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S H Moolgavkar

Publications and source records attributed to S H Moolgavkar.

83 records · Page 5Linked to original sources
PubMed1983

Model for human carcinogenesis: action of environmental agents.

Current statistical prescriptions for low-dosage extrapolation of carcinogenic risk make no distinction between exposure to initiators and exposure to promoters despite the abundant data that these two classes of carcinogens have different modes of action. One reason for this is the lack of an appropriate model. In this paper, a model for carcinogenesis is presented which provides a framework for understanding the roles of "spontaneous" events, hereditary factors, and environmental agents in human carcinogenesis and for interpreting experimental carcinogenesis. This model incorporates two features: transition of target stem cells into cancer cells via an intermediate stage in two irreversible steps and growth and differentiation of normal target and intermediate cells. Cast in mathematical terms, the model can be fitted to age-specific incidence data on human cancers of both children and adults and can illuminate the relative importance of agents that affect transition rates, tissue growth and tissue differentiation. Within the context of the model, initiators act by affecting the transition rates, whereas promoters influence the kinetics of growth, especially of initiated cells. The model provides a good quantitative description of the epidemiology of carcinomas of the breast and of the lung. The data are consistent with the notion that hormones and cigarette smoke act as promoting agents in carcinoma of the breast and of the lung, respectively.

Age Factors↗
PubMed1982

Temporal trends in breast cancer.

Time-depth breast cancer mortality data from the United States, England and Wales, Canada, and Japan, and breast cancer incidence data from Connecticut, Denmark, and Osaka, Japan, were analyzed. The temporal trends in mortality have been similar in the populations examined. Risks for individual cohorts decreased until about the cohort of 1900, when they began to increase. This pattern can account for the observed increases in the rates at perimenopausal ages (40-55 years). Although the magnitudes of mortality rates in Japan are about one fifth those in the West, they have been changing over time in much the same way as in the West. Cohort effects in incidence in Connecticut and Denmark also dipped around 1900. In Osaka, cohort effects rose from the cohort of 1901 to the cohort of 1936.

Adult↗
PubMed1981

Mutation and cancer: a model for human carcinogenesis.

A model for carcinogenesis is presented that provides a framework for understanding the roles of "spontaneous" events, hereditary factors, and environmental agents in human carcinogenesis and for interpreting experimental carcinogenesis. This model incorporates two features: a) transition of target stem cells into cancer cells via an intermediate stage in two irreversible steps, and b) growth and differentiation of normal target and intermediate cells. Cast in mathematical terms, the model can be fitted to age-specific incidence data on human cancers of both children and adults and can illuminate the relative importance of agents that affect transition rates, tissue growth, and tissue differentiation. This is illustrated by application of the model to a) the epidemiology of lung cancer with emphasis on the role of cigarette smoking and b) the epidemiology of breast cancer with emphasis on the roles of hormones, radiation, and hereditary. The nature of the two events and of the intermediate stage is considered in light of hereditary conditions that predispose to cancer in humans. The modes of action of radiation and chemicals in carcinogenesis are discussed, as are predictions based on the model and amenable to experimental verification.

Adult↗
PubMed1981

Smoking and cancers of bladder and pancreas: risks and temporal trends.

Mortality data from carcinomas of the pancreas (1941-75) and bladder (1941-70) in England and Wales were analyzed to study the association between cigarette smoking and these cancers. The analysis revealed that: a) The difference in male and female rates in these cancers is attributable to differences in smoking habits; b) the observed increase in mortality in these diseases is almost entirely due to a dramatic increase among smokers. The mortality rate among nonsmokers increased only slowly for carcinoma of the pancreas and actually fell for carcinoma of the bladder. This analysis, which is based on the total number of deaths in the population, yields estimates of relative risk associated with 20 pack-years of smoking of 1.6 and 3.0 for carcinomas of the pancreas and bladder, respectively. The proportion of deaths from carcinoma of the pancreas attributable to smoking increased from 25% in 1941-45 to 52% in 1971-75 in males and from 2 to 15% in females. The proportion of deaths from carcinoma of the bladder attributable to smoking increased form 53% in 1941-45 to 85% in 1966-70 in males and from 4 to 27% in females.

Adult↗
PubMed1980

Two-stage model for carcinogenesis: Epidemiology of breast cancer in females.

A biologically based two-stage model for carcinogenesis is presented that relates events occurring at the cellular level to epidemiologic features of breast cancer in females. This model, which accommodates the physiologic responses of breast tissue to menarche, menopause, and pregnancy, predicts age-specific incidence curves that are in close quantitative agreement with those observed in six test populations: Connecticut, Denmark, Finland, Slovenia, Iceland, and Osaka, Japan. According to the model, hormones influence the epidemiology of breast cancer in females by their action on the kinetics of growth of nonneoplastic breast tissue. As a consequence, it is argued that hormones are likely to be unimportant in determining overall risk in populations. The protective effect of an early first birth predicted by the model is in good quantitative agreement with data from a multinational study. Other epidemiologic features of breast cancer are logically explained within the framework of the model. No feature of the epidemiology of breast cancer requires that premenopausal and postmenopausal breast cancer be considered distinct entities from the point of view of pathogenesis.

Adolescent↗
PubMed1979

Effect of age on incidence of breast cancer in females.

Incidence and mortality data on breast cancer in females from various Occidental (Western) and Japanese populations were analyzed. After adjustment for birth cohort and year of event, the age curves from all the Western populations were very similar in shape. The age curve for Osaka incidence was very similar in shape to the Western incidence curves. The Osaka curve continued to increase after menopause; the postmenopausal decrease in rates in individual cross sections was the result of a strong cohort effect. The premenopausal mortality curve for Japan was very similar in shape to the Western curves; however, the postmenopausal Japanese mortality curve had a smaller slope at each point.

Adult↗
PubMed1979

Estimation of relative risk from vital data: smoking and cancers of the lung and bladder.

Mortality data from cancers of the lung and bladder in England and Wales were analyzed. With the use of detailed information on cigarette consumption, a nonlinear least-squares analysis showed that the differences between males and females in the rates of these cancers could be explained on the basis of differences in smoking habits. Furthermore, estimates of the relative risk due to smoking were obtained. The relative risks of smoking 146,000 cigarettes (equivalent to 20 cigarettes/day for 20 yr) were 4.3 for lung cancer and 2.9 for bladder cancer. These estimates agree with those obtained by other types of epidemiologic studies.

Adult↗
PubMed1978

The multistage theory of carcinogenesis and the age distribution of cancer in man.

The multistage theory of carcinogenesis is briefly reviewed, and the incidence function predicted by the theory is expressed as an "infinite sum" (convergent power series). This expression for the incidence function has the Armitage-Doll approximation as the first non-zero term and explicitly exhibits the dependence of the incidence function on the transition rates. It is then clear that if the transition rates are not small enough (approximately 10(-4/cell/yr), the Armitage-Doll approximation is inappropriate. Retention of one more term (in the series) leads to a better approximation in these cases. This is illustrated by a hypothetical example. Other assumptions implicit in the theory are discussed.

Adult↗
PubMedDate not supplied

Assessing the adequacy of the logistic regression model for matched case-control studies.

We apply results for the detection of outliers in logistic regression to the analysis of matched pairs data and illustrate the techniques with data from a matched pairs study of the relationship between iron-binding proteins and mortality in the Solomon Islands. Although the study includes 90 matched pairs, the conclusions change substantially with deletion of one or two pairs. Thus, even with reasonably large data sets, single observations may have a great impact on the results of an analysis. The identification of influential observations should constitute part of the analysis of matched case-control data.

Clinical Trials as Topic↗