Cargando…

Computational Biomarker Pipeline from Discovery to Clinical Implementation: Plasma Proteomic Biomarkers for Cardiac Transplantation

Recent technical advances in the field of quantitative proteomics have stimulated a large number of biomarker discovery studies of various diseases, providing avenues for new treatments and diagnostics. However, inherent challenges have limited the successful translation of candidate biomarkers into...

Descripción completa

Detalles Bibliográficos
Autores principales: Cohen Freue, Gabriela V., Meredith, Anna, Smith, Derek, Bergman, Axel, Sasaki, Mayu, Lam, Karen K. Y., Hollander, Zsuzsanna, Opushneva, Nina, Takhar, Mandeep, Lin, David, Wilson-McManus, Janet, Balshaw, Robert, Keown, Paul A., Borchers, Christoph H., McManus, Bruce, Ng, Raymond T., McMaster, W. Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617196/
https://www.ncbi.nlm.nih.gov/pubmed/23592955
http://dx.doi.org/10.1371/journal.pcbi.1002963
_version_ 1782265236447821824
author Cohen Freue, Gabriela V.
Meredith, Anna
Smith, Derek
Bergman, Axel
Sasaki, Mayu
Lam, Karen K. Y.
Hollander, Zsuzsanna
Opushneva, Nina
Takhar, Mandeep
Lin, David
Wilson-McManus, Janet
Balshaw, Robert
Keown, Paul A.
Borchers, Christoph H.
McManus, Bruce
Ng, Raymond T.
McMaster, W. Robert
author_facet Cohen Freue, Gabriela V.
Meredith, Anna
Smith, Derek
Bergman, Axel
Sasaki, Mayu
Lam, Karen K. Y.
Hollander, Zsuzsanna
Opushneva, Nina
Takhar, Mandeep
Lin, David
Wilson-McManus, Janet
Balshaw, Robert
Keown, Paul A.
Borchers, Christoph H.
McManus, Bruce
Ng, Raymond T.
McMaster, W. Robert
author_sort Cohen Freue, Gabriela V.
collection PubMed
description Recent technical advances in the field of quantitative proteomics have stimulated a large number of biomarker discovery studies of various diseases, providing avenues for new treatments and diagnostics. However, inherent challenges have limited the successful translation of candidate biomarkers into clinical use, thus highlighting the need for a robust analytical methodology to transition from biomarker discovery to clinical implementation. We have developed an end-to-end computational proteomic pipeline for biomarkers studies. At the discovery stage, the pipeline emphasizes different aspects of experimental design, appropriate statistical methodologies, and quality assessment of results. At the validation stage, the pipeline focuses on the migration of the results to a platform appropriate for external validation, and the development of a classifier score based on corroborated protein biomarkers. At the last stage towards clinical implementation, the main aims are to develop and validate an assay suitable for clinical deployment, and to calibrate the biomarker classifier using the developed assay. The proposed pipeline was applied to a biomarker study in cardiac transplantation aimed at developing a minimally invasive clinical test to monitor acute rejection. Starting with an untargeted screening of the human plasma proteome, five candidate biomarker proteins were identified. Rejection-regulated proteins reflect cellular and humoral immune responses, acute phase inflammatory pathways, and lipid metabolism biological processes. A multiplex multiple reaction monitoring mass-spectrometry (MRM-MS) assay was developed for the five candidate biomarkers and validated by enzyme-linked immune-sorbent (ELISA) and immunonephelometric assays (INA). A classifier score based on corroborated proteins demonstrated that the developed MRM-MS assay provides an appropriate methodology for an external validation, which is still in progress. Plasma proteomic biomarkers of acute cardiac rejection may offer a relevant post-transplant monitoring tool to effectively guide clinical care. The proposed computational pipeline is highly applicable to a wide range of biomarker proteomic studies.
format Online
Article
Text
id pubmed-3617196
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-36171962013-04-16 Computational Biomarker Pipeline from Discovery to Clinical Implementation: Plasma Proteomic Biomarkers for Cardiac Transplantation Cohen Freue, Gabriela V. Meredith, Anna Smith, Derek Bergman, Axel Sasaki, Mayu Lam, Karen K. Y. Hollander, Zsuzsanna Opushneva, Nina Takhar, Mandeep Lin, David Wilson-McManus, Janet Balshaw, Robert Keown, Paul A. Borchers, Christoph H. McManus, Bruce Ng, Raymond T. McMaster, W. Robert PLoS Comput Biol Research Article Recent technical advances in the field of quantitative proteomics have stimulated a large number of biomarker discovery studies of various diseases, providing avenues for new treatments and diagnostics. However, inherent challenges have limited the successful translation of candidate biomarkers into clinical use, thus highlighting the need for a robust analytical methodology to transition from biomarker discovery to clinical implementation. We have developed an end-to-end computational proteomic pipeline for biomarkers studies. At the discovery stage, the pipeline emphasizes different aspects of experimental design, appropriate statistical methodologies, and quality assessment of results. At the validation stage, the pipeline focuses on the migration of the results to a platform appropriate for external validation, and the development of a classifier score based on corroborated protein biomarkers. At the last stage towards clinical implementation, the main aims are to develop and validate an assay suitable for clinical deployment, and to calibrate the biomarker classifier using the developed assay. The proposed pipeline was applied to a biomarker study in cardiac transplantation aimed at developing a minimally invasive clinical test to monitor acute rejection. Starting with an untargeted screening of the human plasma proteome, five candidate biomarker proteins were identified. Rejection-regulated proteins reflect cellular and humoral immune responses, acute phase inflammatory pathways, and lipid metabolism biological processes. A multiplex multiple reaction monitoring mass-spectrometry (MRM-MS) assay was developed for the five candidate biomarkers and validated by enzyme-linked immune-sorbent (ELISA) and immunonephelometric assays (INA). A classifier score based on corroborated proteins demonstrated that the developed MRM-MS assay provides an appropriate methodology for an external validation, which is still in progress. Plasma proteomic biomarkers of acute cardiac rejection may offer a relevant post-transplant monitoring tool to effectively guide clinical care. The proposed computational pipeline is highly applicable to a wide range of biomarker proteomic studies. Public Library of Science 2013-04-04 /pmc/articles/PMC3617196/ /pubmed/23592955 http://dx.doi.org/10.1371/journal.pcbi.1002963 Text en © 2013 Cohen Freue et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cohen Freue, Gabriela V.
Meredith, Anna
Smith, Derek
Bergman, Axel
Sasaki, Mayu
Lam, Karen K. Y.
Hollander, Zsuzsanna
Opushneva, Nina
Takhar, Mandeep
Lin, David
Wilson-McManus, Janet
Balshaw, Robert
Keown, Paul A.
Borchers, Christoph H.
McManus, Bruce
Ng, Raymond T.
McMaster, W. Robert
Computational Biomarker Pipeline from Discovery to Clinical Implementation: Plasma Proteomic Biomarkers for Cardiac Transplantation
title Computational Biomarker Pipeline from Discovery to Clinical Implementation: Plasma Proteomic Biomarkers for Cardiac Transplantation
title_full Computational Biomarker Pipeline from Discovery to Clinical Implementation: Plasma Proteomic Biomarkers for Cardiac Transplantation
title_fullStr Computational Biomarker Pipeline from Discovery to Clinical Implementation: Plasma Proteomic Biomarkers for Cardiac Transplantation
title_full_unstemmed Computational Biomarker Pipeline from Discovery to Clinical Implementation: Plasma Proteomic Biomarkers for Cardiac Transplantation
title_short Computational Biomarker Pipeline from Discovery to Clinical Implementation: Plasma Proteomic Biomarkers for Cardiac Transplantation
title_sort computational biomarker pipeline from discovery to clinical implementation: plasma proteomic biomarkers for cardiac transplantation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617196/
https://www.ncbi.nlm.nih.gov/pubmed/23592955
http://dx.doi.org/10.1371/journal.pcbi.1002963
work_keys_str_mv AT cohenfreuegabrielav computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT meredithanna computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT smithderek computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT bergmanaxel computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT sasakimayu computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT lamkarenky computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT hollanderzsuzsanna computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT opushnevanina computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT takharmandeep computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT lindavid computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT wilsonmcmanusjanet computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT balshawrobert computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT keownpaula computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT borcherschristophh computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT mcmanusbruce computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT ngraymondt computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT mcmasterwrobert computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation
AT computationalbiomarkerpipelinefromdiscoverytoclinicalimplementationplasmaproteomicbiomarkersforcardiactransplantation