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201. A computational framework for complex disease stratification from multiple large-scale datasets

Author

Meulder, Bertrand de, Lefaudeux, Diane, Bansal, Aruna T., Mazein, Alexander, Chaiboonchoe, Amphun, Ahmed, Hassan, Balaur, Irina, Saqi, Mansoor, Pellet, Johann, Ballereau, Stephane, Lemonnier, Nathanaël, Sun, Kai, Pandis, Ioannis, Yang, Xian, Batuwitage, Manohara, Kretsos, Kosmas, Eyll, Jonathan van, Bedding, Alun, Davison, Timothy, Dodson, Paul, Larminie, Christopher, Postle, Anthony, Corfield, Julie, Djukanovic, Ratko, Chung, Kian Fan, Adcock, Ian M., Guo, Yi-Ke, Sterk, Peter J., Manta, Alexander, Rowe, Anthony, Baribaud, Frédéric, Auffray, Charles, Badorrek, Philipp, Faulenbach, Cornelia, Braun, Armin, Hohlfeld, Jens, Krug, Norbert, and Publica

Subjects
stratification, Omics data, systems medicine, molecular signature
Abstract

Background: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. Methods: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. Results: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. Conclusions: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.

Published
2018

203. IL-17–high asthma with features of a psoriasis immunophenotype

Author

Östling, Jörgen, primary, van Geest, Marleen, additional, Schofield, James P.R., additional, Jevnikar, Zala, additional, Wilson, Susan, additional, Ward, Jonathan, additional, Lutter, Rene, additional, Shaw, Dominick E., additional, Bakke, Per S., additional, Caruso, Massimo, additional, Dahlen, Sven-Erik, additional, Fowler, Stephen J., additional, Horváth, Ildikó, additional, Krug, Norbert, additional, Montuschi, Paolo, additional, Sanak, Marek, additional, Sandström, Thomas, additional, Sun, Kai, additional, Pandis, Ioannis, additional, Auffray, Charles, additional, Sousa, Ana R., additional, Guo, Yike, additional, Adcock, Ian M., additional, Howarth, Peter, additional, Chung, Kian Fan, additional, Bigler, Jeanette, additional, Sterk, Peter J., additional, Skipp, Paul J., additional, Djukanović, Ratko, additional, Vaarala, Outi, additional, Adcock, I.M., additional, Ahmed, H., additional, Auffray, C., additional, Bakke, P., additional, Bansal, A.T., additional, Baribaud, F., additional, Bates, S., additional, Bel, E.H., additional, Bigler, J., additional, Bisgaard, H., additional, Boedigheimer, M.J., additional, Bønnelykke, K., additional, Brandsma, J., additional, Brinkman, P., additional, Bucchioni, E., additional, Burg, D., additional, Bush, A., additional, Caruso, M., additional, Chaiboonchoe, A., additional, Chanez, P., additional, Chung, K.F., additional, Compton, C.H., additional, Corfield, J., additional, D'Amico, A., additional, Dahlen, S.E., additional, De Meulder, B., additional, Djukanovic, R., additional, Erpenbeck, V.J., additional, Erzen, D., additional, Fichtner, K., additional, Fitch, N., additional, Fleming, L.J., additional, Formaggio, E., additional, Fowler, S.J., additional, Frey, U., additional, Gahlemann, M., additional, Geiser, T., additional, Guo, Y., additional, Hashimoto, S., additional, Haughney, J., additional, Hedlin, G., additional, Hekking, P.W., additional, Higenbottam, T., additional, Hohlfeld, J.M., additional, Holweg, C., additional, Horváth, I., additional, Howarth, P., additional, James, A.J., additional, Knowles, R., additional, Knox, A.J., additional, Krug, N., additional, Lefaudeux, D., additional, Loza, M.J., additional, Lutter, R., additional, Manta, A., additional, Masefield, S., additional, Mazein, A., additional, Meiser, A., additional, Middelveld, R.J.M., additional, Miralpeix, M., additional, Montuschi, P., additional, Mores, N., additional, Murray, C.S., additional, Musial, J., additional, Myles, D., additional, Pahus, L., additional, Pandis, I., additional, Pavlidis, S., additional, Powell, P., additional, Praticò, G., additional, Rao, M. Puig N., additional, Riley, J., additional, Roberts, A., additional, Roberts, G., additional, Rowe, A., additional, Sandström, T., additional, Seibold, W., additional, Selby, A., additional, Shaw, D.E., additional, Sigmund, R., additional, Singer, F., additional, Skipp, P.J., additional, Sousa, A.R., additional, Sterk, P.J., additional, Sun, K., additional, Thornton, B., additional, van Aalderen, W.M., additional, van Geest, M., additional, Vestbo, J., additional, Vissing, N.H., additional, Wagener, A.H., additional, Wagers, S.S., additional, Weiszhart, Z., additional, Wheelock, C.E., additional, Wilson, S.J., additional, Aliprantis, Antonios, additional, Allen, David, additional, Alving, Kjell, additional, Badorrek, P., additional, Balgoma, David, additional, Ballereau, S., additional, Barber, Clair, additional, Batuwitage, Manohara Kanangana, additional, Bautmans, A., additional, Bedding, A., additional, Behndig, A.F., additional, Beleta, Jorge, additional, Berglind, A., additional, Berton, A., additional, Bochenek, Grazyna, additional, Braun, Armin, additional, Campagna, D., additional, Carayannopoulos, Leon, additional, Casaulta, C., additional, Chaleckis, Romanas, additional, Dahlén, B., additional, Davison, imothy, additional, De Alba, Jorge, additional, De Lepeleire, Inge, additional, Dekker, Tamara, additional, Delin, Ingrid, additional, Dennison, P., additional, Dijkhuis, Annemiek, additional, Dodson, Paul, additional, Draper, Aleksandra, additional, Dyson, K., additional, Edwards, Jessica, additional, El Hadjam, L., additional, Emma, Rosalia, additional, Ericsson, Magnus, additional, Faulenbach, C., additional, Flood, Breda, additional, Galffy, G., additional, Gallart, Hector, additional, Garissi, D., additional, Gent, J., additional, Gerhardsson de Verdier, M., additional, Gibeon, D., additional, Gomez, Cristina, additional, Gove, Kerry, additional, Gozzard, Neil, additional, Guillmant-Farry, E., additional, Henriksson, E., additional, Hewitt, Lorraine, additional, Hoda, U., additional, Hu, Richard, additional, Hu, Sile, additional, Hu, X., additional, Jeyasingham, E., additional, Johnson, K., additional, Jullian, N., additional, Kamphuis, Juliette, additional, Kennington, Erika J., additional, Kerry, Dyson, additional, Kerry, G., additional, Klüglich, M., additional, Knobel, Hugo, additional, Kolmert, Johan, additional, Konradsen, J.R., additional, Kots, Maxim, additional, Kretsos, Kosmas, additional, Krueger, L., additional, Kuo, Scott, additional, Kupczyk, Maciej, additional, Lambrecht, Bart, additional, Lantz, A.-S., additional, Larminie, Christopher, additional, Larsson, L.X., additional, Latzin, P., additional, Lazarinis, N., additional, Lemonnier, N., additional, Lone-Latif, Saeeda, additional, Lowe, L.A., additional, Manta, Alexander, additional, Marouzet, Lisa, additional, Martin, Jane, additional, Mathon, Caroline, additional, McEvoy, L., additional, Meah, Sally, additional, Menzies-Gow, A., additional, Metcalf, Leanne, additional, Mikus, Maria, additional, Monk, Philip, additional, Naz, Shama, additional, Nething, K., additional, Nicholas, Ben, additional, Nihlén, U., additional, Nilsson, Peter, additional, Niven, R., additional, Nordlund, B., additional, Nsubuga, S., additional, Pacino, Antonio, additional, Palkonen, Susanna, additional, Pellet, J., additional, Pennazza, Giorgio, additional, Petrén, Anne, additional, Pink, Sandy, additional, Pison, C., additional, Postle, Anthony, additional, Rahman-Amin, Malayka, additional, Ravanetti, Lara, additional, Ray, Emma, additional, Reinke, Stacey, additional, Reynolds, Leanne, additional, Riemann, K., additional, Robberechts, Martine, additional, Rocha, J.P., additional, Rossios, C., additional, Russell, Kirsty, additional, Rutgers, Michael, additional, Santini, G., additional, Santoninco, Marco, additional, Saqi, M., additional, Schoelch, Corinna, additional, Scott, S., additional, Sehgal, N., additional, Sjödin, Marcus, additional, Smids, Barbara, additional, Smith, Caroline, additional, Smith, Jessica, additional, Smith, Katherine M., additional, Söderman, P., additional, Sogbessan, A., additional, Spycher, F., additional, Staykova, Doroteya, additional, Stephan, S., additional, Stokholm, J., additional, Strandberg, K., additional, Sunther, M., additional, Szentkereszty, M., additional, Tamasi, L., additional, Tariq, K., additional, Thörngren, John-Olof, additional, Thorsen, Jonathan, additional, Valente, S., additional, van de Pol, Marianne, additional, van Drunen, C.M., additional, Van Eyll, Jonathan, additional, Versnel, Jenny, additional, Vink, Anton, additional, von Garnier, C., additional, Vyas, A., additional, Wald, Frans, additional, Walker, Samantha, additional, Wetzel, Kristiane, additional, Wiegman, Coen, additional, Williams, Siân, additional, Yang, Xian, additional, Yeyasingham, Elizabeth, additional, Amgen, W. Yu, additional, Zetterquist, W., additional, Zolkipli, Z., additional, and Zwinderman, A.H., additional

Published
2019
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206. Toward clinically applicable biomarkers for asthma: An EAACI position paper

Author

Diamant, Zuzana, primary, Vijverberg, Susanne, additional, Alving, Kjell, additional, Bakirtas, Arzu, additional, Bjermer, Leif, additional, Custovic, Adnan, additional, Dahlen, Sven‐Erik, additional, Gaga, Mina, additional, Gerth van Wijk, Roy, additional, Del Giacco, Stefano, additional, Hamelmann, Eckard, additional, Heaney, Liam G., additional, Heffler, Enrico, additional, Kalayci, Ömer, additional, Kostikas, Konstantinos, additional, Lutter, Rene, additional, Olin, Anna‐Carin, additional, Sergejeva, Svetlana, additional, Simpson, Angela, additional, Sterk, Peter J., additional, Tufvesson, Ellen, additional, Agache, Ioana, additional, and Seys, Sven F., additional

Published
2019
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207. Modelling electronic nose sensor deflections by matching Gas Chromatography-Mass Spectrometry exhaled breath samples

Author

Brinkman, Paul, primary, Sinha, Anirban, additional, Lammers, Ariane, additional, Van Bragt, Job J.M.H., additional, Richards, Levi B., additional, Dagelet, Yennece W.F., additional, Ibrahim, Mahmoud I.A., additional, Neerincx, Anne H., additional, Bos, Lieuwe D., additional, Sterk, Peter J., additional, and Maitland-Van Der Zee, Anke-Hilse, additional

Published
2019
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208. eNose breathprints as surrogate biomarkers for classifying asthma patients by atopy

Author

Ibrahim, Mahmoud Ismael Abdelaziz, primary, Brinkman, Paul, additional, Vijverberg, Susanne J. H., additional, Neerincx, Anne H., additional, Hashimoto, Simone, additional, De Vries, Rianne, additional, Dagelet, Yennece W.F., additional, Knipping, Karen, additional, Sterk, Peter J., additional, Kraneveld, Aletta D., additional, and Maitland-Van Der Zee, Anke-Hilse, additional

Published
2019
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209. Late Breaking Abstract - Technical validation of breath analysis by eNose in disease diagnosis: Tidal breathing vs. vital capacity manoeuvre

Author

de Vries, Rianne, primary, Dagelet, Yennece, additional, Dijkers, Erica, additional, Brinkman, Paul, additional, Farzan, Niloufar, additional, Maitland - Van Der Zee, Anke-Hilse, additional, De Jongh, Frans, additional, Haarman, Eric, additional, In ‘T Veen, Hans, additional, Baas, Paul, additional, Lucas, Annelies, additional, and Sterk, Peter J., additional

Published
2019
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210. Subtypes of eosinophilic asthma with discrete gene pathway phenotypes

Author

Perotin-Collard, Jeanne-Marie, primary, Schofield, James Pr, additional, Nicholas, Ben, additional, Strazzeri, Fabio, additional, Brandsma, Joost, additional, Bansal, Aruna T, additional, Yang, Xian, additional, Guo, Yi-Ke, additional, Rowe, Anthony, additional, Corfield, Julie, additional, Wilson, Susan J, additional, Ward, Jonathan, additional, Lutter, Rene, additional, Shaw, Dominick E, additional, Bakke, Per S, additional, Caruso, Massimo, additional, Dahlen, Sven-Erik, additional, Fowler, Stephen J, additional, Horvath, Ildiko, additional, Howarth, Peter, additional, Krug, Norbert, additional, Montuschi, Paolo, additional, Sanak, Marek, additional, Sandström, Thomas, additional, Sun, Kai, additional, Pandis, Ioannis, additional, Riley, John, additional, Auffray, Charles, additional, De Meulder, Bertrand, additional, Lefaudeux, Diane, additional, Sousa, Ana R, additional, Sterk, Peter J, additional, Adcock, Ian M, additional, Chung, Kian Fan, additional, Skipp, Paul J, additional, and Djukanovic, Ratko, additional

Published
2019
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211. Epithelial dysregulation in obese severe asthmatics with gastro-oesophageal reflux

Author

Perotin-Collard, Jeanne-Marie, primary, Schofield, James Pr, additional, Wilson, Susan J, additional, Ward, Jonathan, additional, Brandsma, Joost, additional, Strazzeri, Fabio, additional, Bansal, Aruna T, additional, Yang, Xian, additional, Rowe, Anthony, additional, Corfield, Julie, additional, Lutter, Rene, additional, Shaw, Dominic, additional, Bakke, Per S, additional, Caruso, Massimo, additional, Dahlén, Barbro, additional, Fowler, Stephen J, additional, Horvath, Ildiko, additional, Howarth, Peter, additional, Krug, Norbert, additional, Montuschi, Paolo, additional, Sanak, Marek, additional, Sandström, Thomas, additional, Sun, Kai, additional, Pandis, Ioannis, additional, Auffray, Charles, additional, De Meulder, Bertrand, additional, Lefaudeux, Diane, additional, Riley, John, additional, Sousa, Ana R, additional, Dahlen, Sven-Eric, additional, Adcock, Ian M, additional, Chung, Kian Fan, additional, Sterk, Peter J, additional, Skipp, Paul J, additional, Collins, Jane E, additional, Davies, Donna E, additional, and Djukanovic, Ratko, additional

Published
2019
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212. Exhaled volatile organic compounds as markers for medication use in asthma

Author

Brinkman, Paul, primary, Ahmed, Waqar M., additional, Gómez, Cristina, additional, Knobel, Hugo H., additional, Weda, Hans, additional, Vink, Teunis J., additional, Nijsen, Tamara M., additional, Wheelock, Craig E., additional, Dahlen, Sven-Erik, additional, Montuschi, Paolo, additional, Knowles, Richard G., additional, Vijverberg, Susanne J., additional, Maitland-van der Zee, Anke H., additional, Sterk, Peter J., additional, and Fowler, Stephen J., additional

Published
2019
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218. Eosinophils capture viruses, a capacity that is defective in asthma

Author

Sabogal Piñeros, Yanaika S., primary, Bal, Suzanne M., additional, Dijkhuis, Annemiek, additional, Majoor, Christof J., additional, Dierdorp, Barbara S., additional, Dekker, Tamara, additional, Hoefsmit, Esmée P., additional, Bonta, Peter I., additional, Picavet, Daisy, additional, van der Wel, Nicole N., additional, Koenderman, Leo, additional, Sterk, Peter J., additional, Ravanetti, Lara, additional, and Lutter, René, additional

Published
2019
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223. Effect of long-term corticosteroid treatment on microRNA and gene-expression profiles in COPD

Author

Faiz, Alen, primary, Steiling, Katrina, additional, Roffel, Mirjam P., additional, Postma, Dirkje S., additional, Spira, Avrum, additional, Lenburg, Marc E., additional, Borggrewe, Malte, additional, Eijgenraam, Tim R., additional, Jonker, Marnix R., additional, Koppelman, Gerard H., additional, Pouwels, Simon D., additional, Liu, Gang, additional, Alekseyev, Yuriy O., additional, Lam, Stephen, additional, Hiemstra, Pieter S., additional, Sterk, Peter J., additional, Timens, Wim, additional, Brandsma, Corry-Anke, additional, Heijink, Irene H., additional, and van den Berge, Maarten, additional

Published
2019
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225. Anti–IL-5 in Mild Asthma Alters Rhinovirus-induced Macrophage, B-Cell, and Neutrophil Responses (MATERIAL). A Placebo-controlled, Double-Blind Study

Author

Sabogal Piñeros, Yanaika S., primary, Bal, Suzanne M., additional, van de Pol, Marianne A., additional, Dierdorp, Barbara S., additional, Dekker, Tamara, additional, Dijkhuis, Annemiek, additional, Brinkman, Paul, additional, van der Sluijs, Koen F., additional, Zwinderman, Aeilko H., additional, Majoor, Christof J., additional, Bonta, Peter I., additional, Ravanetti, Lara, additional, Sterk, Peter J., additional, and Lutter, René, additional

Published
2019
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226. Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Author

Jevnikar, Zala, primary, Östling, Jörgen, additional, Ax, Elisabeth, additional, Calvén, Jenny, additional, Thörn, Kristofer, additional, Israelsson, Elisabeth, additional, Öberg, Lisa, additional, Singhania, Akul, additional, Lau, Laurie C.K., additional, Wilson, Susan J., additional, Ward, Jonathan A., additional, Chauhan, Anoop, additional, Sousa, Ana R., additional, De Meulder, Bertrand, additional, Loza, Matthew J., additional, Baribaud, Frédéric, additional, Sterk, Peter J., additional, Chung, Kian Fan, additional, Sun, Kai, additional, Guo, Yike, additional, Adcock, Ian M., additional, Payne, Debbie, additional, Dahlen, Barbro, additional, Chanez, Pascal, additional, Shaw, Dominick E., additional, Krug, Norbert, additional, Hohlfeld, Jens M., additional, Sandström, Thomas, additional, Djukanovic, Ratko, additional, James, Anna, additional, Hinks, Timothy S.C., additional, Howarth, Peter H., additional, Vaarala, Outi, additional, van Geest, Marleen, additional, Olsson, Henric, additional, Adcock, I.M., additional, Ahmed, H., additional, Auffray, C., additional, Bakke, P., additional, Bansal, A.T., additional, Baribaud, F., additional, Bates, S., additional, Bel, E.H., additional, Bigler, J., additional, Bisgaard, H., additional, Boedigheimer, M.J., additional, Bønnelykke, K., additional, Brandsma, J., additional, Brinkman, P., additional, Bucchioni, E., additional, Burg, D., additional, Bush, A., additional, Caruso, M., additional, Chaiboonchoe, A., additional, Chanez, P., additional, Chung, F.K., additional, Compton, C.H., additional, Corfield, J., additional, D'Amico, A., additional, Dahlen, S.E., additional, De Meulder, B., additional, Djukanovic, R., additional, Erpenbeck, V.J., additional, Erzen, D., additional, Fichtner, K., additional, Fitch, N., additional, Fleming, L.J., additional, Formaggio, E., additional, Fowler, S.J., additional, Frey, U., additional, Gahlemann, M., additional, Geiser, T., additional, Goss, V., additional, Guo, Y., additional, Hashimoto, S., additional, Haughney, J., additional, Hedlin, G., additional, Hekking, P.W., additional, Higenbottam, T., additional, Hohlfeld, J.M., additional, Holweg, C., additional, Horváth, I., additional, James, A.J., additional, Knowles, R., additional, Knox, A.J., additional, Krug, N., additional, Lefaudeux, D., additional, Loza, M.J., additional, Manta, A., additional, Matthews, J.G., additional, Mazein, A., additional, Meiser, A., additional, Middelveld, R.J.M., additional, Miralpeix, M., additional, Montuschi, P., additional, Mores, N., additional, Murray, C.S., additional, Musial, J., additional, Myles, D., additional, Pahus, L., additional, Pandis, I., additional, Pavlidis, S., additional, Postle, A., additional, Powel, P., additional, Praticò, G., additional, Rao, N., additional, Riley, J., additional, Roberts, A., additional, Roberts, G., additional, Rowe, A., additional, Sandström, T., additional, Schofield, J.P.R., additional, Seibold, W., additional, Selby, A., additional, Shaw, D.E., additional, Sigmund, R., additional, Singer, F., additional, Skipp, P.J., additional, Sousa, A.R., additional, Sterk, P.J., additional, Sun, K., additional, Thornton, B., additional, van Aalderen, W.M., additional, van Geest, M., additional, Vestbo, J., additional, Vissing, N.H., additional, Wagener, A.H., additional, Wagers, S.S., additional, Weiszhart, Z., additional, Wheelock, C.E., additional, and Wilson, S.J., additional

Published
2019
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227. Morse-clustering of a Topological Data Analysis Network Identifies Phenotypes of Asthma Based on Blood Gene Expression Profiles

Author

Schofield, James P R, primary, Strazzeri, Fabio, additional, Bigler, Jeannette, additional, Boedigheimer, Michael, additional, Adcock, Ian M, additional, Chung, Kian Fan, additional, Bansal, Aruna, additional, Knowles, Richard, additional, Dahlen, Sven-Erik, additional, Wheelock, Craig E., additional, Sun, Kai, additional, Pandis, Ioannis, additional, Riley, John, additional, Auffray, Charles, additional, De Meulder, Bertrand, additional, Lefaudeux, Diane, additional, Ramanan, Devi, additional, Sousa, Ana R, additional, Sterk, Peter J, additional, Ewing, Rob. M, additional, Macarthur, Ben D, additional, Djukanovic, Ratko, additional, Sanchez-Garcia, Ruben, additional, and Skipp, Paul J, additional

Published
2019
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228. Asthma control cost-utility randomized trial evaluation (ACCURATE): the goals of asthma treatment

Author

Honkoop Persijn J, Loymans Rik JB, Termeer Evelien H, Snoeck-Stroband Jiska B, Bakker Moira J, Assendelft Willem JJ, Sterk Peter J, ter Riet Gerben, Schermer Tjard RJ, and Sont Jacob K

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Despite the availability of effective therapies, asthma remains a source of significant morbidity and use of health care resources. The central research question of the ACCURATE trial is whether maximal doses of (combination) therapy should be used for long periods in an attempt to achieve complete control of all features of asthma. An additional question is whether patients and society value the potential incremental benefit, if any, sufficiently to concur with such a treatment approach. We assessed patient preferences and cost-effectiveness of three treatment strategies aimed at achieving different levels of clinical control: 1. sufficiently controlled asthma 2. strictly controlled asthma 3. strictly controlled asthma based on exhaled nitric oxide as an additional disease marker Design 720 Patients with mild to moderate persistent asthma from general practices with a practice nurse, age 18-50 yr, daily treatment with inhaled corticosteroids (more then 3 months usage of inhaled corticosteroids in the previous year), will be identified via patient registries of general practices in the Leiden, Nijmegen, and Amsterdam areas in The Netherlands. The design is a 12-month cluster-randomised parallel trial with 40 general practices in each of the three arms. The patients will visit the general practice at baseline, 3, 6, 9, and 12 months. At each planned and unplanned visit to the general practice treatment will be adjusted with support of an internet-based asthma monitoring system supervised by a central coordinating specialist nurse. Patient preferences and utilities will be assessed by questionnaire and interview. Data on asthma control, treatment step, adherence to treatment, utilities and costs will be obtained every 3 months and at each unplanned visit. Differences in societal costs (medication, other (health) care and productivity) will be compared to differences in the number of limited activity days and in quality adjusted life years (Dutch EQ5D, SF6D, e-TTO, VAS). This is the first study to assess patient preferences and cost-effectiveness of asthma treatment strategies driven by different target levels of asthma control. Trial registration Netherlands Trial Register (NTR): NTR1756

Published
2011
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229. In vivo imaging of the airway wall in asthma: fibered confocal fluorescence microscopy in relation to histology and lung function

Author

Bel Elisabeth H, von der Thüsen Jan H, Yick Ching Yong, Sterk Peter J, and Kunst Peter W

Subjects
Asthma, Confocal Laser Scanning Microscopy, Extracellular Matrix, Respiratory Function Tests, Smooth muscle, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Airway remodelling is a feature of asthma including fragmentation of elastic fibres observed in the superficial elastin network of the airway wall. Fibered confocal fluorescence microscopy (FCFM) is a new and non-invasive imaging technique performed during bronchoscopy that may visualize elastic fibres, as shown by in vitro spectral analysis of elastin powder. We hypothesized that FCFM images capture in vivo elastic fibre patterns within the airway wall and that such patterns correspond with airway histology. We aimed to establish the concordance between the bronchial elastic fibre pattern in histology and FCFM. Second, we examined whether elastic fibre patterns in histology and FCFM were different between asthmatic subjects and healthy controls. Finally, the association between these patterns and lung function parameters was investigated. Methods In a cross-sectional study comprising 16 subjects (8 atopic asthmatic patients with controlled disease and 8 healthy controls) spirometry and bronchoscopy were performed, with recording of FCFM images followed by endobronchial biopsy at the airway main carina. Elastic fibre patterns in histological sections and FCFM images were scored semi-quantitatively. Agreement between histology and FCFM was analysed using linearly weighted kappa κw. Results The patterns observed in histological sections and FCFM images could be divided into 3 distinct groups. There was good agreement between elastic fibre patterns in histology and FCFM patterns (κw 0.744). The semi-quantitative pattern scores were not different between asthmatic patients and controls. Notably, there was a significant difference in post-bronchodilator FEV1 %predicted between the different patterns by histology (p = 0.001) and FCFM (p = 0.048), regardless of asthma or atopy. Conclusion FCFM captures the elastic fibre pattern within the airway wall in humans in vivo. The association between post-bronchodilator FEV1 %predicted and both histological and FCFM elastic fibre patterns points towards a structure-function relationship between extracellular matrix in the airway wall and lung function. Trial registration Netherlands Trial Register NTR1306

Published
2011
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230. Smoking status and anti-inflammatory macrophages in bronchoalveolar lavage and induced sputum in COPD

Author

Rabe Klaus F, Schrumpf Jasmijn A, van Wijngaarden Simone, Timens Wim, Budulac Simona E, Snoeck-Stroband Jiska B, Lapperre Thérèse S, Kunz Lisette IZ, Postma Dirkje S, Sterk Peter J, and Hiemstra Pieter S

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Macrophages have been implicated in the pathogenesis of COPD. M1 and M2 macrophages constitute subpopulations displaying pro- and anti-inflammatory properties. We hypothesized that smoking cessation affects macrophage heterogeneity in the lung of patients with COPD. Our aim was to study macrophage heterogeneity using the M2-marker CD163 and selected pro- and anti-inflammatory mediators in bronchoalveolar lavage (BAL) fluid and induced sputum from current smokers and ex-smokers with COPD. Methods 114 COPD patients (72 current smokers; 42 ex-smokers, median smoking cessation 3.5 years) were studied cross-sectionally and underwent sputum induction (M/F 99/15, age 62 ± 8 [mean ± SD] years, 42 (31-55) [median (range)] packyears, post-bronchodilator FEV1 63 ± 9% predicted, no steroids past 6 months). BAL was collected from 71 patients. CD163+ macrophages were quantified in BAL and sputum cytospins. Pro- and anti-inflammatory mediators were measured in BAL and sputum supernatants. Results Ex-smokers with COPD had a higher percentage, but lower number of CD163+ macrophages in BAL than current smokers (83.5% and 68.0%, p = 0.04; 5.6 and 20.1 ×104/ml, p = 0.001 respectively). The percentage CD163+ M2 macrophages was higher in BAL compared to sputum (74.0% and 30.3%, p < 0.001). BAL M-CSF levels were higher in smokers than ex-smokers (571 pg/ml and 150 pg/ml, p = 0.001) and correlated with the number of CD163+ BAL macrophages (Rs = 0.38, p = 0.003). No significant differences were found between smokers and ex-smokers in the levels of pro-inflammatory (IL-6 and IL-8), and anti-inflammatory (elafin, and Secretory Leukocyte Protease Inhibitor [SLPI]) mediators in BAL and sputum. Conclusions Our data suggest that smoking cessation partially changes the macrophage polarization in vivo in the periphery of the lung towards an anti-inflammatory phenotype, which is not accompanied by a decrease in inflammatory parameters.

Published
2011
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231. Airway inflammation and mannitol challenge test in COPD

Author

Smids-Dierdorp Barbara S, Krouwels Frans H, Dijkers Erica, Lutter Rene, Fens Niki, de Nijs Selma B, van Steenwijk Reindert P, and Sterk Peter J

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD. Methods Twenty-eight patients (age 58 ± 7.8 yr, packyears 40 ± 15.5, post-bronchodilator FEV1 77 ± 14.0%predicted, no inhaled steroids ≥4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum. Results There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL-8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum. Conclusions In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD. Trial registration Netherlands Trial Register (NTR): NTR1283

Published
2011
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232. “T2-high” in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin

Author

Pavlidis, Stelios, primary, Takahashi, Kentaro, additional, Ng Kee Kwong, Francois, additional, Xie, Jiaxing, additional, Hoda, Uruj, additional, Sun, Kai, additional, Elyasigomari, Vahid, additional, Agapow, Paul, additional, Loza, Matthew, additional, Baribaud, Fred, additional, Chanez, Pascal, additional, Fowler, Steve J., additional, Shaw, Dominic E., additional, Fleming, Louise J., additional, Howarth, Peter H., additional, Sousa, Ana R., additional, Corfield, Julie, additional, Auffray, Charles, additional, De Meulder, Bertrand, additional, Knowles, Richard, additional, Sterk, Peter J., additional, Guo, Yike, additional, Adcock, Ian M., additional, Djukanovic, Ratko, additional, and Fan Chung, Kian, additional

Published
2018
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236. Weekly self-monitoring and treatment adjustment benefit patients with partly controlled and uncontrolled asthma: an analysis of the SMASHING study

Author

Assendelft Willem JJ, Roldaan Albert C, Bakker Moira J, van Stel Henk F, van der Meer Victor, Sterk Peter J, Rabe Klaus F, and Sont Jacob K

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Internet-based self-management has shown to improve asthma control and asthma related quality of life, but the improvements were only marginally clinically relevant for the group as a whole. We hypothesized that self-management guided by weekly monitoring of asthma control tailors pharmacological therapy to individual needs and improves asthma control for patients with partly controlled or uncontrolled asthma. Methods In a 1-year randomised controlled trial involving 200 adults (18-50 years) with mild to moderate persistent asthma we evaluated the adherence with weekly monitoring and effect on asthma control and pharmacological treatment of a self-management algorithm based on the Asthma Control Questionnaire (ACQ). Participants were assigned either to the Internet group (n = 101) that monitored asthma control weekly with the ACQ on the Internet and adjusted treatment using a self-management algorithm supervised by an asthma nurse specialist or to the usual care group (UC) (n = 99). We analysed 3 subgroups: patients with well controlled (ACQ ≤ 0.75), partly controlled (0.75>ACQ ≤ 1.5) or uncontrolled (ACQ>1.5) asthma at baseline. Results Overall monitoring adherence was 67% (95% CI, 60% to 74%). Improvements in ACQ score after 12 months were -0.14 (p = 0.23), -0.52 (p < 0.001) and -0.82 (p < 0.001) in the Internet group compared to usual care for patients with well, partly and uncontrolled asthma at baseline, respectively. Daily inhaled corticosteroid dose significantly increased in the Internet group compared to usual care in the first 3 months in patients with uncontrolled asthma (+278 μg, p = 0.001), but not in patients with well or partly controlled asthma. After one year there were no differences in daily inhaled corticosteroid use or long-acting β2-agonists between the Internet group and usual care. Conclusions Weekly self-monitoring and subsequent treatment adjustment leads to improved asthma control in patients with partly and uncontrolled asthma at baseline and tailors asthma medication to individual patients' needs. Trial registration Current Controlled Trials ISRCTN79864465

Published
2010
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239. Comparison of exhaled breath condensate pH using two commercially available devices in healthy controls, asthma and COPD patients

Author

Vogelmeier Claus, Gauw Stefanie A, Bals Robert, Schot Robert, Dragonieri Silvano, Koczulla Rembert, Rabe Klaus F, Sterk Peter J, and Hiemstra Pieter S

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Analysis of exhaled breath condensate (EBC) is a non-invasive method for studying the acidity (pH) of airway secretions in patients with inflammatory lung diseases. Aim To assess the reproducibility of EBC pH for two commercially available devices (portable RTube and non-portable ECoScreen) in healthy controls, patients with asthma or COPD, and subjects suffering from an acute cold with lower-airway symptoms. In addition, we assessed the repeatability in healthy controls. Methods EBC was collected from 40 subjects (n = 10 in each of the above groups) using RTube and ECoScreen. EBC was collected from controls on two separate occasions within 5 days. pH in EBC was assessed after degasification with argon for 20 min. Results In controls, pH-measurements in EBC collected by RTube or ECoScreen showed no significant difference between devices (p = 0.754) or between days (repeatability coefficient RTube: 0.47; ECoScreen: 0.42) of collection. A comparison between EBC pH collected by the two devices in asthma, COPD and cold patients also showed good reproducibility. No differences in pH values were observed between controls (mean pH 8.27; RTube) and patients with COPD (pH 7.97) or asthma (pH 8.20), but lower values were found using both devices in patients with a cold (pH 7.56; RTube, p < 0.01; ECoScreen, p < 0.05). Conclusion We conclude that pH measurements in EBC collected by RTube and ECoScreen are repeatable and reproducible in healthy controls, and are reproducible and comparable in healthy controls, COPD and asthma patients, and subjects with a common cold.

Published
2009
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245. Lipid phenotyping of lung epithelial lining fluid in healthy human volunteers

Author

Brandsma, Joost, Goss, Victoria M., Yang, Xian, Bakke, Per S., Caruso, Massimo, Chanez, Pascal, Dahlén, Sven-Erik, Fowler, Stephen J., Horvath, Ildiko, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sandström, Thomas, Shaw, Dominick E., Chung, Kian Fan, Singer, Florian, Fleming, Louise J., Sousa, Ana R., Pandis, Ioannis, Bansal, Aruna T., Sterk, Peter J., Djukanovic, Ratko, Postle, Anthony D., Brandsma, Joost, Goss, Victoria M., Yang, Xian, Bakke, Per S., Caruso, Massimo, Chanez, Pascal, Dahlén, Sven-Erik, Fowler, Stephen J., Horvath, Ildiko, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sandström, Thomas, Shaw, Dominick E., Chung, Kian Fan, Singer, Florian, Fleming, Louise J., Sousa, Ana R., Pandis, Ioannis, Bansal, Aruna T., Sterk, Peter J., Djukanovic, Ratko, and Postle, Anthony D.

Abstract

Background: Lung epithelial lining fluid (ELF)-sampled through sputum induction-is a medium rich in cells, proteins and lipids. However, despite its key role in maintaining lung function, homeostasis and defences, the composition and biology of ELF, especially in respect of lipids, remain incompletely understood. Objectives: To characterise the induced sputum lipidome of healthy adult individuals, and to examine associations between different ELF lipid phenotypes and the demographic characteristics within the study cohort. Methods: Induced sputum samples were obtained from 41 healthy non-smoking adults, and their lipid compositions analysed using a combination of untargeted shotgun and liquid chromatography mass spectrometry methods. Topological data analysis (TDA) was used to group subjects with comparable sputum lipidomes in order to identify distinct ELF phenotypes. Results: The induced sputum lipidome was diverse, comprising a range of different molecular classes, including at least 75 glycerophospholipids, 13 sphingolipids, 5 sterol lipids and 12 neutral glycerolipids. TDA identified two distinct phenotypes differentiated by a higher total lipid content and specific enrichments of diacyl-glycerophosphocholines, -inositols and -glycerols in one group, with enrichments of sterols, glycolipids and sphingolipids in the other. Subjects presenting the lipid-rich ELF phenotype also had significantly higher BMI, but did not differ in respect of other demographic characteristics such as age or gender. Conclusions: We provide the first evidence that the ELF lipidome varies significantly between healthy individuals and propose that such differences are related to weight status, highlighting the potential impact of (over)nutrition on lung lipid metabolism.

Published
2018
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246. Measures of adherence in patients with severe asthma prescribed systemic steroids in the U-BIOPRED cohort

Author

Alahmadi, Fahad, Simpson, Andrew, Gomez, Christina, Wheelock, Craig, Shaw, Dominick, Fleming, Louise, Roberts, Graham, Riley, John, Bates, Stewart, Sousa, Ana R., Knowles, Richard, Bansal, Aruna, Corfield, Julie, Pandis, Ioannis, Sun, Kai, Bakke, Per, Caruso, Massimo, Chanez, Pascal, Dahlen, Babro, Horvath, Ildiko, Krug, Norbert, Montuschi, Paolo, Sandström, Thomas, Singer, Florian, Wagers, Scott, Adcock, Ian, Djukanovic, Ratko, Chung, Kian, Sterk, Peter J., Dahlen, Sven-Erik, Fowler, Stephen J., Alahmadi, Fahad, Simpson, Andrew, Gomez, Christina, Wheelock, Craig, Shaw, Dominick, Fleming, Louise, Roberts, Graham, Riley, John, Bates, Stewart, Sousa, Ana R., Knowles, Richard, Bansal, Aruna, Corfield, Julie, Pandis, Ioannis, Sun, Kai, Bakke, Per, Caruso, Massimo, Chanez, Pascal, Dahlen, Babro, Horvath, Ildiko, Krug, Norbert, Montuschi, Paolo, Sandström, Thomas, Singer, Florian, Wagers, Scott, Adcock, Ian, Djukanovic, Ratko, Chung, Kian, Sterk, Peter J., Dahlen, Sven-Erik, and Fowler, Stephen J.

Abstract

Introduction: Rates of sub-optimal adherence to medications in asthma range up to 70%; the impact in severe asthma is likely to be particularly high. We measured self-reported adherence in participants in the U-BIOPRED cohort prescribed daily prednisolone using the Medication Adherence Response Scale (MARS), and compared to measured urinary prednisolone and metabolites in order to determine: 1. the prevalence of suboptimal adherence by each method; 2. the ability of MARS to predict urinary steroid detection. Methods: Participants completed the MARS, and/or provided urine samples (analysed for prednisolone and metabolites by LCMS). The performance characteristics of the MARS predicting undetected urinary steroid were calculated in the subgroup having both tests. Results: 181 participants currently taking regular oral corticosteroids were included, 59% female, mean (SD) age 54(12)yrs, FEV1 64.7(20.4)% predicted. Sub-optimal adherence (MARS score < 4.5) was reported in 62 participants, and 76 did not have detectable urinary prednisolone or metabolites. Good adherence by both methods was detected in only 52 participants (34%, see table). There was no difference in daily prednisolone dose between detectable and undetectable metabolites groups (p=0.848). Conclusion: Low levels of adherence to treatment in severe asthma is a common problem, when measured either directly or self-reported. There was very poor agreement (48% concordance) between these two methods, and we suggest that, for now both approaches should be used., Supplement: 62Meeting Abstract: PA3992

Published
2018
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247. Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort

Author

Emma, Rosalia, Bansal, Aruna T., Kolmert, Johan, Wheelock, Craig E., Dahlen, Swen-Erik, Loza, Matthew J., De Meulder, Bertrand, Lefaudeux, Diane, Auffray, Charles, Dahlen, Barbro, Bakke, Per S., Chanez, Pascal, Fowler, Stephen J., Horvath, Ildiko, Montuschi, Paolo, Krug, Norbert, Sanak, Marek, Sandström, Thomas, Shaw, Dominick E., Fleming, Louise J., Djukanovic, Ratko, Howarth, Peter H., Singer, Florian, Sousa, Ana R., Sterk, Peter J., Cortield, Julie, Pandis, Ioannis, Chung, Kian F., Adcock, Ian M., Lutter, Rene, Fabbella, Lorena, Caruso, Massimo, Emma, Rosalia, Bansal, Aruna T., Kolmert, Johan, Wheelock, Craig E., Dahlen, Swen-Erik, Loza, Matthew J., De Meulder, Bertrand, Lefaudeux, Diane, Auffray, Charles, Dahlen, Barbro, Bakke, Per S., Chanez, Pascal, Fowler, Stephen J., Horvath, Ildiko, Montuschi, Paolo, Krug, Norbert, Sanak, Marek, Sandström, Thomas, Shaw, Dominick E., Fleming, Louise J., Djukanovic, Ratko, Howarth, Peter H., Singer, Florian, Sousa, Ana R., Sterk, Peter J., Cortield, Julie, Pandis, Ioannis, Chung, Kian F., Adcock, Ian M., Lutter, Rene, Fabbella, Lorena, and Caruso, Massimo

Abstract

Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF(2 alpha) and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF(2 alpha); IS-transcriptomics; BB-transcriptomics; BBrtranscriptomics). Urinary 8-iso-PGF(2 alpha) was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF(2 alpha) was increased in SAs/ex, median (IQR) = 31.7 (24.5 +/- 44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6 +/- 36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4 +/- 47.7), vs. ESA, median (IQR) = 29.4 (22.3 +/- 40.5), and NSA, median (IQR) = 26.5 (19.6 +/- 16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchia

Published
2018
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248. Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED : an exploratory analysis

Author

Takahashi, Kentaro, Pavlidis, Stelios, Kwong, Francois Ng Kee, Hoda, Uruj, Rossios, Christos, Sun, Kai, Loza, Matthew, Baribaud, Fred, Chanez, Pascal, Fowler, Steve J., Horvath, Ildiko, Montuschi, Paolo, Singer, Florian, Musial, Jacek, Dahlen, Barbro, Dahlen, Sven-Eric, Krug, Norbert, Sandström, Thomas, Shaw, Dominic E., Lutter, Rene, Bakke, Per, Fleming, Louise J., Howarth, Peter H., Caruso, Massimo, Sousa, Ana R., Corfield, Julie, Auffray, Charles, De Meulder, Bertrand, Lefaudeux, Diane, Djukanovic, Ratko, Sterk, Peter J., Guo, Yike, Adcock, Ian M., Chung, Kian Fan, Takahashi, Kentaro, Pavlidis, Stelios, Kwong, Francois Ng Kee, Hoda, Uruj, Rossios, Christos, Sun, Kai, Loza, Matthew, Baribaud, Fred, Chanez, Pascal, Fowler, Steve J., Horvath, Ildiko, Montuschi, Paolo, Singer, Florian, Musial, Jacek, Dahlen, Barbro, Dahlen, Sven-Eric, Krug, Norbert, Sandström, Thomas, Shaw, Dominic E., Lutter, Rene, Bakke, Per, Fleming, Louise J., Howarth, Peter H., Caruso, Massimo, Sousa, Ana R., Corfield, Julie, Auffray, Charles, De Meulder, Bertrand, Lefaudeux, Diane, Djukanovic, Ratko, Sterk, Peter J., Guo, Yike, Adcock, Ian M., and Chung, Kian Fan

Abstract

Severe asthma patients with a significant smoking history have airflow obstruction with reported neutrophilia. We hypothesise that multi-omic analysis will enable the definition of smoking and ex-smoking severe asthma molecular phenotypes. The U-BIOPRED cohort of severe asthma patients, containing current-smokers (CSA), ex-smokers (ESA), nonsmokers and healthy nonsmokers was examined. Blood and sputum cell counts, fractional exhaled nitric oxide and spirometry were obtained. Exploratory proteomic analysis of sputum supernatants and transcriptomic analysis of bronchial brushings, biopsies and sputum cells was performed. Colony-stimulating factor (CSF) 2 protein levels were increased in CSA sputum supernatants, with azurocidin 1, neutrophil elastase and CXCL8 upregulated in ESA. Phagocytosis and innate immune pathways were associated with neutrophilic inflammation in ESA. Gene set variation analysis of bronchial epithelial cell transcriptome from CSA showed enrichment of xenobiotic metabolism, oxidative stress and endoplasmic reticulum stress compared to other groups. CXCL5 and matrix metallopeptidase 12 genes were upregulated in ESA and the epithelial protective genes, mucin 2 and cystatin SN, were downregulated. Despite little difference in clinical characteristics, CSA were distinguishable from ESA subjects at the sputum proteomic level, with CSA patients having increased CSF2 expression and ESA patients showing sustained loss of epithelial barrier processes.

Published
2018
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249. Large-Scale Label-Free Quantitative Mapping of the Sputum Proteome

Author

Burg, Dominic, Schofield, James P. R., Brandsma, Joost, Staykova, Doroteya, Folisi, Caterina, Bansal, Aruna, Nicholas, Ben, Xian, Yang, Rowe, Anthony, Corfield, Julie, Wilson, Susan, Ward, Jonathan, Lutter, Rene, Fleming, Louise, Shaw, Dominick E., Bakke, Per S., Caruso, Massimo, Dahlen, Sven-Erik, Fowler, Stephen J., Hashimoto, Simone, Horvath, Ildiko, Howarth, Peter, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sandström, Thomas, Singer, Florian, Sun, Kai, Pandis, Ioannis, Auffray, Charles, Sousa, Ana R., Adcock, Ian M., Chung, Kian Fan, Sterk, Peter J., Djukanovic, Ratko, Skipp, Paul J., Burg, Dominic, Schofield, James P. R., Brandsma, Joost, Staykova, Doroteya, Folisi, Caterina, Bansal, Aruna, Nicholas, Ben, Xian, Yang, Rowe, Anthony, Corfield, Julie, Wilson, Susan, Ward, Jonathan, Lutter, Rene, Fleming, Louise, Shaw, Dominick E., Bakke, Per S., Caruso, Massimo, Dahlen, Sven-Erik, Fowler, Stephen J., Hashimoto, Simone, Horvath, Ildiko, Howarth, Peter, Krug, Norbert, Montuschi, Paolo, Sanak, Marek, Sandström, Thomas, Singer, Florian, Sun, Kai, Pandis, Ioannis, Auffray, Charles, Sousa, Ana R., Adcock, Ian M., Chung, Kian Fan, Sterk, Peter J., Djukanovic, Ratko, and Skipp, Paul J.

Abstract

Analysis of induced sputum supematant is a minimally invasive approach to study the epithelial lining fluid and, thereby, provide insight into normal lung biology and the pathobiology of lung diseases. We present here a novel proteomics approach to sputum analysis developed within the U-BIOPRED (unbiased biomarkers predictive of respiratory disease outcomes) international project. We present practical and analytical techniques to optimize the detection of robust biomarkers in proteomic studies. The normal sputum proteome was derived using data-independent HDMSE applied to 40 healthy nonsmoking participants, which provides an essential baseline from which to compare modulation of protein expression in respiratory diseases. The "core" sputum proteome (proteins detected in >= 40% of participants) was composed of 284 proteins, and the extended proteome (proteins detected in >= 3 participants) contained 1666 proteins. Quality control procedures were developed to optimize the accuracy and consistency of measurement of sputum proteins and analyze the distribution of sputum proteins in the healthy population. The analysis showed that quantitation of proteins by HDMSE is influenced by several factors, with some proteins being measured in all participants' samples and with low measurement variance between samples from the same patient. The measurement of some proteins is highly variable between repeat analyses, susceptible to sample processing effects, or difficult to accurately quantify by mass spectrometry. Other proteins show high interindividual variance. We also highlight that the sputum proteome of healthy individuals is related to sputum neutrophil levels, but not gender or allergic sensitization. We illustrate the importance of design and interpretation of disease biomarker studies considering such protein population and technical measurement variance.

Published
2018
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250. Exacerbations in adults with asthma : A systematic review and external validation of prediction models

Author

Loymans, Rik Jb, Debray, Thomas Pa, Honkoop, Persijn J, Termeer, Evelien H, Snoeck-Stroband, Jiska B, Schermer, Tjard Rj, Assendelft, Willem Jj, Timp, Merel, Chung, Kian Fan, Sousa, Ana R, Sont, Jaap K, Sterk, Peter J, Reddel, Helen K, Ter Riet, Gerben, Loymans, Rik Jb, Debray, Thomas Pa, Honkoop, Persijn J, Termeer, Evelien H, Snoeck-Stroband, Jiska B, Schermer, Tjard Rj, Assendelft, Willem Jj, Timp, Merel, Chung, Kian Fan, Sousa, Ana R, Sont, Jaap K, Sterk, Peter J, Reddel, Helen K, and Ter Riet, Gerben

Published
2018

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