Risk patterns in drug safety study using relative times by accelerated failure time models when proportional hazards assumption is questionable: an illustrative case study of cancer risk of patients on glucose‐lowering therapies

Observational drug safety studies may be susceptible to confounding or protopathic bias. This bias may cause a spurious relationship between drug exposure and adverse side effect when none exists and may lead to unwarranted safety alerts. The spurious relationship may manifest itself through substantially different risk levels between exposure groups at the start of follow‐up when exposure is deemed too short to have any plausible biological effect of the drug. The restrictive proportional hazards assumption with its arbitrary choice of baseline hazard function renders the commonly used Cox proportional hazards model of limited use for revealing such potential bias. We demonstrate a fully parametric approach using accelerated failure time models with an illustrative safety study of glucose‐lowering therapies and show that its results are comparable against other methods that allow time‐varying exposure effects. Our approach includes a wide variety of models that are based on the flexible generalized gamma distribution and allows direct comparisons of estimated hazard functions following different exposure‐specific distributions of survival times. This approach lends itself to two alternative metrics, namely relative times and difference in times to event, allowing physicians more ways to communicate patient's prognosis without invoking the concept of risks, which some may find hard to grasp. In our illustrative case study, substantial differences in cancer risks at drug initiation followed by a gradual reduction towards null were found. This evidence is compatible with the presence of protopathic bias, in which undiagnosed symptoms of cancer lead to switches in diabetes medication. Copyright © 2015 John Wiley & Sons, Ltd.     

Experimental designs for detecting synergy and antagonism between two drugs in a pre‐clinical study

The identification of synergistic interactions between combinations of drugs is an important area within drug discovery and development. Pre‐clinically, large numbers of screening studies to identify synergistic pairs of compounds can often be ran, necessitating efficient and robust experimental designs. We consider experimental designs for detecting interaction between two drugs in a pre‐clinical in vitro assay in the presence of uncertainty of the monotherapy response. The monotherapies are assumed to follow the Hill equation with common lower and upper asymptotes, and a common variance. The optimality criterion used is the variance of the interaction parameter. We focus on ray designs and investigate two algorithms for selecting the optimum set of dose combinations. The first is a forward algorithm in which design points are added sequentially. This is found to give useful solutions in simple cases but can lack robustness when knowledge about the monotherapy parameters is insufficient. The second algorithm is a more pragmatic approach where the design points are constrained to be distributed log‐normally along the rays and monotherapy doses. We find that the pragmatic algorithm is more stable than the forward algorithm, and even when the forward algorithm has converged, the pragmatic algorithm can still out‐perform it. Practically, we find that good designs for detecting an interaction have equal numbers of points on monotherapies and combination therapies, with those points typically placed in positions where a 50% response is expected. More uncertainty in monotherapy parameters leads to an optimal design with design points that are more spread out. Copyright © 2015 John Wiley & Sons, Ltd.     

Signal Orderings Based on Dispersion and the Supply of Private Information in Auctions

This paper provides a novel approach to ordering signals based on the property that more informative signals lead to greater variability of conditional expectations. We define two nested information criteria (supermodular precision and integral precision) by combining this approach with two variability orders (dispersive and convex orders). We relate precision criteria with orderings based on the value of information to a decision maker. We then use precision to study the incentives of an auctioneer to supply private information. Using integral precision, we obtain two results: (i) a more precise signal yields a more efficient allocation; (ii) the auctioneer provides less than the efficient level of information. Supermodular precision allows us to extend the previous analysis to the case in which supplying information is costly and to obtain an additional finding; (iii) there is a complementarity between information and competition, so that both the socially efficient and the auctioneer's optimal choice of precision increase with the number of bidders.     

Large Risks,Limited Liability,and Dynamic Moral Hazard

We study a continuous‐time principal–agent model in which a risk‐neutral agent with limited liability must exert unobservable effort to reduce the likelihood of large but relatively infrequent losses. Firm size can be decreased at no cost or increased subject to adjustment costs. In the optimal contract, investment takes place only if a long enough period of time elapses with no losses occurring. Then, if good performance continues, the agent is paid. As soon as a loss occurs, payments to the agent are suspended, and so is investment if further losses occur. Accumulated bad performance leads to downsizing. We derive explicit formulae for the dynamics of firm size and its asymptotic growth rate, and we provide conditions under which firm size eventually goes to zero or grows without bounds.     

Single‐Period Two‐Product Assemble‐to‐Order Systems with a Common Component and Uncertain Demand Patterns

We consider a single‐period assemble‐to‐order system that produces two types of end products to satisfy two independent and stochastic customer orders. Each type of product is used to fulfill a particular customer order and these two products share a common component. Furthermore, one customer may confirm her order before the other one, and the manufacturer needs to make a commitment immediately upon the receipt of each customer order on how many products to be delivered. We propose a model for optimizing the inventory and production decisions under the above ATO environment. We also extend our model to the situation where the manufacturer can fulfill the unsatisfied low‐priority demand using the left‐over inventories after fulfilling the high‐priority demand, in case the low‐priority customer arrives first. Numerical experiments are conducted, which provide some interesting insights on the impact of uncertain demand pattern.     

The Role of Pre‐ and Postconception Relationships for First‐Time Parents

Using data from the National Longitudinal Survey of Youth 1997, a nationally representative cohort of young adults, the authors analyzed relationship type at the time of a first birth (N = 4,044). More than 10% of births were to a postconception cohabiting household (cohabitations that were initiated between conception and birth), a higher proportion of births than those born to postconception married households. Individuals in postconception and preconception cohabiting relationships (cohabitations that existed prior to conception) were demographically similar; both groups were associated with lower levels of socioeconomic advantage relative to those in preconception and postconception marriage. Postconception and preconception cohabiting relationships were associated with similar levels of dissolution, as 40% dissolved within 3 years of a child's birth. Having a marital union, rather than whether relationship was established pre‐ or postconception, was more strongly associated with who selected into the relationship and how long the relationship lasted.     

The Retirement Provisions in China,Hong Kong,Singapore and Taiwan: Perspectives on Policy Inputs and Social Outputs

This paper aims to develop an integrated policy index system using a Surface Measure of Overall Performance (SMOP) approach to comprehensively evaluate and compare the policy input and social output of the retirement payment system in urban and rural China, Hong Kong, Singapore and Taiwan. With this, a tool may be developed to help insightfully examine the old‐age income policies and appropriately, and perhaps theoretically in the future, categorize the types of retirement provisions or social security policies as a whole in the East and West. The results indicate that, particularly in urban China, Hong Kong, Singapore and Taiwan, a low level of de‐familization and medium and high levels of gender equality are the common features of these five pensions in China, Hong Kong, Singapore and Taiwan. Furthermore, it is found that the retirement provisions in China, Hong Kong, Singapore and Taiwan can well be divided into two groups based on the level of pension right protection and illustrate different characteristics between them accordingly. In addition, policy implications and suggestions for further reforms of these retirement payment schemes are elaborated in the light of the findings of this policy index system.     

Investments in Marriage and Cohabitation: The Role of Legal and Interpersonal Commitment

Cohabiters have been shown to invest less in their relationship than married couples. This study investigated the role of legal and interpersonal commitment by examining heterogeneity within marital and cohabiting unions. Going beyond the dichotomy of cohabitation versus marriage, different union types were distinguished by their level of legal and interpersonal commitment, followed by an assessment of their association with joint investments (specialization, having children together, purchasing a home). Using panel data from The Netherlands (N =2,362), the authors found considerable heterogeneity within marital and cohabiting unions. Joint investments increased as interpersonal commitment increased, with cohabiters without marriage plans investing the least and couples who directly married without prior cohabitation investing the most. The relationship between investments and legal union types was less straightforward and often challenged expectations, prompting the authors to elaborate on alternative explanations for their findings.     

Canada's Most Wanted: Pioneer Women on the Western Prairies*

Cet article analyse les expériences des femmes pendant la colonisation des Prairies au Canada en mettant l'accent sur leur travail, sur leurs aptitudes et sur les capacites d'adaptation a l'environnement naturel et aux obstacles économiques auxquels ces femmes et leurs families se sont mesurés. Bien que les attitudes patriarcales domi‐nantes, la législation et les principes économiques aient quelque peu occulté les contributions des femmes, les efforts qu'elles ont déployés en Saskatchewan illustrent la «souplesse» dont ont fait preuve les fermières dans l'accomplissement de tâches productives et non productives. L'article démontre que cette souplesse a constitué un facteur déterminant de la survie des fermes familiales et, par là, du succès de l'industrie du blé. This article analyzes women's experiences during the settlement of the western prairie region of Canada. Attention is placed on their labour, skills and ability to adapt to the natural environment and the economic obstacles that they and their families encountered. While prevailing patriarchal attitudes, legislation and economic principles obscured women's contributions, the efforts of women in Saskatchewan are used to highlight the “flexibility” exhibited by farm women in performing productive and non‐productive labour. It is argued that this flexibility was critical to the survival of family farms, and thus to the success of the wheat economy.