptides column represents the total number of peptides found for the said protein and unique peptides are number of unique peptides out of the total peptides for the given protein. Confidence score, ANOVA p value, highest and lowest mean condition, full name of the protein, covariance (p[1]) and correlation (p(corr)[1]) are given in various columns of the table.", "rows": [["Primary accession", "All peptides", "Unique peptides", "Confidence score", "ANOVA p-value", "Fold change", "Highest mean", "Lowest mean", "Description", "p[1]", "p(corr)[1]"], ["A0A075B702", "2", "2", "17.6", "1.07E-05", "4.4", "Control", "Case", "Protein TRAJ41 (Fragment) OS = Homo sapiens GN = TRAJ41 PE = 4 SV = 1", "0.03", "0.81"], ["E9PLW5;R4GN25", "2", "2", "10.8", "3.91E-03", "4.3", "Control", "Case", "Putative protein N-methyltransferase FAM86B1 OS = Homo sapiens GN = FAM86B1 PE = 4 SV = 1", "0.02", "0.80"], ["P01617;A0A0A0MTQ6", "4", "2", "37.2", "6.15E-05", "2.6", "Control", "Case", "Ig kappa chain V-II region TEW OS = Homo sapiens PE = 1 SV = 1", "0.04", "0.79"], ["Q8IU89;H0YMG6;H0YN05", "4", "4", "31.0", "3.96E-04", "1.9", "Control", "Case", "Ceramide synthase 3 OS = Homo sapiens GN = CERS3 PE = 1 SV = 2", "0.03", "0.79"], ["P38935", "2", "2", "9.3", "1.71E-03", "3.6", "Control", "Case", "DNA-binding protein SMUBP-2 OS = Homo sapiens GN = IGHMBP2 PE = 1 SV = 3", "0.02", "0.77"], ["Q7Z3I0;A0A075B7G4;Q8IYB9", "3", "2", "22.4", "5.08E-04", "3.1", "Control", "Case", "Putative uncharacterized protein DKFZp313E1411 OS = Homo sapiens GN = DKFZp313E1411 PE = 2 SV = 1", "0.03", "0.76"], ["O94782;C9JC88;C9JWX4", "3", "2", "16.1", "1.33E-03", "6.0", "Control", "Case", "Ubiquitin carboxyl-terminal hydrolase 1 OS = Homo sapiens GN = USP1 PE = 1 SV = 1", "0.02", "0.74"], ["Q7RTY7;H0YGY6;H0YH00", "6", "3", "37.5", "2.47E-03", "2.3", "Control", "Case", "Ovochymase-1 OS = Homo sapiens GN = OVCH1 PE = 2 SV = 2", "0.03", "0.73"], ["E7EVV8;Q0VG06", "2", "2", "10.9", "1.17E-03", "1.8", "Control", "Case", "Fanconi anemia-associated protein of 100 kDa OS = Homo sapiens GN = FAAP100 PE = 1 SV = 1", "0.03", "0.70"], ["P02763", "48", "38", "239.3", "6.49E-03", "1.6", "Case", "Control", "Alpha-1-acid glycoprotein 1 OS = Homo sapiens GN = ORM1 PE = 1 SV = 1", "-0.30", "-0.71"], ["P07339;C9JH19", "2", "2", "11.9", "3.67E-03", "2.6", "Case", "Control", "Cathepsin D OS = Homo sapiens GN = CTSD PE = 1 SV = 1", "-0.06", "-0.72"], ["P04217;M0R009", "48", "41", "261.3", "1.14E-03", "1.6", "Case", "Control", "Alpha-1B-glycoprotein OS = Homo sapiens GN = A1BG PE = 1 SV = 4", "-0.23", "-0.75"], ["P02750", "40", "37", "186.9", "2.29E-03", "1.6", "Case", "Control", "Leucine-rich alpha-2-glycoprotein OS = Homo sapiens GN = LRG1 PE = 1 SV = 2", "-0.23", "-0.77"], ["A0A087WU16;B2REA4;O75626", "4", "4", "26.7", "7.38E-07", "1.8", "Case", "Control", "PR domain zinc finger protein 1 OS = Homo sapiens GN = PRDM1 PE = 1 SV = 1", "-0.04", "-0.81"]], "row_count": 15, "column_count": 11, "numeric_cells": 128, "header_rows": 1, "locator": "section[14]/table-wrap[1]#pone.0172987.t002"}}, {"id": "asset:table:pmid:28235076:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:b787a5e945a1d051c4dbbd64e6e162563bed91610dd6be8765c34adaa221ad53", "bytes": 1773, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[1]#pone.0172987.t003", "version": null, "note": "Proteins found to be significantly different in S-Plot were analyzed by ROC curve by Analyse-it program.Uniprot accession, full protein name (description), Area under the curve (AUC), 95% confidence interval (95% CI), standard error (SE), optimum threshold, sensitivity at that threshold and 1-specificity at that threshold and cost for the optimum threshold are shown in the table in various columns.", "structure": {"pmcid": "PMC5325609", "section_index": 16, "section_title": "3.6 ROC curve analysis", "row_count": 15, "column_count": 5}, "table": {"label": "Table 3", "caption": "Proteins found to be significantly different in S-Plot were analyzed by ROC curve by Analyse-it program.Uniprot accession, full protein name (description), Area under the curve (AUC), 95% confidence interval (95% CI), standard error (SE), optimum threshold, sensitivity at that threshold and 1-specificity at that threshold and cost for the optimum threshold are shown in the table in various columns.", "rows": [["Primary accession", "Description", "AUC", "95% CI", "SE"], ["A0A075B702", "Protein TRAJ41 (Fragment)", "0.98", "0.933 to 1.027", "0.02"], ["E9PLW5;R4GN25", "Putative protein N-methyltransferase FAM86B1", "1.00", "1 to 1", "0.00"], ["P01617;A0A0A0MTQ6", "Ig kappa chain V-II region TEW", "0.96", "0.886 to 1.034", "0.04"], ["Q8IU89;H0YMG6;H0YN05", "Ceramide synthase 3", "0.94", "0.818 to 1.062", "0.06"], ["P38935", "DNA-binding protein SMUBP-2", "0.97", "0.911 to 1.029", "0.03"], ["Q7Z3I0;A0A075B7G4;Q8IYB9", "Putative uncharacterized protein DKFZp313E1411", "0.98", "0.933 to 1.027", "0.02"], ["O94782;C9JC88;C9JWX4", "Ubiquitin carboxyl-terminal hydrolase 1", "0.97", "0.911 to 1.029", "0.03"], ["Q7RTY7;H0YGY6;H0YH00", "Ovochymase-1", "0.87", "0.712 to 1.028", "0.08"], ["E7EVV8;Q0VG06", "Fanconi anemia-associated protein of 100 kDa", "0.90", "0.748 to 1.052", "0.08"], ["P02763", "Alpha-1-acid glycoprotein 1", "0.83", "0.645 to 1.015", "0.09"], ["P07339;C9JH19", "Cathepsin D", "0.89", "0.694 to 1.086", "0.10"], ["P04217;M0R009", "Alpha-1B-glycoprotein", "0.85", "0.666 to 1.034", "0.09"], ["P02750", "Leucine-rich alpha-2-glycoprotein", "0.86", "0.696 to 1.024", "0.08"], ["A0A087WU16;B2REA4;O75626", "PR domain zinc finger protein 1", "0.99", "0.962 to 1.018", "0.01"]], "row_count": 15, "column_count": 5, "numeric_cells": 69, "header_rows": 1, "locator": "section[16]/table-wrap[1]#pone.0172987.t003"}}], "gaps": ["asset:data:geo:PXD005022 not downloaded", "asset:data:geo:PXD005022 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "group_comparison", "specific": "anova", "label": "Group comparison", "dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "Differences between controls and cases were evaluated with ANOVA on a protein-to-protein basis."}}, {"id": "method-2", "family": "principal_component_analysis", "specific": "pca", "label": "Principal component analysis", "dsl_operations": ["pca_fit"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["wide_numeric_matrix"], "evidence": {"score": 0.7, "band": "medium", "quote": "Principal components analysis"}}, {"id": "method-3", "family": "diagnostic_evaluation", "specific": "roc", "label": "Diagnostic test evaluation", "dsl_operations": ["confusion_counts", "roc_curve", "sensitivity_specificity", "solve_confusion_matrix", "classification_metrics", "published_precision_envelope"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["reference_standard_and_test"], "evidence": {"score": 0.7, "band": "medium", "quote": "ROC curve"}}], "targets": [], "gaps": []}, "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": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: anova."}, "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": ["PXD005022"], "resolved_accessions": ["PXD005022"], "statements": ["The raw files were converted with MSConvert (ProteoWizard) to mzML-files. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD005022."], "basis": "The paper names PXD005022 in ProteomeXchange Consortium via the PRIDE partner repository and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "assets": ["source:pmid:28235076", "data:geo:PXD005022", "asset:table:pmid:28235076:1", "asset:table:pmid:28235076:2", "asset:table:pmid:28235076:3"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:PXD005022"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:30:43Z", "independence": "same_provider"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 8, "usage": {"prompt_tokens": 96342, "completion_tokens": 3200, "cached_tokens": 2105}}, "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:28235076", "type": "paper", "label": "pmid:28235076"}, {"id": "source:pmid:28235076", "type": "manuscript", "label": "PMID 28235076 full text"}, {"id": "data:geo:PXD005022", "type": "dataset", "label": "GEO PXD005022"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:28235076", "type": "paper", "label": "pmid:28235076"}, {"id": "source:pmid:28235076", "type": "manuscript", "label": "PMID 28235076 full text"}, {"id": "data:geo:PXD005022", "type": "dataset", "label": "GEO PXD005022"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-28235076", "type": "extraction", "used": ["source:pmid:28235076"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-PXD005022", "type": "accession_resolution", "used": ["data:geo:PXD005022"], "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:28235076", "parent_hash": "sha256:8b5ae1049ad4846f501e28400f88ace799b2a44709fd4bfc36bfefacdf52645a", "fork_of": null, "generation": 7}, "gaps": ["asset:data:geo:PXD005022 licence not read", "asset:data:geo:PXD005022 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "mass_spectrometry", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.83, "evidence": ["rs with less serious febrile disease. Plasma proteomics, despite its challenges, remains an importan", "can be obtained. We have performed a plasma proteomic analysis, simultaneously at the time of bloo"], "order_basis": "paper_text_order:392", "id": "assay:1"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Differences between controls and cases were evaluated with ANOVA on a protein-to-protein basis."], "order_basis": "consumes_earlier_output", "id": "assay:2"}]}