Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study

Jose D. Herazo-Maya, Jiehuan Sun, Philip L. Molyneaux, Qin Li, Julian A. Villalba, Argyrios Tzouvelekis, Heather Lynn, Brenda M. Juan-Guardela, Cristobal Risquez, Juan C. Osorio, Xiting Yan, George Michel, Nachelle Aurelien, Kathleen O. Lindell, Melinda J. Klesen, Miriam F. Moffatt, William O. Cookson, Yingze Zhang, Joe GN Garcia, Imre NothAntje Prasse, Ziv Bar-Joseph, Kevin F. Gibson, Hongyu Zhao, Erica L. Herzog, Ivan O. Rosas, Toby M. Maher, Naftali Kaminski

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background The clinical course of idiopathic pulmonary fibrosis (IPF) is unpredictable. Clinical prediction tools are not accurate enough to predict disease outcomes. Methods We enrolled patients with IPF diagnosis in a six-cohort study at Yale University (New Haven, CT, USA), Imperial College London (London, UK), University of Chicago (Chicago, IL, USA), University of Pittsburgh (Pittsburgh, PA, USA), University of Freiburg (Freiburg im Breisgau, Germany), and Brigham and Women's Hospital–Harvard Medical School (Boston, MA, USA). Peripheral blood mononuclear cells or whole blood were collected at baseline from 425 participants and from 98 patients (23%) during 4–6 years' follow-up. A 52-gene signature was measured by the nCounter analysis system in four cohorts and extracted from microarray data (GeneChip) in the other two. We used the Scoring Algorithm for Molecular Subphenotypes (SAMS) to classify patients into low-risk or high-risk groups based on the 52-gene signature. We studied mortality with a competing risk model and transplant-free survival with a Cox proportional hazards model. We analysed timecourse data and response to antifibrotic drugs with linear mixed effect models. Findings The application of SAMS to the 52-gene signature identified two groups of patients with IPF (low-risk and high-risk), with significant differences in mortality or transplant-free survival in each of the six cohorts (hazard ratio [HR] range 2·03–4·37). Pooled data showed similar results for mortality (HR 2·18, 95% CI 1·53–3·09; p<0·0001) or transplant-free survival (2·04, 1·52–2·74; p<0·0001). Adding 52-gene risk profiles to the Gender, Age, and Physiology index significantly improved its mortality predictive accuracy. Temporal changes in SAMS scores were associated with changes in forced vital capacity (FVC) in two cohorts. Untreated patients did not shift their risk profile over time. A simultaneous increase in up score and decrease in down score was predictive of decreased transplant-free survival (3·18, 1·16–8·76; p=0·025) in the Pittsburgh cohort. A simultaneous decrease in up score and increase in down score after initiation of antifibrotic drugs was associated with a significant (p=0·0050) improvement in FVC in the Yale cohort. Interpretation The peripheral blood 52-gene expression signature is predictive of outcome in patients with IPF. The potential value of the 52-gene signature in predicting response to therapy should be determined in prospective studies. Funding The Pulmonary Fibrosis Foundation, the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, and the National Heart, Lung, and Blood Institute of the US National Institutes of Health.

Original languageEnglish (US)
Pages (from-to)857-868
Number of pages12
JournalThe Lancet Respiratory Medicine
Volume5
Issue number11
DOIs
StatePublished - Nov 1 2017

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Idiopathic Pulmonary Fibrosis
Multicenter Studies
Cohort Studies
Genes
Transplants
Survival
Mortality
Vital Capacity
National Heart, Lung, and Blood Institute (U.S.)
Medical Faculties
Pulmonary Fibrosis
National Institutes of Health (U.S.)
Medical Schools
Transcriptome
Proportional Hazards Models
Pharmaceutical Preparations
Germany
Blood Cells
Prospective Studies

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis : an international, multicentre, cohort study. / Herazo-Maya, Jose D.; Sun, Jiehuan; Molyneaux, Philip L.; Li, Qin; Villalba, Julian A.; Tzouvelekis, Argyrios; Lynn, Heather; Juan-Guardela, Brenda M.; Risquez, Cristobal; Osorio, Juan C.; Yan, Xiting; Michel, George; Aurelien, Nachelle; Lindell, Kathleen O.; Klesen, Melinda J.; Moffatt, Miriam F.; Cookson, William O.; Zhang, Yingze; Garcia, Joe GN; Noth, Imre; Prasse, Antje; Bar-Joseph, Ziv; Gibson, Kevin F.; Zhao, Hongyu; Herzog, Erica L.; Rosas, Ivan O.; Maher, Toby M.; Kaminski, Naftali.

In: The Lancet Respiratory Medicine, Vol. 5, No. 11, 01.11.2017, p. 857-868.

Research output: Contribution to journalArticle

Herazo-Maya, JD, Sun, J, Molyneaux, PL, Li, Q, Villalba, JA, Tzouvelekis, A, Lynn, H, Juan-Guardela, BM, Risquez, C, Osorio, JC, Yan, X, Michel, G, Aurelien, N, Lindell, KO, Klesen, MJ, Moffatt, MF, Cookson, WO, Zhang, Y, Garcia, JGN, Noth, I, Prasse, A, Bar-Joseph, Z, Gibson, KF, Zhao, H, Herzog, EL, Rosas, IO, Maher, TM & Kaminski, N 2017, 'Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study', The Lancet Respiratory Medicine, vol. 5, no. 11, pp. 857-868. https://doi.org/10.1016/S2213-2600(17)30349-1
Herazo-Maya, Jose D. ; Sun, Jiehuan ; Molyneaux, Philip L. ; Li, Qin ; Villalba, Julian A. ; Tzouvelekis, Argyrios ; Lynn, Heather ; Juan-Guardela, Brenda M. ; Risquez, Cristobal ; Osorio, Juan C. ; Yan, Xiting ; Michel, George ; Aurelien, Nachelle ; Lindell, Kathleen O. ; Klesen, Melinda J. ; Moffatt, Miriam F. ; Cookson, William O. ; Zhang, Yingze ; Garcia, Joe GN ; Noth, Imre ; Prasse, Antje ; Bar-Joseph, Ziv ; Gibson, Kevin F. ; Zhao, Hongyu ; Herzog, Erica L. ; Rosas, Ivan O. ; Maher, Toby M. ; Kaminski, Naftali. / Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis : an international, multicentre, cohort study. In: The Lancet Respiratory Medicine. 2017 ; Vol. 5, No. 11. pp. 857-868.
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abstract = "Background The clinical course of idiopathic pulmonary fibrosis (IPF) is unpredictable. Clinical prediction tools are not accurate enough to predict disease outcomes. Methods We enrolled patients with IPF diagnosis in a six-cohort study at Yale University (New Haven, CT, USA), Imperial College London (London, UK), University of Chicago (Chicago, IL, USA), University of Pittsburgh (Pittsburgh, PA, USA), University of Freiburg (Freiburg im Breisgau, Germany), and Brigham and Women's Hospital–Harvard Medical School (Boston, MA, USA). Peripheral blood mononuclear cells or whole blood were collected at baseline from 425 participants and from 98 patients (23{\%}) during 4–6 years' follow-up. A 52-gene signature was measured by the nCounter analysis system in four cohorts and extracted from microarray data (GeneChip) in the other two. We used the Scoring Algorithm for Molecular Subphenotypes (SAMS) to classify patients into low-risk or high-risk groups based on the 52-gene signature. We studied mortality with a competing risk model and transplant-free survival with a Cox proportional hazards model. We analysed timecourse data and response to antifibrotic drugs with linear mixed effect models. Findings The application of SAMS to the 52-gene signature identified two groups of patients with IPF (low-risk and high-risk), with significant differences in mortality or transplant-free survival in each of the six cohorts (hazard ratio [HR] range 2·03–4·37). Pooled data showed similar results for mortality (HR 2·18, 95{\%} CI 1·53–3·09; p<0·0001) or transplant-free survival (2·04, 1·52–2·74; p<0·0001). Adding 52-gene risk profiles to the Gender, Age, and Physiology index significantly improved its mortality predictive accuracy. Temporal changes in SAMS scores were associated with changes in forced vital capacity (FVC) in two cohorts. Untreated patients did not shift their risk profile over time. A simultaneous increase in up score and decrease in down score was predictive of decreased transplant-free survival (3·18, 1·16–8·76; p=0·025) in the Pittsburgh cohort. A simultaneous decrease in up score and increase in down score after initiation of antifibrotic drugs was associated with a significant (p=0·0050) improvement in FVC in the Yale cohort. Interpretation The peripheral blood 52-gene expression signature is predictive of outcome in patients with IPF. The potential value of the 52-gene signature in predicting response to therapy should be determined in prospective studies. Funding The Pulmonary Fibrosis Foundation, the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, and the National Heart, Lung, and Blood Institute of the US National Institutes of Health.",
author = "Herazo-Maya, {Jose D.} and Jiehuan Sun and Molyneaux, {Philip L.} and Qin Li and Villalba, {Julian A.} and Argyrios Tzouvelekis and Heather Lynn and Juan-Guardela, {Brenda M.} and Cristobal Risquez and Osorio, {Juan C.} and Xiting Yan and George Michel and Nachelle Aurelien and Lindell, {Kathleen O.} and Klesen, {Melinda J.} and Moffatt, {Miriam F.} and Cookson, {William O.} and Yingze Zhang and Garcia, {Joe GN} and Imre Noth and Antje Prasse and Ziv Bar-Joseph and Gibson, {Kevin F.} and Hongyu Zhao and Herzog, {Erica L.} and Rosas, {Ivan O.} and Maher, {Toby M.} and Naftali Kaminski",
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TY - JOUR

T1 - Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis

T2 - an international, multicentre, cohort study

AU - Herazo-Maya, Jose D.

AU - Sun, Jiehuan

AU - Molyneaux, Philip L.

AU - Li, Qin

AU - Villalba, Julian A.

AU - Tzouvelekis, Argyrios

AU - Lynn, Heather

AU - Juan-Guardela, Brenda M.

AU - Risquez, Cristobal

AU - Osorio, Juan C.

AU - Yan, Xiting

AU - Michel, George

AU - Aurelien, Nachelle

AU - Lindell, Kathleen O.

AU - Klesen, Melinda J.

AU - Moffatt, Miriam F.

AU - Cookson, William O.

AU - Zhang, Yingze

AU - Garcia, Joe GN

AU - Noth, Imre

AU - Prasse, Antje

AU - Bar-Joseph, Ziv

AU - Gibson, Kevin F.

AU - Zhao, Hongyu

AU - Herzog, Erica L.

AU - Rosas, Ivan O.

AU - Maher, Toby M.

AU - Kaminski, Naftali

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Background The clinical course of idiopathic pulmonary fibrosis (IPF) is unpredictable. Clinical prediction tools are not accurate enough to predict disease outcomes. Methods We enrolled patients with IPF diagnosis in a six-cohort study at Yale University (New Haven, CT, USA), Imperial College London (London, UK), University of Chicago (Chicago, IL, USA), University of Pittsburgh (Pittsburgh, PA, USA), University of Freiburg (Freiburg im Breisgau, Germany), and Brigham and Women's Hospital–Harvard Medical School (Boston, MA, USA). Peripheral blood mononuclear cells or whole blood were collected at baseline from 425 participants and from 98 patients (23%) during 4–6 years' follow-up. A 52-gene signature was measured by the nCounter analysis system in four cohorts and extracted from microarray data (GeneChip) in the other two. We used the Scoring Algorithm for Molecular Subphenotypes (SAMS) to classify patients into low-risk or high-risk groups based on the 52-gene signature. We studied mortality with a competing risk model and transplant-free survival with a Cox proportional hazards model. We analysed timecourse data and response to antifibrotic drugs with linear mixed effect models. Findings The application of SAMS to the 52-gene signature identified two groups of patients with IPF (low-risk and high-risk), with significant differences in mortality or transplant-free survival in each of the six cohorts (hazard ratio [HR] range 2·03–4·37). Pooled data showed similar results for mortality (HR 2·18, 95% CI 1·53–3·09; p<0·0001) or transplant-free survival (2·04, 1·52–2·74; p<0·0001). Adding 52-gene risk profiles to the Gender, Age, and Physiology index significantly improved its mortality predictive accuracy. Temporal changes in SAMS scores were associated with changes in forced vital capacity (FVC) in two cohorts. Untreated patients did not shift their risk profile over time. A simultaneous increase in up score and decrease in down score was predictive of decreased transplant-free survival (3·18, 1·16–8·76; p=0·025) in the Pittsburgh cohort. A simultaneous decrease in up score and increase in down score after initiation of antifibrotic drugs was associated with a significant (p=0·0050) improvement in FVC in the Yale cohort. Interpretation The peripheral blood 52-gene expression signature is predictive of outcome in patients with IPF. The potential value of the 52-gene signature in predicting response to therapy should be determined in prospective studies. Funding The Pulmonary Fibrosis Foundation, the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, and the National Heart, Lung, and Blood Institute of the US National Institutes of Health.

AB - Background The clinical course of idiopathic pulmonary fibrosis (IPF) is unpredictable. Clinical prediction tools are not accurate enough to predict disease outcomes. Methods We enrolled patients with IPF diagnosis in a six-cohort study at Yale University (New Haven, CT, USA), Imperial College London (London, UK), University of Chicago (Chicago, IL, USA), University of Pittsburgh (Pittsburgh, PA, USA), University of Freiburg (Freiburg im Breisgau, Germany), and Brigham and Women's Hospital–Harvard Medical School (Boston, MA, USA). Peripheral blood mononuclear cells or whole blood were collected at baseline from 425 participants and from 98 patients (23%) during 4–6 years' follow-up. A 52-gene signature was measured by the nCounter analysis system in four cohorts and extracted from microarray data (GeneChip) in the other two. We used the Scoring Algorithm for Molecular Subphenotypes (SAMS) to classify patients into low-risk or high-risk groups based on the 52-gene signature. We studied mortality with a competing risk model and transplant-free survival with a Cox proportional hazards model. We analysed timecourse data and response to antifibrotic drugs with linear mixed effect models. Findings The application of SAMS to the 52-gene signature identified two groups of patients with IPF (low-risk and high-risk), with significant differences in mortality or transplant-free survival in each of the six cohorts (hazard ratio [HR] range 2·03–4·37). Pooled data showed similar results for mortality (HR 2·18, 95% CI 1·53–3·09; p<0·0001) or transplant-free survival (2·04, 1·52–2·74; p<0·0001). Adding 52-gene risk profiles to the Gender, Age, and Physiology index significantly improved its mortality predictive accuracy. Temporal changes in SAMS scores were associated with changes in forced vital capacity (FVC) in two cohorts. Untreated patients did not shift their risk profile over time. A simultaneous increase in up score and decrease in down score was predictive of decreased transplant-free survival (3·18, 1·16–8·76; p=0·025) in the Pittsburgh cohort. A simultaneous decrease in up score and increase in down score after initiation of antifibrotic drugs was associated with a significant (p=0·0050) improvement in FVC in the Yale cohort. Interpretation The peripheral blood 52-gene expression signature is predictive of outcome in patients with IPF. The potential value of the 52-gene signature in predicting response to therapy should be determined in prospective studies. Funding The Pulmonary Fibrosis Foundation, the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, and the National Heart, Lung, and Blood Institute of the US National Institutes of Health.

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