PPARGC1A sequence variation and cardiovascular risk-factor levels: a study of the main genetic effects and gene x environment interactions in children from the European Youth Heart Study.

AIMS/HYPOTHESIS: The PPARGC1A gene coactivates multiple nuclear transcription factors involved in cellular energy metabolism and vascular stasis. In the present study, we genotyped 35 tagging polymorphisms to capture all common PPARGC1A nucleotide sequence variations and tested for association with metabolic and cardiovascular traits in 2,101 Danish and Estonian boys and girls from the European Youth Heart Study, a multicentre school-based cross-sectional cohort study. METHODS: Fasting plasma glucose concentrations, anthropometric variables and blood pressure were measured. Habitual physical activity and aerobic fitness were objectively assessed using uniaxial accelerometry and a maximal aerobic exercise stress test on a bicycle ergometer, respectively. RESULTS: In adjusted models, nominally significant associations were observed for BMI (rs10018239, p = 0.039), waist circumference (rs7656250, p = 0.012; rs8192678 [Gly482Ser], p = 0.015; rs3755863, p = 0.02; rs10018239, beta = -0.01 cm per minor allele copy, p = 0.043), systolic blood pressure (rs2970869, p = 0.018) and fasting glucose concentrations (rs11724368, p = 0.045). Stronger associations were observed for aerobic fitness (rs7656250, p = 0.005; rs13117172, p = 0.008) and fasting glucose concentrations (rs7657071, p = 0.002). None remained significant after correcting for the number of statistical comparisons. We proceeded by testing for gene x physical activity interactions for the polymorphisms that showed nominal evidence of association in the main effect models. None of these tests was statistically significant. CONCLUSIONS/INTERPRETATION: Variants at PPARGC1A may influence several metabolic traits in this European paediatric cohort. However, variation at PPARGC1A is unlikely to have a major impact on cardiovascular or metabolic health in these children.

A word of caution on calculating market-based minimum capital risk requirements

This paper demonstrates that the use of GARCH-type models for the calculation of minimum capital risk requirements (MCRRs) may lead to the production of inaccurate and therefore inefficient capital requirements. We show that this inaccuracy stems from the fact that GARCH models typically overstate the degree of persistence in return volatility. A simple modification to the model is found to improve the accuracy of MCRR estimates in both back- and out-of-sample tests. Given that internal risk management models are currently in widespread usage in some parts of the world (most notably the USA), and will soon be permitted for EC banks and investment firms, we believe that our paper should serve as a valuable caution to risk management practitioners who are using, or intend to use this popular class of models.

Flood risk and climate change: global and regional perspectives

A holistic perspective on changing rainfall-driven flood risk is provided for the late 20th and early 21st centuries. Economic losses from floods have greatly increased, principally driven by the expanding exposure of assets at risk. It has not been possible to attribute rain-generated peak streamflow trends to anthropogenic climate change over the past several decades. Projected increases in the frequency and intensity of heavy rainfall, based on climate models, should contribute to increases in precipitation-generated local flooding (e.g. flash flooding and urban flooding). This article assesses the literature included in the IPCC SREX report and new literature published since, and includes an assessment of changes in flood risk in seven of the regions considered in the recent IPCC SREX report—Africa, Asia, Central and South America, Europe, North America, Oceania and Polar regions. Also considering newer publications, this article is consistent with the recent IPCC SREX assessment finding that the impacts of climate change on flood characteristics are highly sensitive to the detailed nature of those changes and that presently we have only low confidence1 in numerical projections of changes in flood magnitude or frequency resulting from climate change.

In vitro and in vivo models of colorectal cancer: antigenotoxic activity of berries.

The etiology of colorectal cancer (CRC), a common cause of cancer-related mortality globally, has strong associations with diet. There is considerable epidemiological evidence that fruits and vegetables are associated with reduced risk of CRC. This paper reviews the extensive evidence, both from in vitro studies and animal models, that components of berry fruits can modulate biomarkers of DNA damage and that these effects may be potentially chemoprotective, given the likely role that oxidative damage plays in mutation rate and cancer risk. Human intervention trials with berries are generally consistent in indicating a capacity to significantly decrease oxidative damage to DNA, but represent limited evidence for anticarcinogenicity, relying as they do on surrogate risk markers. To understand the effects of berry consumption on colorectal cancer risk, future studies will need to be well controlled, with defined berry extracts, using suitable and clinically relevant end points and considering the importance of the gut microbiota.

The impacts of climate change on river flood risk at the global scale

This paper presents an assessment of the implications of climate change for global river flood risk. It is based on the estimation of flood frequency relationships at a grid resolution of 0.5 × 0.5°, using a global hydrological model with climate scenarios derived from 21 climate models, together with projections of future population. Four indicators of the flood hazard are calculated; change in the magnitude and return period of flood peaks, flood-prone population and cropland exposed to substantial change in flood frequency, and a generalised measure of regional flood risk based on combining frequency curves with generic flood damage functions. Under one climate model, emissions and socioeconomic scenario (HadCM3 and SRES A1b), in 2050 the current 100-year flood would occur at least twice as frequently across 40 % of the globe, approximately 450 million flood-prone people and 430 thousand km2 of flood-prone cropland would be exposed to a doubling of flood frequency, and global flood risk would increase by approximately 187 % over the risk in 2050 in the absence of climate change. There is strong regional variability (most adverse impacts would be in Asia), and considerable variability between climate models. In 2050, the range in increased exposure across 21 climate models under SRES A1b is 31–450 million people and 59 to 430 thousand km2 of cropland, and the change in risk varies between −9 and +376 %. The paper presents impacts by region, and also presents relationships between change in global mean surface temperature and impacts on the global flood hazard. There are a number of caveats with the analysis; it is based on one global hydrological model only, the climate scenarios are constructed using pattern-scaling, and the precise impacts are sensitive to some of the assumptions in the definition and application.

The importance of the volatility risk premium for volatility forecasting

In this paper, we study the role of the volatility risk premium for the forecasting performance of implied volatility. We introduce a non-parametric and parsimonious approach to adjust the model-free implied volatility for the volatility risk premium and implement this methodology using more than 20 years of options and futures data on three major energy markets. Using regression models and statistical loss functions, we find compelling evidence to suggest that the risk premium adjusted implied volatility significantly outperforms other models, including its unadjusted counterpart. Our main finding holds for different choices of volatility estimators and competing time-series models, underlying the robustness of our results.

Disparity-driven vs blur-driven models of accommodation and convergence in binocular vision and intermittent strabismus

Background. Current models of concomitant, intermittent strabismus, heterophoria, convergence and accommodation anomalies are either theoretically complex or incomplete. We propose an alternative and more practical way to conceptualize clinical patterns. Methods. In each of three hypothetical scenarios (normal; high AC/A and low CA/C ratios; low AC/A and high CA/C ratios) there can be a disparity-biased or blur-biased “style”, despite identical ratios. We calculated a disparity bias index (DBI) to reflect these biases. We suggest how clinical patterns fit these scenarios and provide early objective data from small illustrative clinical groups. Results. Normal adults and children showed disparity bias (adult DBI 0.43 (95%CI 0.50-0.36), child DBI 0.20 (95%CI 0.31-0.07) (p=0.001). Accommodative esotropes showed less disparity-bias (DBI 0.03). In the high AC/A and low CA/C scenario, early presbyopes had mean DBI of 0.17 (95%CI 0.28-0.06), compared to DBI of -0.31 in convergence excess esotropes. In the low AC/A and high CA/C scenario near exotropes had mean DBI of 0.27, while we predict that non-strabismic, non-amblyopic hyperopes with good vision without spectacles will show lower DBIs. Disparity bias ranged between 1.25 and -1.67. Conclusions. Establishing disparity or blur bias, together with knowing whether convergence to target demand exceeds accommodation or vice versa explains clinical patterns more effectively than AC/A and CA/C ratios alone. Excessive bias or inflexibility in near-cue use increases risk of clinical problems. We suggest clinicians look carefully at details of accommodation and convergence changes induced by lenses, dissociation and prisms and use these to plan treatment in relation to the model.

Calculating the application criticality and business risk from technology obsolescence

The problem of technology obsolescence in information intensive businesses (software and hardware no longer being supported and replaced by improved and different solutions) and a cost constrained market can severely increase costs and operational, and ultimately reputation risk. Although many businesses recognise technological obsolescence, the pervasive nature of technology often means they have little information to identify the risk and location of pending obsolescence and little money to apply to the solution. This paper presents a low cost structured method to identify obsolete software and the risk of their obsolescence where the structure of a business and its supporting IT resources can be captured, modelled, analysed and the risk to the business of technology obsolescence identified to enable remedial action using qualified obsolescence information. The technique is based on a structured modelling approach using enterprise architecture models and a heatmap algorithm to highlight high risk obsolescent elements. The method has been tested and applied in practice in three consulting studies carried out by Capgemini involving four UK police forces. However the generic technique could be applied to any industry based on plans to improve it using ontology framework methods. This paper contains details of enterprise architecture meta-models and related modelling.

Assessing the business risk of technology obsolescence through enterprise modelling

The problem of technology obsolescence in information intensive businesses (software and hardware no longer being supported and replaced by improved and different solutions) and a cost constrained market can severely increase costs and operational, and ultimately reputation risk. Although many businesses recognise technological obsolescence, the pervasive nature of technology often means they have little information to identify the risk and location of pending obsolescence and little money to apply to the solution. This paper presents a low cost structured method to identify obsolete software and the risk of their obsolescence where the structure of a business and its supporting IT resources can be captured, modelled, analysed and the risk to the business of technology obsolescence identified to enable remedial action using qualified obsolescence information. The technique is based on a structured modelling approach using enterprise architecture models and a heatmap algorithm to highlight high risk obsolescent elements. The method has been tested and applied in practice in two consulting studies carried out by Capgemini involving three UK police forces. However the generic technique could be applied to any industry based on plans to improve it using ontology framework methods. This paper contains details of enterprise architecture meta-models and related modelling.

A toxicokinetic model for thiamethoxam in rats: implications for higher-tier risk assessment

Risk assessment for mammals is currently based on external exposure measurements, but effects of toxicants are better correlated with the systemically available dose than with the external administered dose. So for risk assessment of pesticides, toxicokinetics should be interpreted in the context of potential exposure in the field taking account of the timescale of exposure and individual patterns of feeding. Internal concentration is the net result of absorption, distribution, metabolism and excretion (ADME). We present a case study for thiamethoxam to show how data from ADME study on rats can be used to parameterize a body burden model which predicts body residue levels after exposures to LD50 dose either as a bolus or eaten at different feeding rates. Kinetic parameters were determined in male and female rats after an intravenous and oral administration of 14C labelled by fitting one-compartment models to measured pesticide concentrations in blood for each individual separately. The concentration of thiamethoxam in blood over time correlated closely with concentrations in other tissues and so was considered representative of pesticide concentration in the whole body. Body burden model simulations showed that maximum body weight-normalized doses of thiamethoxam were lower if the same external dose was ingested normally than if it was force fed in a single bolus dose. This indicates lower risk to rats through dietary exposure than would be estimated from the bolus LD50. The importance of key questions that should be answered before using the body burden approach in risk assessment, data requirements and assumptions made in this study are discussed in detail.

Tropical cyclones in the UPSCALE ensemble of high resolution global climate models

The UPSCALE (UK on PRACE: weather-resolving Simulations of Climate for globAL Environmental risk) project, using PRACE (Partnership for Advanced Computing in Europe) resources, constructed and ran an ensemble of atmosphere-only global climate model simulations, using the Met Office Unified Model GA3 configuration. Each simulation is 27 years in length for both the present climate and an end-of-century future climate, at resolutions of N96 (130 km), N216 (60 km) and N512 (25 km), in order to study the impact of model resolution on high impact climate features such as tropical cyclones. Increased model resolution is found to improve the simulated frequency of explicitly tracked tropical cyclones, and correlations of interannual variability in the North Atlantic and North West Pacific lie between 0.6 and 0.75. Improvements in the deficit of genesis in the eastern North Atlantic as resolution increases appear to be related to the representation of African Easterly Waves and the African Easterly Jet. However, the intensity of the modelled tropical cyclones as measured by 10 m wind speed remain weak, and there is no indication of convergence over this range of resolutions. In the future climate ensemble, there is a reduction of 50% in the frequency of Southern Hemisphere tropical cyclones, while in the Northern Hemisphere there is a reduction in the North Atlantic, and a shift in the Pacific with peak intensities becoming more common in the Central Pacific. There is also a change in tropical cyclone intensities, with the future climate having fewer weak storms and proportionally more stronger storms

Parametric preference functionals under risk in the gain domain: a Bayesian analysis

The performance of rank dependent preference functionals under risk is comprehensively evaluated using Bayesian model averaging. Model comparisons are made at three levels of heterogeneity plus three ways of linking deterministic and stochastic models: the differences in utilities, the differences in certainty equivalents and contextualutility. Overall, the"bestmodel", which is conditional on the form of heterogeneity is a form of Rank Dependent Utility or Prospect Theory that cap tures the majority of behaviour at both the representative agent and individual level. However, the curvature of the probability weighting function for many individuals is S-shaped, or ostensibly concave or convex rather than the inverse S-shape commonly employed. Also contextual utility is broadly supported across all levels of heterogeneity. Finally, the Priority Heuristic model, previously examined within a deterministic setting, is estimated within a stochastic framework, and allowing for endogenous thresholds does improve model performance although it does not compete well with the other specications considered.

Associations between flavan-3-ol intake and CVD risk in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk)

Background: Dietary intervention studies suggest that flavan-3-ol intake can improve vascular function and reduce the risk of cardiovascular diseases (CVD). However, results from prospective studies failed to show a consistent beneficial effect. Objective: To investigate associations between flavan-3-ol intake and CVD risk in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). Design: Data was available from 24,885 (11,252 men; 13,633 women) participants, recruited between 1993 and 1997 into the EPIC-Norfolk study. Flavan-3-ol intake was assessed using 7-day food diaries and the FLAVIOLA Flavanol Food Composition database. Missing data for plasma cholesterol and vitamin C were imputed using multiple imputation. Associations between flavan-3-ol intake and blood pressure at baseline were determined using linear regression models. Associations with CVD risk were estimated using Cox regression analyses. Results: Median intake of total flavan-3-ols was 1034 mg/d (range: 0 – 8531 mg/d) for men and 970 mg/d (0 – 6695 mg/d) for women, median intake of flavan-3-ol monomers was 233 mg/d (0 – 3248 mg/d) for men and 217 (0 – 2712 mg/d) for women. There were no consistent associations between flavan-3-ol monomer intake and baseline systolic and diastolic blood pressure (BP). After 286,147 person-years of follow up, there were 8463 cardio-vascular events and 1987 CVD related deaths; no consistent association between flavan-3-ol intake and CVD risk (HR 0.93, 95% CI:0.87; 1.00; Q1 vs Q5) or mortality was observed (HR 0.93, 95% CI: 0.84; 1.04). Conclusions: Flavan-3-ol intake in EPIC-Norfolk is not sufficient to achieve a statistically significant reduction in CVD risk.

Models agree on forced response pattern of precipitation and temperature extremes

Model projections of heavy precipitation and temperature extremes include large uncertainties. We demonstrate that the disagreement between individual simulations primarily arises from internal variability, whereas models agree remarkably well on the forced signal, the change in the absence of internal variability. Agreement is high on the spatial pattern of the forced heavy precipitation response showing an intensification over most land regions, in particular Eurasia and North America. The forced response of heavy precipitation is even more robust than that of annual mean precipitation. Likewise, models agree on the forced response pattern of hot extremes showing the greatest intensification over midlatitudinal land regions. Thus, confidence in the forced changes of temperature and precipitation extremes in response to a certain warming is high. Although in reality internal variability will be superimposed on that pattern, it is the forced response that determines the changes in temperature and precipitation extremes in a risk perspective.

Responsibility effects in decision making under risk

We systematically explore decision situations in which a decision maker bears responsibility for somebody else's outcomes as well as for her own in situations of payoff equality. In the gain domain we confirm the intuition that being responsible for somebody else's payoffs increases risk aversion. This is however not attributable to a 'cautious shift' as often thought. Indeed, looking at risk attitudes in the loss domain, we find an increase in risk seeking under responsibility. This raises issues about the nature of various decision biases under risk, and to what extent changed behavior under responsibility may depend on a social norm of caution in situations of responsibility versus naive corrections from perceived biases. To further explore this issue, we designed a second experiment to explore risk-taking behavior for gain prospects offering very small or very large probabilities of winning. For large probabilities, we find increased risk aversion, thus confirming our earlier finding. For small probabilities however, we find an increase of risk seeking under conditions of responsibility. The latter finding thus discredits hypotheses of a social rule dictating caution under responsibility, and can be explained through flexible self-correction models predicting an accentuation of the fourfold pattern of risk attitudes predicted by prospect theory. An additional accountability mechanism does not change risk behavior, except for mixed prospects, in which it reduces loss aversion. This indicates that loss aversion is of a fundamentally different nature than probability weighting or utility curvature. Implications for debiasing are discussed.