Helen Tremlett

Background: Although some progress has been made in understanding the period preceding the classical recognition of MS, further research is necessary to fully define this period and assess the influence of bias. The thesis objectives in the period before a first demyelinating disease claim or MS symptom onset included: (1) to describe the diversity of clinical pathways; (2) to describe the joint trajectories of physician visits, hospitalizations, and prescription drug classes; (3) to re-examine the association between MS and depression/anxiety after correcting for three major sources of bias; (4) to investigate the mediating relationship between MS, physician visits, and hospitalizations; and (5) to investigate the association between MS and fractures, dislocations/sprains/strains, and burns.Methods: This was a cohort study using clinical and population-based health administrative data in British Columbia, Canada (1991–2020). A multichannel state-sequence analysis of clinical pathways and group-based multi-trajectory modelling of physician visits, hospitalizations, and prescription drug classes was conducted. Probabilistic quantitative bias analyses were used to correct for misclassification and differential surveillance, and time-distribution matching to correct for misclassified person-time. A causal mediation analysis was conducted of MS, physician visits, and hospitalizations. A modified Poisson regression analysis was used to investigate fractures, dislocations/sprains/strains, and burns, with hdPS adjustment and targeted maximum likelihood estimation.Results: In the state-sequence analysis, nine pathways were identified before a first demyelinating claim, and five before MS symptom onset. In the trajectory analysis, low, moderate, and high health care use trajectories were identified before a first demyelinating claim and MS symptom onset. Correction for misclassification, differential surveillance, and misclassified person-time yielded a stronger association between depression/anxiety and MS. Before both a first demyelinating disease claim and MS symptom onset, the largest proportion of the total effect of MS on hospitalizations was mediated through physician visits related to the nervous system and mental health, and the risk of a fracture, dislocation/sprain/strain, and burn was higher among MS cases.Conclusion: Findings suggest that there is potential to identify and manage MS earlier. The advanced methods used enabled a more comprehensive understanding of the period preceding the classical recognition of MS.

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A growing body of evidence points to the gut microbiota playing a role in immune-mediated, neurological disease, such as multiple sclerosis (MS). An important initial step to understanding the relationship between the gut microbiota and MS is to compare the gut microbial community composition and metagenome in individuals with and without MS. In order to investigate the differences between the gut microbiome of MS patients and unaffected individuals, I conducted a systematic review of ten published articles from 2008-2018. The majority of studies found no difference in gut microbiota diversity, but consistent taxonomic differences were observed.To further investigate the MS microbiome, I conducted a case-control study using stool samples from individuals under the age of 22 with and without pediatric-onset MS who were enrolled in the Canadian Pediatric Demyelinating Disease Network. The study compared microbial taxonomy, gene annotations, metabolic pathways, and predicted metabolites in stool samples derived from metagenomic reads between MS cases and controls. I also assessed the relationship between diet, gut microbiota composition, and MS risk in the same population.The results of this dissertation showed subtle differences in individual taxa and functions between the gut microbiota of MS cases and controls. Additionally, a healthier diet rich in fiber was associated with a lower risk of MS and the MS-associated microbiota composition was also associated with aspects of diet. Overall, this research suggests that the gut microbiome plays a role in MS and that the potential interaction between diet and the gut microbiota is relevant in the development of MS.While gut microbiota diversity didn't significantly differ between MS cases and controls, we observed subtle differences in the relative abundance of individual taxa and functions. Future studies with larger sample sizes and longitudinal data collection are needed to both confirm findings and to verify interpretation of these findings. Understanding the role of the gut microbiota in MS may lead to the development of novel prevention and treatment strategies for this debilitating disease.

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Few population-based, methodologically rigorous studies have evaluated the association between mental health and health behaviours in MS. The goal of this dissertation is to contribute to the broader understanding of these relationships and their potential impact on MS. This dissertation was based on two main cohorts: 1) a multi-site clinic-based longitudinal cohort from across Canada; 2) a population-based health administrative and clinical cohort in British Columbia. A large (n=949) sample of MS patients were recruited from four Canadian MS clinics. Participants completed a series of questionnaires at three visits over two years. The prevalence of psychiatric comorbidities (depression and anxiety ), and adverse health behaviours (smoking and non-adherence to disease-modifying therapies (DMTs) ) was high. Alcohol dependence was associated with increased odds of anxiety (Odds Ratio (OR):1.84;95% confidence interval (CI):1.32–2.58) and depression (OR:1.53;95%CI:1.05–2.23), as was smoking (anxiety OR:1.29;95% CI:1.02–1.63; depression OR:1.37;95%CI:1.04–1.78). Non-adherence (80% of expected doses reported as taken in the previous 30 days) was associated with alcohol dependence (OR:2.14;95% CI:1.23–3.75). When compared to adherence rates estimated from prescription dispensation information in pharmacy records in the prior year, self-reported non-adherence was found to be highly specific (0.96), but only moderately sensitive (0.38). Those who self-reported non-adherence were at high risk of non-adherence over the following year.We identified cases of mood or anxiety disorders using a validated algorithm applied to health administrative data. The presence of a mood or anxiety disorder was associated with significantly increased neurologic disability, measured by the Expanded Disability Status Scale (β-coefficient:0.45; p0.0001) among 1250 incident cases of MS followed for an average of 9 years. Last, we identified incident cases of MS who did not access an MS clinic, using a validated algorithm applied to administrative data. Sex and socioeconomic status distributions were similar, but non-MS clinic users were older (46 vs 41 years, p0.001), and had a higher comorbidity burden than MS clinic-users (Rate ratio:1.08;95%CI:1.02-1.15). MS is an unpredictable disease with considerable variability in health outcomes. This dissertation provides evidence that psychiatric conditions and adverse health behaviours are common, and may explain some of this heterogeneity.

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Drug-induced liver injury is a common cause of acute liver failure; it is also the leading reason for a drug’s withdrawal from the market. Interferon-beta (IFN-β) is a commonly used disease-modifying drug for multiple sclerosis (MS) and is generally safe. However, 30-60% of IFN-β exposed patients experience liver aminotransferase elevations, with an unknown proportion experiencing more severe, medically significant elevations. To date, there are no means of predicting who will experience this adverse drug reaction (ADR), although the application of pharmacogenomics could assist with identifying predictive genomic factors. The purpose of this dissertation was to identify predictive factors associated with IFN-β induced liver injury to mitigate toxicity.The research in this dissertation commenced with a review article summarizing the potential application of pharmacogenomics to severe ADRs in MS and a case report of a patient experiencing a hepatic autoimmune-like complication of IFN-β therapy. An original research article followed; utilizing 942 IFN-β exposed MS patients, primarily from Canada. This population-based study examined the rate of liver injury due to IFN-β in MS patients. Approximately 1 in 50 (or 1.9%) IFN-β exposed patients’ experienced liver injury.A pharmacogenomic case-control study followed, involving 182 patients and a genome-wide scan of 785,230 genomic variants, to identify predictors of IFN-β induced liver injury. A genetic variant within synaptotagmin-14 was strongly associated with the ADR (odds ratio 9.83, 95% confidence interval 4.01-24.10, P-value 9.39 x 10-9) and was specific for liver injury from IFN-β and has been previously correlated with hepatic expression of interferon regulatory factor 6. This represents the first genome-wide association study of an ADR from an MS drug and of drug induced liver injury due to a biological therapy.The clinical, demographic and genomic characteristics identified here could modify the risk of experiencing a clinically significant ADR that often results in the cessation of a potentially useful treatment. Predictive characteristics of those at an increased risk will direct preventative strategies, such as enhanced monitoring for early signs of toxicity or alternative treatment regimens. This dissertation contributes towards the personalization of MS therapy and to the broader pharmacogenomic literature on biological therapies.

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Multiple sclerosis (MS) is a putative autoimmune disease of the central nervoussystem, affecting many adults of childbearing age. Although extensive research hasexamined the association between MS and traditional perinatal outcomes (i.e. cesareansection, birth weight and preterm birth), other important outcomes are understudied,partly due to existing methodological challenges. Using comprehensive populationbaseddatabases including the British Columbia (BC) MS Database, BC PerinatalDatabase Registry, Vital Statistics Birth Registry, Population Data BC Consolidation Fileand Census GeoData, this dissertation investigated the association between MS (andrelated clinical factors) with: labour induction and augmentation; obstetrical epidural andspinal anesthesia; length of birth hospitalization in mothers and their newborns; as wellas birth outcomes in fathers with MS. Overall, individuals with MS were not at increasedrisk for the investigated outcomes compared to the general population with theexception that multiparous women with MS had higher rates of epidural anesthesiacompared to multiparous women in the general population. Within MS women, thosewith longer disease duration had less epidural anesthesia and those with greaterdisability had more labor induction. Men with greater MS disability tended to fatheroffspring with lower mean birth weight, but their newborns were still within the normalrange for the general population.Individuals with MS who wish to have children must also decide betweeninitiating disease-modifying drug (DMD) early to minimize relapses (i.e. MS attacks) ordelaying/stopping therapy prior to conception to avoid potential fetal harm from in uteroDMD exposure. This dissertation explored perinatal outcomes in women and men with iiiMS exposed to DMDs and includes a systematic review of DMD exposure on perinatal outcomes. Data from BC suggest that DMD exposure in men and women with MS does not increase the risk of unfavorable perinatal outcomes. However, best evidence from the systematic review indicates that interferon-beta exposure in women with MS is associated with preterm birth, lower mean birth weight and shorter mean birth length in newborns; nonetheless, growth parameters of exposed newborns remained within normal values for the general population and preterm births tended to be close to term.

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