On criteria for evaluating models of absolute risk

Absolute risk is the probability that an individual who is free of a given disease at an initial age, a, will develop that disease in the subsequent interval (a, t]. Absolute risk is reduced by mortality from competing risks. Models of absolute risk that depend on covariates have been used to design intervention studies, to counsel patients regarding their risks of disease and to inform clinical decisions, such as whether or not to take tamoxifen to prevent breast cancer. Several general criteria have been used to evaluate models of absolute risk, including how well the model predicts the observed numbers of events in subsets of the population ("calibration"), and "discriminatory power," measured by the concordance statistic. In this paper we review some general criteria and develop specific loss function-based criteria for two applications, namely whether or not to screen a population to select subjects for further evaluation or treatment and whether or not to use a preventive intervention that has both beneficial and adverse effects. We find that high discriminatory power is much more crucial in the screening application than in the preventive intervention application. These examples indicate that the usefulness of a general criterion such as concordance depends on the application, and that using specific loss functions can lead to more appropriate assessments.     

Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women

Background

Rotating night shift work disrupts circadian rhythms and has been associated with obesity, metabolic syndrome, and glucose dysregulation. However, its association with type 2 diabetes remains unclear. Therefore, we aimed to evaluate this association in two cohorts of US women.

Methods and Findings

We followed 69,269 women aged 42–67 in Nurses'' Health Study I (NHS I, 1988–2008), and 107,915 women aged 25–42 in NHS II (1989–2007) without diabetes, cardiovascular disease, and cancer at baseline. Participants were asked how long they had worked rotating night shifts (defined as at least three nights/month in addition to days and evenings in that month) at baseline. This information was updated every 2–4 years in NHS II. Self-reported type 2 diabetes was confirmed by a validated supplementary questionnaire. We documented 6,165 (NHS I) and 3,961 (NHS II) incident type 2 diabetes cases during the 18–20 years of follow-up. In the Cox proportional models adjusted for diabetes risk factors, duration of shift work was monotonically associated with an increased risk of type 2 diabetes in both cohorts. Compared with women who reported no shift work, the pooled hazard ratios (95% confidence intervals) for participants with 1–2, 3–9, 10–19, and ≥20 years of shift work were 1.05 (1.00–1.11), 1.20 (1.14–1.26), 1.40 (1.30–1.51), and 1.58 (1.43–1.74, p-value for trend <0.001), respectively. Further adjustment for updated body mass index attenuated the association, and the pooled hazard ratios were 1.03 (0.98–1.08), 1.06 (1.01–1.11), 1.10 (1.02–1.18), and 1.24 (1.13–1.37, p-value for trend <0.001).

Conclusions

Our results suggest that an extended period of rotating night shift work is associated with a modestly increased risk of type 2 diabetes in women, which appears to be partly mediated through body weight. Proper screening and intervention strategies in rotating night shift workers are needed for prevention of diabetes. Please see later in the article for the Editors'' Summary     

Prospective cohort studies on risk factors for cardiovascular events in systemic lupus erythematosus: a major challenge

Cardiovascular disease (CVD) has been identified as a major contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE). The etiology of premature CVD in SLE is supposed to have many factors, including traditional coronary artery disease (CAD) risk factors, antiphospholipid antibodies, and metabolic and inflammatory factors. Despite the overwhelming interest in CVD in SLE research, prospective studies evaluating risk factors for hard endpoints (that is, cardiovascular events) are relatively scarce. The article by Gustafsson and colleagues suggests that prothrombotic factors play an important role in SLE-related CVD and that the influence of traditional CAD risk factors might be limited.     

Main dietary compounds and pancreatic cancer risk. The quantitative analysis of case-control and cohort studies

Objective: Estimation of the role of main dietary compounds in the risk of developing pancreatic cancer. Research methods and procedures: Literature published till 2010 was reviewed and selected for further analysis. The used terms were: red meat, minced meat, ham, bacon, sausages, white meat, poultry, vegetables, fish, eggs, fruits, lifestyle, diet, pancreatic cancer and pancreatic neoplasm. The collected data were meta-analysed with calculation of combined relative risk and 95% confidence interval as well as studies heterogeneity. Results: A meta-analysis of 11 case–control studies indicates that red meat ingestion elevates pancreatic cancer risk by 48% (95% CI = 1.25–1.76). The vegetables and fruit reduce the risk by 38% (95% CI = 0.54–0.73) and 29% (95% CI = 0.59–0.84), respectively. The pooled analyses of 10 cohort studies do not show significant relations between main dietary compound ingestion and pancreatic cancer risk. Conclusion: The red meat intake is associated with elevated risk of pancreatic cancer in contrast to vegetables and fruit ingestion. The ingestion of red meat, vegetables and fruit in cohort studies was not influenced on pancreatic cancer risk. The role of fish, poultry and eggs was not significant in both case–control and cohort studies, thus further studies were needed.     

Estimates of radiological risk from a terrorist attack using plutonium

The possible use of radioactivity dispersal devices by terrorist groups has been recently reported in the news. In this paper, we discuss the threat of terrorist attacks by plutonium, with particular attention to the dispersal of plutonium by explosion or fire. Doses resulting from inhalation of radioactive aerosol induced by a plutonium explosion or fire are simulated using a Gaussian plume model (the HOTSPOT code) for different meteorological conditions. Ground contamination and resuspension of dust are also considered in the simulations. Our simulations suggest that acute effects from a plutonium dispersal attack are very unlikely. For late stochastic effects, the explosion poses a greater hazard than fire. However, even in the worst-case scenario, the dispersed plutonium would cause relatively few excess cancers (around 80 in a city of 2 million inhabitants) after many years from the explosion, and these excess cancers would remain undetected against the background of cancer fatalities.     

Paraoxonase and other coronary risk factors in a community-based cohort

Oxidative damage to circulating lipids and vascular tissues contributes to the initiation and progression of atherosclerosis. High density lipoprotein provides protection from atherosclerosis and the enzyme paraoxonase may contribute to this effect. The aim of the present study was to examine the trends in paraoxonase activity during the course of a community-directed life-style intervention, and relationships of paraoxonase activity to other coronary heart disease risk factors, in a cohort of Australian Aboriginal people.     

X-ray diffraction studies on the absolute configuration of alpha- and beta-anordrins

The molecular structures and absolute configurations of alpha- and beta-anordrins are reported. Pure alpha- and beta-epimers were obtained with recrystallization and column chromatography combined with high-pressure liquid chromatography methods; they were identified by high-resolution infrared and mass spectra and 1H and 13C nuclear magnetic resonance. By single crystal x-ray diffraction analysis, the crystals of alpha- and beta-epimers were found to belong to the orthorhombic space groups P2(1)2(1)2(1) and P2(1)2(1)2, respectively. The molecular structures of these two epimers were determined. The absolute configurations were deduced by conformation analysis, 1H nuclear magnetic resonance, and comparison with the absolute configuration of the starting material. The absolute configurations of asymmetric centers of alpha- and beta-epimers were observed to be 2R, 5S, 8R, 9S, 10S, 13S, 14S, 17R, and 2S, 5S, 8R, 9S, 10S, 13S, 14S, 17R, respectively. These results were confirmed by the x-ray diffraction determination of the absolute configuration of 2 alpha,17 alpha-diethynyl-A-nor-5 alpha- androstane-2 beta, 17 beta-diol dichloroacetate.     

Analysis of family- and population-based samples in cohort genome-wide association studies

Cohort studies typically sample unrelated individuals from a population, although family members of index cases may also be recruited to investigate shared familial risk factors. Recruitment of family members may be incomplete or ancillary to the main cohort, resulting in a mixed sample of independent family units, including unrelated singletons and multiplex families. Multiple methods are available to perform genome-wide association (GWA) analysis of binary or continuous traits in families, but it is unclear whether methods known to perform well on ascertained pedigrees, sibships, or trios are appropriate in analysis of a mixed unrelated cohort and family sample. We present simulation studies based on Multi-Ethnic Study of Atherosclerosis (MESA) pedigree structures to compare the performance of several popular methods of GWA analysis for both quantitative and dichotomous traits in cohort studies. We evaluate approaches suitable for analysis of families, and combined the best performing methods with population-based samples either by meta-analysis, or by pooled analysis of family- and population-based samples (mega-analysis), comparing type 1 error and power. We further assess practical considerations, such as availability of software and ability to incorporate covariates in statistical modeling, and demonstrate our recommended approaches through quantitative and binary trait analysis of HDL cholesterol (HDL-C) in 2,553 MESA family- and population-based African-American samples. Our results suggest linear modeling approaches that accommodate family-induced phenotypic correlation (e.g., variance-component model for quantitative traits or generalized estimating equations for dichotomous traits) perform best in the context of combined family- and population-based cohort GWAS.     

Population studies in northern Sweden. XVII. Estimates of Finnish and Saamish influence

The North-Swedish population is a mixture of Finnish, Saamish and Central-Swedish ethnic groups. We have studied the Finnish and Saamish admixture by means of genetic markers in 23 North-Swedish subpopulations. The Finnish influence was estimated using the transferrin genes B0-1, DCHI and C3 and the enzyme gene SOD1*2, and markers for Saamish influence were the blood group gene ABO*A2, the serum group gene GC*1F and the enzyme gene 6PGD*C. In the subpopulations the Finnish influence (admixture) varied between 0 and 84% and the Saamish influence between 0 and 34%. The Saamish influence was strongest in the western and northern parts of the area. In the northern part of the area, between 1/4 and 1/3 of the gene pool of the present-day population may be Saamish in origin. The Finnish influence was strongest in the northern and northeastern parts of the area. In the subpopulations along the Finnish border, between 60 and 80% of the gene pool may be Finnish in origin. Significant correlations were found between the Saamish marker genes and between the Finnish marker genes. Due to geographical overlapping of Finnish and Saamish influence, significant correlations were also found between Finnish and Saamish marker genes. The geographical pictures of Saamish and Finnish influence in northern Sweden showed a fair agreement with the expectations derived from historical knowledge. Although a substantial part of the genetic heterogeneity of the North-Swedish population is ethnic in origin, it is obvious that founder effect and genetic drift also have played an important role.     

A cohort study of breast cancer risk in breast reduction patients.

Surgical reduction of the female breast (reduction mammaplasty) is very common in plastic surgery. The purpose of this study was to determine whether women who have undergone breast reduction surgery are at the same, greater, or lesser risk of developing breast cancer than women who have not undergone breast reduction surgery. This study incorporates a population-based, non-concurrent cohort linkage methodology. The Canadian Institute for Health Information hospital records were used to identify all Ontario women who had undergone breast reduction surgery in Ontario between 1979 and 1992. Three computerized probabilistic record linkages were performed. The first linkage was between a file of the 28,042 Ontario women who had undergone bilateral breast reduction surgery between April 1, 1979, and December 31, 1992, and a file of incident cancer cases among Ontario women for the calendar period 1979 to 1993. Follow-up of the cohort was undertaken starting from the date of breast reduction surgery, and vital status was ascertained as of December 31, 1993, by record linkage with the Ontario Mortality Database maintained at the Ontario Cancer Registry. The incidence of cancer in the Ontario breast reduction cohort was compared with the cancer incidence of the general Ontario population after appropriate adjustments for age and calendar time period. The expected number of cancers was calculated using the "PERSON YEARS" computer program. Within the cohort, followed for an average of 6.5 years after bilateral breast reduction surgery, 101 breast cancers were observed and 165.8 were expected, for a standardized incidence ratio of 0.61 (0.50 to 0.74, 95 percent confidence interval). This effect was independent of patient age at breast reduction. This study demonstrates that there is no increased risk of breast cancer after bilateral breast reduction surgery and, in fact, a significant decreased risk existed in women followed for an average of 6.5 years.     

Determination of the absolute redox potential of Rutin: experimental and theoretical studies

The conditional formal potential, E degrees', of Rutin has been studied by cyclic voltammetry using a Rutin film deposited at the multi-wall carbon nanotubes modified glassy carbon electrode (GCE) as the working electrode in different pH phosphate buffered solutions. The experimental standard redox potential, E degrees, of Rutin is obtained to be 0.88 V versus SHE (Standard Hydrogen Electrode). High-level ab initio calculations have been also performed on a chemical model of Rutin and the absolute reduction potential has been calculated. The theoretical standard reduction potential relative to SHE (0.83 V) is in relatively good agreement with experiment.     

Genes, environment and the value of prospective cohort studies

Case-control studies have many advantages for identifying disease-related genes, but are limited in their ability to detect gene-environment interactions. The prospective cohort design provides a valuable complement to case-control studies. Although it has disadvantages in duration and cost, it has important strengths in characterizing exposures and risk factors before disease onset, which reduces important biases that are common in case-control studies. This and other strengths of prospective cohort studies make them invaluable for understanding gene-environment interactions in complex human disease.     

A method for determining weights for excess relative risk and excess absolute risk when applied in the calculation of lifetime risk of cancer from radiation exposure

Radiation-related risks of cancer can be transported from one population to another population at risk, for the purpose of calculating lifetime risks from radiation exposure. Transfer via excess relative risks (ERR) or excess absolute risks (EAR) or a mixture of both (i.e., from the life span study (LSS) of Japanese atomic bomb survivors) has been done in the past based on qualitative weighting. Consequently, the values of the weights applied and the method of application of the weights (i.e., as additive or geometric weighted means) have varied both between reports produced at different times by the same regulatory body and also between reports produced at similar times by different regulatory bodies. Since the gender and age patterns are often markedly different between EAR and ERR models, it is useful to have an evidence-based method for determining the relative goodness of fit of such models to the data. This paper identifies a method, using Akaike model weights, which could aid expert judgment and be applied to help to achieve consistency of approach and quantitative evidence-based results in future health risk assessments. The results of applying this method to recent LSS cancer incidence models are that the relative EAR weighting by cancer solid cancer site, on a scale of 0–1, is zero for breast and colon, 0.02 for all solid, 0.03 for lung, 0.08 for liver, 0.15 for thyroid, 0.18 for bladder and 0.93 for stomach. The EAR weighting for female breast cancer increases from 0 to 0.3, if a generally observed change in the trend between female age-specific breast cancer incidence rates and attained age, associated with menopause, is accounted for in the EAR model. Application of this method to preferred models from a study of multi-model inference from many models fitted to the LSS leukemia mortality data, results in an EAR weighting of 0. From these results it can be seen that lifetime risk transfer is most highly weighted by EAR only for stomach cancer. However, the generalization and interpretation of radiation effect estimates based on the LSS cancer data, when projected to other populations, are particularly uncertain if considerable differences exist between site-specific baseline rates in the LSS and the other populations of interest. Definitive conclusions, regarding the appropriate method for transporting cancer risks, are limited by a lack of knowledge in several areas including unknown factors and uncertainties in biological mechanisms and genetic and environmental risk factors for carcinogenesis; uncertainties in radiation dosimetry; and insufficient statistical power and/or incomplete follow-up in data from radio-epidemiological studies.