BrainVis: Visualization and Statistical Analysis of Brain Connectivity in Alzheimer’s Disease Yuliya Plotka Thesis to obtain the Master of Science Degree in Information Systems and Computer Engineering Supervisors: Prof. Sandra Pereira Gama Prof. Hugo Alexandre Teixeira Duarte Ferreira Examination Committee Chairperson: Prof. Jose´ Carlos Alves Pereira Monteiro Supervisor: Prof. Sandra Pereira Gama Member of the Committee: Prof. Hugo Miguel Aleixo Albuquerque Nicolau October 2018 Acknowledgments Is this real life? Thank you, Acknowledgments section, for existing. You gave me a great amount of motivation because writing you means one more stage of my life is done, which, now that I think about it, gives me a bittersweet feeling. Thank you, prof. Sandra Gama for all the help and feedback. Thank you, prof. Hugo Ferreira and IBEB for providing the data for the development of this work, and for the feedback. Thank you, Tecnico,´ for the opportunity you gave me to grow, to expand my horizons, to discover beautiful Lisbon and most importantly, to meet wonderful human beings. Our love-hate relationship will never end as I will constantly remember you while plucking my emerging white hairs. Thank you, Climber & Climber Mafia, for showing me the world of professional work in an outstanding way. To trust in me and to teach me, patiently, and to drive me to thrive every day. To lead me to meet unforgettable people. Ricardo, thank you for being the most intellectually energetic person (? - not sure about this) I know, for making me see that nothing is impossible and that anyone can learn anything. Mario,´ thank you for waking my love for mountains and to being a living legend. Cruzinha, thank you for being a great friend. Thank you for your craziness, for all the adventures, for being an amazing person, the biggest cat lover, and for buying all my bikes. Thank you Filipe F., Daniela, Carlos, and everyone I made group projects with. This opportunity of working with different people taught me to be more adaptable and helped me to prepare me for the real world, thank you for that. Thank you Gonc¸alo, Shima, Andre,´ Xico, Ricardo, Joao, Fred, Fabio,´ Durao,˜ and all the friends whom I met in LEIC and MEIC. You made all these past years much better. Andreia and Sara, thank you for all the companionship, the trips, the support and the nights out. You are amazing. Lucas, thank you for all the movie sessions, and for fighting for your dreams and never give up. You inspire me. Nicolau, Taniaˆ and Pedro, thank you for all the cycling adventures. Thank you for all the fun, uplifting mood and for helping me feed this passion. Pedro, thank you for always challenging the standards of knowledge. People like you change the world and inspire me. Inesˆ and Lucia,´ thank you for being my best friends for the last 10 years. I could not ask for better friends to grow up with. Thank you for teaching me that friendship is more important than pride. I will never forget you. Miguel Rosa, thank you for being there, especially in the dark moments in life. Thank you for all the cooking sessions. I promise I’ll pay you all the bets I lost, one day. Manel, thank you for all the mindfulness sessions. For all your teaching, for remembering me to always give unconditionally. For bringing me back to earth, when needed. For reassuring me that the happiest people in life are the simplest. Thank you, Ventura, Carol, Raquel, Gui, Bia, Ricardo, Valentin, for being great friends. For everything being the same even when we don’t see each other for months. With you, I feel at home. My parents, Svitlana and Stanislav, thank you for teaching me the value of sacrifice. For being great role models. For the unconditional love and support. For showing me that no matter the challenge, there’s always a way. Thank you for making lovely Portugal our home. I could never thank you enough. My brother, Sasha, thank you for being always there. My late cat, Maska, thank you for being a great companion for 15 years, and for making my nights warmer. The rest of my family, thank you all for your support, even living far away. Tiago, thank you for your spontaneity and for coming to Sanabria with me. Thank for your kindness, silliness, warmness, for taking care, for unconditional support, love, and for everything. Thank you for making my life a little bit better, every day. You inspire me to be a better person, every day. To each and every one of you - thank you. There will always be a special spot for you in my heart and my mind; well, unless I get Alzheimer’s, then entirely in my heart. ii Abstract Alzheimer’s disease is the most frequent cause of dementia in the western population. It is a neurode- generative disorder marked by a cognitive and behavioral impairment that significantly interferes with social and occupational functioning. There are many ways to obtain data from the brain, but it is very difficult to analyze it in text or tabular form because of the complex structure of the brain, having a very large number of regions. Three different connectivity metrics were used, for 114 regions of the brain. A tool using data visualization and statistical analysis was developed, aiming to analyze the brain data and its connectivity, in order to understand what are the relevant metrics and regions associated with Alzheimer’s disease. In the first phase, low-fidelity prototypes were developed aiming to understand the dimensions of the available data. Later, more useful idioms were generated, along with several statistical analysis tests, used to bring more useful insights. The interface contains four different screens, using several information visualizations techniques and additional results from the statistical tests, providing multiple discoveries, through analysis and interaction, of several groups of patients, in different stages of Alzheimer’s disease. To validate the system, usability tests were performed with users who validated the usability and utility of our solution. Keywords Alzheimer’s disease, Brain Connectivity, Information Visualization iii Contents 1 Introduction 1 1.1 Visualization of Brain Connectivity...............................3 1.2 Alzheimer’s disease.......................................3 1.3 Organization of the Document..................................4 2 Related Work 5 2.1 Brain Visualization Tools.....................................7 2.1.1 BrainNet Viewer.....................................7 2.1.2 Connectome Viewer Toolkit...............................9 2.1.3 NetworkCube....................................... 11 2.1.4 Multimodal Imaging Brain Connectivity Analysis (MIBCA) toolbox......... 12 2.1.5 CortechsLabs....................................... 13 2.1.6 Assessa.......................................... 14 2.1.7 Brain Modulyzer: Interactive Visual Analysis of Functional Brain Connectivity... 15 2.2 Medical and Statistics Visualization Tools........................... 16 2.2.1 AnamneVis........................................ 17 2.2.2 Affinity........................................... 18 2.2.3 Similan.......................................... 19 2.2.4 DICON.......................................... 20 2.2.5 PhenoBlocks....................................... 21 2.2.6 PatternFinder....................................... 22 2.2.7 A rank-by-feature framework for interactive exploration of multidimensional data.. 23 2.3 Discussion............................................ 23 3 BrainVis 27 3.1 Requirements analysis...................................... 29 3.1.1 Instituto de Biof´ısica e Engenharia Biomedica´ ..................... 29 3.2 Data treatment and organization................................ 31 3.2.1 Original data structure.................................. 32 v 3.2.2 Data processing..................................... 33 3.3 Learning phase.......................................... 35 3.4 First prototype.......................................... 38 3.5 Functional prototype....................................... 40 3.5.1 User interface components............................... 40 3.5.1.A Distribution analysis.............................. 42 3.5.1.B Normality Test................................. 45 3.5.1.C Comparing Mean and Median........................ 46 3.5.1.D Correlation analysis.............................. 48 3.5.2 Statistical analysis.................................... 49 3.6 Tool selection and development environment......................... 53 3.6.1 Programming Language................................. 53 3.6.2 R packages........................................ 53 3.6.3 Shiny........................................... 55 3.6.4 External libraries..................................... 56 3.7 Architecture............................................ 57 4 Evaluation 59 4.1 Protocol.............................................. 61 4.2 Results.............................................. 62 4.3 Discussion............................................ 63 5 Conclusions and future work 67 A User testing - Presentation and Contextualization 75 B User testing - Available tasks 77 vi List of Figures 1.1 Representing space in functional connectivity graphs. [van der Flier and Scheltens, 2005]4 2.1 BrainNet Viewer [Xia et al., 2013]................................8 2.2 Connectome Viewer Toolkit [Gerhard et al., 2011]....................... 10 2.3 NetworkCube [Bach et al., 2015]................................ 11 2.4 MIBCA toolbox [Ribeiro et al., 2015].............................. 12 2.5 Neuroquant Hippocampal Asymmetry Report [CortechsLabs, 2018]...........