A total of 50,112 participants were included in the analysis. The numbers of participants excluded and the reasons for exclusion are shown in . The mean age among eligible participants in 1986 was 52.5 years, and the distributions of the other risk factors are shown in . There were a total of 4,893 deaths between 1986 and 2004: 1,026 from cardiovascular disease (21%), 931 from smoking-related cancers (19%), 1,430 from cancers not related to smoking (29%), and 1,506 from all other causes (31%).
Study population and exclusions in the Nurses’ Health Study between study initiation in 1976 and current follow-up analysis beginning in 1986. CHD, coronary heart disease; NHS, Nurses’ Health Study.
The associations of each risk factor with all-cause mortality are shown in . Risk of mortality increased sharply with age (hazard ratio (HR) per 19 years = 5.78). Both greater body mass index at age 18 years and weight change since age 18 were associated with increased risk, although the association was stronger for body mass index at age 18 (HR per 7 kg/m2 = 1.23). Height also was positively associated with all-cause mortality (HR per 6 inches = 1.16; 1 inch = 2.54 cm). Both current smoking (HR vs. never = 1.48) and greater total pack-years of smoking (HR per 46 pack-years = 2.08) were associated with increased mortality risk, whereas physical activity was associated with decreased risk (HR per 33 MET-hours/week = 0.87). For alcohol consumption, there was a small decrease in risk for 0.1 g/day–9.9 g/day and 10 g/day–29.9 g/day (HRs vs. none = 0.90 and 0.91, respectively), but not for ≥30 g/day. Glycemic load (HR per 41 units = 1.22) and cholesterol intake (HR per 105 mg/1,000 kcal = 1.17) were positively associated with mortality, whereas nut consumption (HR for ≥2 servings/week vs. none or almost none = 0.86), polyunsaturated fat intake (HR per 3% of total energy intake = 0.85), and cereal fiber intake (HR per 4 g = 0.84) were inversely associated with risk. Initial models also included other dietary factors (e.g., intakes of fruit and vegetables, trans fat), but these were eliminated from the final model because of nonsignificant associations with mortality after adjustment for other risk factors (data not shown). Systolic blood pressure (HR for ≥160 vs. <120 mm Hg = 1.49), use of blood pressure medications (HR = 1.19), personal history of diabetes (HR = 2.45), parental myocardial infarction before age 60 years (HR = 1.14), and time since menopause (HR per 13 years = 1.15) were positively associated with all-cause mortality. Based on multiplication of the individual hazard ratios, the hazard ratio for all-cause mortality for the “worst” versus the “best” risk profile for all of the modifiable risk factors (body mass index at age 18 years, weight change, smoking status and amount/duration, physical activity, alcohol intake, and all of the dietary factors) was 12.32.
Associations of Risk Factors With All-Cause Mortality From a Cox Proportional Hazards Model Among 50,112 Participants in the Nurses’ Health Study, 1986–2004a
The associations of each risk factor with cause-specific mortality are shown in . The relations of many factors with risk of death differed across causes. For example, age was more strongly associated with risk of death from cardiovascular disease (HR per 19 years = 6.98) and other causes (HR = 8.03) than from smoking-related cancers or other cancers, and the positive association for body mass index at age 18 years was stronger for risk of death from cardiovascular disease (HR per 7 kg/m2 = 1.61) than for any other causes. Weight change since age 18 years was positively associated with risk of death from cardiovascular disease (HR per 23 kg = 1.25) and other cancers (HR = 1.31), but inversely associated with risk of death from other causes (HR = 0.85). Current smoking was associated with increased risk of death from cardiovascular disease (HR vs. never = 2.02), smoking-related cancers (HR = 1.88), and other causes (HR = 1.57), but not from other cancers. Total number of pack-years of smoking was positively associated with risk of death from all of the causes, but most strongly for smoking-related cancers (HR per 46 pack-years = 3.54). Physical activity was most strongly inversely associated with risk of death from other causes (HR per 33 MET-hours/week = 0.76). The U-shaped association for alcohol consumption was observed only for risk of death from cardiovascular disease (HR for 0.1–9.9 g/day vs. none = 0.72) and other causes (HR = 0.83). Systolic blood pressure, use of blood pressure medications, and personal history of diabetes were positively associated with risk of death from cardiovascular disease and other causes, but not from smoking-related cancers or other cancers. Time since menopause was positively associated with risk of death from cardiovascular disease, smoking-related cancers, and other causes, but inversely associated with risk of death from other cancers. The hazard ratio for the “worst” versus the “best” risk profile for the modifiable risk factors was 24.14 for cardiovascular disease mortality, 16.02 for smoking-related cancer mortality, 5.73 for other cancer mortality, and 12.50 for other cause mortality.
Associations of Risk Factors With Cause-specific Mortality From a Competing Risks Model Among 50,112 Participants in the Nurses’ Health Study, 1986–2004, Assuming Different Associations of All Risk Factors With Each Specific Causea
In secondary analyses, we further explored the relation of height with individual causes of cardiovascular disease mortality, including coronary heart disease (407 deaths), stroke and cerebrovascular disease (266 deaths), and other cardiovascular disease (353 deaths), because of some previous studies suggesting that height may be inversely related to incidence of cardiovascular disease (29
). In these models, height was not associated with risk of mortality from coronary heart disease (HR per 6 inches = 1.04, 95% confidence interval (CI): 0.81, 1.33) or stroke (HR = 1.00, 95% CI: 0.74, 1.36), but was positively associated with other cardiovascular disease (HR per 6 inches = 1.52, 95% CI: 1.18, 1.98). This is consistent with an analysis from the Physicians’ Health Study showing that taller height was associated with increased risk of venous thromboembolism but not coronary events or stroke (31
The results from the final competing risks model obtained from the stepwise down procedure, in which risk factors with PLRT ≥ 0.10 were set to have equal effects and all other risk factors had different effects across specific causes of death, are shown in . Consistent with the results from the original Cox proportional hazards model for all-cause mortality (), taller height, higher glycemic load, higher dietary cholesterol, and parental myocardial infarction before age 60 years were associated with increased risk of death from all causes, whereas greater nut consumption and cereal fiber intake were associated with decreased risk. Although polyunsaturated fat intake was inversely associated with death from all causes, we maintained its separate associations with different causes of death because the PLRT in the final competing risks model in , after equating the effects of other risk factors, was less than 0.10.
Table 4. Associations of Risk Factors With Cause-specific Mortality From the Final Competing Risks Model Among 50,112 Participants in the Nurses’ Health Study, 1986–2004, Equating Risk Factors With Similar Effects and Allowing Other Risk Factors (more ...)
To evaluate the performance of the final competing risks model in , we first examined the area under the curve (AUC or C
statistic) with an approach described by Chambless and Diao (28
), which uses recursive calculation over the ordered time of events, analogous to the Kaplan-Meier approach to survival function estimation. The AUC for the standard Cox proportional hazards model for all-cause mortality () was 0.74 at 5 years, 0.75 at 10 years, and 0.76 at 15 years into the follow-up period; these values were almost identical for the final competing risks model in , indicating similar discriminatory accuracy.
Because the C
statistic may not be very sensitive to change for time-to-event data (32
), we also used likelihood ratio tests to compare the models. The difference in the log likelihoods of the Cox proportional hazards model for all-cause mortality () and the final competing risks model () was 652.96 (df = 54; P
< 0.0001), indicating a significant improvement with the competing risks model. The fit of the final competing risks model () was not significantly different from that of the initial full model () (difference in log likelihoods = 13.14, df = 21, P