Discussion

There are two principal conclusions derived from this analysis. First, the MS-penetrance of the genetically-susceptible subset, (G), is greater than that of the population, (Z), and, thus, not everyone in the population is genetically-susceptible. Consequently, some members of the population (Z) cannot develop MS regardless of their environmental experiences. And second, at maximum exposure-levels, the limiting probability of developing MS in susceptible men ( c ) is less than that for susceptible women ( d ). These two conclusions, stated explicitly, are:

1. P(G) ≤ 0.52

2. c < d ≤ 1.

Conclusion #1 seems inescapable (see Results). Indeed, given any of the reported MZ-twin concordance rates, the notion that the MS-penetrance for (G) is the same as that for (Z) is untenable (see table 4 of reference #3). Therefore, a large proportion of the population (Z) must be impervious to developing MS, regardless of any environmental events they either have experienced or could have experienced.

However, considering Conclusion #2—ie, that: ( c < d )—there are scenarios, in which the condition of: ( c = d ≤1) might be possible. Principal among these is the possibility of non-proportional hazards, which requires female-MS and male-MS to be different diseases (see Methods: Longitudinal models: Proportional hazard; see also online supplemental material section 7h). However, given the genetic and environmental evidence, this possibility, also, seems untenable. For example, all but 1 of the 233 MS-associated loci are autosomal, and the single X-chromosome risk variant is present in both sexes.6 In this case, any difference between sexes in the genetics of MS is unlikely (see online supplemental material section 7f). In addition, the pattern of the MS association with the different HLA-haplotypes is the same for both sexes (see tables 3 & 4 of reference 4). Family studies also suggest a common genetic basis for MS in women and men.2–5 8 22 27 Thus, both twin and non-twin siblings (male or female) of an MS-proband have increased MS risk, regardless of proband sex.5 8 27 Similarly, both sons and daughters of conjugal couples have markedly increased MS risk.8 27 Also, male and female full-siblings or half-siblings with an MS-proband parent (mother or father) have increased MS risk.2 8 22 27 Each of these observations supports the view that the genetic basis for MS is similar (if not the same) in both sexes.

Moreover, for all non-proportional hazard conditions where: ( c = d ≤1), the ‘current’ condition—that is, where the ratio of: (Zw/Zm) is both greater than one and increasing over time—can only be explained by the fact that, ‘currently’, susceptible women are more likely to experience a ‘sufficient’ environmental-exposure compared with susceptible men (see Methods: Longitidinal models: Proportional hazard; see also online supplemental material sections 3a, 5d and 10a). Nevertheless, contrary to this requirement, women do not seem to be more likely than men to experience the various MS-associated environmental events, regardless of whether these events are known or just suspected. In addition, women and men do not seem to require different environmental events. Thus, for both sexes, the month-of-birth effect is equally evident2 4 9–11; the latitude gradient is the same2 4 12; the impact of intrauterine/perinatal environments is similar (online supplemental material section 2c); EBV infection is equally common and disease associated2 4 13 14; vitamin D levels are the same2 4 15 16; and smoking tobacco is actually less common among women.2 4 Collectively, these observations suggest that, currently, each sex experiences the same relevant environmental events in an approximately equivalent manner. Taken together, this genetic and environmental evidence implies that female-MS and male-MS represent the same underlying disease process and, therefore, that the hazards must be proportional (Methods: Longitudinal models: Proportional hazard; see also o nline supplemental material section 7h).

In addition, several lines of evidence indicate that, when the hazards are proportional, the condition of: ( c = d ≤1) is also unlikely. First, in all circumstances where the proportionality factor (R) is greater than unity—that is, where (R>1)—as it must be whenever: ( c = d ≤1)—see Methods: Longitudinal models: Proportional hazard—susceptible women, compared with susceptible men, must be more responsive to the changes in the environmental exposure-level, which have taken place over the past 50 years. As discussed in connection with non-proportional hazards (see Discussion, above), there is little current evidence for this. Second, the genetic and environmental observations (described in the Results and Discussion) suggest that: (R ^app >R≈1), which is impossible whenever: ( c = d ≤1) (Methods: Longitidinal models: Proportional hazard). Third, as in figure 1, whenever (λ≤0) or whenever (R≤1), the condition that: ( c < d ) is established (see Methods: Longitudinal models: Proportional hazard; see also online supplemental material section 5d and 7d–g). Fourth, the alternative of: (R>1) & (λ>0) creates a potential paradox (see Methods: Longitudinal models: Proportional hazard). Although there are ways to rationalise this paradox with: ( c = d ≤1), in every case, the conditions required whenever: ( c < d ≤1) are far less extreme (see fi gures 5 and S1–S3 in reference4. Finally, the response curves when: ( c = d ≤1) & (R>1) are steeply ascending and present only a very narrow exposure-window to explain the Canadian (F:M) sex-ratio data23 (see figure 2A and B). Moreover, following this narrow window, the (F:M) sex-ratio decreases with increasing exposure. By contrast, the Canadian MS data documents a steadily progressive rise in the (F:M) sex-ratio over a 50-year time-span4 23 (see also online supplemental material figure S1).

Nevertheless, whenever ( c < d ), some susceptible men will never develop MS, even when a susceptible genotype co-occurs with a ‘sufficient’ exposure. Thus, the Canadian MS data5 8 9 17–23 seems to indicate that MS pathogenesis involves a ‘truly’ random mechanism. This cannot be attributed to other, unidentified, environmental factors (eg, other infections, diseases, nutritional deficiencies, toxic exposures) because each set of environmental exposures is defined to be ‘sufficient’, by itself, to cause MS in a specific susceptible individual. If other conditions were necessary for this individual to develop MS, then one (or more) of the ‘sufficient’ exposure-sets within their {E _i} family would include these conditions (see Methods: Environmental susceptibility). This also cannot be attributed to the possibility that some individuals can only develop MS under improbable conditions. Thus, the estimates for ( c ) and ( d ) are based solely on ‘observable’ parameter-values (see Methods: Longitidinal models: Proportional hazard). Finally, this cannot be attributed to mild or asymptomatic disease (eg, clinically, or radiographically, isolated syndromes) because this disease-type occurs disproportionately often among women compared with the current (F:M) sex-ratio in MS.4 23 Naturally, invoking ‘truly’ random events in MS disease expression requires replication. Nevertheless, any finding that: ( c < d ) indicates that the behaviour of some complex physical systems (eg, organisms) involves ‘truly’ random mechanisms.

Moreover, considering those circumstances where: (R=1) & ( d =1) and, also, considering a man, randomly selected from the (M,G) subset, who experiences a ‘sufficient’ environment, the chance that he will not develop MS is: 21–99% (see Results). Consequently, both the genetic and environmental data, which support the conclusion that: (R≈1)—see immediately above—also, support the conclusion that it is this random mechanism of disease pathogenesis, which is primarily responsible for the difference in MS disease expression currently-observed between susceptible women and susceptible men. Importantly, the fact that a process favours disease development in women over men does not imply that the process must be non-random. For example, when flipping a biased coin compared with a fair coin—if both processes are random—the only difference is that, for the biased coin, the two possible outcomes are not equally likely. In the context of MS pathogenesis, the characteristics of ‘female-ness’ and ‘male-ness’ would each simply be envisioned as biasing the coin differently. It is unclear what characteristics might be implied by these two terms although, perhaps, the general differences in anatomy, physiology and gene or RNA expression, which exist between males and females, create a ‘different milieu’ that translates to setting a different bias for each sex. Moreover, these general differences between the sexes are deeply rooted in our evolutionary tree and, presumably, are highly conserved in all animal species that reproduce sexually. Therefore, it seems very likely that these general differences between sexes do not change appreciably from one generation of human beings to the next, so that whatever biases are introduced by them will also be essentially unchanging.

Other authors, modelling immune system function, also invoke random events in MS disease expression (see reference 4 for a review). In these cases, however, randomness is incorporated into their Models to reproduce the MS disease process more faithfully. However, the fact that including randomness improves a model’s performance does not constitute a test of whether ‘true’ randomness ever occurs. For example, the outcome of a dice roll may be most accurately modelled by treating this outcome as a random variable with a well-defined probability distribution. Nevertheless, the question remains whether this probability distribution represents a complete description of the process, or whether this distribution is merely a convenience, compensating for our ignorance about the initial conditions of the dice (eg, its orientation and weight) and the direction, location and magnitude of the forces that act on the dice during the roll.4 28 29

In 1814, the French polymath and scholar, Pierre-Simon de Laplace, introduced the concept of causal determinism based on well-established and strongly confirmed physical laws.4 29 Following this introduction, deterministic views of nature became increasingly prevalent among scientists and this notion is still current among many (perhaps most) authorities today.4 29 For example, in 1908, the physicist Henri Poincaré, clearly articulated this point-of-view, stating that: ‘every phenomenon, however trifling it be, has a cause, and a mind infinitely powerful and infinitely well-informed concerning the laws of nature could have foreseen it from the beginning of the ages. If a being with such a mind existed, we could play no game of chance with him; we should always lose’.4 29 Similarly, in a 1926 letter to Max Born, Albert Einstein, reflecting on the evolving notions of quantum uncertainty, expressed his belief that ‘[God] does not play dice’. Nevertheless, to Poincaré’s point (above), even if she or he did play dice, likely, the game would not be random. Many contemporary authorities, also, largely agree with such deterministic ideas. For example, the physicist Brian Greene, states that, although ‘the quantum equations lay out many possible futures, … they deterministically chisel the likelihood of each in mathematical stone’.4 The physicist, Stephen Hawking, writes that ‘the wave function contains all that one can know of the particle, both its position, and its speed. If you know the wave function at one time, then its values at other times are determined by what is called the Schrödinger equation. Thus, one still has a kind of determinism, but it is not the sort that Laplace envisaged.’ Nevertheless, despite agreeing that the quantum equations imply this certain kind of determinism and also envisioning an early universe with minimal entropy, Hawking further argues that the existence of black hole radiations implies that ‘the loss of particles and information down black holes [means] that the particles that [come] out [are] random. One [can] calculate probabilities, but one [cannot] make any definite predictions. Thus, the future of the universe is not completely determined by the laws of science.4

By contrast, other authorities find it very difficult to rationalise any notion that the outcomes of complex biological processes such as evolution by natural selection or immune system function are predetermined, especially considering the fact that each of these processes is so remarkably adaptive to contemporary external events.4 29 Nevertheless, proving that any macroscopic process includes ‘truly’ random mechanisms is difficult. This requires an experiment (ie, a test), in which the outcome predicted by determinism differs from that predicted by non-determinism.

The longitudinal MS data from Canada provides an opportunity to apply just such a test. For example, the widely-held deterministic view requires that: ( c = d =1). By contrast, any observation that either: ( c < d =1) or: ( c ≤ d <1) indicates that ‘true’ randomness must be a component of disease development and undermines the deterministic hypothesis. Thus, the Canadian MS data,5 8 9 17–23 which strongly implies that: ( c < d ), provides empirical evidence in support of the non-deterministic hypothesis. Importantly, this analysis explicitly includes all those genetic factors and environmental events (including their interactions), which are necessary for MS pathogenesis, regardless of whether these factors, events, and interactions are known, suspected, or as yet unrecognised. Nevertheless, in addition to these necessary prerequisites, ‘true’ randomness also seems to play a critical role in MS disease pathogenesis. Moreover, both sexes seem to have the same underlying disease. Thus, both sexes seem to have a similar genetic basis and, also, a similar response to the same environmental disease determinants (see Discussion). These observations suggest both that the hazards are proportional (Methods: Longitidinal models: Proportional hazard) and that (R≈1). If correct, this indicates that it is this ‘truly’ random mechanism in disease pathogenesis, which is primarily responsible for the currently-observed differences in MS disease expression between susceptible women and susceptible men.