Airway pathological heterogeneity in asthma: Visualization of disease microclusters using topological data analysis - 06/11/18
, Aarti Shikotra, BSc, PhD a, Matthew Richardson, BSc, PhD a, Emma Doran, PhD b, David Choy, BSc b, Alex Bell, MMath a, d, Cary D. Austin, MD, PhD b, Jeffrey Eastham-Anderson, MS b, Beverley Hargadon, RGN a, Joseph R. Arron, MD, PhD b, Andrew Wardlaw, FRCP, PhD a, Christopher E. Brightling, FRCP, PhD a, Liam G. Heaney, FRCP, MD c, Peter Bradding, FRCP, DM aAbstract |
Background |
Asthma is a complex chronic disease underpinned by pathological changes within the airway wall. How variations in structural airway pathology and cellular inflammation contribute to the expression and severity of asthma are poorly understood.
Objectives |
Therefore we evaluated pathological heterogeneity using topological data analysis (TDA) with the aim of visualizing disease clusters and microclusters.
Methods |
A discovery population of 202 adult patients (142 asthmatic patients and 60 healthy subjects) and an external replication population (59 patients with severe asthma) were evaluated. Pathology and gene expression were examined in bronchial biopsy samples. TDA was applied by using pathological variables alone to create pathology-driven visual networks.
Results |
In the discovery cohort TDA identified 4 groups/networks with multiple microclusters/regions of interest that were masked by group-level statistics. Specifically, TDA group 1 consisted of a high proportion of healthy subjects, with a microcluster representing a topological continuum connecting healthy subjects to patients with mild-to-moderate asthma. Three additional TDA groups with moderate-to-severe asthma (Airway Smooth MuscleHigh, Reticular Basement MembraneHigh, and RemodelingLow groups) were identified and contained numerous microclusters with varying pathological and clinical features. Mutually exclusive TH2 and TH17 tissue gene expression signatures were identified in all pathological groups. Discovery and external replication applied to the severe asthma subgroup identified only highly similar “pathological data shapes” through analyses of persistent homology.
Conclusions |
We have identified and replicated novel pathological phenotypes of asthma using TDA. Our methodology is applicable to other complex chronic diseases.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Severe asthma, remodeling, airway inflammation, topological data analysis, phenotyping
Abbreviations used : ASM, BOBCAT, GINA, GMA, IQR, TDA
Plan
| Supported by the National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit and project grants (to S.S., P.B., J.R.A., and L.G.H.) from Asthma UK (AUK-PG-2013-208 [project title: Endotyping asthma for the benefit of patients]) and from the Jules Thorne Trust Clinical Senior Lecturer Award (“Systems medicine: novel mathematical approaches to personalised care in asthma patients”; to S.S.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Additional funding was received from Genentech (to P.B.) to support this study. Biopsy samples and additional funding from the GlaxoSmithKline-sponsored studies RES100767 (clinicaltrials.gov: NCT00331058) and RES100769 (clinicaltrials.gov: NCT00327197) were provided by GlaxoSmithKline (to A.J.W.) to support this study. In addition, biopsy samples were provided by C.E.B. to support this study from studies funded by an MRC intermediate and a Wellcome Trust senior fellowship award. |
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| Disclosure of potential conflict of interest: S. Siddiqui declares grants from the Jules Thorne Trust Grant for Clinical Senior Lecturers, an Asthma UK Project Grant, a grant from the NIHR Biomedical Research Centre and consultancy with AstraZeneca, GlaxoSmithKline, Owlstone, Mundipharma, and Boehringer Ingelheim. D. Choy is employed by Genentech, a member of the Roche Group; holds patents (planned, pending or issued) with Genentech, a member of the Roche Group; and has stock/stock options with Roche. C. D. Austin is employed by, has stock/stock options with, and has received travel/accommodation/meeting expenses unrelated to activities listed from Genentech. J. R. Arron is employed by Genentech and has stock/stock options with Roche Holdings. A. Wardlaw has received a grant from GlaxoSmithKline; holds board membership with TEVA; has been a consultant for GlaxoSmithKline, Pulmocide, Boehringer, and KNOPP; and has received grants from/has grants pending with Pfizer. C. E. Brightling has received grants from the Wellcome Trust, Asthma UK, and the MRC; has consultant arrangements with GlaxoSmithKline, AstraZeneca/MedImmune, Chiesi, Novartis, Roche/Genentech, Theravance, Sanofi/Regeneron, Vectura, and Prep; and has grants from/grants pending with Roche/Genentech, Novartis, GlaxoSmithKline, AstraZeneca/MedImmune, Mologic, and Pfizer. L. G. Heaney has received grants from Northern Ireland Chest, Heart & Stroke Association and Genentech; has consultant arrangements with Hoffman la Roche, AstraZeneca, Novartis, GlaxoSmithKline, and TEVA; has received grants from/has grants pending with Novartis UK, Roche/Genentech, MedImmune, and GlaxoSmithKline; has received payment for lectures, including service on speakers' bureaus, from Hoffman la Roche, Novartis, and TEVA; and has received travel/accommodation/meeting expenses unrelated to activities listed from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, TEVA, Chiesi, and Napp. P. Bradding has received a grant from Genentech and has Consultant arrangements with Roche. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 5
P. 1457-1468 - novembre 2018 Retour au numéro
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