Appendix S1. Table S1. Meta-analysed male and female cohorts. Data are slope (95% CI). † = five registers from England, Ireland, Italy, the Netherlands and Scotland. ‡ = this study. § = calculated in this study using reported confidence intervals and coefficient ¶ = expected that the majority are included in the age-groups used for regression analysis.

Table S2. Male to female ratio in ALS and the population.

Table S3. Additional diagnosis numbers.

Table S4. Results summary. † = reflects the baseline risk in our analysis (25–29 years), ‡ = intercept is the estimated log-incidence at the baseline *Significant (after Bonferroni correction, seven tests including meta-analysis, P < 0.0071).

Figure S1. Relationship of log-incidence and log-age in the Danish registries for all ALS cases (b = 2.8, 95% CI: 2.0–3.5, R² = 0.80) (16–100 years), male (in orange) (b = 2.7, 95% CI: 2.1–3.4, R² = 0.8) (16–100 years) and female (in purple) (b = 2.9, 95% CI: 2.1–3.7, R² = 0.79).

Figure S2. Step differences between males and females across cohorts (mean difference ± 95% CI).

Figure S3. ALS, CVD and psychiatric diagnosis log-incidence and log-age. The CVD diagnosis was consistent with the multistep hypothesis (b = 4.35, 95% CI: 4.10–4.60, R² = 0.99, P = 5.8 × 10⁻¹⁰) to reflect five to six steps to CVD onset (similar to ALS), whereas a psychiatric diagnosis did not reflect a multistep model to onset (b = −0.28, 95% CI: −0.097 to−0.45, R² = 0.53, P = 0.02).

Figure S4. The ratio of males to females diagnosed with ALS in the Danish registries decreases with age (blue line is the raw data, orange line is corrected for male to female population ratio, dotted line is a linear trendline of the adjusted ratio (y = −0.12× + 2.33, R² = 0.58) (Table S2 for numbers). Estimated time of menopause is marked in grey.