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 G.N.
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
N1 - Funding Information:
JDH-M received funding from The Pulmonary Fibrosis Foundation and the Robert Wood Johnson Foundation under the Harold Amos Medical Faculty Development Program. PLM received an Asmarley trust grant. AP received grants from the E-RARE project, JRC 2011 IPF-AE (DLR 01GM1210A). ELH received RO1 HL109233 and RO1 HL125850 grants from the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health (NIH). IOR received P01 HL11450 and RO1 HL15024 grants from the NHLBI of the NIH. TMM received a UK National Institute for Health Research Clinician Scientist Fellowship (NIHR reference number CS-2013–13–017). NK received U01 HL112707, R01 HL127349, U01 HL108642, and UH3 HL123886 grants from the NHLBI of the NIH.
Funding Information:
JDH-M has a patent on marker panels for idiopathic pulmonary fibrosis (IPF) diagnosis and evaluation pending. WOC and MFM report grants from the Wellcome Trust, during the conduct of the study. AP reports personal fees from Boehringer Ingelheim, Roche Pharma, Sanofi Aventis, Bayer, and AstraZeneca, outside of the submitted work. IN reports grants and personal fees from Veracyte, Boehringer Ingelheim, and Genentech, and personal fees from Immuneworks, Global blood therapeutics, and Sanofi, outside of the submitted work. Additionally, IN has a patent TOLLIP in IPF pending, and a patent for plasma proteins in IPF MMP7 issued. ELH reports grants from the National Heart, Lung, and Blood Institute of the US National Institutes of Health, and from the Greenfield Foundation, during the conduct of the study; and personal fees from Boehringer lngelheim, grants from Sanofi, Biogen ldec, Bristol-Myers Squibb, Navitor, and Promedior, outside of the submitted work. AP reports personal fees from Boehringer Ingelheim, Roche Pharma, Sanofi Aventis, Bayer, and AstraZeneca, outside of the submitted work. TMM has, via his institution, received industry-academic funding from GlaxoSmithKline R&D and UCB, and has received consultancy or speakers fees from Apellis, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, GlaxoSmithKline R&D, InterMune, ProMetic, Roche, Sanofi Aventis, Samumed, and UCB. NK reports grants and personal fees from Biogen Idec, personal fees from Boehringer Ingelheim, stock options from Moereae Matrix, personal fees and stock options from Pliant, no funds from Samumed, non-financial support from Actelion and Miragen, and past personal fees from Third Rock, all outside of the submitted work. Additionally, NK has patents on new therapies in pulmonary fibrosis issued, and biomarker panels in pulmonary fibrosis. NK is a member of the Scientific Advisory Committee, the Research Advisory Forum, and the Board of the Pulmonary Fibrosis Foundation, and serves as Deputy Editor of Thorax for the BMJ . All other authors declare no competing interests.
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/11
Y1 - 2017/11
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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U2 - 10.1016/S2213-2600(17)30349-1
DO - 10.1016/S2213-2600(17)30349-1
M3 - Article
C2 - 28942086
AN - SCOPUS:85029640399
VL - 5
SP - 857
EP - 868
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
SN - 2213-2600
IS - 11
ER -