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Abstract

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.