Is high socioeconomic status a risk factor for multiple sclerosis? Robert Goulden Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal. Submission date: September 2014 | © Robert Goulden 2014 A thesis submitted to McGill University in partial fulfilment of the requirements of the degree of M.Sc. in Epidemiology. Table of Contents Abstract ...................................................................................................................................... 6 Résumé....................................................................................................................................... 7 Acknowledgements .................................................................................................................. 10 Preface and contributions of authors ...................................................................................... 11 1. Introduction ......................................................................................................................... 12 2. Multiple sclerosis: pathophysiology, clinical features, and epidemiology .......................... 14 Pathophysiology ................................................................................................................... 14 Clinical features .................................................................................................................... 14 Epidemiology and risk factors .............................................................................................. 16 Descriptive epidemiology and demographic features ..................................................... 16 Epstein Barr Virus ............................................................................................................. 18 Vitamin D and sunlight exposure ..................................................................................... 19 Genetics ........................................................................................................................... 19 Other factors .................................................................................................................... 20 Socioeconomic status ...................................................................................................... 20 3. Manuscript 1. Is high socioeconomic status a risk factor for multiple sclerosis? A systematic review. ................................................................................................................... 24 Authors ................................................................................................................................. 24 Abstract ................................................................................................................................ 25 2 Background ...................................................................................................................... 25 Methods ........................................................................................................................... 25 Results .............................................................................................................................. 25 Conclusions ...................................................................................................................... 25 Background .......................................................................................................................... 26 Methods ............................................................................................................................... 26 Search strategy and study selection ................................................................................ 26 Data extraction ................................................................................................................ 27 Quality assessment .......................................................................................................... 28 Results .................................................................................................................................. 28 Literature search .............................................................................................................. 28 Studies reporting an association with high SES ............................................................... 34 Studies not reporting an association with SES ................................................................ 34 Studies reporting an association with low SES ................................................................ 34 Study quality .................................................................................................................... 35 Synthesis .......................................................................................................................... 40 Discussion............................................................................................................................. 41 Conclusion ........................................................................................................................ 43 4. EnvIMS: a multi-national case control study of MS ............................................................. 44 5. Manuscript 2. Does low socioeconomic status in early life protect against multiple sclerosis? A multi-national, case-control study. ...................................................................... 47 3 Authors ................................................................................................................................. 47 Abstract ................................................................................................................................ 48 Background ...................................................................................................................... 48 Methods ........................................................................................................................... 48 Results .............................................................................................................................. 48 Conclusions ...................................................................................................................... 49 Background .......................................................................................................................... 49 Methods ............................................................................................................................... 50 Study population and design ........................................................................................... 50 Exposure ........................................................................................................................... 52 Statistical analysis ............................................................................................................ 54 Participant consent and ethics approval ......................................................................... 56 Results .................................................................................................................................. 56 Discussion............................................................................................................................. 59 Risk of bias ....................................................................................................................... 60 Comparison with other research ..................................................................................... 61 Conclusion ........................................................................................................................ 62 Appendix to manuscript 2 .................................................................................................... 62 Multiple imputation ......................................................................................................... 62 Supplementary tables ...................................................................................................... 64 4 6. Discussion and conclusions .................................................................................................. 69 References ............................................................................................................................... 72 5 Abstract Multiple sclerosis (MS) is a chronic disease of the central nervous system characterised by inflammation and neurodegeneration. An increased risk of the disease among those of high socioeconomic status (SES) was first observed over 50 years ago. This is in contrast to a more common pattern whereby adverse health outcomes are generally associated with low SES. Most MS risk factors, such as smoking, obesity, and a late age of EBV infection, vary in their prevalence by SES, and thus all provide pathways through which SES could affect disease risk. Alternatively, stress-related immune changes linked to SES could influence disease susceptibility. To establish the strength and nature of the association between SES and MS, two studies were performed as part of this manuscript-based thesis. The first manuscript is a systematic review of published cohort and case-control studies that examined the association between SES and MS risk. 21 articles were included. 5 studies, all from countries with higher levels of income inequality, reported an association between high SES and increased MS risk. 13 studies reported insufficient