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Diagnosis of T-cell-mediated kidney rejection by biopsy-based proteomic biomarkers and machine learning
BACKGROUND: Biopsy-based diagnosis is essential for maintaining kidney allograft longevity by ensuring prompt treatment for graft complications. Although histologic assessment remains the gold standard, it carries significant limitations such as subjective interpretation, suboptimal reproducibility,...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9939643/ https://www.ncbi.nlm.nih.gov/pubmed/36814924 http://dx.doi.org/10.3389/fimmu.2023.1090373 |
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author | Fang, Fei Liu, Peng Song, Lei Wagner, Patrick Bartlett, David Ma, Liane Li, Xue Rahimian, M. Amin Tseng, George Randhawa, Parmjeet Xiao, Kunhong |
author_facet | Fang, Fei Liu, Peng Song, Lei Wagner, Patrick Bartlett, David Ma, Liane Li, Xue Rahimian, M. Amin Tseng, George Randhawa, Parmjeet Xiao, Kunhong |
author_sort | Fang, Fei |
collection | PubMed |
description | BACKGROUND: Biopsy-based diagnosis is essential for maintaining kidney allograft longevity by ensuring prompt treatment for graft complications. Although histologic assessment remains the gold standard, it carries significant limitations such as subjective interpretation, suboptimal reproducibility, and imprecise quantitation of disease burden. It is hoped that molecular diagnostics could enhance the efficiency, accuracy, and reproducibility of traditional histologic methods. METHODS: Quantitative label-free mass spectrometry analysis was performed on a set of formalin-fixed, paraffin-embedded (FFPE) biopsies from kidney transplant patients, including five samples each with diagnosis of T-cell-mediated rejection (TCMR), polyomavirus BK nephropathy (BKPyVN), and stable (STA) kidney function control tissue. Using the differential protein expression result as a classifier, three different machine learning algorithms were tested to build a molecular diagnostic model for TCMR. RESULTS: The label-free proteomics method yielded 800-1350 proteins that could be quantified with high confidence per sample by single-shot measurements. Among these candidate proteins, 329 and 467 proteins were defined as differentially expressed proteins (DEPs) for TCMR in comparison with STA and BKPyVN, respectively. Comparing the FFPE quantitative proteomics data set obtained in this study using label-free method with a data set we previously reported using isobaric labeling technology, a classifier pool comprised of features from DEPs commonly quantified in both data sets, was generated for TCMR prediction. Leave-one-out cross-validation result demonstrated that the random forest (RF)-based model achieved the best predictive power. In a follow-up blind test using an independent sample set, the RF-based model yields 80% accuracy for TCMR and 100% for STA. When applying the established RF-based model to two public transcriptome datasets, 78.1%-82.9% sensitivity and 58.7%-64.4% specificity was achieved respectively. CONCLUSIONS: This proof-of-principle study demonstrates the clinical feasibility of proteomics profiling for FFPE biopsies using an accurate, efficient, and cost-effective platform integrated of quantitative label-free mass spectrometry analysis with a machine learning-based diagnostic model. It costs less than 10 dollars per test. |
format | Online Article Text |
id | pubmed-9939643 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99396432023-02-21 Diagnosis of T-cell-mediated kidney rejection by biopsy-based proteomic biomarkers and machine learning Fang, Fei Liu, Peng Song, Lei Wagner, Patrick Bartlett, David Ma, Liane Li, Xue Rahimian, M. Amin Tseng, George Randhawa, Parmjeet Xiao, Kunhong Front Immunol Immunology BACKGROUND: Biopsy-based diagnosis is essential for maintaining kidney allograft longevity by ensuring prompt treatment for graft complications. Although histologic assessment remains the gold standard, it carries significant limitations such as subjective interpretation, suboptimal reproducibility, and imprecise quantitation of disease burden. It is hoped that molecular diagnostics could enhance the efficiency, accuracy, and reproducibility of traditional histologic methods. METHODS: Quantitative label-free mass spectrometry analysis was performed on a set of formalin-fixed, paraffin-embedded (FFPE) biopsies from kidney transplant patients, including five samples each with diagnosis of T-cell-mediated rejection (TCMR), polyomavirus BK nephropathy (BKPyVN), and stable (STA) kidney function control tissue. Using the differential protein expression result as a classifier, three different machine learning algorithms were tested to build a molecular diagnostic model for TCMR. RESULTS: The label-free proteomics method yielded 800-1350 proteins that could be quantified with high confidence per sample by single-shot measurements. Among these candidate proteins, 329 and 467 proteins were defined as differentially expressed proteins (DEPs) for TCMR in comparison with STA and BKPyVN, respectively. Comparing the FFPE quantitative proteomics data set obtained in this study using label-free method with a data set we previously reported using isobaric labeling technology, a classifier pool comprised of features from DEPs commonly quantified in both data sets, was generated for TCMR prediction. Leave-one-out cross-validation result demonstrated that the random forest (RF)-based model achieved the best predictive power. In a follow-up blind test using an independent sample set, the RF-based model yields 80% accuracy for TCMR and 100% for STA. When applying the established RF-based model to two public transcriptome datasets, 78.1%-82.9% sensitivity and 58.7%-64.4% specificity was achieved respectively. CONCLUSIONS: This proof-of-principle study demonstrates the clinical feasibility of proteomics profiling for FFPE biopsies using an accurate, efficient, and cost-effective platform integrated of quantitative label-free mass spectrometry analysis with a machine learning-based diagnostic model. It costs less than 10 dollars per test. Frontiers Media S.A. 2023-02-06 /pmc/articles/PMC9939643/ /pubmed/36814924 http://dx.doi.org/10.3389/fimmu.2023.1090373 Text en Copyright © 2023 Fang, Liu, Song, Wagner, Bartlett, Ma, Li, Rahimian, Tseng, Randhawa and Xiao https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Fang, Fei Liu, Peng Song, Lei Wagner, Patrick Bartlett, David Ma, Liane Li, Xue Rahimian, M. Amin Tseng, George Randhawa, Parmjeet Xiao, Kunhong Diagnosis of T-cell-mediated kidney rejection by biopsy-based proteomic biomarkers and machine learning |
title | Diagnosis of T-cell-mediated kidney rejection by biopsy-based proteomic biomarkers and machine learning |
title_full | Diagnosis of T-cell-mediated kidney rejection by biopsy-based proteomic biomarkers and machine learning |
title_fullStr | Diagnosis of T-cell-mediated kidney rejection by biopsy-based proteomic biomarkers and machine learning |
title_full_unstemmed | Diagnosis of T-cell-mediated kidney rejection by biopsy-based proteomic biomarkers and machine learning |
title_short | Diagnosis of T-cell-mediated kidney rejection by biopsy-based proteomic biomarkers and machine learning |
title_sort | diagnosis of t-cell-mediated kidney rejection by biopsy-based proteomic biomarkers and machine learning |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9939643/ https://www.ncbi.nlm.nih.gov/pubmed/36814924 http://dx.doi.org/10.3389/fimmu.2023.1090373 |
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