Richard R. Monson

A Prospective Study of Obesity and Risk of Coronary Heart Disease in Women

We examined the incidence of nonfatal and fatal coronary heart disease in relation to obesity in a prospective cohort study of 115,886 U.S. women who were 30 to 55 years of age in 1976 and free of diagnosed coronary disease, stroke, and cancer. During eight years of follow-up (775,430 person-years), we identified 605 first coronary events, including 306 nonfatal myocardial infarctions, 83 deaths due to coronary heart disease, and 216 cases of confirmed angina pectoris. A higher Quetelet index (weight in kilograms divided by the square of the height in meters) was positively associated with the occurrence of each category of coronary heart disease. For increasing levels of current Quetelet index (less than 21, 21 to less than 23, 23 to less than 25, 25 to less than 29, and greater than or equal to 29), the relative risks of nonfatal myocardial infarction and fatal coronary heart disease combined, as adjusted for age and cigarette smoking, were 1.0, 1.3, 1.3, 1.8, and 3.3 (Mantel-extension chi for trend = 7.29; P less than 0.00001). As expected, control for a history of hypertension, diabetes mellitus, and hypercholesterolemia--conditions known to be biologic effects of obesity--attenuated the strength of the association. The current Quetelet index was a more important determinant of coronary risk than that at the age of 18; an intervening weight gain increased risk substantially. These prospective data emphasize the importance of obesity as a determinant of coronary heart disease in women. After control for cigarette smoking, which is essential to assess the true effects of obesity, even mild-to-moderate overweight increased the risk of coronary disease in middle-aged women.

Relative and Absolute Excess Risks of Coronary Heart Disease among Women Who Smoke Cigarettes

We prospectively examined the incidence of coronary heart disease in relation to cigarette smoking in a cohort of 119,404 female nurses who were 30 to 55 years of age in 1976 and were free of diagnosed coronary disease. During six years of follow-up, 65 of the women died of fatal coronary heart disease and 242 had a nonfatal myocardial infarction. The number of cigarettes smoked per day was positively associated with the risk of fatal coronary heart disease (relative risk = 5.5 for greater than or equal to 25 cigarettes per day), nonfatal myocardial infarction (relative risk = 5.8), and angina pectoris (relative risk = 2.6). Even smoking 1 to 4 or 5 to 14 cigarettes per day was associated with a twofold to three-fold increase in the risk of fatal coronary heart disease or nonfatal infarction. Overall, cigarette smoking accounted for approximately half these events. The attributable (absolute excess) risk of coronary heart disease due to current smoking was highest among women who were already at increased risk because of older age, a parental history of myocardial infarction, a higher relative weight, hypertension, hypercholesterolemia, or diabetes. In contrast, former smokers had little, if any, increase in risk. These prospective data emphasize the importance of cigarette smoking as a determinant of coronary heart disease in women, as well as the markedly increased hazards associated with this habit in combination with other risk factors for this disease.

Analysis of relative survival and proportional mortality

Abstract A computer program utilizing cause-age-time-sex-race-specific mortality or incidence rates is described. The program is used to determine the expected number of deaths or cases of disease in a cohort. Also, among a group of persons known to be dead, the number expected to have died of each cause can be calculated using proportional mortalities. Mortality rates based on United States vital statistics have been assembled for 57 causes of death for white males, white females and non-white males for each five-year age and time period from 1925 through 1969. Proportional mortalities and proportional cancer mortalities have been calculated. Incidence rates from the Connecticut Cancer Registry are available. The computer program is general and can be modified to use other sets of rates in determining the expected number of deaths in any study population.

Frequent chest X-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts

The incidence of breast cancer was determined in 4940 women treated for tuberculosis between 1925 and 1954 in Massachusetts. Among 2573 women examined by X-ray fluoroscopy an average of 88 times during lung collapse therapy and followed for an average of 30 years, 147 breast cancers occurred in contrast to 113.6 expected [observed/expected (O/E) = 1.29; 95% confidence interval (CI) = 1.1-1.5]. No excess of breast cancer was seen among 2367 women treated by other means: 87 observed versus 100.9 expected. Increased rates for breast cancer were not apparent until about 10 to 15 years after the initial fluoroscopy examination. Excess risk then remained high throughout all intervals of follow-up, up to 50 years after first exposure. Age at exposure strongly influenced the risk of radiation-induced breast cancer with young women being at highest risk and those over age 40 being at lowest risk [relative risk (RR) = 1.06]. Mean radiation dose to the breast was estimated to be 79 cGy, and there was strong evidence for a linear relationship between dose and breast cancer risk. Allowing for a 10-year minimum latent period, the relative risk at 1 Gy was estimated as 1.61 and the absolute excess as 10.7 per 10(4) woman-years per gray. When compared to other studies, our data suggest that the breast is one of the most sensitive tissues to the carcinogenic force of radiation, that fractionated exposures are similar to single exposures of the same total dose in their ability to induce breast cancer, that risk remains high for many years after exposure, and that young women are especially vulnerable to radiation injury.

Diphenylhydantoin and Selected Congenital Malformations

Abstract In a cohort of 50,897 pregnancies, frequencies of malformations, selected on the basis of reports in the literature, were compared between four groups of children born to epileptic mothers and those born to nonepileptic mothers. The highest malformation rate (61 per 1000) was observed in 98 children exposed during the early months of pregnancy to daily diphenylhydantoin (phenytoin) use. The rate was lowest in 50,591 children born to nonepileptic women (25 per 1000). It was intermediate in children of epileptic mothers exposed before delivery to sporadic or late use of diphenylhydantoin, and in children of such mothers who were not exposed to the drug. Among epileptic women with varying or no exposure to diphenylhydantoin, the malformation rates did not differ significantly. The difference in the malformation rates between children exposed regularly to diphenylhydantoin during early gestation and children born to nonepileptic mothers could reflect the teratogenic effect of the drug, of epilepsy it...

No association between coffee consumption and adverse outcomes of pregnancy.

We analyzed interview and medical-record data of 12,205 non-diabetic, non-asthmatic women to evaluate the relation between coffee consumption and adverse outcomes of pregnancy. Low birth weight and short gestation occurred more often among offspring of women who drank four or more cups of coffee a day and more often among the offspring of smokers. After controlling for smoking, other habits, demographic characteristics, and medical history by standardization and logistic regression, we found no relation between low birth weight or short gestation and heavy coffee consumption. Furthermore, there was no excess of malformations among coffee drinkers. These negative results suggest that coffee consumption has a minimal effect, if any, on the outcome of pregnancy.

Harvard Report on Cancer Prevention Volume 4: Harvard Cancer Risk Index

AbstractObjective: Prediction of cancer risk is a minor component of current health risk appraisals. Perception of individual cancer risk is poor. A Cancer Risk Index was developed to predict individual cancer risk for cancers accounting for 80% of the cancer burden in the United States. Methods: We used group consensus among researchers at the Harvard Medical School and Harvard School of Public Health to identify risk factors as definite, probable and possible causes of cancer. Risk points were allocated according to the strength of the causal association and summed. Population average risk of cancer and cumulative 10-year risk was obtained from SEER data. Individual ranking relative to the population average was determined. The risk index was evaluated for validity using colon cancer incidence in prospective cohort data. Results: The Harvard Cancer Risk Index provides a broad classification of cancer risk. Validation against cohort data shows good agreement for colon cancer. Conclusion: The Harvard Cancer Risk Index offers a simple estimation of personal risk of cancer. It may help inform users of the major risk factors for cancer and identify changes in lifestyle that will reduce their risk. It offers the potential for tailored health-promotion messages.

Mortality among arthritics.

Abstract It has been suggested that the chronic ingestion of aspirin might lower the incidence of arterial thrombosis in general and coronary artery disease in particular. To evaluate the association between long-term aspirin ingestion and arteriosclerotic heart disease, mortality was determined in a group of chronic aspirin users—persons with rheumatoid arthritis or with osteoarthritis—and compared to the general population. Relative to the general populations of Massachusetts and of the United States, death among arthritics from arteriosclerotic heart disease was more common than expected. Among persons with rheumatoid arthritis, deaths from all causes were increased by 86%. Among persons with osteoarthritis, deaths from all causes were increased by only 11%, suggesting a mortality factor related to the underlying disease as strong or stronger than any effect of the medication taken. The largest relative excesses occurred from deaths due to diseases of the bones and joints, of the gastrointestinal system, and of the respiratory system.

Observations on the healthy worker effect.

Follow-up mortality data from ten groups of employed persons are compared to the mortality rates of the United States general population. Comparisons related to the healthy worker effect (HWE) are computed. As measured by a relative comparison, the standardized mortality ratio (SMR), the HWE is seen to have a dynamic phase and a plateau phase in relation to length of follow-up. In contrast, the HWE as measured by an absolute comparison has little relationship to length of follow-up. Age at entrance into follow-up is strongly related to the absolute risk of mortality, but has little or no relation to the relative risk (SMR). Issues related to the evaluation and minimization of the healthy worker effect are discussed.

Cardiovascular birth defects and antenatal exposure to female sex hormones.

In a cohort of 50,282 pregnancies 19 children with cardiovascular defects were born to 1042 women who received female hormones during early pregnancy (18.2 per 1000). Among 49,240 children not exposed in utero to these agents there were 385 with cardiovascular malformations (7.8 per 1000). Six children with cardiovascular defects were born to a sub-group of 278 women who used oral contraceptives during early pregnancy (21.5 per 1000). After the data were controlled for a wide variety of potentially confounding factors by multivariate methods, the association between in utero exposure to female hormones and cardiovascular birth defects was statistically significant.