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Spectral Analysis and Quantitation in Maldi-Ms Imaging

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Spectral Analysis and Quantitation in Maldi-Ms Imaging SPECTRAL ANALYSIS AND QUANTITATION IN MALDI-MS IMAGING A THESIS SUBMITTED TO THE UNIVERSITY OF MANCHESTER FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN THE FACULTY OF BIOLOGY, MEDICINE AND HEALTH 2019 SOMRUDEE DEEPAISARN SCHOOL OF HEALTH SCIENCES DIVISION OF INFORMATICS, IMAGING AND DATA SCIENCES ‘Blank page’ 2 Contents Abstract ............................................................................................................. 22 Declaration ........................................................................................................ 23 Copyright Statement .......................................................................................... 24 Acknowledgement ............................................................................................. 25 Chapter 1 Introduction ..................................................................................... 26 1.1 Important Concepts ........................................................................................ 26 1.2 Aims and Objectives ....................................................................................... 31 1.3 Thesis Overview .............................................................................................. 32 1.4 List of Outputs ................................................................................................ 35 Chapter 2 Background I: Mass Spectrometry Instrumentation and Applications 37 2.1 Fundamentals of Mass Spectrometry ............................................................ 38 2.1.1 General Background ................................................................................. 39 2.1.2 Ionisation Techniques .............................................................................. 40 2.1.2.1 Electron Ionisation ............................................................................ 41 2.1.2.2 Chemical Ionisation ........................................................................... 41 2.1.2.3 Fast Atom Bombardment .................................................................. 42 2.1.2.4 Electrospray Ionisation ...................................................................... 43 2.1.3 Types of Mass Analysers .......................................................................... 44 2.1.3.1 Electric/Magnetic Sectors ................................................................. 44 2.1.3.2 Transmission Quadrupole ................................................................. 45 2.1.3.3 Orbitrap ............................................................................................. 46 2.1.3.4 Fourier Transform Ion Cyclotron Resonance .................................... 46 2.2 MALDI Mass Spectrometry ............................................................................. 47 2.2.1 Invention .................................................................................................. 47 2.2.2 MALDI Ionisation ...................................................................................... 50 3 2.2.3 Ion Acceleration ....................................................................................... 52 2.2.4 The Time-of-flight Mass Analyser ............................................................ 54 2.2.4.1 Linear Time-of-flight Mass Spectrometer ......................................... 54 2.2.4.2 Reflectron Time-of-flight Mass Spectrometer .................................. 56 2.2.4.3 Curved Field Reflectron Mass Spectrometer .................................... 57 2.2.5 Ion Detection ........................................................................................... 57 2.2.6 Mass Resolution ....................................................................................... 58 2.2.7 MALDI Matrices ....................................................................................... 59 2.2.8 Sample Preparation (Sample-matrix Depositions) .................................. 60 2.2.9 Tandem Mass Spectrometry .................................................................... 62 2.3 Lipidomics and the Application of MALDI-MS in Lipidomics .......................... 64 2.3.1 Lipid Types and Functions ........................................................................ 64 2.3.2 Cellular Lipids ........................................................................................... 65 2.3.3 Lipid Extraction Techniques ..................................................................... 67 2.3.4 Spectral Analysis (in Lipid Classification) ................................................. 68 2.3.5 Limitations and Challenges ...................................................................... 71 2.3.6 Lipids in the Brain .................................................................................... 72 2.4 Mass Spectrometry Imaging for Lipid Analysis .............................................. 74 2.4.1 General MS Imaging Instrumentation ..................................................... 74 2.4.2 Understanding the Mass Spectrometry Imaging Data Formats .............. 74 2.4.3 MALDI-MS Imaging of Lipids .................................................................... 76 2.4.4 Other Mass Spectrometry Imaging Techniques ...................................... 79 Chapter 3 Background II: Quantitative Mass Spectrometry ............................... 81 3.1 The Scope of Quantitative Mass Spectrometry ............................................. 82 3.1.1 Problems in MALDI-MS Quantitation ...................................................... 83 3.1.2 Uses of Standards .................................................................................... 85 3.1.2.1 Internal Standards ............................................................................. 85 3.1.2.2 External Standards ............................................................................ 87 3.1.3 Conventional Peak Analysis ..................................................................... 87 3.1.4 Supporting Software for Mass Spectrometry Data Analysis ................... 89 3.2 Computational Analysis Methods for MALDI-MS Data .................................. 90 4 3.2.1 Data Mining .............................................................................................. 91 3.2.2 Computational Approaches ..................................................................... 92 3.2.2.1 Support Vector Machine ................................................................... 92 3.2.2.2 Nearest Neighbours .......................................................................... 93 3.2.2.3 Random Forest .................................................................................. 93 3.2.2.4 Neural Networks ............................................................................... 94 3.2.2.5 Discussion and Comparison of Some Approaches to MALDI-MS Data Analysis ............................................................................................................ 96 3.2.3 Understanding Signal and Noise and the Associated Analysis Requirements.................................................................................................... 101 3.3 Pre-processing of Mass Spectra for LP-ICA................................................... 104 3.3.1 Windowing and Resolution Reduction .................................................. 105 3.3.2 Alignment ............................................................................................... 106 3.3.3 Baseline Correction ................................................................................ 106 3.3.4 Peak Detection and Integration ............................................................. 107 3.4 Linear Poisson Independent Component Analysis ....................................... 109 3.4.1 Correlation of Numerical Data ............................................................... 109 3.4.2 Standard PCA and ICA ............................................................................ 110 3.4.2.1 Principal Component Analysis (PCA) ............................................... 110 3.4.2.2 Independent Component Analysis (ICA) ......................................... 111 3.4.3 Distribution of Data: Gaussian vs. Poisson ............................................ 112 3.4.4 MALDI-MS Data Characteristics ............................................................. 115 3.4.5 Linear Poisson Independent Component Analysis (LP-ICA) Modelling . 116 3.4.6 Maximisation Separation (MAX SEP) ..................................................... 119 Chapter 4 Optimisation of Experimental Parameters ...................................... 122 4.1 Introduction .................................................................................................. 122 4.2 Instrumentation ............................................................................................ 124 4.2.1 The AXIMA.............................................................................................. 124 4.2.2 The 7090................................................................................................. 124 4.2.3 Standard Apparatus Settings ................................................................. 125 4.3 Sample Preparation ...................................................................................... 125 5 4.3.1 Materials ................................................................................................ 125 4.3.2 Preparation of Milk Samples ................................................................. 127 4.3.3
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