Table 4.
Analyses decomposing the difference between the primary and sibling-comparison analyses of offspring mortality and paternal age, for outcomes causing >10,000 deaths in the main dataset.
| Outcome | Deaths (main data) | Deaths (restricted data) | N (restricted data) | Hazard ratio per five years of father’s age at offspring’s birth (or per five years of offspring’s DOB for secular trend) | ||||
|---|---|---|---|---|---|---|---|---|
| Primary analysis (main data) | Secular trend (main data) | Primary analysis plus mediation (main data) | Primary analysis (restricted data) | Sibling-comparison analysis (restricted data) | ||||
| All-cause | 293,470 | 190,579 | 451,278 | 0.98 (0.97, 0.98) | 0.94 (0.94, 0.94) | 0.92 (0.91, 0.93) | 0.98 (0.98, 0.98) | 0.93 (0.92, 0.94) |
| Cardiovascular disease | 76,352 | 45,690 | 118,949 | 0.97 (0.96, 0.98) | 0.88 (0.87, 0.88) | 0.85 (0.84, 0.86) | 0.98 (0.97, 0.99) | 0.87 (0.84, 0.90) |
| Coronary heart disease | 41,853 | 25,182 | 67,910 | 0.96 (0.95, 0.97) | 0.84 (0.83, 0.85) | 0.81 (0.80, 0.83) | 0.98 (0.97, 0.98) | 0.82 (0.79, 0.86) |
| Stroke | 14,692 | 8,356 | 22,951 | 0.97 (0.95, 0.99) | 0.86 (0.84, 0.88) | 0.83 (0.81, 0.86) | 0.98 (0.96, 0.99) | 0.81 (0.76, 0.87) |
| Respiratory diseases | 12,187 | 6,863 | 18,556 | 0.95 (0.93, 0.98) | 0.92 (0.90, 0.94) | 0.88 (0.86, 0.91) | 0.99 (0.98, 1.01) | 0.87 (0.80, 0.93) |
| External causes | 38,658 | 26,951 | 73,616 | 0.99 (0.97, 1.00) | 0.97 (0.96, 0.98) | 0.96 (0.95, 0.98) | 0.97 (0.96, 0.98) | 0.93 (0.90, 0.96) |
| Suicide | 15,565 | 11,062 | 30,489 | 1.01 (0.99, 1.03) | 0.97 (0.95, 0.98) | 0.98 (0.95, 1.00) | 0.98 (0.97, 0.99) | 0.95 (0.90, 0.99) |
| Any cancer | 113,597 | 71,927 | 185,758 | 0.99 (0.98, 0.99) | 0.93 (0.92, 0.94) | 0.92 (0.91, 0.93) | 0.98 (0.98, 0.99) | 0.94 (0.92, 0.96) |
| Lung cancer | 20,752 | 12,939 | 35,479 | 0.97 (0.96, 0.99) | 0.93 (0.91, 0.95) | 0.91 (0.89, 0.93) | 0.98 (0.97, 0.99) | 0.91 (0.87, 0.96) |
| Breast cancer | 10,887 | 4,630 | 10,967 | 1.02 (0.99, 1.04) | 0.91 (0.89, 0.93) | 0.93 (0.90, 0.95) | 0.97 (0.95, 0.99) | 0.92 (0.85, 1.00) |
| Colorectal cancer | 12,325 | 7,354 | 20,003 | 1.00 (0.98, 1.02) | 0.97 (0.95, 1.00) | 0.97 (0.94, 1.00) | 0.98 (0.97, 0.99) | 0.95 (0.88, 1.02) |
Results for all causes of death may be seen in Supplementary Table S5. Primary analyses used Cox proportional hazards regression of 2,658,132 male and 2,546,301 female offspring. Age was the time axis and robust standard errors were clustered by paternal identity. Adjustment set (e) (offspring sex and date of birth (DOB), maternal and paternal occupational and educational SEP, offspring birth order, and maternal age) was used. The secular trend per five years of offspring DOB was assessed using a similar model but without paternal age. The primary analysis was repeated with adjustment for paternal, not offspring, DOB to account for confounding, but not mediation, by secular trends. To examine whether the restricted dataset used for sibling-comparison analyses was representative of the main dataset, the primary analysis was repeated on this subset. Finally, the sibling-comparison analysis used Cox regression stratified by paternal identity and was restricted to offspring in families with discordant outcomes (maximum N = 451,376 for all-cause mortality). All family-level confounding was intrinsically adjusted for and adjustment for offspring DOB or maternal age were not possible. Explicit adjustment was therefore limited to offspring sex and birth order.