Ascertaining Patterns of Asthma Symptoms in Childhood using Machine Learning Methods A thesis submitted to The University of Manchester for the degree of Doctor of Philosophy In the Faculty of Biology, Medicine and Health. 2019 Matea Deliu School of Health Sciences Division of Informatics, Imaging and Data Science Blank page 2 Table of Contents List of Tables ................................................................................................................... 6 List of Figures .................................................................................................................. 8 Abstract .......................................................................................................................... 9 Declaration .....................................................................................................................11 Copyright Statement.......................................................................................................11 Acknowledgements ........................................................................................................12 About the Author ...........................................................................................................13 1.1 Candidate Degrees ........................................................................................................... 13 1.2 Research Interests ............................................................................................................ 13 1.3 Publications ..................................................................................................................... 13 Chapter 1 General Introduction.......................................................................................15 1.1 Background and Rationale for Thesis ................................................................................ 15 1.1.2 What is Machine Learning?................................................................................................ 15 1.1.3 Machine Learning and Utilisation in Understanding Asthma .......................................... 15 1.2 Research Questions and Thesis Structure .......................................................................... 17 1.3 Author Contributions ........................................................................................................ 17 1.4 References ....................................................................................................................... 19 Chapter 2 Identification of asthma subtypes using clustering methodologies ...................20 1.1 Abstract ........................................................................................................................... 20 2.1 Introduction ..................................................................................................................... 20 2.2 What is clustering? ........................................................................................................... 22 2.2.1 Selection of variables / features and dimension reduction ............................................. 23 2.2.2 Clustering methods ............................................................................................................ 23 2.2.3 Stability of resulting clusters ............................................................................................. 26 2.3 Clustering methods in asthma subtyping ........................................................................... 27 2.3.1 The use of principal components analysis/ factor analysis in asthma subtyping ........... 27 2.3.2 Asthma subtype classification with model-free approaches ........................................... 30 2.3.3 Asthma subtyping and model-based approaches ............................................................. 37 2.4 Challenges in asthma clustering ........................................................................................ 39 2.4.1 Mixed types of data ........................................................................................................... 39 2.4.2 Lack of robustness to choice of variables and clustering methods .................................. 40 2.4.3 Differing subtypes across populations .............................................................................. 41 2.5 Conclusion ....................................................................................................................... 42 2.6 References ....................................................................................................................... 43 Chapter 3 Asthma phenotypes in childhood ....................................................................48 3.1 Abstract ........................................................................................................................... 48 3.2 Introduction ..................................................................................................................... 48 3.3 Wheeze phenotypes ......................................................................................................... 51 3.3.1 Wheeze phenotypes based on age of onset and remission (temporal pattern) ............. 51 3.3.2 Wheeze phenotypes based on triggers ............................................................................. 55 3.4 Phenotypes of severe asthma ........................................................................................... 57 3.5 Use of biomarkers to identify phenotypes ......................................................................... 58 3.5.1 Fractional concentration of exhaled Nitric Oxide (FeNO) ................................................ 58 3.5.2 Exhaled Breath Condensate ............................................................................................... 59 3.5.3 Periostin .............................................................................................................................. 59 3 3.6 Asthma phenotypes and genetic studies ........................................................................... 59 3.7 Conclusion ....................................................................................................................... 61 3.7.1 Lack of cohesive methodology for understanding asthma phenotypes in childhood .... 61 3.7.2 Clinical implications of defining asthma phenotypes in childhood ................................. 62 3.8 References ....................................................................................................................... 64 Chapter 4 Features of asthma which provide meaningful insights for understanding the disease heterogeneity.....................................................................................................70 4.1 Rationale for the study ..................................................................................................... 70 4.2 Abstract ........................................................................................................................... 70 4.3 Introduction ..................................................................................................................... 71 4.4 Methods .......................................................................................................................... 73 4.4.1 Study design, setting and participants .............................................................................. 73 4.4.2 Data sources/measurements ............................................................................................. 73 4.4.3 Statistical methods ............................................................................................................. 74 4.5 Results ............................................................................................................................. 75 4.5.1 Participants and descriptive data ...................................................................................... 75 4.5.2 Data-driven analyses: Dimensionality reduction vs. clustering using all available variables ....................................................................................................................................... 76 4.5.3 Blending the data and bio-statistical expertise with clinical expert domain knowledge 77 4.6 Discussion ........................................................................................................................ 83 4.6.1 Limitations/strengths ......................................................................................................... 83 4.6.2 Interpretation ..................................................................................................................... 84 4.7 References ....................................................................................................................... 88 4.7 Supplementary Material/ Appendix .................................................................................. 91 4.7.1 Methods.............................................................................................................................. 91 4.7.2 Results................................................................................................................................. 94 4.8 Supplementary References ............................................................................................. 115 Chapter 5 Longitudinal trajectories of wheeze exacerbations from infancy to school age and their association with