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     

Are cancer risks associated with exposures to ionising radiation from internal emitters greater than those in the Japanese A-bomb survivors?

After ingestion or inhalation of radionuclides, internal organs of the human body will be exposed to ionising radiation. Current risk estimates of radiation-associated cancer from internal emitters are largely based on extrapolation of risk from high-dose externally exposed groups. Concerns have been expressed that extrapolated risk estimates from internal emitters are greatly underestimated, by factors of ten or more, thus implying a severe underestimation of the true risks. Therefore, data on cancer mortality and incidence in a number of groups who received exposure predominantly from internal emitters are examined and excess relative risks per Sv are compared with comparable (age at exposure, time since exposure, gender) matched subsets of the Japanese atomic bomb survivor cohort. Risks are examined separately for low LET and high LET internal emitters. There are eight studies informative for the effects of internal low LET radiation exposure and 12 studies informative for the effects of internal high LET radiation. For 11 of the 20 cancer endpoints (subgroups of particular study cohorts) examined in the low LET internal emitter studies, the best estimate of the excess relative risk is greater than the corresponding estimate in the Japanese atomic bomb survivors and for the other nine it is less. For four of these 20 studies, the relative risk is significantly (2-sided P < 0.05) different from that in the Japanese atomic bomb survivors, in three cases greater than the atomic bomb survivor relative risk and in one case less. Considering only those six low LET studies/endpoints with 100 or more deaths or cases, for four out of six studies/endpoints the internal emitter risk is greater than that in the Japanese atomic bomb survivors. For seven of the 24 cancer endpoints examined in the high LET internal emitter studies the best estimate of the ERR in the internal emitter study is greater than the corresponding estimate in the Japanese atomic bomb survivors and for the other 17 it is less. For six studies, the relative risk is significantly (2-sided P < 0.05) different from that in the Japanese atomic bomb survivors, in one case greater than the atomic bomb survivor relative risk and in five cases less. Considering only those eight high LET studies/endpoints with 100 or more deaths or cases, for five out of eight studies/endpoints the internal emitter risk is greater than that in the Japanese atomic bomb survivors. These results suggest that excess relative risks in the internal emitter studies do not appreciably differ from those in the Japanese atomic bomb survivors. However, there are substantial uncertainties in estimates of risks in the internal emitter studies, particularly in relation to lung cancer associated with radon daughter (alpha particle) exposure, so a measure of caution should be exercised in these conclusions.     

A heterogeneity measure for cluster identification with application to disease mapping

Mapping of disease incidence has long been of importance to epidemiology and public health. In this paper, we consider identification of clusters of spatial units with elevated disease rates and develop a new approach that estimates the relative disease risk in association with potential risk factors and simultaneously identifies clusters corresponding to elevated risks. A heterogeneity measure is proposed to enable the comparison of a candidate cluster and its complement under a pair of complementary models. A quasi-likelihood procedure is developed for estimating the model parameters and identifying the clusters. An advantage of our approach over traditional spatial clustering methods is the identification of clusters that can have arbitrary shapes due to abrupt or noncontiguous changes while accounting for risk factors and spatial correlation. Asymptotic properties of the proposed methodology are established and a simulation study shows empirically sound finite-sample properties. The mapping and clustering of enterovirus 71 infections in Taiwan are carried out for illustration.     

Covariate Adjustment and Ranking Methods to Identify Regions with High and Low Mortality Rates

Summary Identifying regions with the highest and lowest mortality rates and producing the corresponding color‐coded maps help epidemiologists identify promising areas for analytic etiological studies. Based on a two‐stage Poisson–Gamma model with covariates, we use information on known risk factors, such as smoking prevalence, to adjust mortality rates and reveal residual variation in relative risks that may reflect previously masked etiological associations. In addition to covariate adjustment, we study rankings based on standardized mortality ratios (SMRs), empirical Bayes (EB) estimates, and a posterior percentile ranking (PPR) method and indicate circumstances that warrant the more complex procedures in order to obtain a high probability of correctly classifying the regions with the upper 100γ% and lower 100γ% of relative risks for γ= 0.05, 0.1 , and 0.2. We also give analytic approximations to the probabilities of correctly classifying regions in the upper 100γ% of relative risks for these three ranking methods. Using data on mortality from heart disease, we found that adjustment for smoking prevalence has an important impact on which regions are classified as high and low risk. With such a common disease, all three ranking methods performed comparably. However, for diseases with smaller event counts, such as cancers, and wide variation in event counts among regions, EB and PPR methods outperform ranking based on SMRs.     

Tar yield of cigarettes and risk of acute myocardial infarction. GISSI-EFRIM Investigators.

OBJECTIVE--To analyse the relation between tar and nicotine yield of cigarettes smoked in the recent past and the risk of myocardial infarction. DESIGN--Multicentre case-control study conducted between September 1988 and June 1989. SETTING--Over 80 coronary care units in various Italian regions. SUBJECTS--916 patients with acute myocardial infarction without history of ischaemic heart disease and 1106 controls admitted to hospital for acute conditions not related to known or suspected risk factors for ischaemic heart disease. MAIN OUTCOME MEASURES--Relative risk of myocardial infarction according to type of cigarette smoked adjusted for identified potential confounding factors. Brands of cigarettes classified according to yield of tar and nicotine. RESULTS--Patients with acute myocardial infarction were more often smokers and among smokers they tended to smoke more cigarettes. Compared with non-smokers their estimated relative risks were 3.8, 4.3, 3.2, and 3.7 in the four categories of tar yield (< 10, 10-15, > 15-20, and > 20 mg, respectively). No trend in risk across yields was evident when analysis was restricted to smokers and allowance was made for number of cigarettes. Compared with risks in subjects in the lowest category of tar yield the relative risks were 1.2, 0.8, and 1.0 for the subsequent yields. Compared with risks in non-smokers the relative risks ranged from 9.3 to 12.6 below the age of 50 but no trend was observed with increasing yield. CONCLUSIONS--Changing to cigarettes with a lower tar yield is not an effective means of reducing tobacco related morbidity from myocardial infarction.     

The conversion of exposures due to radon into the effective dose: the epidemiological approach

The risks and dose conversion coefficients for residential and occupational exposures due to radon were determined with applying the epidemiological risk models to ICRP representative populations. The dose conversion coefficient for residential radon was estimated with a value of 1.6 mSv year^?1 per 100 Bq m^?3 (3.6 mSv per WLM), which is significantly lower than the corresponding value derived from the biokinetic and dosimetric models. The dose conversion coefficient for occupational exposures with applying the risk models for miners was estimated with a value of 14 mSv per WLM, which is in good accordance with the results of the dosimetric models. To resolve the discrepancy regarding residential radon, the ICRP approaches for the determination of risks and doses were reviewed. It could be shown that ICRP overestimates the risk for lung cancer caused by residential radon. This can be attributed to a wrong population weighting of the radon-induced risks in its epidemiological approach. With the approach in this work, the average risks for lung cancer were determined, taking into account the age-specific risk contributions of all individuals in the population. As a result, a lower risk coefficient for residential radon was obtained. The results from the ICRP biokinetic and dosimetric models for both, the occupationally exposed working age population and the whole population exposed to residential radon, can be brought in better accordance with the corresponding results of the epidemiological approach, if the respective relative radiation detriments and a radiation-weighting factor for alpha particles of about ten are used.     

Meta-analysis of relation between cigarette smoking and stroke.

There is a lack of consensus among studies on the possible risks of stroke from cigarette smoking; because of this a meta-analysis was conducted. All published data on the association were sought and the relative risk for each study obtained whenever possible. The pooled relative risks were calculated by using estimates of the precision of the individual relative risks to weight their contribution to the meta-analysis. Thirty two separate studies were analysed. The overall relative risk of stroke associated with cigarette smoking was 1.5 (95% confidence interval 1.4 to 1.6). Considerable differences were seen in relative risks among the subtypes: cerebral infarction 1.9, cerebral haemorrhage 0.7, and subarachnoid haemorrhage 2.9. An effect of age on the relative risk was also noted; less than 55 years 2.9, 55-74 years 1.8, and greater than or equal to 75 years 1.1. A dose response between the number of cigarettes smoked and relative risk was noted, and there was a small increased risk in women compared with men. Ex-smokers under the age of 75 seemed to retain an appreciably increased risk of stroke (1.5); for all ages the relative risk in ex-smokers was 1.2. The meta-analysis provides strong evidence of an excess risk of stroke among cigarette smokers. Stroke should therefore be added to the list of diseases related to smoking.     

Asymptotic Interval Estimation of Some Cause-Specific Mortality Risk Measures in Epidemiologic Studies

The present paper describes the algebraic and statistical relationships between the population-based mortality risk measures, the Standardized Mortality Ratio (SMR) and the Standardized Risk Ratio (SRR), and their respective proportional mortality-based counterparts, the internally and externally Standardized Proportional Mortality Ratios (SPMR, S_ePMR). The paper shows, how under some reasonable assumptions, asymptotically precise inferences about population-based risk measures can be made from studies of proportional mortality. Through application of the asymptotic multivariate normal approximation to the multinomial distribution, shortest confidence intervals for the relative SMR (RSMR) involving the corresponding SPMR are constructed for any cause of death. This same technique is also used to construct asymptotic prediction intervals about the cause-specific S_ePMR which, with high probability, contains the corresponding relative SRR (RSRR). The utility of the proportional mortality measures SPMR and S_ePMR as estimators of the corresponding cause-specific risks RSMR and RSRR in occupational epidemiologic research is empirically evaluated using data from two recent occupational cohort studies. Asymptotic Bonferroni type simultaneous inferential techniques are also developed for these measures which facilitate the assessment of overall risk in the presence of several competing factors.     

Comprehensive comparison of probabilistic health risks of soil heavy metals in China’s mining areas

Abstract

To assess the health risks caused by soil heavy metal in China’s mining areas, concentration data for eight heavy metals in 77 mines were collected from previous literature. Monte Carlo simulation was used to analyze the corresponding carcinogenic risks and noncarcinogenic risks, and sensitivity analysis was carried out for each parameter. The results showed that among the different types of mining areas, multi-metal mines have the highest risk of carcinogenesis, followed by tungsten and antimony mines. Their carcinogenic risk values are all greater than 10^?4, which is unacceptable. Pb is a heavy metal with highest noncarcinogenic risk. The log-transformed value is 3.2, which is much larger than the threshold of 0; Pb is followed by As and Hg. Therefore, Pb, As, and Hg are the heavy metals that should be controlled preferentially in polluted mining areas. Sensitivity analysis showed that the soil ingestion rate, exposure frequency, and pollutant concentration level are the factors that have the greatest impacts on health risks. More attention should be paid to these factors when addressing heavy metal pollution in mining areas. In addition, for the surveyed mines, children had a greater health risk than adults, so children should be given extra attention.     

Risk prediction of complex diseases from family history and known susceptibility loci, with applications for cancer screening

Risk prediction based on genomic profiles has raised a lot of attention recently. However, family history is usually ignored in genetic risk prediction. In this study we proposed a statistical framework for risk prediction given an individual's genotype profile and family history. Genotype information about the relatives can also be incorporated. We allow risk prediction given the current age and follow-up period and consider competing risks of mortality. The framework allows easy extension to any family size and structure. In addition, the predicted risk at any percentile and the risk distribution graphs can be computed analytically. We applied the method to risk prediction for breast and prostate cancers by using known susceptibility loci from genome-wide association studies. For breast cancer, in the population the 10-year risk at age 50 ranged from 1.1% at the 5th percentile to 4.7% at the 95th percentile. If we consider the average 10-year risk at age 50 (2.39%) as the threshold for screening, the screening age ranged from 62 at the 20th percentile to 38 at the 95th percentile (and some never reach the threshold). For women with one affected first-degree relative, the 10-year risks ranged from 2.6% (at the 5th percentile) to 8.1% (at the 95th percentile). For prostate cancer, the corresponding 10-year risks at age 60 varied from 1.8% to 14.9% in the population and from 4.2% to 23.2% in those with an affected first-degree relative. We suggest that for some diseases genetic testing that incorporates family history can stratify people into diverse risk categories and might be useful in targeted prevention and screening.     

Cigarette smoking as risk factor for late fetal and early neonatal death.

Risk factors for late fetal death and early neonatal mortality were examined in a population based prospective study. Practically all Swedish births between 1983 and 1985 were included, 281,808 births in all. The overall rates of late fetal death and early neonatal mortality were 3.5 and 3.1 per 1000, respectively. About 30% of the pregnant women were recorded as being daily smokers. Logistic regression analyses showed significant relative risks for late fetal death for high maternal age (1.4), nulliparity (1.4), multiparity (greater than or equal to 2) (1.3), smoking (1.4), and multiple births (2.8). Significant relative risks for early neonatal mortality were found for multiple births (4.9) and smoking (1.2). Smokers aged under 35 faced a relative risk of late fetal death ranging from 1.1 to 1.6, while the risk for late fetal death was doubled if the mothers were aged 35 years or more and smoked. In countries like Sweden, where maternal cigarette smoking is prevalent, smoking may be the most important preventable risk factor for late fetal death.     

Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners' oral contraception study.

To determine the pattern of risk factors for acute myocardial infarction associated solely with women a nested case-control study was carried out on cohort data collected during the Royal College of General Practitioners'' oral contraception study. Smoking (adjusted relative risk 1.7 for light smokers and 4.3 for heavy smokers), hypertension (2.4), toxaemia of pregnancy (2.8), and diabetes mellitus (6.9) were associated with a significantly increased risk of myocardial infarction. There was no significant trend of risk with social class. Current use of the pill increased the risk only among women who also smoked (relative risk 20.8 for heavy smokers). Previous use of the pill did not influence the risk of myocardial infarction. If heavy smokers also had a history of toxaemia of pregnancy their risk of myocardial infarction was further increased (relative risk 41.0). Other variables associated solely with women, such as parity, hysterectomy, and hormone replacement therapy, had little effect on the risk of having a myocardial infarction. Overall, smoking was the most important independent risk factor and had a strong influence on risks associated with other factors.     

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.     

Risk factors for early death in non-insulin dependent diabetes and men with known glucose tolerance status.

OBJECTIVE--To identify risk factors for all cause mortality according to glucose tolerance status. DESIGN--Cohort study with an average 15.6 years'' follow up. SETTING--Paris, France. SUBJECTS--7166 working men aged 44-55 in 1968-72 in the Paris prospective study cohort, with non-insulin dependent diabetes or known result of two hour 75 g oral glucose tolerance test. MAIN OUTCOME MEASURES--Risk factors for death from all causes. RESULTS--128 men were known to be diabetic, 180 had diabetes diagnosed, and 697 had impaired glucose tolerance diagnosed. Compared with normoglycaemic men the relative risks of death in these groups were 2.0 (95% confidence interval 1.4 to 3.0), 2.7 (2.0 to 3.6), and 1.6 (1.3 to 2.0) respectively. Obesity, smoking, high blood pressure, and high non-esterified fatty acid concentration were risk factors for death in all subjects and were unaffected by glucose tolerance. The risks for fasting and two hour insulin concentrations and mean corpuscular volume were two times higher in known diabetic men than in men not known to be diabetic. Central obesity was significant only in men not known to be diabetic (1.6 (1.4 to 1.9)). In known diabetic men a two hour glucose concentration higher than 11.1 mmol/l carried a relative risk of death of 3.8 (1.4 to 9.4). CONCLUSIONS--Diabetic men have similar risk factors for early mortality to other men but are at higher risk from hyperinsulinaemia, hyperglycaemia, and high mean corpuscular volume.     

Hypertensive disease in twin pregnancies: a review.

Reports over the past seventy years show that twin gestations lead to an increased risk of hypertensive disorders. Numerous studies discuss the incidence of hypertensive disease in twin versus singleton gestations, as well as effects of parity, race, age, income level, smoking, zygosity and heritability on this condition. The range of relative risk of gestational hypertension, preeclampsia and eclampsia for twin compared to singleton gestations is 1.2 to 2.7, 2.8 to 4.4 and 3.4 to 5.1 respectively. Parity, African-American ethnicity, and young maternal age are all factors that increase the relative risk of acquiring hypertensive disease to 4.0, 1.8 and 1.5 in mothers of twin gestations. Factors such as maternal smoking, income level and zygosity have a negligible effect on the relative risk of acquiring hypertensive disease in twin gestations. In addition to twin mothers exhibiting a higher incidence of hypertensive disease compared to their singleton counterparts, they also exhibit an earlier onset of hypertensive disease at both 35 and 37 weeks of gestation comparatively. Uric acid levels measured at 30-31 weeks of gestation in twin mothers predicted the onset of preeclampsia with a sensitivity of 73% and a specificity of 74%. The range of risks presented in the literature is wide and the therapies avocated are diverse. We therefore decided to summarize the risks in a comparative fashion and to review current therapeutic strategies for the convenience of clinicians who confront increasing numbers of multiple pregnancies. The tables bring all recent published risks together in the first comparative analysis in which the data has been converted to relative risks and confidence intervals. Because the literature is relatively silent on specific management of hypertensive disease in twin pregnancies, general management recommendations for singleton gestations should be used by practitioners caring over twin gestations.     

Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.

OBJECTIVE--To compare the relative risks of serious gastrointestinal complications reported with individual non-steroidal anti-inflammatory drugs. DESIGN--Systematic review of controlled epidemiological studies that found a relation between use of the drugs and admission to hospital for haemorrhage or perforation. SETTING--Hospital and community based case-control and cohort studies. MAIN OUTCOME MEASURES--(a) Estimated relative risks of gastrointestinal complications with use of individual drugs, exposure to ibuprofen being used as reference; (b) a ranking that best summarised the sequence of relative risks observed in the studies. RESULTS--12 studies met the inclusion criteria. 11 provided comparative data on ibuprofen and other drugs. Ibuprofen ranked lowest or equal lowest for risk in 10 of the 11 studies. Pooled relative risks calculated with exposure to ibuprofen used as reference were all significantly greater than 1.0 (interval of point estimates 1.6 to 9.2). Overall, ibuprofen was associated with the lowest relative risk, followed by diclofenac. Azapropazone, tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin, naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of ibuprofen were associated with relative risks similar to those with naproxen and indomethacin. CONCLUSIONS--The low risk of serious gastrointestinal complications with ibuprofen seems to be attributable mainly to the low doses of the drug used in clinical practice. In higher doses ibuprofen is associated with a similar risk to other non-steroidal anti-inflammatory drugs. Use of low risk drugs in low dosage as first line treatment would substantially reduce the morbidity and mortality due to serious gastrointestinal toxicity from these drugs.     

Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study

Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose-response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8-31.5). At thyroid radiation doses >20 Gy, a downturn in the dose-response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P = 0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.     

Melanoma and ionizing radiation: is there a causal relationship?

This review was initiated in response to concerns that ionizing radiation could be a cause of melanoma. Studies presenting the relative risks for melanoma after external ionizing radiation exposure were in seven categories: (1) The Canadian Radiation Dose Registry, (2) nuclear industry workers, (3) subjects near nuclear test blasts, (4) survivors of the atomic bombings of Japan, (5) airline pilots and cabin attendants, (6) recipients of medical radiation, and (7) radiological technicians. Relative risks for leukemia in each of the studies were used to confirm the likelihood of exposure to ionizing radiation. When studies within a category were compatible, meta-analytic methods were used to obtain combined estimates of the relative risk, and a meta-regression analysis of melanoma relative risk compared to leukemia relative risk was used to examine consistency across exposure categories. Generally, exposure categories with elevated relative risks of leukemia had proportionately elevated relative risks of melanoma. This suggests that people exposed to ionizing radiation may be at increased risk of developing melanoma, although alternative explanations are possible. Future epidemiological studies of ionizing radiation effects should include melanoma as an outcome of interest.     

Information needed to decide about cardiovascular treatment in primary care.

There is growing consensus that treatment of cardiovascular risks should be based on multiple rather than single factors and on absolute rather than relative risks. Thresholds for treatment should reflect the level of absolute risk at which the benefits and hazards of treating outweigh the benefits and hazards of not treating. Once a decision has been made to initiate a treatment programme, clinicians need to know the patient''s absolute risk. At this level of risk do the benefits of treatment outweigh the hazards? Given this information, which treatment option does the patient prefer? Using cardiovascular disease as an example, I review some measures that assist decision making in primary care. Practice guidelines should routinely include accessible presentation of treatment outcomes on benefit, hazard, and costs for a range of absolute risks. These measures enable patients and their doctors to weigh the pros and cons of treatment in their particular circumstances.     

Analytical Relationship between Family History and Genetic and Environmental risks,with Application to Female Breast Cancer

It is well established in genetic epidemiology that family history is an important indicator of familial aggregation of disease in a family. A strong genetic risk factor or an environmental risk factor with high familial correlation can result in a strong family history. In this paper, family history refers to the number of first‐degree relatives affected with the disease. Cui and Hopper (Journal of Epidemiology and Biostatistics 2001; 6 : 331–342) proposed an analytical relationship between family history and relevant genetic parameters. In this paper we expand the relationship to both genetic and environmental risk factors. We established a closed‐form formula for family history as a function of genetic and environmental parameters which include genetic and environmental relative risks, genotype frequency, prevalence and familial correlation of the environmental risk factor. The relationship is illustrated by an example of female breast cancer in Australia. For genetic and environmental relative risks less than 10, most of the female breast cancer cases occur between the age of 40 and 60 years. A higher genetic or environmental relative risk will move the peak of the distribution to a younger age. A more common disease allele or more prevalent environmental risk factor will move the peak to an older age. For a proband with breast cancer, it is most likely (with probability ≥80%) that none of her first‐degree relatives is affected with the disease. To enable the probability of having a positive family history to reach 50%, the environmental relative risks must be extremely as high as 100, the familial correlation as high as 0.8 and the prevalence as low as 0.1. For genetic risk alone, even the relative risk is as high as 100, the probability of having a positive family history can only reach about 30%. This suggests that the environmental risk factor seems to play a more important role in determining a strong family history than the genetic risk factor. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)