Estimating tumor incidence rates in animal carcinogenicity experiments

Tumor incidence is the primary measure of carcinogenesis. This article focuses on estimating time-dependent incidence rates in animal experiments with few sacrifices. When the context of observation is known for none or all of the animals dying with the tumor of interest, previous results are obtained under relaxed assumptions. The link with existing semiparametric and nonparametric procedures based on latent failure times is exploited by using these methods to compute maximum likelihood estimates of the incidence rates without introducing latent random variables. Nonparametric estimators that are appropriate when all contexts of observation are known are generalized to the case in which the contexts of observation are unknown for a subset of the tumor-bearing animals.     

Dynamical behavior of epidemiological models with nonlinear incidence rates

Epidemiological models with nonlinear incidence rates I ^pS^qshow a much wider range of dynamical behaviors than do those with bilinear incidence rates IS. These behaviors are determined mainly by p and , and secondarily by q. For such models, there may exist multiple attractive basins in phase space; thus whether or not the disease will eventually die out may depend not only upon the parameters, but also upon the initial conditions. In some cases, periodic solutions may appear by Hopf bifurcation at critical parameter values.     

A method to estimate demographic intensities via cumulative incidence rates

In many situations it is impossible to calculate the occurrence/exposure rates which are so important for analysis in demography, epidemiology, and other fields, because the only information available for each age group is the occurrences and total exposure, but not the distribution of the latter over the various separate statuses. The literature contains a method to estimate the occurrence/ exposure rates from cumulative incidence rates for closed cohorts in some simple situations of this kind. The purpose of this paper is to justify the method by a probabilistic argument, to generalize it to cover a much broader set of cases, described as time-continuous Markov chains, and to illustrate it with some new sets of data. The method is originally based on an assumption of nondifferential mortality, but our findings suggest that it is strongly robust against deviations from this assumption. We also comment upon the effect of migration.     

Risk-adjusted female breast cancer incidence rates in the United States

A method has been previously proposed for estimating risk-adjusted incidence rates (RAIRs) from cancer data from the Surveillance, Epidemiology, and End Results (SEER) program. Unlike conventionally reported SEER-based cancer incidence rates in the United States, but similar to the approach taken by the International Association of Cancer Registries and the International Agency for Research on Cancer, the method uses only the first primary cancer of the given site. In addition, it also adjusts for population-based cancer prevalence in order to obtain a better population-based measure of cancer risk. For most cancers multiple cancer primaries are rare and the prevalence of the disease is low. However, female breast cancer has a comparatively high risk of subsequent breast cancers and is the most prevalent cancer in women. Hence, in white women RAIRs are 3.0% lower in ages 30-39, 4.2% lower in ages 40-49, 4.0% lower in ages 50-59, 4.1% lower in ages 60-69, 3.8% lower in ages 70-79, and 4.3% lower in ages 80 years and older compared with conventional rates. Corresponding lower percentages for black women are 3.9%, 6.9%, 5.1%, 7.8%, 6.0%, and 2.2%, respectively. Age-group specific trends in breast cancer incidence rates differed between RAIRs and conventional incidence rates, increasingly so with older age. The number of cancer cases in the United States is estimated from conventional incidence rates and population estimates. In 2007, the estimated number of malignant breast cancer cases was 181,665 for white women and 20,203 for black women. The estimated number of breast cancer cases decreased by 4.8% for whites and 6.5% for blacks when based on RAIRs. RAIRs are a better measure of breast cancer risk and trends in RAIRs are better for monitoring the effect of risk factors.     

Demographic analysis of the variation in the rates of multiple maternities in Sweden since 1751

To elucidate the causes and mechanisms of twinning and higher multifetal maternities, we have taken advantage of the statistical sources of Sweden, where continuous statistics for the whole population are the oldest available. We found strong secular and regional fluctuations. The rates of multiple maternities were the highest during the last three decades of the 18th century, when the twinning rate was more than 17 per 1,000, the triplet rate was more than 3 per 10,000, and the quadruplet rate was almost 7 per 1 million maternities. During 1849-1873 the twinning rate in Sweden was 14.2 per 1,000, but this rate showed great regional differences, being 18.0 per 1,000 on the island of Gotland and 12.6 per 1,000 in the county of Alvsborg. During this period the twinning rate in the countryside in the county of Stockholm was 20.4, but in the city of Stockholm it was only 14.1 per 1,000. In Sweden after the 1930s there was a marked decrease in the twinning rate, which by the 1960s had fallen to only about half of what it had been two centuries earlier. The corresponding reductions for triplet and quadruplet rates were about 75%. The aim of this paper was to study the temporal and regional variations in multiple maternities in Sweden from 1751 to 1960 based on demographic and some socioeconomic data for the counties. We confirmed our earlier studies that maternal age and parity cannot satisfactorily explain the secular and regional differences in the twinning rates. In contrast to studies in France (1901-1968), we found no unequivocal association between the twinning rates and the crude birth rates. The correlation coefficients between the twinning rate and the crude birth rate showed statistically significant regional and temporal variations. After eliminating the temporal trends, regional differences in the correlation coefficients remained. The twinning rates for the counties seem to converge toward a common low level, 10-12 per 1,000. The observed convergence toward relatively similar levels may be caused by the increased matrimonial migration distances and decreased endogamy of the citizens as a consequence of better communications. The increased urbanization and industrialization that started in the last decades of the 19th century broke up the old static agrarian isolates and caused Sweden, within 2-3 generations, to develop from a poor nation to one of the most prosperous in the world. A more urban and affluent lifestyle, a better diet, and increased stress and sedentary occupations may have reduced the physical capacity of mothers to carry gestations with multiple embryos or fetuses to completion.     

p53 mutations associated with aging-related rise in cancer incidence rates

TP53’s role as guardian of the genome diminishes with age, as the probability of mutation increases. Previous studies have shown an association between p53 gene mutations and cancer. However, the role of somatic TP53 mutations in the steep rise in cancer rates with aging has not been investigated at a population level. This relationship was quantified using the International Agency for Research on Cancer (IARC) TP53 and GLOBOCAN cancer databases. The power function exponent of the cancer rate was calculated for 5-y age-standardized incidence or mortality rates for up to 25 cancer sites occurring in adults of median age 42 to 72 y. Linear regression analysis of the mean percentage of a cancer’s TP53 mutations and the corresponding cancer exponent was conducted for four populations: worldwide, Japan, Western Europe, and the United States. Significant associations (P ≤ 0.05) were found for incidence rates but not mortality rates. Regardless of the population studied, positive associations were found for all cancer sites, with more significant associations for solid tumors, excluding the outlier prostate cancer or sex-related tumors. Worldwide and Japanese populations yielded P values as low as 0.002 and 0.005, respectively. For the United States, a significant association was apparent only when analysis utilized the Surveillance, Epidemiology, and End Results (SEER) database. This study found that TP53 mutations accounts for approximately one-quarter and one-third of the aging-related rise in the worldwide and Japanese incidence of all cancers, respectively. These significant associations between TP53 mutations and the rapid rise in cancer incidence with aging, considered with previously published literature, support a causal role for TP53 according to the Bradford-Hill criteria. However, questions remain concerning the contribution of TP53 mutations to neoplastic development and the role of factors such as genetic instability, obesity, and gene deficiencies other than TP53 that reduce p53 activity.     

Relationship of age-specific incidence rates to immunological aspects of Hashimoto's thyroiditis

Studies of the age-specific incidence rates of the appearance of Hashimoto''s thyroiditis indicate that this disorder appears at random in a genetically preselected population. Following an initial lag in the first few years of life, the disease appears at a constant rate thereafter in this population.The age-specific incidence rates were similar to those previously reported for Graves'' disease. Moreover, there is considerable evidence implicating cell-mediated immunity in both diseases, with the likelihood of cooperating humoral antibodies as well. It may be hypothesized that the two diseases are primarily due to genetic defects in immunological surveillance, which result in an inability to destroy or control a specific forbidden clone of thymicderived lymphocytes which may arise by normal random mutation. The T-lymphocyte interacts with its complementary antigen (on a hitherto normal thyroid cell), setting up a cell-mediated immune response; in addition it may cooperate with bursa-equivalent lymphocytes, which then produce humoral antibodies. It is possible that both cell-mediated immunity and humoral antibodies are necessary for the full expression of the disease.     

Asymptotically robust variance estimation for person‐time incidence rates

Person‐time incidence rates are frequently used in medical research. However, standard estimation theory for this measure of event occurrence is based on the assumption of independent and identically distributed (iid) exponential event times, which implies that the hazard function remains constant over time. Under this assumption and assuming independent censoring, observed person‐time incidence rate is the maximum‐likelihood estimator of the constant hazard, and asymptotic variance of the log rate can be estimated consistently by the inverse of the number of events. However, in many practical applications, the assumption of constant hazard is not very plausible. In the present paper, an average rate parameter is defined as the ratio of expected event count to the expected total time at risk. This rate parameter is equal to the hazard function under constant hazard. For inference about the average rate parameter, an asymptotically robust variance estimator of the log rate is proposed. Given some very general conditions, the robust variance estimator is consistent under arbitrary iid event times, and is also consistent or asymptotically conservative when event times are independent but nonidentically distributed. In contrast, the standard maximum‐likelihood estimator may become anticonservative under nonconstant hazard, producing confidence intervals with less‐than‐nominal asymptotic coverage. These results are derived analytically and illustrated with simulations. The two estimators are also compared in five datasets from oncology studies.     

Semiparametric analysis of tumor incidence rates in survival/sacrifice experiments

This paper addresses the problem of comparing treatment groups with respect to the rate of tumor development for animals in a survival experiment with some serial sacrifices. The analysis specifies a parametric model for the tumor incidence function, but places no parametric restrictions on the death rates. The procedure is feasible with as few as two sacrifice times and requires no individual data on cause of death. Other diseases need not act independently of the tumor of interest, nor are any restrictions imposed on tumor lethality or the relationship between the onset and death times for tumor-bearing animals. The proposed methods are illustrated with some survival/sacrifice data.     

Transitioning to an obese India: Demographic and structural determinants of the rapid rise in overweight incidence

India, which has long suffered from undernutrition, has seen a rapid rise in overweight incidence in the last decade and a half. These changes are characterized by significant within-country differences in overweight incidence that vary by gender and regional development levels. In this paper, we provide an integrative framework, linking the income-gradient hypothesis of obesity with biological, obesogenic, and environmental factors to provide an explanation on the emergence of within-country differences in overweight patterns. We utilize measured body mass index (BMI), along with individual- and household-level data of over 800,000 men and women surveyed in the National Family Health Surveys of 2005–06 and 2015–16 to identify correlates of within-country differences in overweight incidence. A decomposition analysis reveals that among women, in addition to increasing access to obesogenic technologies, biological factors are associated with overweight incidence. Among men, obesogenic factors related to technology use and health behaviors are associated with the rise in overweight incidence, but biological factors are not. At lower levels of regional development, overweight incidence is associated with greater access to obesogenic technology such as motorized transport, which reduces physical activity among men at higher rates than women. At higher levels of economic development, obesogenic behaviors, such as watching more television and reducing smoking, are associated with overweight incidence. Our results corroborate the call by public health experts for group-specific policies to stem the rise of overweight incidence in developing countries.     

Recent trends in incidence rates of pleural mesothelioma in British Columbia.

A total of 64 cases of pleural mesothelioma were reported in British Columbia between 1973 and 1980, 54 in males and 10 in females. There was a significant (p less than 0.05) increase in the incidence among males. The overall incidence rates were 4.9 and 0.9 per million person-years for males and females respectively. The age distribution of the cases was roughly exponential up to age 70 years. Almost all of the cases were clustered in Cowichan Valley, Capital and Greater Vancouver counties, where there was a high level of shipbuilding activity 30 to 40 years ago. The increased incidence in males may be related to this activity, which involved exposure to asbestos.