On optimal designs for clinical trials: An updated review

Optimization of clinical trial designs can help investigators achieve higher qualityresults for the given resource constraints. The present paper gives an overviewof optimal designs for various important problems that arise in different stages ofclinical drug development, including phase I dose–toxicity studies; phase I/II studiesthat consider early efficacy and toxicity outcomes simultaneously; phase IIdose–response studies driven by multiple comparisons (MCP), modeling techniques(Mod), or their combination (MCP–Mod); phase III randomized controlled multiarmmulti-objective clinical trials to test difference among several treatment groups;and population pharmacokinetics–pharmacodynamics experiments. We find thatmodern literature is very rich with optimal design methodologies that can be utilizedby clinical researchers to improve efficiency of drug development

A comparison of methods for treatment selection in seamless phase II/III clinical trials incorporating information on short-term endpoints

In an adaptive seamless phase II/III clinical trial interim analysis data are used for treatment selection, enabling resources to be focussed on comparison of more effective treatment(s) with a control. In this paper we compare two methods recently proposed to enable use of short-term endpoint data for decision-making at the interim analysis. The comparison focusses on the power and the probability of correctly identifying the most promising treatment. We show that the choice of method depends on how well short-term data predict the best treatment, which may be measured by the correlation between treatment effects on short-term and long-term endpoints

Statistical Analysis in Art Conservation Research

Evaluates all components of data analysis and shows that statistical methods in conservation are vastly underutilized. Also offers specific examples of possible improvements

Speculative Attack and Informational Structure: An Experimental Study

This paper addresses the question whether public information destabilises the economy in the context of signals of different nature. We present an experiment on the speculative attack game of Morris and Shin (1998). Our objective is double: (i) evaluating whether public information destabilises the economy in a context of signals of different nature; and (ii) enlarging the results of Heinemann, Nagel and Ockenfels (2002). Our evidence suggests that in sessions with both private and common signals, the fact that the public signal plays a focal role enhances the central bank's welfare: it reduces the probability of crisis and increases its predictability. In terms of economic policy, the central bank has more control on the beliefs of traders if it discloses one clear signal when agents also get private information from other sources.private information; public information; speculative attack

Design and Analysis of Multi-Arm Trials with a Common Control Using Order Restrictions

PhDTrials for comparing I treatments with a control are considered, where the aim is to identify one treatment (if at least one exists) which is better than control. Tests are developed which use all of the data simultaneously, rather than combining separate tests of a single arm versus control. The null hypothesis H0 : i 0 is tested against H1 : i > 0 for at least one i, where i represents the scaled di erence in response between treatment i and the control, i = 1; : : : ; I, and, if rejected, the best treatment is selected. A likelihood ratio test (LRT) is developed using order restricted inference, a family of tests is de ned and it is shown that the LRT and Dunnett-type tests are members of this family. Tests are compared by simulation, both under normality and for binary data, an exact test being developed for the latter case. The LRT compares favourably with other tests in terms of power and a simple loss function. Proportions of subjects on the control close to ( p I 1)=(I 1) are found to maximise the power and minimise the expected loss. Two-stage adaptive designs for comparing two experimental arms with a control are developed, in which the trial is stopped early if the di erence between the best treatment and the control is less than C1; otherwise, it continues, with one arm if one experimental treatment is better than the other by at least C2, or with both arms otherwise. Values of the constants C1 and C2 are compared and the adaptive design is found to be more powerful than the xed design. The new tests can make a contribution to improving the analysis of multi-arm clinical trials and further research in their application is recommended

A review of instrumental variables estimation in the applied health sciences

Health scientists often use observational data to estimate treatment effects when controlled experiments are not feasible. A limitation of observational research is non-random selection of subjects into different treatments, potentially leading to selection bias. The 2 commonly used solutions to this problem – covariate adjustment and fully parametric models – are limited by strong and untestable assumptions. Instrumental variables estimation can be a viable alternative. In this paper, I review examples of the application of IV in the health and social sciences, I show how the IV estimator works, I discuss the factors that affect its performance, I review how the interpretation of the IV estimator changes when treatment effects vary by individual, and consider the application of IV to nonlinear models.instrumental variables, treatment effects, health outcomes

Reproductive success through high pollinator visitation rates despite self incompatibility in an endangered wallflower

PREMISE OF THE STUDY: Self incompatibility (SI) in rare plants presents a unique challenge—SI protects plants from inbreeding depression, but requires a sufficient number of mates and xenogamous pollination. Does SI persist in an endangered polyploid? Is pollinator visitation sufficient to ensure reproductive success? Is there evidence of inbreeding/outbreeding depression? We characterized the mating system, primary pollinators, pollen limitation, and inbreeding/outbreeding depression in Erysimum teretifolium to guide conservation efforts. METHODS: We compared seed production following self pollination and within- and between-population crosses. Pollen tubes were visualized after self pollinations and between-population pollinations. Pollen limitation was tested in the field. Pollinator observations were quantified using digital video. Inbreeding/outbreeding depression was assessed in progeny from self and outcross pollinations at early and later developmental stages. KEY RESULTS: Self-pollination reduced seed set by 6.5× and quadrupled reproductive failure compared with outcross pollination. Pollen tubes of some self pollinations were arrested at the stigmatic surface. Seed-set data indicated strong SI, and fruit-set data suggested partial SI. Pollinator diversity and visitation rates were high, and there was no evidence of pollen limitation. Inbreeding depression (δ) was weak for early developmental stages and strong for later developmental stages, with no evidence of outbreeding depression. CONCLUSIONS: The rare hexaploid E. teretifolium is largely self incompatible and suffers from late-acting inbreeding depression. Reproductive success in natural populations was accomplished through high pollinator visitation rates consistent with a lack of pollen limitation. Future reproductive health for this species will require large population sizes with sufficient mates and a robust pollinator community

The Effects of Beliefs versus Risk Preferences on Bargaining Outcomes

In bargaining environments with uncertain impasse outcomes (e.g., litigation or labor strike outcomes), there is an identification problem that confounds data interpretation. In such environments, the minimally acceptable settlement value from a risk-averse (risk-loving) but unbiased bargainer is empirically indistinguishable from what one could get with risk-neutrality and pessimism (optimism). This paper reports data from a controlled bargaining experiment where risk preferences and beliefs are both measured in order to assess their relative importance in bargaining outcomes. The average lab subject is risk-averse, yet optimistic, which is consistent with existing studies that examine each in isolation. I also find that the effects of optimism dominate those of risk-aversion. Optimistic bargainers are significantly more likely to dispute and have aggressive final bargaining positions. Dispute rates are not statistically affected by risk preferences, but there is some evidence that risk aversion leads to less aggressive bargaining positions and lower payoff outcomes. A key implication is that increased settlement rates are more likely achieved by minimizing impasse uncertainty (to limit the potential for optimism) rather than maximizing uncertainty (to weaken the reservation point of risk-averse bargainers), as has been argued in the dispute resolution literature.risk preference, optimism, bargaining, experiments

Nonbinding Suggestions: The Relative Effects of Focal Points versus Uncertainty Reduction on Bargaining Outcomes

This paper focuses on the effects of nonbinding recommendations on bargaining outcomes. Recommendations are theorized to have two effects: they can create a focal point for final bargaining positions, and they can decrease outcome uncertainty should dispute persist. While the focal point effect may help lower dispute rates, the uncertainty reduction effect is predicted to do the opposite for risk-averse bargainers. Which of these effects dominates is of critical importance in the optimal design of alternative dispute resolution (ADR) procedures, which are becoming increasingly utilized to help resolve disputes in a variety of settings. We theoretically examine the effects of recommendations on the bargaining contract zone. Our theoretical framework, which allows bargainers’ final positions to influence a binding outcome should negotiations fail, provides for a more stringent test of focal points than previously considered. We also present data from controlled laboratory bargaining experiments that are consistent with our model of recommendation effects. Recommendations are empirically shown to influence final bargaining positions and negotiated settlement values. Furthermore, dispute rates are significantly lower when one includes recommendations, even where the recommendation is completely ignored in final-stage arbitration. This highlights a potentially significant role for the use of nonbinding procedures, such as mediation, as a preliminary stage in developing more efficient ADR procedures.