Study Population

The Nurses' Health Study was initiated in 1976, when 121,700 female registered nurses 30 to 55 years of age completed a mailed questionnaire. Since 1976, information on disease status and lifestyle factors has been collected from this same cohort every 2 years. Diet was assessed by means of a semiquantitative food-frequency questionnaire in 1980, 1984, 1986, 1990, 1994, and 1998; 98,462 women completed the 1980 questionnaire.

For this investigation we excluded all women at baseline who left 10 or more food items blank or had implausibly high (>3500 kcal) or low (<500 kcal) daily energy intakes on the food-frequency questionnaire. We further excluded women with a history of diabetes, cancer, or cardiovascular disease before 1980, because these diagnoses may cause alterations in diet. After these exclusions, 82,802 women remained in this investigation. The study was approved by the Human Research Committee of Brigham and Women's Hospital in Boston; the completion of the self-administered questionnaire was considered to imply informed consent.

Assessment of Diet and Glycemic Load

The 1980 food-frequency questionnaire included 61 food items and was revised in 1984 to include about twice that number.14,15 Study participants reported average frequency of consumption of specific foods throughout the previous year. The validity and reproducibility of the questionnaire have been documented elsewhere.14,15

To calculate the intake of specific foods, a commonly used portion size for each food was specified (e.g., one egg or one slice of bread) and participants were asked how often, on average, during the previous year they had consumed that amount. The possible responses ranged from never or less than once per month to six or more times per day.

Nutrient values were computed by multiplying the frequency of consumption of each food by the nutrient content of the portion and then adding these products across all food items. All food-composition values were obtained from the Harvard University food-composition database, which was derived from U.S. Department of Agriculture sources16 and supplemented with information from the manufacturer. The validity of estimated nutrient intake as assessed by the questionnaire has previously been evaluated with the use of multiple diet records. The correlation between the 1986 questionnaire and the average of six 1-week diet records collected in 1980 and 1986 was 0.73 for carbohydrate, 0.67 for total fat, and 0.56 for protein.15

The method used to assess glycemic load in the Nurses' Health Study has been described elsewhere.17 Briefly, we calculated the total dietary glycemic load by multiplying the carbohydrate content of each food by its glycemic index (the glycemic index of glucose is 100) and then multiplied this value by the frequency of consumption and summed these values for all foods. Dietary glycemic load, therefore, represents both the quality and quantity of carbohydrate consumed. Each unit of glycemic load represents the equivalent blood glucose–raising effect of 1 g of pure glucose.

Calculation of the Low-Carbohydrate-Diet Score

Table 1. Table 1. Criteria for Determining the Low-Carbohydrate-Diet Score.

We divided the study participants into 11 strata each of fat, protein, and carbohydrate intake, expressed as a percentage of energy (Table 1). For fat and protein, women in the highest stratum received 10 points for that macronutrient, women in the next stratum received 9 points, and so on down to women in the lowest stratum, who received 0 points. For carbohydrate, the order of the strata was reversed; those with the lowest carbohydrate intake received 10 points and those with the highest carbohydrate intake received 0 points. We used the percentage of energy consumed instead of absolute intake to reduce bias due to underreporting of food consumption and to represent dietary composition.

The points for each of the three macronutrients were then summed to create the overall diet score, which ranged from 0 (the lowest fat and protein intake and the highest carbohydrate intake) to 30 (the highest protein and fat intake and the lowest carbohydrate intake). Therefore, the higher the score, the more closely the participant's diet followed the pattern of a low-carbohydrate diet. Thus, the score was termed the “low-carbohydrate-diet score.”

We also created two additional low-carbohydrate-diet scores. One was calculated according to the percentage of energy as carbohydrate, the percentage of energy as animal protein, and the percentage of energy as animal fat, and the other was calculated according to the percentage of energy as carbohydrate, the percentage of energy as vegetable protein, and the percentage of energy as vegetable fat (Table 1).

Measurement of Nondietary Factors

In 1976, women provided information regarding parental history of myocardial infarction. Beginning in 1976, participants also provided information every 2 years on the use of postmenopausal hormones, smoking status, body weight, and other covariates. They provided information on aspirin use repeatedly throughout the follow-up. The correlation coefficient between self-reported body weight and measured weight was 0.96.18 Physical activity was assessed in 1980, 1982, 1986, 1988, 1992, 1996, and 1998, and we calculated the cumulative average number of hours per week spent in moderate or vigorous physical activity.19

Outcome

The outcome of this study was incident coronary heart disease, including nonfatal myocardial infarctions or fatal coronary events. Each participant contributed follow-up time from the date of returning the 1980 questionnaire to the date of the first end point (death or nonfatal myocardial infarction) or until the censoring date of June 1, 2000.

We requested permission to examine the medical records of all participants who reported a diagnosis of coronary heart disease on one of the follow-up questionnaires that were completed every two years. A myocardial infarction was considered to be confirmed if it met the World Health Organization criteria of symptoms and either typical electrocardiographic changes or elevated cardiac-enzyme levels.20 Infarctions that necessitated a hospital admission and for which confirmatory information was obtained by interview or letter but for which no medical records were available were designated as probable and were included in the analysis.

Deaths were identified from state vital records and the National Death Index or reported by the participants' next of kin or the U.S. Postal Service.21 Fatal coronary heart disease was confirmed by an examination of autopsy or hospital records, by a listing of coronary heart disease as the cause of death on the death certificate, and by the availability of evidence of previous coronary heart disease. Those deaths in which coronary heart disease was the underlying cause on the death certificate but for which no medical records were available were designated as deaths from presumed coronary disease.

Statistical Analysis

We divided women into 10 categories (deciles) according to their low-carbohydrate-diet score. To represent long-term intake and reduce measurement error, we calculated the cumulative average low-carbohydrate-diet score based on the information from the 1980, 1984, 1986, 1990, 1994, and 1998 questionnaires.22 For example, the low-carbohydrate-diet score from the 1980 questionnaire was related to the incidence of coronary heart disease between 1980 and 1984, and the low-carbohydrate-diet score from the average of the 1980 and 1984 questionnaires was related to the incidence of coronary heart disease between 1984 and 1986. Incidence rates for coronary heart disease were calculated by dividing cases by the person-years of follow-up for each decile of the low-carbohydrate-diet score. Relative risks of coronary heart disease were calculated by dividing the rate of occurrence of coronary heart disease in each decile by the rate in the first (lowest) decile. We used Cox proportional-hazards models23 to adjust for potentially confounding variables. Because low-carbohydrate diets may decrease subsequent energy intake,24 we did not control for total energy intake in multivariate models. However, further adjustment for caloric intake was performed in a secondary analysis. We also examined the association between each macronutrient and the risk of coronary heart disease in multivariate nutrient-density models.22 All P values are two-sided.