Sufficiency of a sufficient statistic for equivariant estimation

Suppose an estimation problem is invariant under a group of transformations and one is interested in finding an optimal equivariant estimator. The usual proactice is to confine attention to non-randomized equivariant estimators based on a minimal sufficient statistic. A justification of this restriction to a smaller clas of estimators is given in this paper under certain conditions.     

The cross-product ratio in bivariate lognormal and gamma distributions,with an application to non-randomized trials

Non-randomized trials can give a biased impression of the effectiveness of any intervention. We consider trials in which incidence rates are compared in two areas over two periods. Typically, one area receives an intervention, whereas the other does not. We outline and illustrate a method to estimate the bias in such trials under two different bivariate models. The illustrations use data in which no particular intervention is operating. The purpose is to illustrate the size of the bias that could be observed purely due to regression towards the mean (RTM). The illustrations show that the bias can be appreciably different from zero, and even when centred on zero, the variance of the bias can be large. We conclude that the results of non-randomized trials should be treated with caution, as interventions which show small effects could be explained as artefacts of RTM.     

A permutation test approach to phase II historical control trials

In this note we outline 15 years of Gynecologic Oncology Group (GOG) experience conducting a series of phase II second-line intraperitoneal trials in the treatment of ovarian cancer. Using this information, the goal is to define a new permutation approach to historical control phase II trials in ovarian cancer. We utilize seven previous phase II GOG trials in our database to illustrate our methodology.     

Decomposition analysis as a framework for understanding heterogeneity of treatment effects in non-randomized health care studies

This paper uses the decomposition framework from the economics literature to examine the statistical structure of treatment effects estimated with observational data compared to those estimated from randomized studies. It begins with the estimation of treatment effects using a dummy variable in regression models and then presents the decomposition method from economics which estimates separate regression models for the comparison groups and recovers the treatment effect using bootstrapping methods. This method shows that the overall treatment effect is a weighted average of structural relationships of patient features with outcomes within each treatment arm and differences in the distributions of these features across the arms. In large randomized trials, it is assumed that the distribution of features across arms is very similar. Importantly, randomization not only balances observed features but also unobserved. Applying high dimensional balancing methods such as propensity score matching to the observational data causes the distributional terms of the decomposition model to be eliminated but unobserved features may still not be balanced in the observational data. Finally, a correction for non-random selection into the treatment groups is introduced via a switching regime model. Theoretically, the treatment effect estimates obtained from this model should be the same as those from a randomized trial. However, there are significant challenges in identifying instrumental variables that are necessary for estimating such models. At a minimum, decomposition models are useful tools for understanding the relationship between treatment effects estimated from observational versus randomized data.     

Some statistical issues in weather experimentation

A number of topics of statistical methodology in weather modification are discussed. The time sequence of unit definition, classification and randomization is shown to affect the types of units that can be used validly, and this casts doubt on the value of blocking. Re-randomization (permutation) tests are recommended as the only reliable method of confirmatory inference for weather experiments. Some aspects of such tests are examined, including a procedure for multiple comparisons. The plague of multiplicity of tests is discussed and warned against. Doubts about cumulative evaluations of "all" experiment's are expressed. A case is argued for examination of some non-randomized seeding operations. Consid¬ering the dearth of randomized data, it is argued that careful evaluation of seeding operations should be undertaken.     

Defining estimands for efficacy assessment in single arm phase 1b or phase 2 clinical trials in oncology early development

The addendum of the ICH E9 guideline on the statistical principles for clinical trials introduced the estimand framework. The framework is designed to strengthen the dialog between different stakeholders, to introduce greater clarity in the clinical trial objectives and to provide alignment between the estimand and statistical analysis. Estimand framework related publications thus far have mainly focused on randomized clinical trials. The intention of the Early Development Estimand Nexus (EDEN), a task force of the cross-industry Oncology Estimand Working Group ( www.oncoestimand.org ), is to apply it to single arms Phase 1b or Phase 2 trials designed to detect a treatment-related efficacy signal, typically measured by objective response rate. Key recommendations regarding the estimand attributes include that in a single arm early clinical trial, the treatment attribute should start when the first dose is received by the participant. Focusing on the estimation of an absolute effect, the population-level summary measure should reflect only the property used for the estimation. Another major component introduced in the ICH E9 addendum is the definition of intercurrent events and the associated possible ways to handle them. Different strategies reflect different clinical questions of interest that can be answered based on the journeys an individual subject can take during a trial. We provide detailed strategy recommendations for intercurrent events typically seen in early-stage oncology. We highlight where implicit assumptions should be made transparent as whenever follow-up is suspended, a while-on-treatment strategy is implied.