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Multidimensional endotypes of asthma: topological data analysis of cross-sectional clinical, pathological, and immunological data
Poster Abstracts
Multidimensional endotypes of asthma: topological data analysis of cross-sectional clinical, pathological, and immunological data Timothy Hinks, Xiaoying Zhou, Karl Staples, Borislav Dimitrov, Alexander Manta, Tanya Petrossian, Pek Lum, Caroline Smith, Jon Ward, Peter Howarth, Andrew Walls, Stephan D Gadola, Ratko Djukanović
Abstract Published Online February 26, 2015 Poster 24 Southampton NIHR Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, UK (T Hinks MD, C Smith RN); Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, UK (X Zhou PhD, K Staples PhD, J Ward BSc, P Howarth MD, A Walls PhD, R Djukanović MD); Primary Care and Population Sciences, University of Southampton Faculty of Medicine, Southampton University Hospital, Southampton, UK (B Dimitrov MD); MantaMatics UG, Dompfaffenweg, Geretsried, Germany (A Manta PhD); Ayasdi Inc, Palo Alto, CA, USA (T Petrossian PhD, P Lum PhD); and Novartis Institute of Biomedical Research, Basel, Switzerland (S D Gadola MD) Correspondence to: Dr Timothy Hinks, University of Southampton School of Medicine, Academic Unit of Clinical and Experimental Sciences, Mailpoint 810, Level F, South Block, Southampton General Hospital, Southampton SO16 6YD, UK [email protected]
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Background Incomplete understanding of mechanisms and clinicopathobiological heterogeneity in asthma hinders research progress. Pathogenic roles for T-helper-type 17 (Th17) cells and invariant T cells implied by murine data have yet to be assessed in man. We aimed to investigate the role of Th17 and mucosal associated invariant T (MAIT) cells in airway inflammation; to characterise associations between diverse clinical and immunological features of asthma; and to identify novel multidimensional asthma endotypes. Methods In this single-centre, cross-sectional observational study in the UK, we assessed volunteers with mild-to-severe asthma and healthy non-atopic controls using clinical and physiological assessment and immunological sampling of blood, induced sputum, endobronchial biopsy, and bronchoalveolar lavage for flow cytometry and multiplex-electrochemiluminescence assays. Primary outcomes were changes in frequencies of Th17 and MAIT cells between health and asthma using Mann-Whitney U tests and the Jonckheere-Terpstra test (linear trend across ranked groups). The study had 80% power to detect 60% differences in T-cell frequencies at p<0·05. Bayesian Network Analysis (BNA) was used to explore associations between parameters. Topological Data Analysis (TDA) was used to identify multidimensional endotypes. The study had local research ethics approval. All participants provided informed consent. Findings Participants were 84 male and female volunteers (60 with mild-to-severe asthma and 24 healthy, non-atopic controls) aged 18–70 years recruited from clinics and research cohorts. Th17 cells and γδ17 cells were not associated with asthma, even in severe neutrophilic forms. MAIT-cell frequencies were strikingly reduced in asthma compared with health (median frequency in blood 0·9% of CD3+ cells [IQR 0·3–1·8] in asthma vs 1·6 [1·2–2·6] in health, p=0·005; in sputum 1·1 [0·7–2·0] vs 1·8 [1·6–2·3], p=0·002; and in biopsy samples 1·3 [0·7–2·3] vs 3·9% [1·3–5·3%], p=0·02), especially in severe asthma where BAL regulatory T cells were also reduced compared with those in health (4·4, 3·1–6·1, vs 8·1, 5·6–10; p=0·02). BNA and TDA identified six novel clinicopathobiological clusters of underlying disease mechanisms, with elevated mast cell mediators tryptase (p<0·0001), chymase (p=0·02), and carboxypeptidase A3 (p=0·02) in severe asthma. Interpretation This study suggests that Th17 cells do not have a major pathogenic role in human asthma. We describe a novel deficiency of MAIT cells in severe asthma. We also provide proof of concept for application of TDA to identification of multidimensional clinicopathobiological endotypes. Endotypes will require validation in further cohorts. Funding Wellcome Trust. Contributors TH, SDG, and RD conceived the study. TH, KS, CS, JW, and PH conducted the study recruitment and sample collection. TH conducted all assays except the mast cell assays which were conducted by XZ and AW. TH, BD, AM, TP, and PYL performed the data analysis. All authors contributed to drafting and approving the final abstract. Declaration of interests AW and XZ declare that they have a patent EP 1982191 issued (assay for carboxypeptidase A3), and a patent USPA 12/161409 pending (assay for carboxypeptidase A3). PL and TP are both employees at Ayasdi, Inc, and have received stock options in this company whose software for TDA (Iris) was used in this study. All other authors declare no competing interests.
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Multidimensional endotypes of asthma: topological data analysis of cross-sectional clinical, pathological, and immunological data Timothy Hinks, Xiaoying Zhou, Karl Staples, Borislav Dimitrov, Alexander Manta, Tanya Petrossian, Pek Lum, Caroline Smith, Jon Ward, Peter Howarth, Andrew Walls, Stephan D Gadola, Ratko Djukanović
Abstract Published Online February 26, 2015 Poster 24 Southampton NIHR Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, UK (T Hinks MD, C Smith RN); Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, UK (X Zhou PhD, K Staples PhD, J Ward BSc, P Howarth MD, A Walls PhD, R Djukanović MD); Primary Care and Population Sciences, University of Southampton Faculty of Medicine, Southampton University Hospital, Southampton, UK (B Dimitrov MD); MantaMatics UG, Dompfaffenweg, Geretsried, Germany (A Manta PhD); Ayasdi Inc, Palo Alto, CA, USA (T Petrossian PhD, P Lum PhD); and Novartis Institute of Biomedical Research, Basel, Switzerland (S D Gadola MD) Correspondence to: Dr Timothy Hinks, University of Southampton School of Medicine, Academic Unit of Clinical and Experimental Sciences, Mailpoint 810, Level F, South Block, Southampton General Hospital, Southampton SO16 6YD, UK [email protected]
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Background Incomplete understanding of mechanisms and clinicopathobiological heterogeneity in asthma hinders research progress. Pathogenic roles for T-helper-type 17 (Th17) cells and invariant T cells implied by murine data have yet to be assessed in man. We aimed to investigate the role of Th17 and mucosal associated invariant T (MAIT) cells in airway inflammation; to characterise associations between diverse clinical and immunological features of asthma; and to identify novel multidimensional asthma endotypes. Methods In this single-centre, cross-sectional observational study in the UK, we assessed volunteers with mild-to-severe asthma and healthy non-atopic controls using clinical and physiological assessment and immunological sampling of blood, induced sputum, endobronchial biopsy, and bronchoalveolar lavage for flow cytometry and multiplex-electrochemiluminescence assays. Primary outcomes were changes in frequencies of Th17 and MAIT cells between health and asthma using Mann-Whitney U tests and the Jonckheere-Terpstra test (linear trend across ranked groups). The study had 80% power to detect 60% differences in T-cell frequencies at p<0·05. Bayesian Network Analysis (BNA) was used to explore associations between parameters. Topological Data Analysis (TDA) was used to identify multidimensional endotypes. The study had local research ethics approval. All participants provided informed consent. Findings Participants were 84 male and female volunteers (60 with mild-to-severe asthma and 24 healthy, non-atopic controls) aged 18–70 years recruited from clinics and research cohorts. Th17 cells and γδ17 cells were not associated with asthma, even in severe neutrophilic forms. MAIT-cell frequencies were strikingly reduced in asthma compared with health (median frequency in blood 0·9% of CD3+ cells [IQR 0·3–1·8] in asthma vs 1·6 [1·2–2·6] in health, p=0·005; in sputum 1·1 [0·7–2·0] vs 1·8 [1·6–2·3], p=0·002; and in biopsy samples 1·3 [0·7–2·3] vs 3·9% [1·3–5·3%], p=0·02), especially in severe asthma where BAL regulatory T cells were also reduced compared with those in health (4·4, 3·1–6·1, vs 8·1, 5·6–10; p=0·02). BNA and TDA identified six novel clinicopathobiological clusters of underlying disease mechanisms, with elevated mast cell mediators tryptase (p<0·0001), chymase (p=0·02), and carboxypeptidase A3 (p=0·02) in severe asthma. Interpretation This study suggests that Th17 cells do not have a major pathogenic role in human asthma. We describe a novel deficiency of MAIT cells in severe asthma. We also provide proof of concept for application of TDA to identification of multidimensional clinicopathobiological endotypes. Endotypes will require validation in further cohorts. Funding Wellcome Trust. Contributors TH, SDG, and RD conceived the study. TH, KS, CS, JW, and PH conducted the study recruitment and sample collection. TH conducted all assays except the mast cell assays which were conducted by XZ and AW. TH, BD, AM, TP, and PYL performed the data analysis. All authors contributed to drafting and approving the final abstract. Declaration of interests AW and XZ declare that they have a patent EP 1982191 issued (assay for carboxypeptidase A3), and a patent USPA 12/161409 pending (assay for carboxypeptidase A3). PL and TP are both employees at Ayasdi, Inc, and have received stock options in this company whose software for TDA (Iris) was used in this study. All other authors declare no competing interests.
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