Proteomic Discovery and Validation of the Confounding Effect of Heparin Administration on the Analysis of Candidate Cardiovascular Biomarkers

Hans C Beck, Lisette O Jensen, Charlotte Gils, Albertine M M Ilondo, Martin Frydland, Christian Hassager, Ole K Møller-Helgestad, Jacob E Møller, Lars M Rasmussen

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Abstract

BACKGROUND: Several plasma proteins have been suggested as markers for a variety of cardiovascular conditions but fail to qualify in independent patient cohorts. This may relate to interference of medication on plasma protein concentrations. We used proteomics to identify plasma proteins that changed in concentration with heparin administration and therefore potentially may confound their evaluation as biomarkers in situations in which heparin is used.

METHODS: We used a proteomic approach based on isobaric tagging and nano-LC-MS/MS analysis to quantify several hundred proteins in a discovery study in which individual plasma samples from 9 patients at intravascular ultrasound follow-up 12 months after an acute myocardial infarction before heparin administration and 2, 15, and 60 min after heparin administration; we validated our findings in 500 individual plasma samples obtained at admission from patients with suspected ST segment elevation myocardial infarction (STEMI), of whom 363 were treated with heparin before admission.

RESULTS: In the discovery study, 25 of 653 identified plasma proteins displayed a changed concentration after heparin administration (Bonferroni-corrected P value at P < 7.66 × 10-5). Fourteen of the proteins changed significantly among heparin-treated patients in the validation study (nominal significance level of P < 6.92 × 10-5). Among heparin-affected proteins in both the discovery study and the validation study were midkine, spondin 1, secreted frizzled-like protein 1, lipoprotein lipase, and follistatin, all previously associated with STEMI.

CONCLUSIONS: Medications such as heparin administration given before blood sampling may confound biomarker discovery and should be carefully considered in such studies.

Original languageEnglish
JournalClinical Chemistry
Volume64
Issue number10
Pages (from-to)1474-1484
ISSN0009-9147
DOIs
Publication statusPublished - Oct 2018

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Biomarkers
Heparin
Blood Proteins
Validation Studies
Proteins
Follistatin
Plasmas
Proteomics
Lipoprotein Lipase
Patient Admission
Blood
Ultrasonics
Sampling

Cite this

@article{747aa06303bd4d808227371b020a4203,
title = "Proteomic Discovery and Validation of the Confounding Effect of Heparin Administration on the Analysis of Candidate Cardiovascular Biomarkers",
abstract = "BACKGROUND: Several plasma proteins have been suggested as markers for a variety of cardiovascular conditions but fail to qualify in independent patient cohorts. This may relate to interference of medication on plasma protein concentrations. We used proteomics to identify plasma proteins that changed in concentration with heparin administration and therefore potentially may confound their evaluation as biomarkers in situations in which heparin is used.METHODS: We used a proteomic approach based on isobaric tagging and nano-LC-MS/MS analysis to quantify several hundred proteins in a discovery study in which individual plasma samples from 9 patients at intravascular ultrasound follow-up 12 months after an acute myocardial infarction before heparin administration and 2, 15, and 60 min after heparin administration; we validated our findings in 500 individual plasma samples obtained at admission from patients with suspected ST segment elevation myocardial infarction (STEMI), of whom 363 were treated with heparin before admission.RESULTS: In the discovery study, 25 of 653 identified plasma proteins displayed a changed concentration after heparin administration (Bonferroni-corrected P value at P < 7.66 × 10-5). Fourteen of the proteins changed significantly among heparin-treated patients in the validation study (nominal significance level of P < 6.92 × 10-5). Among heparin-affected proteins in both the discovery study and the validation study were midkine, spondin 1, secreted frizzled-like protein 1, lipoprotein lipase, and follistatin, all previously associated with STEMI.CONCLUSIONS: Medications such as heparin administration given before blood sampling may confound biomarker discovery and should be carefully considered in such studies.",
author = "Beck, {Hans C} and Jensen, {Lisette O} and Charlotte Gils and Ilondo, {Albertine M M} and Martin Frydland and Christian Hassager and M{\o}ller-Helgestad, {Ole K} and M{\o}ller, {Jacob E} and Rasmussen, {Lars M}",
note = "{\circledC} 2018 American Association for Clinical Chemistry.",
year = "2018",
month = "10",
doi = "10.1373/clinchem.2017.282665",
language = "English",
volume = "64",
pages = "1474--1484",
journal = "Clinical Chemistry",
issn = "0009-9147",
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Proteomic Discovery and Validation of the Confounding Effect of Heparin Administration on the Analysis of Candidate Cardiovascular Biomarkers. / Beck, Hans C; Jensen, Lisette O; Gils, Charlotte; Ilondo, Albertine M M; Frydland, Martin; Hassager, Christian; Møller-Helgestad, Ole K; Møller, Jacob E; Rasmussen, Lars M.

In: Clinical Chemistry, Vol. 64, No. 10, 10.2018, p. 1474-1484.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Proteomic Discovery and Validation of the Confounding Effect of Heparin Administration on the Analysis of Candidate Cardiovascular Biomarkers

AU - Beck, Hans C

AU - Jensen, Lisette O

AU - Gils, Charlotte

AU - Ilondo, Albertine M M

AU - Frydland, Martin

AU - Hassager, Christian

AU - Møller-Helgestad, Ole K

AU - Møller, Jacob E

AU - Rasmussen, Lars M

N1 - © 2018 American Association for Clinical Chemistry.

PY - 2018/10

Y1 - 2018/10

N2 - BACKGROUND: Several plasma proteins have been suggested as markers for a variety of cardiovascular conditions but fail to qualify in independent patient cohorts. This may relate to interference of medication on plasma protein concentrations. We used proteomics to identify plasma proteins that changed in concentration with heparin administration and therefore potentially may confound their evaluation as biomarkers in situations in which heparin is used.METHODS: We used a proteomic approach based on isobaric tagging and nano-LC-MS/MS analysis to quantify several hundred proteins in a discovery study in which individual plasma samples from 9 patients at intravascular ultrasound follow-up 12 months after an acute myocardial infarction before heparin administration and 2, 15, and 60 min after heparin administration; we validated our findings in 500 individual plasma samples obtained at admission from patients with suspected ST segment elevation myocardial infarction (STEMI), of whom 363 were treated with heparin before admission.RESULTS: In the discovery study, 25 of 653 identified plasma proteins displayed a changed concentration after heparin administration (Bonferroni-corrected P value at P < 7.66 × 10-5). Fourteen of the proteins changed significantly among heparin-treated patients in the validation study (nominal significance level of P < 6.92 × 10-5). Among heparin-affected proteins in both the discovery study and the validation study were midkine, spondin 1, secreted frizzled-like protein 1, lipoprotein lipase, and follistatin, all previously associated with STEMI.CONCLUSIONS: Medications such as heparin administration given before blood sampling may confound biomarker discovery and should be carefully considered in such studies.

AB - BACKGROUND: Several plasma proteins have been suggested as markers for a variety of cardiovascular conditions but fail to qualify in independent patient cohorts. This may relate to interference of medication on plasma protein concentrations. We used proteomics to identify plasma proteins that changed in concentration with heparin administration and therefore potentially may confound their evaluation as biomarkers in situations in which heparin is used.METHODS: We used a proteomic approach based on isobaric tagging and nano-LC-MS/MS analysis to quantify several hundred proteins in a discovery study in which individual plasma samples from 9 patients at intravascular ultrasound follow-up 12 months after an acute myocardial infarction before heparin administration and 2, 15, and 60 min after heparin administration; we validated our findings in 500 individual plasma samples obtained at admission from patients with suspected ST segment elevation myocardial infarction (STEMI), of whom 363 were treated with heparin before admission.RESULTS: In the discovery study, 25 of 653 identified plasma proteins displayed a changed concentration after heparin administration (Bonferroni-corrected P value at P < 7.66 × 10-5). Fourteen of the proteins changed significantly among heparin-treated patients in the validation study (nominal significance level of P < 6.92 × 10-5). Among heparin-affected proteins in both the discovery study and the validation study were midkine, spondin 1, secreted frizzled-like protein 1, lipoprotein lipase, and follistatin, all previously associated with STEMI.CONCLUSIONS: Medications such as heparin administration given before blood sampling may confound biomarker discovery and should be carefully considered in such studies.

U2 - 10.1373/clinchem.2017.282665

DO - 10.1373/clinchem.2017.282665

M3 - Journal article

C2 - 30115630

VL - 64

SP - 1474

EP - 1484

JO - Clinical Chemistry

JF - Clinical Chemistry

SN - 0009-9147

IS - 10

ER -