Lung cancer risk in mice: analysis of fractionation effects and neutron RBE with a biologically motivated model

Data from Argonne National Laboratory on lung cancer in 15,975 mice with acute and fractionated exposures to gamma rays and neutrons are analyzed with a biologically motivated model with two rate-limiting steps and clonal expansion. Fractionation effects and effects of radiation quality can be explained well by the estimated kinetic parameters. Both an initiating and a promoting action of neutrons and gamma rays are suggested. While for gamma rays the initiating event is described well with a linear dose-rate dependence, for neutrons a nonlinear term is needed, with less effectiveness at higher dose rates. For the initiating event, the neutron RBE compared to gamma rays is about 10 when the dose rate during each fraction is low. For higher dose rates this RBE decreases strongly. The estimated lifetime relative risk for radiation-induced lung cancers from 1 Gy of acute gamma-ray exposure at an age of 110 days is 1.27 for male mice and 1.53 for female mice. For doses less than 1 Gy, the effectiveness of fractionated exposure to gamma rays compared to acute exposure is between 0.4 and 0.7 in both sexes. For lifetime relative risk, the RBE from acute neutrons at low doses is estimated at about 10 relative to acute gamma-ray exposure. It decreases strongly with dose. For fractionated neutrons, it is lower, down to about 4 for male mice.     

Promoting action of radiation in the atomic bomb survivor carcinogenesis data?

The age-time patterns of risk in the atomic bomb survivor data on incidence of solid cancers suggest an action of low-LET radiation not only on the initiating event but also on promotion in a biologically motivated model that allows for both actions. The favored model indicates a decrease of radiation risks with age at exposure due to the initiating effect and with time since exposure due to the promoting effect. These result in a relative risk that depends mostly on attained age for ages at exposure above 20 years. According to the model, a dose of 100 mGy is inducing about the same number of initiating events that occur spontaneously in 1 year. Assuming that several mutations are needed to obtain intermediate cells with growth advantage does not improve the quality of fit. The estimated promoting effect could be explained if the number of intermediate cells increases by 80% at 1 Gy, e.g. due to stimulated cell repopulation.     

Relative risks of radiation-associated cancer: comparison of second cancer in therapeutically irradiated populations with the Japanese atomic bomb survivors

In this paper the radiation-associated relative risks of second primary cancer incidence in groups treated for first primary cancer by radiotherapy are compared with radiation-associated relative risk estimates in the Japanese atomic bomb survivor cancer incidence data. For four cancer sites, namely lung cancer, bone cancer, ovarian cancer and leukaemia, the relative risks in the comparable (age at exposure, time since exposure, sex matched) subsets of the Japanese data are significantly greater than those in the majority of second cancer studies. Even when the differences between the relative risks in the Japanese atomic bomb survivors and the medical series do not approach conventional levels of statistical significance, relative risks tend to be higher in the Japanese data than in the second cancer studies. At least for leukaemia, the discrepancy between the Japanese and second cancer risks can be largely explained by cell- sterilisation effects. There are few indications of modification of radiation-associated second cancer relative risk among those treated with adjuvant chemotherapy, nor are there strong indications of modification of radiation- associated relative risk by heritable genetic factors. If anything, there is evidence that second cancer relative excess risks are lower among those patients with cancer-prone disorders than among non-susceptible patients. However, the higher underlying cancer risk in some of these medically exposed populations should also be considered, in particular for those with cancer-prone conditions, so that the absolute excess risk is sometimes higher than in the Japanese data. Received: 14 May 1999 / Accepted in revised form: 17 September 1999     

Quantifying the underestimation of relative risks from genome-wide association studies

Genome-wide association studies (GWAS) have identified hundreds of associated loci across many common diseases. Most risk variants identified by GWAS will merely be tags for as-yet-unknown causal variants. It is therefore possible that identification of the causal variant, by fine mapping, will identify alleles with larger effects on genetic risk than those currently estimated from GWAS replication studies. We show that under plausible assumptions, whilst the majority of the per-allele relative risks (RR) estimated from GWAS data will be close to the true risk at the causal variant, some could be considerable underestimates. For example, for an estimated RR in the range 1.2-1.3, there is approximately a 38% chance that it exceeds 1.4 and a 10% chance that it is over 2. We show how these probabilities can vary depending on the true effects associated with low-frequency variants and on the minor allele frequency (MAF) of the most associated SNP. We investigate the consequences of the underestimation of effect sizes for predictions of an individual's disease risk and interpret our results for the design of fine mapping experiments. Although these effects mean that the amount of heritability explained by known GWAS loci is expected to be larger than current projections, this increase is likely to explain a relatively small amount of the so-called "missing" heritability.     

Studies of the mortality of atomic bomb survivors. report 12, part I. Cancer: 1950-1990

This continues the series of periodic general reports on cancer mortality in the cohort of A-bomb survivors followed by the Radiation Effects Research Foundation. The follow-up is extended by the 5 years 1986-1990, and analysis includes an additional 10,500 survivors with recently estimated radiation doses. Together these extensions add about 550,000 person-years of follow-up. The cohort analyzed consists of 86,572 subjects, of which about 60% have dose estimates of at least 0.005 Sv. During 1950-1990 there have been 3086 and 4741 cancer deaths for the less than and greater than 0.005 Sv groups, respectively. It is estimated that among these there have been approximately 420 excess cancer deaths during 1950-1990, of which about 85 were due to leukemia. For cancers other than leukemia (solid cancers), about 25% of the excess deaths in 1950-1990 occurred during the last 5 years; for those exposed as children this figure is nearly 50%. For leukemia only about 3% of the excess deaths in 1950-1990 occurred in the last 5 years. Whereas most of the excess for leukemia occurred in the first 15 years after exposure, for solid cancers the pattern of excess risk is apparently more like a life-long elevation of the natural age-specific cancer risk. Taking advantage of the lengthening follow-up, increased attention is given to clarifying temporal patterns of the excess cancer risk. Emphasis is placed on describing these patterns in terms of absolute excess risk, as well as relative risk. For example: (a) although it is becoming clearer that the excess relative risk for those exposed as children has declined over the follow-up, the excess absolute risk has increased rapidly with time; and (b) although the excess relative risk at a given age depends substantially on sex and age at exposure, the age-specific excess absolute risk depends little on these factors. The primary estimates of excess risk are now given as specific to sex and age at exposure, and these include projections of dose-specific lifetime risks for this cohort. The excess lifetime risk per sievert for solid cancers for those exposed at age 30 is estimated at 0.10 and 0.14 for males and females, respectively. Those exposed at age 50 have about one-third these risks. Projection of lifetime risks for those exposed at age 10 is more uncertain. Under a reasonable set of assumptions, estimates for this group range from about 1.0-1.8 times the estimates for those exposed at age 30. The excess life-time risk for leukemia at 1 Sv for those exposed at either 10 or 30 years is estimated as about 0.015 and 0.008 for males and females, respectively. Those exposed at age 50 have about two-thirds that risk. Excess risks for solid cancer appear quite linear up to about 3 Sv, but for leukemia apparent nonlinearity in dose results in risks at 0.1 Sv estimated at about 1/20 of those for 1.0 Sv. Site-specific risk estimates are given, but it is urged that great care be taken in interpreting these, because most of their variation can be explained simply by imprecision in the estimates.     

A meta-analysis of cigarette smoking,bone mineral density and risk of hip fracture: recognition of a major effect.

OBJECTIVE: To determine the magnitude and importance of the relation between smoking, bone mineral density, and risk of hip fracture according to age. DESIGN: Meta-analysis of 29 published cross sectional studies reporting the difference in bone density in 2156 smokers and 9705 non-smokers according to age, and of 19 cohort and case-control studies recording 3889 hip fractures reporting risk in smokers relative to non-smokers. RESULTS: In premenopausal women bone density was similar in smokers and non-smokers. Postmenopausal bone loss was greater in current smokers than non-smokers, bone density diminishing by about an additional 2% for every 10 year increase in age, with a difference of 6% at age 80. In current smokers relative to non-smokers the risk of hip fracture was similar at age 50 but greater thereafter by an estimated 17% at age 60, 41% at 70, 71% at 80, and 108% at 90. These estimates of relative risk by age, derived directly from a regression analysis of the studies of smoking and hip fracture, were close to estimates using the difference in bone density between smokers and non-smokers and the association between bone density and risk of hip fracture. The estimated cumulative risk of hip fracture in women in England was 19% in smokers and 12% in non-smokers to age 85; 37% and 22% to age 90. Among all women, one hip fracture in eight is attributable to smoking. Limited data in men suggest a similar proportionate effect of smoking as in women. The association was not explained by smokers being thinner, younger at menopause, and exercising less nor by actions of smoking on oestrogen, but smoking may have a direct action on bone. CONCLUSIONS: Hip fracture in old age is a major adverse effect of smoking after the menopause. The cumulative excess bone loss over decades is substantial, increasing the lifetime risk of hip fracture by about half.     

The effect of changes in dosimetry on cancer mortality risk estimates in the atomic bomb survivors

In the spring of 1986 the Radiation Effects Research Foundation (RERF) received a new atomic bomb dosimetry system. This report presents the comparisons of leukemia and nonleukemia cancer mortality risk estimates under the old and new dosimetries. In terms of total kerma (essentially whole-body gamma plus neutron exposure), risk estimates for both classes of cancer are 75-85% higher with the new dosimetry. This and other summary comparisons allow for possible nonlinearity at high estimated doses. Changes are also considered in relation to organ doses and assumptions about the relative biological effectiveness (RBE) of neutrons. Without regard to RBE, the risk estimates for total organ dose are essentially unchanged by the dosimetry revision. However, with increasing assumed values of RBE, the estimated low-LET risk decreases much less rapidly under the new dosimetry, due to the smaller neutron component. Thus at an assumed constant RBE of 10, for example, the effect of the dosimetry revision is to increase organ dose risk estimates, relative to those based on the old dosimetry, by 30% for nonleukemia and 80% for leukemia. At an RBE of 20 these increases are 72 and 136%, respectively. A number of other issues are discussed. The city difference in dose is no longer statistically significant, even at an RBE of one. Estimation of RBE is even less feasible with new dosimetry. There is substantial question of the linearity in dose response, in the sense of a leveling off at higher doses. Finally, some indication is given of how risks estimated from this dosimetry and the current data may compare to widely used estimates based largely on the RERF data with the previous dosimetry.     

Correcting for variable age of onset in the estimation of familial relative risk when there is a secular trend in incidence of disease

We discuss the effects that a secular trend in incidence would have on estimation of familial relative risk (ratio of observed to expected cumulative incidence among relatives of index cases). For example, when age-specific incidence rates of a condition have increased during the lifetimes of relatives among whom relative risk is to be estimated, familial relative risk will be biased downward if cross-sectional, age-specific incidence data are used to estimate expected cumulative incidence among relatives. The stronger the trend and the older the ages of unaffected relatives, the greater the bias will be. Incorporating different age-specific incidence curves for different birth cohorts into the analysis is an approach we suggest for correcting the bias.     

New models for evaluation of radiation-induced lifetime cancer risk and its uncertainty employed in the UNSCEAR 2006 report

Generalized relative and absolute risk models are fitted to the latest Japanese atomic bomb survivor solid cancer and leukemia mortality data (through 2000), with the latest (DS02) dosimetry, by classical (regression calibration) and Bayesian techniques, taking account of errors in dose estimates and other uncertainties. Linear-quadratic and linear-quadratic-exponential models are fitted and used to assess risks for contemporary populations of China, Japan, Puerto Rico, the U.S. and the UK. Many of these models are the same as or very similar to models used in the UNSCEAR 2006 report. For a test dose of 0.1 Sv, the solid cancer mortality for a UK population using the generalized linear-quadratic relative risk model is estimated as 5.4% Sv(-1) [90% Bayesian credible interval (BCI) 3.1, 8.0]. At 0.1 Sv, leukemia mortality for a UK population using the generalized linear-quadratic relative risk model is estimated as 0.50% Sv(-1) (90% BCI 0.11, 0.97). Risk estimates varied little between populations; at 0.1 Sv the central estimates ranged from 3.7 to 5.4% Sv(-1) for solid cancers and from 0.4 to 0.6% Sv(-1) for leukemia. Analyses using regression calibration techniques yield central estimates of risk very similar to those for the Bayesian approach. The central estimates of population risk were similar for the generalized absolute risk model and the relative risk model. Linear-quadratic-exponential models predict lower risks (at least at low test doses) and appear to fit as well, although for other (theoretical) reasons we favor the simpler linear-quadratic models.     

Studies of the mortality of atomic bomb survivors. Report 12, part II. Noncancer mortality: 1950-1990.

This report updates the data on noncancer mortality for 86,572 atomic bomb survivors with dose estimates in the Radiation Effects Research Foundation's Life Span Study cohort. The primary analyses are based on more than 27,000 noncancer disease deaths that occurred in the cohort between October 1, 1950, and December 31, 1990, 30% more than in the previous report. The present analyses strengthen earlier findings of a statistically significant increase in noncancer disease death rates with radiation dose. Increasing trends are observed for diseases of the circulatory, digestive and respiratory systems. Rates for those exposed to 1 Sv are elevated about 10%, a relative increase that is considerably smaller than that for cancer. However, estimates of the number of radiation-related noncancer deaths in the cohort to date (140 to 280) are 50 to 100% of the number for solid cancer. The data do not yet clarify the shape of the dose response. There is no significant evidence against linearity, but the data are statistically consistent with curvilinear dose-response functions that posit essentially zero risk for doses below 0.5 Sv. Similarly, while the data are consistent with substantial variation in the excess relative risk with age at exposure or attained age, there is no statistically significant dependence on these factors. In view of the small relative risks and the lack of understanding of biological mechanisms, we emphasize consideration of whether the findings could be explained by misclassification, confounding or selection effects. Based on available data, we conclude that such factors are unlikely to fully explain the observed dose response. A significant dose response is also seen for deaths from blood diseases with an excess relative risk that is several times greater than that seen for solid cancer. Particular attention is paid to the possibility that this apparent effect is a consequence of the attribution of leukemia or other cancer deaths to noncancer blood diseases. We find that misclassification does not explain this excess risk. As in earlier reports, suicide rates tend to decrease with increasing dose.     

Estimating relative risks from significant family-based association studies

Two approaches are described to estimate relative risks from significant family-based association studies. They can be used to obtain either point estimates or confidence regions. The approaches are evaluated by a simulation study and illustrated by application to a real data set. It is shown that both approaches largely reduce the bias in the relative risk estimates which can occur in case that the significant outcome of the study from which the relative risks are estimated is ignored.     

Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients.

This paper presents the analysis of familial cancer data collected in a hospital-based study of 159 childhood soft-tissue-sarcoma patients. Two different statistical models detected excess aggregation of cancer, which could be explained by a rare dominant gene. For each kindred, we estimated the probability of the observed cancer distribution under the dominant-gene model and identified 12 families that are the most likely to be segregating the gene. Two of those families have confirmed germ-line mutations in the p53 tumor-suppressor gene. The relative risk of affection for children who are gene carriers was estimated to be 100 times the background rate. Females were found to have a slightly higher age-specific penetrance, but maternal and paternal lineages made equal contributions to the evidence in favor of the dominant gene. The proband's histology, ethnicity, and age at diagnosis were evaluated to determine whether any of these altered the probability of affection in family members. Only embryonal rhabdomyosarcoma was found to be a significant covariate under the dominant-gene model. While molecular genetic studies of familial cancer will eventually provide answers to the questions of genetic heterogeneity, age- and site-specific penetrance, mutation rates, and gene frequency, information from statistical models is useful for setting priorities and defining hypotheses.     

Breast cancer and oral contraceptives: findings in Oxford-Family Planning Association contraceptive study.

Among the 17 032 women taking part in the Oxford-Family Planning Association contraceptive study, 72 were first diagnosed as having breast cancer between the date they were admitted to the study and 1 September 1980. The relative risk of developing the disease in women who had used oral contraceptives in comparison with those who had never used them was estimated to be 0.96 (95% confidence limits 0.59 to 1.63). Among women aged under 35 years, the corresponding relative risk (based on only 14 women with breast cancer) was estimated to be 0.61. No relation was apparent between the risk of developing breast cancer and duration of oral-contraceptive use or interval since first oral-contraceptive use in any age group. The data in this study are thus reassuring; but observations based on women with long-term use of oral contraceptives, especially those starting to use the preparations at an early age, are few.     

Thyroid neoplasia following low-dose radiation in childhood

The thyroid gland is highly sensitive to the carcinogenic effects of ionizing radiation. Previously, we reported a significant increase of thyroid cancer and adenomas among 10,834 persons in Israel who received radiotherapy to the scalp for ringworm. These findings have now been extended with further follow-up and revised dosimetry. Overall, 98 thyroid tumors were identified among the exposed and 57 among 10,834 nonexposed matched population and 5392 sibling comparison subjects. An estimated thyroid dose of 9 cGy was linked to a fourfold (95% Cl = 2.3-7.9) increase of malignant tumors and a twofold (95% Cl = 1.3-3.0) increase of benign tumors. The dose-response relationship was consistent with linearity. Age was an important modifier of risk with those exposed under 5 years being significantly more prone to develop thyroid tumors than older children. The pattern of radiation risk over time could be described on the basis of a constant multiplication of the background rate, and an absolute risk model was not compatible with the observed data. Overall, the excess relative risk per cGy for thyroid cancer development after childhood exposure is estimated as 0.3, and the absolute excess risk as 13 per 10(6) PY-cGy. For benign tumors the estimated excess relative risk was 0.1 per cGy and the absolute risk was 15 per 10(6) PY-cGy.     

Weight calibration to improve the efficiency of pure risk estimates from case-control samples nested in a cohort

Cohort studies provide information on relative hazards and pure risks of disease. For rare outcomes, large cohorts are needed to have sufficient numbers of events, making it costly to obtain covariate information on all cohort members. We focus on nested case-control designs that are used to estimate relative hazard in the Cox regression model. In 1997, Langholz and Borgan showed that pure risk can also be estimated from nested case-control data. However, these approaches do not take advantage of some covariates that may be available on all cohort members. Researchers have used weight calibration to increase the efficiency of relative hazard estimates from case-cohort studies and nested cased-control studies. Our objective is to extend weight calibration approaches to nested case-control designs to improve precision of estimates of relative hazards and pure risks. We show that calibrating sample weights additionally against follow-up times multiplied by relative hazards during the risk projection period improves estimates of pure risk. Efficiency improvements for relative hazards for variables that are available on the entire cohort also contribute to improved efficiency for pure risks. We develop explicit variance formulas for the weight-calibrated estimates. Simulations show how much precision is improved by calibration and confirm the validity of inference based on asymptotic normality. Examples are provided using data from the American Association of Retired Persons Diet and Health Cohort Study.     

Linking behavioral thermoregulation,boldness, and individual state in male Carpetan rock lizards

Mechanisms affecting consistent interindividual behavioral variation (i.e., animal personality) are of wide scientific interest. In poikilotherms, ambient temperature is one of the most important environmental factors with a direct link to a variety of fitness‐related traits. Recent empirical evidence suggests that individual differences in boldness are linked to behavioral thermoregulation strategy in heliothermic species, as individuals are regularly exposed to predators during basking. Here, we tested for links between behavioral thermoregulation strategy, boldness, and individual state in adult males of the high‐mountain Carpetan rock lizard (Iberolacerta cyreni). Principal component analysis revealed the following latent links in our data: (i) a positive relationship of activity with relative limb length and color brightness (PC1, 23% variation explained), (ii) a negative relationship of thermoregulatory precision with parasite load and risk‐taking (PC2, 20.98% variation explained), and (iii) a negative relationship between preferred body temperature and relative limb length (PC3, 19.23% variation explained). We conclude that differences in boldness and behavioral thermoregulatory strategy could be explained by both stable and labile state variables. The moderate link between behavioral thermoregulatory strategy and risk‐taking personality in our system is plausibly the result of differences in reproductive state of individuals or variation in ecological conditions during the breeding season.     

Heterogeneity of cancer risk due to stochastic effects: emphasis on radiation-induced effects

Persons with exactly the same genetic background, behavior and environment may differ in radiation cancer risk, due to the stochastic nature of cancer development. These differences are estimated quantitatively by means of the two stage clonal expansion model, in which the number of intermediate cells on their way to malignancy varies stochastically between individuals. For liver cancer after injection of Thorotrast, the estimated relative risk for persons without intermediate cells at age 40 is a factor of more than 10 larger than that for persons with a large number of intermediate cells. The population-based estimate of the relative risk represents an underestimation for most persons at most ages, because for persons showing a large number of intermediate cells liver cancer is not a rare disease.     

A Regional Ecological Risk Assessment of the Kaipara Harbour,New Zealand,Using a Relative Risk Model

A regional ecological risk assessment was conducted for the Kaipara Harbour catchment in New Zealand. The Relative Risk Model was used to prioritize management of the sources of stress and habitats of concern in the basin. Semi-structured interviews with 25 representative stakeholders were conducted to obtain the resource-users’ perspectives and to identify the regional stressor sources and receptor habitat data for the model. For this risk analysis we divided the catchment into nine ecological districts. Mixed-methodological approaches including content analysis, geospatial analysis, and source documentation were used to categorize source and habitat rankings, based on the relative abundance of each in the nine ecological districts. Risk characterization revealed that fishing pressure and tidal energy pose the largest sources of perceived risk to the catchment; shellfish and Maui dolphin habitats are the receptors estimated to be at greatest risk; and the Kaipara and Rodney ecological districts are the sub-regions estimated with the greatest combined risk. A Monte Carlo analysis confirmed the source inputs and revealed greater uncertainty than the estimated habitat input results. The results of this assessment can be used by policy-makers, conservation groups, and municipalities to inform the future management efforts in the harbor and catchment.     

Smoking and ulcerative colitis.

In a case-control study of smoking and ulcerative colitis patients with the disease were much less likely to smoke than community controls matched for age and sex. The difference was substantial, with an estimated relative risk of 3.8 for non-smoking on current habits, was even larger (6.2) when habits at onset of the disease were examined, and was mainly accounted for by 42 of 55 patients who had given up smoking a mean of eight years before onset. The association could not be explained by confounding by social class. These findings suggest that smoking directly or indirectly confers protection against ulcerative colitis.     

Influence of maternal age, parity and social class on perinatal mortality in Scotland: 1960-82

This study examines secular changes in the influence of maternal age, parity and social class on perinatal mortality in Scotland. Using cross-sectional national data on all Scottish legitimate births the effects of these factors are estimated on the risk of stillbirths, neonatal and perinatal deaths, and the extent to which the current pattern of relative risks in the early 1980s has changed over the past 2 decades is investigated. Social class is used as a crude measure of relative as opposed to absolute differences in socioeconomic conditions which may influence reproductive outcomes. The effects of age, parity and social class are estimated using logistic models. The most parsimonious model adequately describing the data is provided by a main effects model without interactions. Despite changes in reproductive behavior, improved access to maternity services and more effective perinatal care, the influence of maternal age and social class on perinatal mortality remained unchanged between 1960 and 1982. Although the absolute risks of stillbirths and neonatal deaths declined in all maternal age groups, this improvement was not accompained by a significant change in the relative risks traditionally associated with age. Despite no significant changes in the traditional J-shaped association between parity and stillbirths, cross-sectional analysis shows that in the early 1980s the risk of both neonatal and perinatal deaths decreased as parity increased. This finding is consistent with the pattern of risks observed in longitudinal studies and retrospective surveys of reproductive histories. In view of the stability of age, parity and social class effects on the risk of perinatal mortality, little if any of the overall decrease in Scottish stillbirth and neonatal death rates can be attributed to a significant narrowing of relative risks. The results suggest that the attributable risk of high maternal age or low social class on perinatal mortality is negligible. Future improvements in perinatal mortality are thus likely to result from a continuation of the uniform decrease in perinatal mortality for women of all ages, parities and social classes and not from a diminishing of differences in relative risks which are now virtually identical for a large and growing % of women in Scotland.