TABLE 2.
Risk of CRC according to folate intake with different latency periods, Nurses’ Health Study, 1980–20161
| Baseline | Cumulative | Simple update (0–4 y lag) | 4–8 y lag | 8–12 y lag | 12–16 y lag | 16–20 y lag | 20–24 y lag | 24–28 y lag | |
|---|---|---|---|---|---|---|---|---|---|
| Cases, n | 1988 | 1988 | 1687 | 1563 | 1385 | 1180 | 961 | 708 | 459 |
| Total folate | |||||||||
| Quintile 1 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| Quintile 2 | 0.95 (0.82, 1.09) | 1.06 (0.91, 1.24) | 0.91 (0.77, 1.07) | 1.13 (0.96, 1.33) | 0.96 (0.81, 1.14) | 0.86 (0.72, 1.03) | 0.85 (0.70, 1.04) | 0.99 (0.79, 1.25) | 1.12 (0.84, 1.49) |
| Quintile 3 | 0.92 (0.79, 1.07) | 1.11 (0.94, 1.30) | 0.94 (0.78, 1.12) | 0.92 (0.77, 1.11) | 0.84 (0.69, 1.01) | 0.85 (0.70, 1.03) | 0.88 (0.71, 1.08) | 1.00 (0.79, 1.28) | 1.02 (0.74, 1.39) |
| Quintile 4 | 0.85 (0.73, 1.00) | 1.02 (0.85, 1.23) | 0.91 (0.75, 1.11) | 0.89 (0.73, 1.09) | 0.92 (0.74, 1.13) | 0.76 (0.61, 0.94) | 0.75 (0.59, 0.94) | 0.92 (0.71, 1.21) | 1.13 (0.81, 1.58) |
| Quintile 5 | 0.81 (0.66, 0.98) | 0.92 (0.73, 1.15) | 0.85 (0.68, 1.06) | 0.76 (0.60, 0.97) | 0.82 (0.63, 1.07) | 0.77 (0.58, 1.02) | 0.69 (0.52, 0.92) | 0.63 (0.45, 0.88) | 0.90 (0.59, 1.38) |
| P-trend | 0.007 | 0.50 | 0.25 | 0.25 | 0.46 | 0.09 | <0.001 | 0.03 | 0.24 |
| Per 400 DFE/d | 0.90 (0.83, 0.97) | 0.97 (0.88, 1.07) | 0.97 (0.93, 1.02) | 0.97 (0.91, 1.02) | 0.97 (0.91, 1.05) | 0.93 (0.85, 1.01) | 0.83 (0.75, 0.92) | 0.87 (0.77, 0.99) | 0.91 (0.78, 1.07) |
| Per 400 DFE/d2 | 0.86 (0.76, 0.97) | —3 | 0.96 (0.90, 1.03) | 0.95 (0.88, 1.04) | 0.96 (0.87, 1.07) | 0.90 (0.79, 1.02) | 0.77 (0.66, 0.91) | 0.82 (0.69, 0.99) | 0.87 (0.70, 1.10) |
| Dietary folate | |||||||||
| Quintile 1 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| Quintile 2 | 0.98 (0.85, 1.13) | 0.98 (0.84, 1.15) | 0.93 (0.78, 1.11) | 1.00 (0.84, 1.19) | 1.08 (0.91, 1.29) | 0.89 (0.74, 1.06) | 0.88 (0.72, 1.08) | 1.00 (0.79, 1.26) | 0.97 (0.72, 1.32) |
| Quintile 3 | 1.00 (0.87, 1.16) | 1.07 (0.91, 1.26) | 0.93 (0.77, 1.11) | 1.07 (0.90, 1.28) | 1.02 (0.85, 1.23) | 0.79 (0.65, 0.96) | 0.85 (0.68, 1.05) | 1.02 (0.80, 1.31) | 1.16 (0.85, 1.57) |
| Quintile 4 | 0.99 (0.84, 1.15) | 1.03 (0.86, 1.23) | 0.91 (0.75, 1.11) | 0.95 (0.78, 1.17) | 0.90 (0.73, 1.10) | 0.77 (0.62, 0.95) | 0.93 (0.75, 1.17) | 0.87 (0.66, 1.13) | 1.10 (0.79, 1.53) |
| Quintile 5 | 0.96 (0.80, 1.14) | 0.97 (0.79, 1.18) | 0.82 (0.66, 1.02) | 0.97 (0.77, 1.21) | 1.01 (0.80, 1.28) | 0.76 (0.60, 0.98) | 0.83 (0.64, 1.08) | 0.98 (0.73, 1.31) | 1.15 (0.80, 1.67) |
| P-trend | 0.54 | 0.78 | 0.36 | 0.44 | 0.73 | 0.03 | 0.15 | 0.49 | 0.22 |
| Per 400 DFE/d | 0.94 (0.79, 1.13) | 0.97 (0.77, 1.22) | 0.94 (0.83, 1.07) | 0.94 (0.81, 1.09) | 1.03 (0.87, 1.21) | 0.78 (0.62, 0.98) | 0.83 (0.64, 1.07) | 0.90 (0.67, 1.21) | 1.24 (0.88, 1.73) |
| Per 400 DFE/d2 | 0.84 (0.49, 1.46) | —3 | 0.83 (0.56, 1.23) | 0.84 (0.54, 1.31) | 1.09 (0.67, 1.78) | 0.48 (0.24, 0.97) | 0.57 (0.26, 1.24) | 0.73 (0.30, 1.79) | 1.88 (0.68, 5.21) |
| Synthetic folic acid | |||||||||
| Quintile 1 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| Quintile 2 | 1.04 (0.90, 1.20) | 1.13 (0.97, 1.32) | 0.93 (0.79, 1.10) | 0.94 (0.80, 1.10) | 0.89 (0.76, 1.05) | 1.07 (0.90, 1.26) | 0.86 (0.72, 1.04) | 0.96 (0.77, 1.20) | 0.81 (0.61, 1.09) |
| Quintile 3 | 1.03 (0.90, 1.17) | 1.15 (0.98, 1.36) | 0.88 (0.73, 1.05) | 0.89 (0.74, 1.05) | 0.92 (0.77, 1.09) | 0.96 (0.80, 1.16) | 0.93 (0.77, 1.13) | 0.97 (0.77, 1.21) | 1.03 (0.78, 1.35) |
| Quintile 4 | 0.83 (0.72, 0.96) | 1.12 (0.94, 1.35) | 0.88 (0.72, 1.07) | 0.87 (0.72, 1.06) | 0.95 (0.78, 1.16) | 0.90 (0.73, 1.11) | 0.68 (0.54, 0.86) | 0.84 (0.65, 1.08) | 0.89 (0.65, 1.21) |
| Quintile 5 | 0.86 (0.72, 1.03) | 1.04 (0.83, 1.30) | 0.87 (0.70, 1.08) | 0.81 (0.64, 1.02) | 0.82 (0.64, 1.06) | 0.82 (0.62, 1.07) | 0.78 (0.59, 1.02) | 0.78 (0.57, 1.07) | 0.83 (0.56, 1.23) |
| P-trend | 0.32 | 0.60 | 0.32 | 0.97 | 0.67 | 0.37 | 0.02 | 0.07 | 0.21 |
| Per 400 DFE/d | 0.97 (0.92, 1.03) | 1.02 (0.95, 1.10) | 0.98 (0.93, 1.02) | 1.00 (0.95, 1.05) | 0.99 (0.93, 1.05) | 0.97 (0.90, 1.04) | 0.91 (0.84, 0.99) | 0.91 (0.83, 1.01) | 0.93 (0.82, 1.05) |
| Per 400 DFE/d1 | 0.96 (0.89, 1.04) | —3 | 0.97 (0.91, 1.03) | 1.00 (0.93, 1.07) | 0.98 (0.90, 1.07) | 0.96 (0.87, 1.06) | 0.88 (0.78,0.99) | 0.89 (0.77, 1.01) | 0.90 (0.76, 1.06) |
| Natural folate | |||||||||
| Quintile 1 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
| Quintile 2 | 0.93 (0.80, 1.07) | 1.05 (0.90, 1.21) | 1.02 (0.87, 1.19) | 0.89 (0.76, 1.05) | 1.01 (0.85, 1.19) | 0.86 (0.72, 1.03) | 0.88 (0.72, 1.08) | 1.07 (0.84, 1.34) | 1.15 (0.86, 1.55) |
| Quintile 3 | 0.94 (0.81, 1.09) | 0.93 (0.80, 1.09) | 1.04 (0.88, 1.23) | 1.00 (0.85, 1.17) | 1.03 (0.86, 1.23) | 0.88 (0.73, 1.06) | 0.91 (0.73, 1.12) | 0.92 (0.71, 1.18) | 1.01 (0.74, 1.39) |
| Quintile 4 | 0.94 (0.81, 1.10) | 0.93 (0.79, 1.10) | 1.10 (0.93, 1.30) | 0.87 (0.73, 1.04) | 0.92 (0.77, 1.11) | 0.71 (0.58, 0.87) | 0.93 (0.75, 1.16) | 0.99 (0.77, 1.28) | 1.05 (0.76, 1.46) |
| Quintile 5 | 0.99 (0.83, 1.18) | 1.04 (0.87, 1.24) | 1.05 (0.87, 1.26) | 0.95 (0.79, 1.14) | 0.97 (0.79, 1.18) | 0.87 (0.70, 1.08) | 0.95 (0.75, 1.20) | 0.93 (0.70, 1.23) | 1.15 (0.81, 1.64) |
| p trend | 0.65 | 0.84 | 0.42 | 0.89 | 0.74 | 0.31 | 0.66 | 0.70 | 0.10 |
| per 400 DFE/d | 1.06 (0.82, 1.37) | 0.96 (0.66, 1.40) | 1.13 (0.84, 1.51) | 1.02 (0.76, 1.38) | 0.95 (0.68, 1.31) | 0.83 (0.57, 1.19) | 0.91 (0.61, 1.36) | 0.91 (0.57, 1.45) | 1.58 (0.91, 2.72) |
| per 400 DFE/d2 | 1.24 (0.50, 3.07) | —3 | 1.53 (0.54, 4.31) | 1.08 (0.37, 3.15) | 0.82 (0.26, 2.62) | 0.51 (0.14, 1.90) | 0.73 (0.18, 2.99) | 0.72 (0.14, 3.73) | 5.04 (0.68, 37.1) |
1
All values are HRs (95% CIs), stratified by age and calendar year and adjusted for family history of CRC, endoscopy, height, BMI, pack-y of smoking before age 30 y, physical activity, duration of regular aspirin or other NSAIDs use, duration of multivitamin use (for dietary folate and natural folate analysis), menopausal status and menopausal hormone use, alcohol intake, total energy, dietary fiber, total vitamin D (for total folate and synthetic folic acid analysis), dietary vitamin D (for dietary folate and natural folate analysis), total calcium (for total folate and synthetic folic acid analysis), dietary calcium (for dietary folate and natural folate analysis), red meat, and processed meat. CRC, colorectal cancer; DFE, dietary folate equivalent; NSAID, nonsteroidal anti-inflammatory drug.
2
Corrected for measurement error using regression calibration approach.
3
The regression calibration approach was not appropriate for cumulative average models.