Introduction
Methods
Model fitting issues
Time frame
Description of the log-incidence model of breast cancer
Results
Risk factor prevalence differences (Tables 1, 2)
Variable | NHS | CTS | ||||
---|---|---|---|---|---|---|
Mean ± SD | Range |
N
| Mean ± SD | Range |
N
| |
Age | 54.8 ± 3.1 | 47–59 | 18,308 | 54.0 ± 3.3 | 47–59 | 11,419 |
Age at menarche | 12.4 ± 1.3 | 9–21 | 18,308 | 12.5 ± 1.4 | 10–17 | 11,419 |
Age at menopause | 47.9 ± 5.1 | 21–59 | 18,308 | 48.0 ± 4.8 | 35–56 | 11,419 |
Type of menopause | ||||||
Natural | 13,910 (76 %) | 8,393 (74 %) | ||||
Bilateral oophorectomy | 4,398 (24 %) | 3,026 (26 %) | ||||
Nulliparous (%) | 1,075 (6 %) | 2,858 (25 %) | ||||
Age at 1st birtha
| 24.6 ± 3.0 | 15–46 | 17,233 | 25.6 ± 4.6 | 14–46 | 8,561 |
Parity | ||||||
0 | 1,075 (6 %) | 2,858 (25 %) | ||||
1 | 1,355 (7 %) | 1,695 (15 %) | ||||
2 | 6,016 (33 %) | 4,094 (36 %) | ||||
≥3 | 9,862 (53 %) | 2,772 (24 %) | ||||
Mean | 2.7 ± 1.4 | 0–15 | 18,308 | 1.7 ± 1.3 | 0–10 | 11,419 |
Birth index | 58.0 ± 33.9 | 0–236 | 18,308 | 36.3 ± 32.6 | 0–316 | 11,419 |
Age at 1st birth–age at menarche | 12.2 ± 3.3 | 1–32 | 17,233 | 13.1 ± 4.8 | 0–32 | 8,561 |
Current PMH use | 10,232 (56 %) | 7,975 (70 %) | ||||
Past PMH use | 2,457 (13 %) | 1,168 (10 %) | ||||
Duration E use (years) | 1.4 ± 3.6 | 0–34.0 | 18,308 | 2.0 ± 4.1 | 0–20.0 | 11,419 |
Duration E&P use (years) | 1.2 ± 2.1 | 0–14.0 | 18,308 | 2.1 ± 3.0 | 0–20.0 | 11,419 |
Current BMI (kg/m2) | 26.6 ± 5.3 | 12.5–68.7 | 18,308 | 25.3 ± 5.3 | 16.2–60.6 | 11,419 |
BMI at age 18 (kg/m2) | 21.3 ± 2.9 | 13.1–43.3 | 18,308 | 21.4 ± 3.4 | 14.5–53.3 | 11,419 |
Height | 64.6 ± 2.4 | 48–79 | 18,308 | 64.8 ± 2.6 | 45–76 | 11,419 |
Alcohol (g/day) | 5.0 ± 9.3 | 0–292.8 | 18,308 | 7.9 ± 9.6 | 0–112.8 | 11,419 |
Alcohol at age 18 (g/day) | 3.2 ± 5.1 | 0–108.1 | 18,308 | 5.3 ± 8.2 | 0–157.2 | 11,419 |
Benign breast disease (%) (biopsy confirmed) | 4,203 (23 %) | 2,181 (19 %) | ||||
Family Hx breast cancer (%) | 2,049 (11 %) | 1,497 (13 %) |
Variable | NHS | CTS | Variable | NHS | CTS | Variable |
---|---|---|---|---|---|---|
Mean ± SD | Range | Mean ± SD | Range | |||
Age | 66.0 ± 3.8 | 60–74 | 27,434 | 66.1 ± 4.1 | 60–74 | 11,222 |
Age at menarche | 12.7 ± 1.4 | 9–21 | 27,434 | 12.6 ± 1.4 | 10–17 | 11,222 |
Age at menopause | 49.2 ± 4.8 | 20–66 | 27,434 | 49.8 ± 4.8 | 35–56 | 11,222 |
Type of menopause | ||||||
Natural | 21,838 (80 %) | 9,097 (81 %) | ||||
Bilateral oophorectomy | 5,596 (20 %) | 2,125 (19 %) | ||||
Nulliparous (%) | 1,744 (6 %) | 2,012 (18 %) | ||||
Age at 1st birtha
| 25.7 ± 3.6 | 16–47 | 25,690 | 25.3 ± 4.2 | 14–46 | 9,210 |
Parity | ||||||
0 | 1,744 (6 %) | 2,012 (18 %) | ||||
1 | 1,879 (7 %) | 1,147 (10 %) | ||||
2 | 6,281 (23 %) | 3,037 (27 %) | ||||
≥3 | 17,530 (64 %) | 5,026 (45 %) | ||||
Mean | 3.2 ± 1.8 | 0–16 | 27,434 | 2.3 ± 1.6 | 0–13 | 11,222 |
Birth index | 64.8 ± 39.4 | 0–259 | 27,434 | 52.2 ± 40.6 | 0–321 | 11,222 |
Age at 1st birth–age at menarche | 13.0 ± 3.8 | 1–35 | 25,690 | 12.6 ± 4.3 | 1–34 | 9,210 |
Current PMH use | 9,474 (35 %) | 5,942 (53 %) | ||||
Past PMH use | 7,580 (28 %) | 1,854 (17 %) | ||||
Duration E use (years) | 2.4 ± 5.2 | 0–48.4 | 27,434 | 3.8 ± 6.5 | 0–20.0 | 11,222 |
Duration E&P use (years) | 0.9 ± 2.1 | 0–14.0 | 27,434 | 3.2 ± 4.8 | 0–20.0 | 11,222 |
Current BMI (kg/m2) | 26.1 ± 5.0 | 12.9–69.4 | 27,434 | 25.3 ± 4.8 | 16.0–60.4 | 11,222 |
BMI at age 18 (kg/m2) | 21.3 ± 3.0 | 10.8–59.3 | 27,434 | 21.5 ± 3.1 | 15.0–48.4 | 11,222 |
Height | 64.4 ± 2.4 | 39–79 | 27,434 | 64.4 ± 2.5 | 56–74 | 11,222 |
Alcohol (g/day) | 5.1 ± 9.6 | 0–113.4 | 27,434 | 8.2 ± 10.4 | 0–130.8 | 11,222 |
Alcohol at age 18 (g/day) | 2.5 ± 4.9 | 0–161.3 | 27,434 | 3.6 ± 6.4 | 0–116.1 | 11,222 |
Benign breast disease (%) (biopsy confirmed) | 6,133 (22 %) | 2,408 (21 %) | ||||
Family Hx breast cancer (%) | 3,684 (13 %) | 1,687 (15 %) |
Incidence rates (Table 3)
Age group | NHS | CTS | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Cases |
p_years | Incidence rate (per 105 py) | Cases |
p_years | Incidence rate (per 105 py) | IRR | ||||
47–49 | 7 | 1,764 | 396.8 | 2 | 2,511 | 79.6 | 0.20 | |||
50–54 | 74 | 23,452 | 315.5 | 48 | 18,792 | 255.4 | 0.81 | |||
55–59 | 275 | 66,427 | 414.0 | 177 | 43,889 | 403.3 | 0.97 | |||
60–64 | 434 | 109,802 | 395.3 | 298 | 60,673 | 491.2 | 1.24 | |||
65–69 | 523 | 127,301 | 410.8 | 328 | 61,539 | 533.0 | 1.30 | |||
70–74 | 460 | 117,401 | 391.8 | 274 | 50,987 | 537.4 | 1.37 | |||
75–79 | 217 | 68,627 | 316.2 | 197 | 32,853 | 599.6 | 1.90 | |||
80–87 | 36 | 25,844 | 139.3 | 76 | 16,867 | 450.6 | 3.23 | |||
Total | 2,026 | 540,618 | 1,400 | 288,111 | ||||||
Crude | 374.8 | 485.9 | 1.30 | |||||||
Age-adjusted | 374.8 | 500.5 | 1.32 | |||||||
Crude IRR | 1.30 | |||||||||
95 % CI | 1.21 | 1.39 | ||||||||
Age-adjusted IRR | 1.32 | |||||||||
95 % CI | 1.24 | 1.42 |
Comparing parameter estimates in each cohort (Table 4)
Variable | Beta | NHS | California Teachers Study | |||
---|---|---|---|---|---|---|
2,026 cases | 1,400 cases | |||||
540,618 person–years | 288,111 person–years | |||||
s.e. |
p value | Beta | s.e. |
p value | ||
Constant | −7.420 | 0.352 | <0.001 | −8.048 | 0.322 | <0.001 |
Duration of premenopause | 0.044 | 0.009 | <0.001 | 0.056 | 0.008 | <0.001 |
Duration postmenopause | ||||||
Natural menopause | −0.009 | 0.005 | 0.069 | 0.017 | 0.006 | 0.002 |
Bilateral oophorectomy | −0.015 | 0.006 | 0.013 | 0.012 | 0.008 | 0.15 |
Pregnancy history | ||||||
Gynecologic age at 1st birtha
| 0.0089 | 0.0048 | 0.062 | 0.0055 | 0.0041 | 0.18 |
Birth index | −0.0032 | 0.0007 | <0.001 | −0.0026 | 0.0008 | 0.001 |
BBD | ||||||
BBD (yes vs. no) | 0.237 | 0.588 | 0.69 | 0.314 | 0.834 | 0.71 |
BBD × age at menarche | 0.021 | 0.024 | 0.37 | 0.078 | 0.039 | 0.046 |
BBD × duration of premenopause | −0.002 | 0.011 | 0.84 | −0.021 | 0.014 | 0.14 |
BBD × duration postmenopause | −0.012 | 0.006 | 0.051 | −0.018 | 0.009 | 0.044 |
HT use | ||||||
Duration oral estrogen alone | 0.021 | 0.007 | <0.001 | 0.016 | 0.008 | 0.047 |
Duration oral estrogen plus progesterone | 0.015 | 0.008 | 0.056 | 0.035 | 0.008 | <0.001 |
Current use | 0.368 | 0.093 | <0.001 | 0.202 | 0.118 | 0.087 |
Past use | 0.087 | 0.065 | 0.18 | 0.092 | 0.098 | 0.35 |
BMI (kg/m2) | ||||||
Estrogen positiveb
| −0.00082 | 0.00024 | <0.001 | 0.00000 | 0.00024 | 0.99 |
Estrogen negativec
| 0.00195 | 0.00042 | <0.001 | 0.00038 | 0.00056 | 0.50 |
Height (in.) | ||||||
Estrogen positive | 0.00035 | 0.00032 | 0.27 | 0.00031 | 0.00020 | 0.12 |
Estrogen negative | 0.00033 | 0.00098 | 0.74 | −0.00030 | 0.00015 | 0.049 |
Alcohol intake (g) | ||||||
Premenopause | 0.00048 | 0.00014 | <0.001 | 0.00042 | 0.00021 | 0.039 |
Postmenopause, while on HT | 0.00004 | 0.0003 | 0.99 | 0.00015 | 0.00045 | 0.74 |
Postmenopause, while not on HT | 0.00013 | 0.00019 | 0.48 | −0.00032 | 0.00037 | 0.39 |
Family history of breast cancer | 0.403 | 0.059 | <0.001 | 0.346 | 0.069 | <0.001 |
Summary model performance in NHS and CTS cohorts (Table 5)
Time period | Age group | Number of cases | Log-incidence model | Gail model | Difference | |||||
---|---|---|---|---|---|---|---|---|---|---|
AUC | SE | AUC | SE | AUC | SE |
z value |
p value | |||
NHS | ||||||||||
1994–2008 | 47–87 | 2,026 | 0.597 | 0.007 | 0.562 | 0.006 | 0.034 | 0.007 | 4.857 | 1.191E−06 |
1994–1999 | 47–69 | 852 | 0.608 | 0.011 | 0.569 | 0.010 | 0.040 | 0.011 | 3.636 | 2.765E−04 |
1994–1999 | 70–87 | 301 | 0.587 | 0.016 | 0.555 | 0.017 | 0.032 | 0.017 | 1.882 | 0.060 |
2000–2008 | 47–69 | 461 | 0.599 | 0.013 | 0.572 | 0.013 | 0.026 | 0.012 | 2.167 | 0.030 |
2000–2008 | 70–87 | 412 | 0.577 | 0.016 | 0.543 | 0.014 | 0.034 | 0.016 | 2.125 | 0.034 |
California Teachers Study | ||||||||||
1995–2009 | 47–87 | 1,400 | 0.586 | 0.009 | 0.547 | 0.008 | 0.040 | 0.009 | 4.444 | 8.812E−06 |
1995–2000 | 47–69 | 422 | 0.609 | 0.015 | 0.572 | 0.014 | 0.037 | 0.014 | 2.643 | 0.008 |
1995–2000 | 70–87 | 144 | 0.564 | 0.025 | 0.516 | 0.024 | 0.048 | 0.028 | 1.714 | 0.086 |
2001–2009 | 47–69 | 431 | 0.591 | 0.016 | 0.537 | 0.014 | 0.054 | 0.015 | 3.600 | 0.000 |
2001–2009 | 70–87 | 403 | 0.565 | 0.015 | 0.543 | 0.014 | 0.023 | 0.016 | 1.438 | 0.151 |
Comparison of c statistic for actual NHS data versus the use of imputed values in that cohort (Table 6)
Time period | Age groupa
| Imputation of follow-up HT datac
| Time period | Age groupb
| Actual updated HT data | ||||
---|---|---|---|---|---|---|---|---|---|
Number of cases | AUC | SE | Number of cases | AUC | SE | ||||
1994–2008 | 47–87 | 2,026 | 0.600 | 0.006 | 1994–2008 | 47–87 | 2,026 | 0.616 | 0.006 |
1994–1999 | 47–69 | 852 | 0.620 | 0.010 | 1994–1999 | 47–69 | 851 | 0.618 | 0.010 |
1994–1999 | 70–87 | 301 | 0.585 | 0.016 | 1994–1999 | 70–87 | 302 | 0.590 | 0.016 |
2000–2008 | 47–69 | 461 | 0.595 | 0.013 | 2000–2008 | 47–69 | 457 | 0.641 | 0.013 |
2000–2008 | 70–87 | 412 | 0.575 | 0.015 | 2000–2008 | 70–87 | 416 | 0.626 | 0.014 |
Calibration observed and expected counts in CTS by decile of risk, predicted with NHS betas
Risk decile | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | ||
Observed number of cases | 71.6 | 94.6 | 111.6 | 119.6 | 126.0 | 129.6 | 152.0 | 150.4 | 195.6 | 248.8 | |
Expected number of cases | 66.6 | 88.6 | 103.1 | 116.3 | 128.6 | 143.6 | 160.3 | 181.4 | 208.0 | 272.4 | |
α
| −0.048 | ||||||||||
SE (α) | 0.027 | ||||||||||
p value | 0.074 |
Discussion
General issues on validating
Variable | Ever/never use of estrogen alone (n = 45,742)a
| ln(duration estrogen alone) (n = 9,145)b
| ||||
---|---|---|---|---|---|---|
Beta | SE |
p value | Beta | SE |
p value | |
Constant | −3.078 | 0.212 | 0.762 | 0.105 | ||
Duration of premenopause | −0.002 | 0.005 | 0.68 | −0.004 | 0.003 | 0.15 |
Duration postmenopause | ||||||
Natural menopause | −0.045 | 0.004 | <0.001 | −0.020 | 0.002 | <0.001 |
Bilateral oophorectomy | 0.011 | 0.004 | 0.005 | −0.007 | 0.002 | 0.002 |
Pregnancy history | ||||||
Gynecologic age at 1st birthc
| 0.0033 | 0.0035 | 0.35 | −0.0022 | 0.0019 | 0.25 |
Birth index | 0.0031 | 0.0005 | <0.001 | 0.00052 | 0.00027 | 0.049 |
BBD | ||||||
BBD (yes vs. no) | 0.863 | 0.371 | 0.020 | 0.213 | 0.181 | 0.24 |
BBD × age at menarche | −0.035 | 0.017 | 0.032 | −0.0001 | 0.0085 | 0.99 |
BBD × duration of premenopause | −0.011 | 0.007 | 0.10 | −0.0032 | 0.0032 | 0.32 |
BBD × duration postmenopause | −0.007 | 0.005 | 0.16 | −0.0080 | 0.0025 | 0.001 |
HT use | ||||||
Duration oral estrogen alone | 0.235 | 0.005 | <0.001 | 0.0282 | 0.0017 | <0.001 |
Duration oral estrogen + progesterone | −0.041 | 0.007 | <0.001 | −0.0027 | 0.0041 | 0.52 |
Current use | 1.978 | 0.053 | <0.001 | 0.993 | 0.037 | <0.001 |
Past use | 0.580 | 0.059 | <0.001 | 0.275 | 0.041 | <0.001 |
BMI (kg/m2) | ||||||
Estrogen positived
| 0.00035 | 0.00015 | 0.015 | −0.00007 | 0.00007 | 0.34 |
Estrogen negativee
| −0.00081 | 0.00045 | 0.074 | −0.00002 | 0.00027 | 0.94 |
Height (in.) | ||||||
Estrogen positived
| 0.00003 | 0.00019 | 0.88 | −0.00015 | 0.00009 | 0.10 |
Estrogen negativee
| −0.00024 | 0.00090 | 0.79 | 0.00113 | 0.00052 | 0.030 |
Alcohol intake (g) | ||||||
Premenopause | −0.00012 | 0.00010 | 0.23 | −0.00006 | 0.00006 | 0.26 |
Postmenopause, while on HT | −0.00102 | 0.00023 | <0.001 | 0.00009 | 0.00009 | 0.29 |
Postmenopause, while not on HT | 0.00073 | 0.00018 | <0.001 | −0.00013 | 0.00012 | 0.29 |
Family history of breast cancer | 0.148 | 0.046 | 0.30 | −0.041 | 0.025 | 0.099 |
c statistic | 0.871 | – | ||||
R
2
| – | 0.271 |
Variable | Ever/never use of E&P (n = 45,742)a
| ln(duration E&P) (n = 11,516)b
| ||||
---|---|---|---|---|---|---|
Beta | SE |
p value | Beta | SE |
p value | |
Constant | 0.405 | 0.212 | 1.291 | 0.115 | ||
Duration of premenopause | −0.041 | 0.005 | <0.001 | −0.0061 | 0.0030 | 0.038 |
Duration postmenopause | ||||||
Natural menopause | −0.077 | 0.003 | <0.001 | −0.018 | 0.002 | <0.001 |
Bilateral oophorectomy | −0.309 | 0.008 | <0.001 | −0.043 | 0.004 | <0.001 |
Pregnancy history | ||||||
Gynecologic age at 1st birthc
| 0.0010 | 0.0031 | 0.74 | 0.0012 | 0.0016 | 0.48 |
Birth index | 0.0000 | 0.0004 | 0.94 | −0.0008 | 0.0002 | <0.001 |
BBD | ||||||
BBD (yes vs. no) | −0.336 | 0.399 | 0.40 | −0.344 | 0.211 | 0.10 |
BBD × age at menarche | −0.003 | 0.016 | 0.84 | 0.0100 | 0.0080 | 0.21 |
BBD × duration of premenopause | 0.009 | 0.008 | 0.24 | 0.0049 | 0.0041 | 0.23 |
BBD × duration postmenopause | 0.001 | 0.004 | 0.84 | −0.0016 | 0.0025 | 0.52 |
HT use | ||||||
Duration oral estrogen alone | −0.048 | 0.007 | <0.001 | 0.012 | 0.004 | 0.001 |
Duration oral estrogen plus progesterone | 0.414 | 0.008 | <0.001 | 0.062 | 0.003 | <0.001 |
Current use | 1.356 | 0.037 | <0.001 | 0.471 | 0.023 | <0.001 |
Past use | 0.453 | 0.041 | <0.001 | −0.179 | 0.028 | <0.001 |
Body mass index (kg/m2) | ||||||
Estrogen positived
| −0.00032 | 0.00014 | 0.027 | −0.00003 | 0.00008 | 0.65 |
Estrogen negativee
| −0.00088 | 0.00042 | 0.036 | −0.00011 | 0.00028 | 0.69 |
Height (in.) | ||||||
Estrogen positived
| −0.00026 | 0.00019 | 0.19 | 0.00005 | 0.00009 | 0.58 |
Estrogen negativee
| 0.00031 | 0.00084 | 0.71 | −0.00079 | 0.00051 | 0.12 |
Alcohol intake (g) | ||||||
Premenopause | 0.00010 | 0.00009 | 0.29 | −0.00001 | 0.00005 | 0.88 |
Postmenopause, while on HT | −0.00121 | 0.00032 | <0.001 | −0.00001 | 0.00014 | 0.96 |
Postmenopause, while not on HT | 0.00016 | 0.00017 | 0.37 | −0.00023 | 0.00012 | 0.055 |
Family history of breast cancer | −0.23 | 0.044 | <0.001 | −0.035 | 0.024 | 0.14 |
c statistic | 0.870 | – | ||||
R
2
| – | 0.207 |