An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study

Toby M. Maher; Eunice Oballa; Juliet K. Simpson; Joanne Porte; Anthony Habgood; William A. Fahy; Aiden Flynn; Philip L. Molyneaux; Rebecca Braybrooke; Hrushikesh Divyateja; Helen Parfrey; Doris Rassl; Anne Marie Russell; Gauri Saini; Elisabetta A. Renzoni; Anne Marie Duggan; Richard Hubbard; Athol U. Wells; Pauline T. Lukey; Richard P. Marshall; R. Gisli Jenkins

doi:10.1016/S2213-2600(17)30430-7

An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study

Toby M. Maher, Eunice Oballa, Juliet K. Simpson, Joanne Porte, Anthony Habgood, William A. Fahy, Aiden Flynn, Philip L. Molyneaux, Rebecca Braybrooke, Hrushikesh Divyateja, Helen Parfrey, Doris Rassl, Anne Marie Russell, Gauri Saini, Elisabetta A. Renzoni, Anne Marie Duggan, Richard Hubbard, Athol U. Wells, Pauline T. Lukey, Richard P. MarshallR. Gisli Jenkins^*

^*Corresponding author for this work

Nursing and Midwifery

Research output: Contribution to journal › Article › peer-review

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess potential biomarkers to predict outcomes for people with IPF. Methods PROFILE is a large prospective longitudinal cohort of treatment-naive patients with IPF. We adopted a two-stage discovery and validation design using patients from the PROFILE cohort. For the discovery analysis, we examined 106 patients and 50 age and sex matched healthy controls from Nottingham University Hospitals NHS Trust and the Royal Brompton Hospital. We did an unbiased, multiplex immunoassay assessment of 123 biomarkers. We further investigated promising novel markers by immunohistochemical assessment of IPF lung tissue. In the validation analysis, we examined samples from 206 people with IPF from among the remaining 212 patients recruited to PROFILE Central England. We used the samples to attempt to replicate the biomarkers identified from the discovery analysis by use of independent immunoassays for each biomarker. We investigated the predictive power of the selected biomarkers to identify individuals with IPF who were at risk of progression or death. The PROFILE studies are registered on ClinicalTrials.gov, numbers NCT01134822 (PROFILE Central England) and NCT01110694 (PROFILE Royal Brompton Hospital). Findings In the discovery analysis, we identified four serum biomarkers (surfactant protein D, matrix metalloproteinase 7, CA19-9, and CA-125) that were suitable for replication. Histological assessment of CA19-9 and CA-125 suggested that these proteins were markers of epithelial damage. Replication analysis showed that baseline values of surfactant protein D (46·6 ng/mL vs 34·6 ng/mL, p=0·0018) and CA19-9 (53·7 U/mL vs 22·2 U/mL; p<0·0001) were significantly higher in patients with progressive disease than in patients with stable disease, and rising concentrations of CA-125 over 3 months were associated with increased risk of mortality (HR 2·542, 95% CI 1·493–4·328, p=0·00059). Interpretation We have identified serum proteins secreted from metaplastic epithelium that can be used to predict disease progression and death in IPF. Funding GlaxoSmithKline R&D and the UK Medical Research Council.

Original language	English
Pages (from-to)	946-955
Number of pages	10
Journal	The Lancet Respiratory Medicine
Volume	5
Issue number	12
DOIs	https://doi.org/10.1016/S2213-2600(17)30430-7
Publication status	Published - Dec 2017

Bibliographical note

Funding Information:
The PROFILE study was funded by the Medical Research Council (G0901226) and GSK R&D (CRT114316), and was sponsored by Nottingham University and Royal Brompton and Harefield NHS Foundation Trust. Additionally, TMM is supported by an NIHR Clinician Scientist Fellowship (NIHR ref CS-2013-13-017). RGJ has received support from the Medical Research Council (MICA grant G0901226). We are grateful to all patients for their participation in the PROFILE study and to the Brompton/Imperial NIHR Biomedical Research Unit for infrastructure support in the collection and processing of samples. Tissue used in this study was obtained from the Papworth Hospital Research Tissue Bank and the MRC Nottingham Molecular Pathology Node.

Publisher Copyright:
© 2017 Elsevier Ltd

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

Access to Document

10.1016/S2213-2600(17)30430-7

Cite this

Maher, T. M., Oballa, E., Simpson, J. K., Porte, J., Habgood, A., Fahy, W. A., Flynn, A., Molyneaux, P. L., Braybrooke, R., Divyateja, H., Parfrey, H., Rassl, D., Russell, A. M., Saini, G., Renzoni, E. A., Duggan, A. M., Hubbard, R., Wells, A. U., Lukey, P. T., ... Jenkins, R. G. (2017). An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study. The Lancet Respiratory Medicine, 5(12), 946-955. https://doi.org/10.1016/S2213-2600(17)30430-7

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title = "An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study",

abstract = "Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess potential biomarkers to predict outcomes for people with IPF. Methods PROFILE is a large prospective longitudinal cohort of treatment-naive patients with IPF. We adopted a two-stage discovery and validation design using patients from the PROFILE cohort. For the discovery analysis, we examined 106 patients and 50 age and sex matched healthy controls from Nottingham University Hospitals NHS Trust and the Royal Brompton Hospital. We did an unbiased, multiplex immunoassay assessment of 123 biomarkers. We further investigated promising novel markers by immunohistochemical assessment of IPF lung tissue. In the validation analysis, we examined samples from 206 people with IPF from among the remaining 212 patients recruited to PROFILE Central England. We used the samples to attempt to replicate the biomarkers identified from the discovery analysis by use of independent immunoassays for each biomarker. We investigated the predictive power of the selected biomarkers to identify individuals with IPF who were at risk of progression or death. The PROFILE studies are registered on ClinicalTrials.gov, numbers NCT01134822 (PROFILE Central England) and NCT01110694 (PROFILE Royal Brompton Hospital). Findings In the discovery analysis, we identified four serum biomarkers (surfactant protein D, matrix metalloproteinase 7, CA19-9, and CA-125) that were suitable for replication. Histological assessment of CA19-9 and CA-125 suggested that these proteins were markers of epithelial damage. Replication analysis showed that baseline values of surfactant protein D (46·6 ng/mL vs 34·6 ng/mL, p=0·0018) and CA19-9 (53·7 U/mL vs 22·2 U/mL; p<0·0001) were significantly higher in patients with progressive disease than in patients with stable disease, and rising concentrations of CA-125 over 3 months were associated with increased risk of mortality (HR 2·542, 95% CI 1·493–4·328, p=0·00059). Interpretation We have identified serum proteins secreted from metaplastic epithelium that can be used to predict disease progression and death in IPF. Funding GlaxoSmithKline R&D and the UK Medical Research Council.",

author = "Maher, {Toby M.} and Eunice Oballa and Simpson, {Juliet K.} and Joanne Porte and Anthony Habgood and Fahy, {William A.} and Aiden Flynn and Molyneaux, {Philip L.} and Rebecca Braybrooke and Hrushikesh Divyateja and Helen Parfrey and Doris Rassl and Russell, {Anne Marie} and Gauri Saini and Renzoni, {Elisabetta A.} and Duggan, {Anne Marie} and Richard Hubbard and Wells, {Athol U.} and Lukey, {Pauline T.} and Marshall, {Richard P.} and Jenkins, {R. Gisli}",

note = "Funding Information: The PROFILE study was funded by the Medical Research Council (G0901226) and GSK R&D (CRT114316), and was sponsored by Nottingham University and Royal Brompton and Harefield NHS Foundation Trust. Additionally, TMM is supported by an NIHR Clinician Scientist Fellowship (NIHR ref CS-2013-13-017). RGJ has received support from the Medical Research Council (MICA grant G0901226). We are grateful to all patients for their participation in the PROFILE study and to the Brompton/Imperial NIHR Biomedical Research Unit for infrastructure support in the collection and processing of samples. Tissue used in this study was obtained from the Papworth Hospital Research Tissue Bank and the MRC Nottingham Molecular Pathology Node. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

year = "2017",

month = dec,

doi = "10.1016/S2213-2600(17)30430-7",

language = "English",

volume = "5",

pages = "946--955",

journal = "The Lancet Respiratory Medicine",

issn = "2213-2600",

publisher = "Elsevier",

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}

Maher, TM, Oballa, E, Simpson, JK, Porte, J, Habgood, A, Fahy, WA, Flynn, A, Molyneaux, PL, Braybrooke, R, Divyateja, H, Parfrey, H, Rassl, D, Russell, AM, Saini, G, Renzoni, EA, Duggan, AM, Hubbard, R, Wells, AU, Lukey, PT, Marshall, RP & Jenkins, RG 2017, 'An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study', The Lancet Respiratory Medicine, vol. 5, no. 12, pp. 946-955. https://doi.org/10.1016/S2213-2600(17)30430-7

TY - JOUR

T1 - An epithelial biomarker signature for idiopathic pulmonary fibrosis

T2 - an analysis from the multicentre PROFILE cohort study

AU - Maher, Toby M.

AU - Oballa, Eunice

AU - Simpson, Juliet K.

AU - Porte, Joanne

AU - Habgood, Anthony

AU - Fahy, William A.

AU - Flynn, Aiden

AU - Molyneaux, Philip L.

AU - Braybrooke, Rebecca

AU - Divyateja, Hrushikesh

AU - Parfrey, Helen

AU - Rassl, Doris

AU - Russell, Anne Marie

AU - Saini, Gauri

AU - Renzoni, Elisabetta A.

AU - Duggan, Anne Marie

AU - Hubbard, Richard

AU - Wells, Athol U.

AU - Lukey, Pauline T.

AU - Marshall, Richard P.

AU - Jenkins, R. Gisli

N1 - Funding Information: The PROFILE study was funded by the Medical Research Council (G0901226) and GSK R&D (CRT114316), and was sponsored by Nottingham University and Royal Brompton and Harefield NHS Foundation Trust. Additionally, TMM is supported by an NIHR Clinician Scientist Fellowship (NIHR ref CS-2013-13-017). RGJ has received support from the Medical Research Council (MICA grant G0901226). We are grateful to all patients for their participation in the PROFILE study and to the Brompton/Imperial NIHR Biomedical Research Unit for infrastructure support in the collection and processing of samples. Tissue used in this study was obtained from the Papworth Hospital Research Tissue Bank and the MRC Nottingham Molecular Pathology Node. Publisher Copyright: © 2017 Elsevier Ltd

PY - 2017/12

Y1 - 2017/12

N2 - Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess potential biomarkers to predict outcomes for people with IPF. Methods PROFILE is a large prospective longitudinal cohort of treatment-naive patients with IPF. We adopted a two-stage discovery and validation design using patients from the PROFILE cohort. For the discovery analysis, we examined 106 patients and 50 age and sex matched healthy controls from Nottingham University Hospitals NHS Trust and the Royal Brompton Hospital. We did an unbiased, multiplex immunoassay assessment of 123 biomarkers. We further investigated promising novel markers by immunohistochemical assessment of IPF lung tissue. In the validation analysis, we examined samples from 206 people with IPF from among the remaining 212 patients recruited to PROFILE Central England. We used the samples to attempt to replicate the biomarkers identified from the discovery analysis by use of independent immunoassays for each biomarker. We investigated the predictive power of the selected biomarkers to identify individuals with IPF who were at risk of progression or death. The PROFILE studies are registered on ClinicalTrials.gov, numbers NCT01134822 (PROFILE Central England) and NCT01110694 (PROFILE Royal Brompton Hospital). Findings In the discovery analysis, we identified four serum biomarkers (surfactant protein D, matrix metalloproteinase 7, CA19-9, and CA-125) that were suitable for replication. Histological assessment of CA19-9 and CA-125 suggested that these proteins were markers of epithelial damage. Replication analysis showed that baseline values of surfactant protein D (46·6 ng/mL vs 34·6 ng/mL, p=0·0018) and CA19-9 (53·7 U/mL vs 22·2 U/mL; p<0·0001) were significantly higher in patients with progressive disease than in patients with stable disease, and rising concentrations of CA-125 over 3 months were associated with increased risk of mortality (HR 2·542, 95% CI 1·493–4·328, p=0·00059). Interpretation We have identified serum proteins secreted from metaplastic epithelium that can be used to predict disease progression and death in IPF. Funding GlaxoSmithKline R&D and the UK Medical Research Council.

AB - Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess potential biomarkers to predict outcomes for people with IPF. Methods PROFILE is a large prospective longitudinal cohort of treatment-naive patients with IPF. We adopted a two-stage discovery and validation design using patients from the PROFILE cohort. For the discovery analysis, we examined 106 patients and 50 age and sex matched healthy controls from Nottingham University Hospitals NHS Trust and the Royal Brompton Hospital. We did an unbiased, multiplex immunoassay assessment of 123 biomarkers. We further investigated promising novel markers by immunohistochemical assessment of IPF lung tissue. In the validation analysis, we examined samples from 206 people with IPF from among the remaining 212 patients recruited to PROFILE Central England. We used the samples to attempt to replicate the biomarkers identified from the discovery analysis by use of independent immunoassays for each biomarker. We investigated the predictive power of the selected biomarkers to identify individuals with IPF who were at risk of progression or death. The PROFILE studies are registered on ClinicalTrials.gov, numbers NCT01134822 (PROFILE Central England) and NCT01110694 (PROFILE Royal Brompton Hospital). Findings In the discovery analysis, we identified four serum biomarkers (surfactant protein D, matrix metalloproteinase 7, CA19-9, and CA-125) that were suitable for replication. Histological assessment of CA19-9 and CA-125 suggested that these proteins were markers of epithelial damage. Replication analysis showed that baseline values of surfactant protein D (46·6 ng/mL vs 34·6 ng/mL, p=0·0018) and CA19-9 (53·7 U/mL vs 22·2 U/mL; p<0·0001) were significantly higher in patients with progressive disease than in patients with stable disease, and rising concentrations of CA-125 over 3 months were associated with increased risk of mortality (HR 2·542, 95% CI 1·493–4·328, p=0·00059). Interpretation We have identified serum proteins secreted from metaplastic epithelium that can be used to predict disease progression and death in IPF. Funding GlaxoSmithKline R&D and the UK Medical Research Council.

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U2 - 10.1016/S2213-2600(17)30430-7

DO - 10.1016/S2213-2600(17)30430-7

M3 - Article

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AN - SCOPUS:85033779884

SN - 2213-2600

VL - 5

SP - 946

EP - 955

JO - The Lancet Respiratory Medicine

JF - The Lancet Respiratory Medicine

IS - 12

ER -

An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study

Abstract

Bibliographical note

ASJC Scopus subject areas

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