1. Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study
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Loza, M. J., Djukanovic, R., Chung, K. F., Horowitz, D., Ma, K., Branigan, P., Barnathan, E. S., Susulic, V. S., Silkoff, P. E., Sterk, P. J., Baribaud, F., Strambu, I., Laviolette, M., Singh, D., Fitzgerald, J. M., Lam, S., Kelsen, S., Eich, A., Ludwig-Sengpiel, A., Hupp, G. C., Backer, V., Porsbjerg, C., Girodet, P. O., Berger, P., Leigh, R., Kline, J., Dransfield, M., Calhoun, W., Hussaini, A., Khatri, S., Chanez, P., Ian, A., Fleming Louis, J., David, G., Sile, H., Scott, K., Sally, M., Andrea, M., Stelios, P., Christos, R., Kirsty, R., Kai, S., Coen, W., Xian, Y., Nora, A., Ariane, W., Kees, v. D., Marianne, v. d. P., Wim, v. A., Sterk Peter, J., Barbara, S., Lara, R., Rene, L., Paul, B., Elisabeth, B., Koos, Z., Tamara, D., Simone, H., Annemiek, D., Pieter-Paul, H., Saeeda, L. -L., Hassan, A., Betrand, D. M., Diane, L., Antonios, A., Kjell, A., Charles, A., Philipp, B., Per, B., David, B., Sven-Erik, D., Ingrid, D., Cristina, G., James Anna, J., Roelinde, M., Shama, N., Anne, P., Stacey, R., Wheelock Craig, E., Hector, G., Maciej, K., Johan, K., Marcus, S., Bansal Aruna, T., Frederic, B., Navin, R., An, B., Inge, D. L., Martine, R., Behndig Annelie, F., Thomas, S., Jorge, B., De Jorge, A., Ann, B., Gunilla, H., Nordlund, Bjorn, Jon, K., Wilhelm, Z., Alix, B., Jorgen, O., van Marleen, G., de Maria, G. V., Lars, L., Ulf, N., Jeannette, B., Boedigheimer Michel, J., Richard, H., Xugang, H., Wen, Y., Hans, B., Klaus, B., Jonathan, T., Nadja, V., Grazyna, B., Jacek, M., Joost, B., Ben, N., Anthony, P., Doroteya, S., Armin, B., Jens, H., Norbert, K., Dominic, B., Schofield James, P. R., Skipp Paul, J., Leon, C., Bob, T., Caruso, Massimo, Rocha Joao Pedro, C. P., Julaiha, G., Andrew, M. -G., Adesimbo, S., Amphun, C., Romanas, C., Caroline, M., Pascal, C., Courtney, C., Jessica, E., Val, H., Kennington Erika, J., Leanne, M., Malayka, R. -A., Leanne, R., Jessica, S., Jenny, V., Samantha, W., Breda, F., Amanda, R., David, S., Chris, C., David, M., John, R., Sousa Ana, R., Julie, C., D'Amico, Arnaldo, Giorgio, P., Marco, S., Barbro, D., Ann-Sofie, L., Pim, B., Patrick, D., Kamran, T., Clair, B., Kerry, G., Aleksandra, D., Neil, F., Trevor, G., Scott, W., Rosalia, E., Davide, C., Magnus, E., Veit, E., Damijan, E., Klaus, F., Katja, N., Corinna, S., Frans, W., Kathrin, R., Kluglich, Matthias, Fowler Stephen, J., Murray Clare, S., Jorgen, V., Ashley, W., Urs, F., Martina, G., Gabriella, G., Ildiko, H., Marton, S., Lilla, T., Zsoka, W., Thomas, G., Neil, G., Yi-ke, G., John, H., Sian, W., Elisabeth, H., Nikos, L., Karin, S., Lorraine, H., Lisa, M., Jane, M., Sandy, P., Emma, R., Caroline, S., Tim, H., Uruj, H., Cecile, H., Matthews John, G., Peter, H., Graham, R., Juliette, K., Dyson, K., Hugo, K., Anton, V., Richard, K., Alan, K., Shaw Dominick, E., Maxim, K., Linn, K., Bart, L., Sarah, M., Pippa, P., Alexander, M., Maria, M., Peter, N., Montse, M., Philip, M., Paolo, M., Nadia, M., Giuseppe, S., Salvatore, V., Antonio, P., Laurie, P., Susanna, P., Ioannis, P., Anthony, R., Wolfgang, S., Kristiane, W., Florian, S., Smith Katherine, M., Paivi, S., John-Olof, T., von Christophe, G., Jonathan, W., Wilson Susan, J., Elizabeth, Y., AII - Amsterdam institute for Infection and Immunity, Pulmonology, Graduate School, Experimental Immunology, APH - Amsterdam Public Health, Epidemiology and Data Science, Medical Research Council (MRC), Commission of the European Communities, and National Institute for Health Research
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Oncology ,Time Factors ,AIRWAY INFLAMMATION ,Respiratory System ,Vital Capacity ,Disease ,Severity of Illness Index ,0302 clinical medicine ,RESEARCH-PROGRAM ,Forced Expiratory Volume ,Observational study ,Eosinophilic ,Medicine and Health Sciences ,030212 general & internal medicine ,Longitudinal Studies ,Lung ,SEVERE EOSINOPHILIC ASTHMA ,INDUCED SPUTUM ,Interleukin-13 ,Biological markers ,Adept ,Prognosis ,ADEPT (Airways Disease Endotyping for Personalized Therapeutics) and U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome Consortium) investigators ,Phenotype ,3. Good health ,Cohort ,Biomarker (medicine) ,Inflammation Mediators ,Life Sciences & Biomedicine ,medicine.drug ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Genotype ,QUESTIONNAIRE ,610 Medicine & health ,1102 Cardiovascular Medicine And Haematology ,03 medical and health sciences ,Th2 Cells ,Cluster analysis ,Fuzzy Logic ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Asthma ,Science & Technology ,IDENTIFICATION ,business.industry ,MEPOLIZUMAB ,Research ,Biology and Life Sciences ,Reproducibility of Results ,1103 Clinical Sciences ,medicine.disease ,Cross-Sectional Studies ,030228 respiratory system ,Gene Expression Regulation ,Immunology ,Interleukin-4 ,business ,Mepolizumab - Abstract
Background Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Methods Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Results Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was “mild, good lung function, early onset”, with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a “moderate, hyper-responsive, eosinophilic” phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a “mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic” phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a “severe uncontrolled, severe reversible obstruction, mixed granulocytic” phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Conclusions Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. Trial registration NCT01274507 (ADEPT), registered October 28, 2010 and NCT01982162 (U-BIOPRED), registered October 30, 2013. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0482-9) contains supplementary material, which is available to authorized users.
- Published
- 2016
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