An Exact Analysis of the Multistage Model Explaining Dose-Response Concavity

The traditional multistage (MS) model of carcinogenesis implies several empirically testable properties for dose-response functions. These include convex (linear or upward-curving) cumulative hazards as a function of dose; symmetric effects on lifetime tumor probability of transition rates at different stages; cumulative hazard functions that increase without bound as stage-specific transition rates increase without bound; and identical tumor probabilities for individuals with identical parameters and exposures. However, for at least some chemicals, cumulative hazards are not convex functions of dose. This paper shows that none of these predicted properties is implied by the mechanistic assumptions of the MS model itself. Instead, they arise from the simplifying "rare-tumor" approximations made in the usual mathematical analysis of the model. An alternative exact probabilistic analysis of the MS model with only two stages is presented, both for the usual case where a carcinogen acts on both stages simultaneously, and also for idealized initiation-promotion experiments in which one stage at a time is affected. The exact two-stage model successfully fits bioassay data for chemicals (e.g., 1,3-butadiene) with concave cumulative hazard functions that are not well-described by the traditional MS model. Qualitative properties of the exact two-stage model are described and illustrated by least-squares fits to several real datasets. The major contribution is to show that properties of the traditional MS model family that appear to be inconsistent with empirical data for some chemicals can be explained easily if an exact, rather than an approximate model, is used. This suggests that it may be worth using the exact model in cases where tumor rates are not negligible (e.g., in which they exceed 10%). This includes the majority of bioassay experiments currently being performed.     

Limits of Applicability for the Deterministic Approximation of the Two-Step Clonal Expansion Model

Motivated by a hypothesis published recently, the limits of applicability of the deterministic approximation of the two-step clonal expansion model are investigated. The approximate hazard increases unlimited, while the exact hazard is approaching a constant value. The approximate solution becomes inapplicable for hazards in the order of that constant rate. When the initiation rate is much larger than the cell division rate, the survival rate is small when the approximation becomes inapplicable. The simplicity of the exact solutions suggests using them in all situations.     

An Improved Approximation to the Exact Solution of the Two-Stage Clonal Growth Model of Cancer

Multistage clonal growth models are of interest for cancer risk assessment because they can explicitly incorporate data on cell replication. Both approximate and exact formulations of the two stage growth model have been described. The exact solution considers the conditional probability of tumors arising in previously tumor-free animals; the approximate solution estimates total probability of tumor formation. The exact solution is much more computationally intensive when time-dependent cell growth parameters are included. The approximate solution deviates from the exact solution at high incidences and probabilities of tumor. This report describes a computationally tractable,'improved approximation'to the exact solution. Our improved approximation includes a correction term to adjust the unconditional expectation of intermediate cells based on the time history of formation of intermediate cells by mutation of normal cells (recruitment) or by cell division in the intermediate cell population (expansion). The improved approximation provided a much better match to the exact solution than the approximate solution for a wide range of parameter values. The correction term also appears to provide insight into the biological factors that contribute to the variance of the expectation for the number of intermediate cells over time.     

An Alternative Exact Solution of the Two-Stage Clonal Growth Model of Cancer

The approximate solution of the two-stage clonal expansion model of cancer may substantially deviate from the exact solution, and may therefore lead to erroneous conclusions in particular applications. However, for time-varying parameters the exact solution (method of characteristics) is not easy to implement, hampering the accessibility of the model to nonmathematicians. Based on intuitive reasoning, Clewell et al. (1995) proposed an improved approximate solution that is easy to implement whatever time-varying behavior the parameters may have. Here we provide the mathematical foundation for the approximation suggested by Clewell et al. (1995) and show that, after a slight modification, it is in fact an exact solution for the case of time-constant parameters. We were not able to prove that it is an exact solution for time-varying parameters as well. However, several computer simulations showed that the numerical results do not differ from the exact solution as proposed by Moolgavkar and Luebeck (1990). The advantage of this alternative solution is that the hazard rate of the first malignant cell can be evaluated by numerically integrating a single differential equation.     

Approximate versus Exact Equilibria in Dynamic Economies

This paper develops theoretical foundations for an error analysis of approximate equilibria in dynamic stochastic general equilibrium models with heterogeneous agents and incomplete financial markets. While there are several algorithms that compute prices and allocations for which agents' first‐order conditions are approximately satisfied (“approximate equilibria”), there are few results on how to interpret the errors in these candidate solutions and how to relate the computed allocations and prices to exact equilibrium allocations and prices. We give a simple example to illustrate that approximate equilibria might be very far from exact equilibria. We then interpret approximate equilibria as equilibria for close‐by economies; that is, for economies with close‐by individual endowments and preferences. We present an error analysis for two models that are commonly used in applications, an overlapping generations (OLG) model with stochastic production and an asset pricing model with infinitely lived agents. We provide sufficient conditions that ensure that approximate equilibria are close to exact equilibria of close‐by economies. Numerical examples illustrate the analysis.     

Multistage Models of Carcinogenesis: An Approximation for the Size and Number Distribution of Late-Stage Clones

Multistage models have become the basic paradigm for modeling carcinogenesis. One model, the two-stage model of carcinogenesis, is now routinely used in the analysis of cancer risks from exposure to environmental chemicals. In its most general form, this model has two states, an initiated state and a neoplastic state, which allow for growth of cells via a simple linear birth-death process. In all analyses done with this model, researchers have assumed that tumor incidence is equivalent to the formation of a single neoplastic cell and the growth kinetics in the neoplastic state have been ignored. Some researchers have discussed the impact of this assumption on their analyses, but no formal methods were available for a more rigorous application of the birth-death process. In this paper, an approximation is introduced which allows for the application of growth kinetics in the neoplastic state. The adequacy of the approximation against simulated data is evaluated and methods are developed for implementing the approximation using data on the number and size of neoplastic clones.     

On the Exact Hazard and Survival Functions of the MVK Stochastic Carcinogenesis Model

The MVK two-stage carcinogenesis model is one of the most widely accepted mechanistic models in carcinogenesis modeling. However, due to a perceived difficulty in obtaining analytic solutions for the hazard and survival functions, approximations and numerical methods have been used to calculate these two fundamental quantities. This paper focuses on a special case of the homogeneous MVK model where the number of normal cells is constant. The probability generating function (pgf) for the number of tumor cells is derived, and the exact analytic solutions to the hazard and survival functions are obtained from the pgf.     

基于重现时间间隔分析的极端收益预测及交易策略研究

极端收益的预测在金融风险管理中非常重要。本文系统研究了极端收益重现时间间隔的统计规律，提出了一种基于重现时间间隔分析的早期预警模型，并对极端收益的重现进行预测，检验了模型在样本内外的预测性能；最后分别针对极端正收益和极端负收益的样本外预测结果，设计了看涨和看跌的两种交易策略，并以中国上证指数、法国CAC40指数、英国富时指数、香港恒生指数和日本日经指数为例，对交易策略的日均收益率进行了统计显著性检验。研究结果表明，极端收益的重现时间间隔具有右偏、尖峰厚尾和强自相关等典型特征；极端收益预测模型在样本内和样本外检验中都具有良好的预测能力；看涨和看跌交易策略在卖出区间均能有效地避开下跌阶段，看涨策略有更显著的盈利水平。     

A Polynomial Optimization Approach to Principal–Agent Problems

This paper presents a new method for the analysis of moral hazard principal–agent problems. The new approach avoids the stringent assumptions on the distribution of outcomes made by the classical first‐order approach and instead only requires the agent's expected utility to be a rational function of the action. This assumption allows for a reformulation of the agent's utility maximization problem as an equivalent system of equations and inequalities. This reformulation in turn transforms the principal's utility maximization problem into a nonlinear program. Under the additional assumptions that the principal's expected utility is a polynomial and the agent's expected utility is rational in the wage, the final nonlinear program can be solved to global optimality. The paper also shows how to first approximate expected utility functions that are not rational by polynomials, so that the polynomial optimization approach can be applied to compute an approximate solution to nonpolynomial problems. Finally, the paper demonstrates that the polynomial optimization approach extends to principal–agent models with multidimensional action sets.     

Probabilistic Multiple Hazard Resilience Model of an Interdependent Infrastructure System

Multiple hazard resilience is of significant practical value because most regions of the world are subject to multiple natural and technological hazards. An analysis and assessment approach for multiple hazard spatiotemporal resilience of interdependent infrastructure systems is developed using network theory and a numerical analysis. First, we define multiple hazard resilience and present a quantitative probabilistic metric based on the expansion of a single hazard deterministic resilience model. Second, we define a multiple hazard relationship analysis model with a focus on the impact of hazards on an infrastructure. Subsequently, a relationship matrix is constructed with temporal and spatial dimensions. Further, a general method for the evaluation of direct impacts on an individual infrastructure under multiple hazards is proposed. Third, we present an analysis of indirect multiple hazard impacts on interdependent infrastructures and a joint restoration model of an infrastructure system. Finally, a simplified two‐layer interdependent infrastructure network is used as a case study for illustrating the proposed methodology. The results show that temporal and spatial relationships of multiple hazards significantly influence system resilience. Moreover, the interdependence among infrastructures further magnifies the impact on resilience value. The main contribution of the article is a new multiple hazard resilience evaluation approach that is capable of integrating the impacts of multiple hazard interactions, interdependence of network components (layers), and restoration strategy.     

Quantitative Risk Assessment: Developing a Bayesian Approach to Dichotomous Dose–Response Uncertainty

Model averaging for dichotomous dose–response estimation is preferred to estimate the benchmark dose (BMD) from a single model, but challenges remain regarding implementing these methods for general analyses before model averaging is feasible to use in many risk assessment applications, and there is little work on Bayesian methods that include informative prior information for both the models and the parameters of the constituent models. This article introduces a novel approach that addresses many of the challenges seen while providing a fully Bayesian framework. Furthermore, in contrast to methods that use Monte Carlo Markov Chain, we approximate the posterior density using maximum a posteriori estimation. The approximation allows for an accurate and reproducible estimate while maintaining the speed of maximum likelihood, which is crucial in many applications such as processing massive high throughput data sets. We assess this method by applying it to empirical laboratory dose–response data and measuring the coverage of confidence limits for the BMD. We compare the coverage of this method to that of other approaches using the same set of models. Through the simulation study, the method is shown to be markedly superior to the traditional approach of selecting a single preferred model (e.g., from the U.S. EPA BMD software) for the analysis of dichotomous data and is comparable or superior to the other approaches.     

Performance analysis of re-entrant flow shop with single-job and batch machines using mean value analysis

We propose an approximate method based on the mean value analysis for estimating the average performance of re-entrant flow shop with single-job machines and batch machines. The main focus is on the steady-state averages of the cycle time and the throughput of the system. Characteristics of the re-entrant flow and inclusion of the batch machines complicate the exact analysis of the system. Thus, we propose an approximate analytic method for obtaining the mean waiting time at each buffer of the workstation and a heuristic method to improve the result of the analytic method. We compare the results of the proposed approach with a simulation study using some numerical examples.     

An Integrated Risk Assessment Model of Township‐Scaled Land Subsidence Based on an Evidential Reasoning Algorithm and Fuzzy Set Theory

Land subsidence risk assessment (LSRA) is a multi‐attribute decision analysis (MADA) problem and is often characterized by both quantitative and qualitative attributes with various types of uncertainty. Therefore, the problem needs to be modeled and analyzed using methods that can handle uncertainty. In this article, we propose an integrated assessment model based on the evidential reasoning (ER) algorithm and fuzzy set theory. The assessment model is structured as a hierarchical framework that regards land subsidence risk as a composite of two key factors: hazard and vulnerability. These factors can be described by a set of basic indicators defined by assessment grades with attributes for transforming both numerical data and subjective judgments into a belief structure. The factor‐level attributes of hazard and vulnerability are combined using the ER algorithm, which is based on the information from a belief structure calculated by the Dempster‐Shafer (D‐S) theory, and a distributed fuzzy belief structure calculated by fuzzy set theory. The results from the combined algorithms yield distributed assessment grade matrices. The application of the model to the Xixi‐Chengnan area, China, illustrates its usefulness and validity for LSRA. The model utilizes a combination of all types of evidence, including all assessment information—quantitative or qualitative, complete or incomplete, and precise or imprecise—to provide assessment grades that define risk assessment on the basis of hazard and vulnerability. The results will enable risk managers to apply different risk prevention measures and mitigation planning based on the calculated risk states.     

Analysing Wage Differences between the USA and Germany Using Proportional Hazards Models

We analyse differences between the wage distributions in the USA and Germany in 2001 for both women and men. The empirical analysis is based on the decomposition of differences using Cox's marginal (partial) likelihood. The approach based on rank invariant estimators such as Cox's is borrowed from the literature on failure time data. Donald et al. pioneered this approach in 2000. However, they did not use the full power of the semi‐parametric approach. Instead, they argued for using a piecewise constant hazard rate model. We improve on their work by showing that the semi‐parametric features of Cox's marginal likelihood are as appropriate for the analysis of wage decompositions and as easy to interpret. Moreover, we extend their approach by allowing for non‐linear regression effects. We show empirically that this formulation both increases the flexibility of their approach and improves the discriminatory power between wage regimes.     

A Stochastic Two-Stage Model for Cancer Risk Assessment. I. The Hazard Function and the Probability of Tumor

We present a mathematical treatment of a two-mutation model for carcinogenesis with time-dependent parameters. This model has previously been shown to be consistent with epidemiologic and experimental data. An approximate hazard function used in previous papers is critically evaluated.     

Risk Ranking of Antimicrobial‐Resistant Hazards Found in Meat in Switzerland

Human exposure to bacteria resistant to antimicrobials and transfer of related genes is a complex issue and occurs, among other pathways, via meat consumption. In a context of limited resources, the prioritization of risk management activities is essential. Since the antimicrobial resistance (AMR) situation differs substantially between countries, prioritization should be country specific. The objective of this study was to develop a systematic and transparent framework to rank combinations of bacteria species resistant to selected antimicrobial classes found in meat, based on the risk they represent for public health in Switzerland. A risk assessment model from slaughter to consumption was developed following the Codex Alimentarius guidelines for risk analysis of foodborne AMR. Using data from the Swiss AMR monitoring program, 208 combinations of animal species/bacteria/antimicrobial classes were identified as relevant hazards. Exposure assessment and hazard characterization scores were developed and combined using multicriteria decision analysis. The effect of changing weights of scores was explored with sensitivity analysis. Attributing equal weights to each score, poultry‐associated combinations represented the highest risk. In particular, contamination with extended‐spectrum β‐lactamase/plasmidic AmpC‐producing Escherichia coli in poultry meat ranked high for both exposure and hazard characterization. Tetracycline‐ or macrolide‐resistant Enterococcus spp., as well as fluoroquinolone‐ or macrolide‐resistant Campylobacter jejuni , ranked among combinations with the highest risk. This study provides a basis for prioritizing future activities to mitigate the risk associated with foodborne AMR in Switzerland. A user‐friendly version of the model was provided to risk managers; it can easily be adjusted to the constantly evolving knowledge on AMR.     

MORAL HAZARD AND DYNAMIC INSURANCE DATA

This paper exploits dynamic features of insurance contracts in the empirical analysis of moral hazard. We first show that experience rating implies negative occurrence dependence under moral hazard: individual claim intensities decrease with the number of past claims. We then show that dynamic insurance data allow to distinguish this moral‐hazard effect from dynamic selection on unobservables. We develop nonparametric tests and estimate a flexible parametric model. We find no evidence of moral hazard in French car insurance. Our analysis contributes to a recent literature based on static data that has problems distinguishing between moral hazard and selection and dealing with dynamic features of actual insurance contracts. Methodologically, this paper builds on and extends the literature on state dependence and heterogeneity in event‐history data. (JEL: D82, G22, C41, C14)     

The Beta Poisson Dose-Response Model Is Not a Single-Hit Model

The choice of a dose-response model is decisive for the outcome of quantitative risk assessment. Single-hit models have played a prominent role in dose-response assessment for pathogenic microorganisms, since their introduction. Hit theory models are based on a few simple concepts that are attractive for their clarity and plausibility. These models, in particular the Beta Poisson model, are used for extrapolation of experimental dose-response data to low doses, as are often present in drinking water or food products. Unfortunately, the Beta Poisson model, as it is used throughout the microbial risk literature, is an approximation whose validity is not widely known. The exact functional relation is numerically complex, especially for use in optimization or uncertainty analysis. Here it is shown that although the discrepancy between the Beta Poisson formula and the exact function is not very large for many data sets, the differences are greatest at low doses--the region of interest for many risk applications. Errors may become very large, however, in the results of uncertainty analysis, or when the data contain little low-dose information. One striking property of the exact single-hit model is that it has a maximum risk curve, limiting the upper confidence level of the dose-response relation. This is due to the fact that the risk cannot exceed the probability of exposure, a property that is not retained in the Beta Poisson approximation. This maximum possible response curve is important for uncertainty analysis, and for risk assessment of pathogens with unknown properties.     

Landslide Risk Models for Decision Making

This contribution presents a quantitative procedure for landslide risk analysis and zoning considering hazard, exposure (or value of elements at risk), and vulnerability. The method provides the means to obtain landslide risk models (expressing expected damage due to landslides on material elements and economic activities in monetary terms, according to different scenarios and periods) useful to identify areas where mitigation efforts will be most cost effective. It allows identifying priority areas for the implementation of actions to reduce vulnerability (elements) or hazard (processes). The procedure proposed can also be used as a preventive tool, through its application to strategic environmental impact analysis (SEIA) of land-use plans. The underlying hypothesis is that reliable predictions about hazard and risk can be made using models based on a detailed analysis of past landslide occurrences in connection with conditioning factors and data on past damage. The results show that the approach proposed and the hypothesis formulated are essentially correct, providing estimates of the order of magnitude of expected losses for a given time period. Uncertainties, strengths, and shortcomings of the procedure and results obtained are discussed and potential lines of research to improve the models are indicated. Finally, comments and suggestions are provided to generalize this type of analysis.     

Dynamic Financial Constraints: Distinguishing Mechanism Design From Exogenously Incomplete Regimes

We formulate and solve a range of dynamic models of constrained credit/insurance that allow for moral hazard and limited commitment. We compare them to full insurance and exogenously incomplete financial regimes (autarky, saving only, borrowing and lending in a single asset). We develop computational methods based on mechanism design, linear programming, and maximum likelihood to estimate, compare, and statistically test these alternative dynamic models with financial/information constraints. Our methods can use both cross‐sectional and panel data and allow for measurement error and unobserved heterogeneity. We estimate the models using data on Thai households running small businesses from two separate samples. We find that in the rural sample, the exogenously incomplete saving only and borrowing regimes provide the best fit using data on consumption, business assets, investment, and income. Family and other networks help consumption smoothing there, as in a moral hazard constrained regime. In contrast, in urban areas, we find mechanism design financial/information regimes that are decidedly less constrained, with the moral hazard model fitting best combined business and consumption data. We perform numerous robustness checks in both the Thai data and in Monte Carlo simulations and compare our maximum likelihood criterion with results from other metrics and data not used in the estimation. A prototypical counterfactual policy evaluation exercise using the estimation results is also featured.