ObjectiveTo explore and describe the basis and implications of genetic and environmental susceptibility to multiple sclerosis (MS) using the Canadian population-based data.BackgroundCertain parameters of MS-epidemiology are directly observable (e.g., the recurrence-risk of MS in siblings and twins, the proportion ofwomenamong MS patients, the population-prevalence of MS, and the time-dependent changes in thesex-ratio). By contrast, other parameters can only be inferred from the observed parameters (e.g., the proportion of the population that is “genetically susceptible”, the proportion ofwomenamong susceptible individuals, the probability that a susceptible individual will experience an environment “sufficient” to cause MS, and if they do, the probability that they will develop the disease).Design/methodsThe “genetically susceptible” subset (G) of the population (Z) is defined to include everyone withanynon-zero life-time chance of developing MS undersomeenvironmental conditions. The value for each observed and non-observed epidemiological parameter is assigned a “plausible” range. Using both aCross-sectional Modeland aLongitudinal Model, together with established parameter relationships, we explore, iteratively, trillions of potential parameter combinations and determine those combinations (i.e., solutions) that fall within the acceptable range for both the observed and non-observed parameters.ResultsBothModelsand all analyses intersect and converge to demonstrate that probability of genetic-susceptibitly,P(G), is limited to only a fraction of the population {i.e.,P(G) ≤ 0.52)} and an even smaller fraction ofwomen{i.e.,P(G│F) < 0.32)}. Consequently, most individuals (particularlywomen) have no chance whatsoever of developing MS, regardless of their environmental exposure. However, for any susceptible individual to develop MS,requiresthat they also experience a “sufficient” environment. We use the Canadian data to derive, separately, the exponential response-curves formenandwomenthat relate the increasing likelihood of developing MS to an increasing probability that a susceptible individual experiences an environment “sufficient” to cause MS. As the probability of a “sufficient” exposure increases, we define, separately, the limiting probability of developing MS inmen(c) andwomen(d). These Canadian data strongly suggest that: (c<d≤ 1). If so, this observation establishes both that there must be a “truly” random factor involved in MS pathogenesis and that it is this difference, rather than any difference in genetic or environmental factors, which primarily accounts for thepenetrancedifference betweenwomenandmen.ConclusionsThe development of MS (in an individual) requires both that they have an appropriate genotype (which is uncommon in the population) and that they have an environmental exposure “sufficient” to cause MS given their genotype. Nevertheless, the two principal findings of this study are that:P(G) ≤ 0.52)} and: (c<d≤ 1). Threfore, even when the necessary genetic and environmental factors, “sufficient” for MS pathogenesis, co-occur for an individual, they still may or may not develop MS. Consequently, disease pathogenesis, even in this circumstance, seems to involve an important element of chance. Moreover, the conclusion that the macroscopic process of disease development for MS includes a “truly” random element, if replicated (either for MS or for other complex diseases), provides empiric evidence that our universe is non-deterministic.