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A novel hybrid high speed mass spectrometer allows rapid translation from biomarker candidates to targeted clinical tests using 15N labeled proteins

ABSTRACT: Recent developments in affinity binder or mass spectrometry (MS)-based plasma proteomics are now producing panels of potential biomarker candidates for diagnosis or prognosis. However, clinical validation and implementation of these biomarkers remain limited by the reliance on dated triple quadrupole MS technology. Here, we evaluate a novel hybrid high-speed mass spectrometer, Stellar MS, which integrates the robustness of triple quadrupoles with the enhanced capabilities of an advanced linear ion trap detector. This instrument allows for extremely rapid and sensitive parallel reaction monitoring (PRM) and MS3 targeting. We successfully targeted thousands of peptides measured on Orbitrap Astral MS on the Stellar MS, achieving high reproducibility and low coefficients of variation (CV) as well as sensitivity and specificity sufficient for more than the top 1000 plasma proteins. Furthermore, we developed targeted assays for alcohol-related liver disease (ALD) biomarkers, showcasing the potential of Stellar MS in clinical applications. Absolute quantification is typically a requirement for clinical assays and we explore the use of 15N labeled protein standards in a rapid, streamlined and generic manner. Our results indicate that Stellar MS can bridge the gap between proteomics discovery and routine clinical testing, enhancing the diagnostic and prognostic utility of protein biomarkers.

INSTRUMENT(S): Orbitrap Astral, Stellar, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Matthias Mann

PROVIDER: MSV000095051 | MassIVE | Mon Jun 17 08:40:00 BST 2024

SECONDARY ACCESSION(S): PXD053174

REPOSITORIES: MassIVE

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A Novel Hybrid High-Speed Mass Spectrometer Allows Rapid Translation From Biomarker Candidates to Targeted Clinical Tests Using <sup>15</sup>N-Labeled Proteins.

Wahle Maria M Remes Philip M PM Albrecht Vincent V Baggio Lorenz Michael M Mueller-Reif Johannes J Steigerwald Sophia S Heymann Tim T Niu Lili L Lössl Philip P Horning Stevan S Jacob Cristina C CC Mann Matthias M

Molecular & cellular proteomics : MCP 20250813 9

Recent developments in affinity binder or mass spectrometry (MS)-based plasma proteomics are now producing panels of potential biomarker candidates for diagnosis or prognosis. However, clinical validation and implementation of these biomarkers remain limited by the reliance on dated triple quadrupole MS technology. Here, we evaluate a novel hybrid high-speed mass spectrometer, Stellar MS, which integrates the robustness of triple quadrupoles with the enhanced capabilities of an advanced linear i ...[more]

PMID: 40816420

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Project description:Rationale There is a need for new and better biomarkers for hypertrophic cardiomyopathy (HCM) which correlate more closely with disease progression as determined by clinical imaging and biohumoral information. We have used a combination of heart tissue and plasma proteomics to identify potential biomarkers for HCM and developed them into an exploratory targeted proteomic assay. Objective To identify informative staging biomarkers for HCM and develop them into a blood test. The test using 10 µl of plasma, was developed into a 10 min liquid chromatography-tandem/mass spectrometry (LC-MS/MS) assay to analyze multiple candidate biomarkers and evaluate their association with clinical phenotypes in patients with HCM. Methods and Results Myocardial tissue and plasma samples from patients with HCM and healthy volunteers (controls) were screened using a combined gel- and nano-LC quadrupole time of flight MS approach. Twenty-six potential biomarkers were identified from the proteomics screens and developed into a multiplexed targeted proteomic assay. Their association with clinical phenotypes was tested in plasma samples collected from 207 prospectively recruited participants: 110 patients with HCM (50.1 ± 15.0 years, 70% male; 48 [44%] with identified genetic mutations) and 97 controls (49.6 ± 13.4 years, 58% male), randomly split into training (80 HCM, 67 controls) and validation datasets (30 HCM, 30 controls). Six markers (Aldolase Fructose-Bisphosphate A, Complement C3, Glutathione S-Transferase Omega 1, Ras Suppressor Protein 1, Talin 1, and Thrombospondin 1) were significantly increased (P<0.006) in the plasma of HCM patients compared to controls in the training dataset. These markers correlated with left ventricular (LV) wall thickness, LV mass and % myocardial scar on cardiovascular magnetic resonance imaging. Using supervized machine learning (ML) this panel differentiated HCM from controls (area under the curve: 0.89 in the training dataset, sensitivity 96%, 95% confidence interval [CI] 77–93; specificity 87%, 95%CI 77–94; and 0.87 in the validation dataset, sensitivity 97%, 95%CI 83–100; specificity 77%, 95%CI 58–90). Four of the biomarkers as well as the composite ML score of the plasma proteome correlated with the presence of nonsustained ventricular tachycardia and the estimated 5-year risk of sudden cardiac death. Conclusion By developing a high-throughput, multiplex, and targeted proteomic plasma assay we identified 6 biomarkers that correlate with the presence of disease and with clinical risk score for sudden cardiac death.

Dataset Information

A novel hybrid high speed mass spectrometer allows rapid translation from biomarker candidates to targeted clinical tests using 15N labeled proteins

Dataset's files

Publications

A Novel Hybrid High-Speed Mass Spectrometer Allows Rapid Translation From Biomarker Candidates to Targeted Clinical Tests Using <sup>15</sup>N-Labeled Proteins.

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Dataset Information

A novel hybrid high speed mass spectrometer allows rapid translation from biomarker candidates to targeted clinical tests using 15N labeled proteins

Dataset's files

Publications

A Novel Hybrid High-Speed Mass Spectrometer Allows Rapid Translation From Biomarker Candidates to Targeted Clinical Tests Using &lt;sup&gt;15&lt;/sup&gt;N-Labeled Proteins.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A Novel Hybrid High-Speed Mass Spectrometer Allows Rapid Translation From Biomarker Candidates to Targeted Clinical Tests Using <sup>15</sup>N-Labeled Proteins.