Defining estimands using a mix of strategies to handle intercurrent events in clinical trials

Randomized controlled trials (RCTs) are the gold standard for evaluation of the efficacy and safety of investigational interventions. If every patient in an RCT were to adhere to the randomized treatment, one could simply analyze the complete data to infer the treatment effect. However, intercurrent events (ICEs) including the use of concomitant medication for unsatisfactory efficacy, treatment discontinuation due to adverse events, or lack of efficacy may lead to interventions that deviate from the original treatment assignment. Therefore, defining the appropriate estimand (the appropriate parameter to be estimated) based on the primary objective of the study is critical prior to determining the statistical analysis method and analyzing the data. The International Council for Harmonisation (ICH) E9 (R1), adopted on November 20, 2019, provided five strategies to define the estimand: treatment policy, hypothetical, composite variable, while on treatment, and principal stratum. In this article, we propose an estimand using a mix of strategies in handling ICEs. This estimand is an average of the “null” treatment difference for those with ICEs potentially related to safety and the treatment difference for the other patients if they would complete the assigned treatments. Two examples from clinical trials evaluating antidiabetes treatments are provided to illustrate the estimation of this proposed estimand and to compare it with the estimates for estimands using hypothetical and treatment policy strategies in handling ICEs.     

Diversification and Performance in Developed and Emerging Market Contexts: A Review of the Literature*

The link between diversification and performance has become an important topic for research in diverse fields such as strategic management, industrial organization and financial management. However, a synthesis of the research done in developed and emerging markets is missing. This paper attempts such a synthesis by comparing and contrasting the past cumulative empirical research evidence on the relationship between diversification and firm performance in the context of developed economies to the more recent work in the emerging economies. The empirical literature has been divided into three broad perspectives, and the paper highlights the considerable diversity in its findings in developed and emerging markets across each of these perspectives. Based on this study, it is proposed that related diversification is preferable in developed economies and should be based on specific resources, whereas unrelated diversification is appropriate in emerging economies and should be based on generic resources. Although agency problems exist in both contexts, it is argued that the type of problem differs in developed and emerging markets. The paper concludes by identifying three directions for future research. First, the relationship between diversification and performance should be examined across each industry separately and not in aggregate. Secondly, future research needs to examine the organizational mechanisms required to make diversification successful. Finally, the relationship needs to be examined under unstable and dynamic situations such as the current global economic downturn.     

Serial Review Index

Abstract

The Program for Cooperative Cataloging (PCC) is working to make tools available to catalogers of electronic serials and integrating resources. These resources are being developed to help catalogers understand and implement the 2002 revision of Anglo-American Cataloguing Rules, 2d ed. (AACR2), related Library of Congress Rule Interpretations, and new MARC 21 coding. This column focuses on the revision plans for documentation of the program components of the PCC and new workshops from the Serials Cataloging Cooperative Training Program. Serials Review 2003; 29:40–42.     

Building a National Strategy for Digital Preservation: Issues in Digital Media Archiving

Abstract

Workflow mapping can yield valuable results wherever complex processes are used. Some of its many benefits include knowledge retention, identification of inefficiencies, and more effective decision making. However, despite the promise of improved productivity and stewardship of library resources, tackling diagrams of complex and often long-unexamined workflows can seem too daunting a task to even attempt—at least without the right tool. This review takes a look at the robust features for flowchart creation offered by Lucidchart, a free online software that greatly reduces the challenges of constructing complicated diagrams. Lucidchart’s intuitive interface and built-in library of templates and design elements bring the benefits of visual mapping well within the reach of busy librarians and managers attempting to chart, understand, and streamline workflows in their units.     

On the sampling distribution of clement's capability index

Most of the research effort concerning the development and statistical study of capability indices has been devoted to normal processes. In this paper a statistical study of a capability index for non-normal processes proposed by Clements (1989) is developed. An approximate distribution for the natural estimator of the index is obtained from a distribution free point of view and a simulation study is used to compare it with its empirical distribution. An approximate conservative lower confidence limit for the index is also constructed.     

Extended critical vawes of the multivariate extreme deviate test for detecting a single spurious observation

The Institute of Mathematical Statistics has published a table of critical values for the multivariate extreme deviate test. However, the critical values, derived by a Monte Carlo simulation, are given for only the dimensions 2 through 5. We present new critical values for the dimensions 6 through 10, 12, 15, and 20. The results are presented in both table and graphical form. All critical values for the test statistic have been generated by a Monte Carlo simulation using 10,000 observations per case. An example is presented using the new critical values.     

On confidence intervals for semiparametric expectile regression

In regression scenarios there is a growing demand for information on the conditional distribution of the response beyond the mean. In this scenario quantile regression is an established method of tail analysis. It is well understood in terms of asymptotic properties and estimation quality. Another way to look at the tail of a distribution is via expectiles. They provide a valuable alternative since they come with a combination of preferable attributes. The easy weighted least squares estimation of expectiles and the quadratic penalties often used in flexible regression models are natural partners. Also, in a similar way as quantiles can be seen as a generalisation of median regression, expectiles offer a generalisation of mean regression. In addition to regression estimates, confidence intervals are essential for interpretational purposes and to assess the variability of the estimate, but there is a lack of knowledge regarding the asymptotic properties of a semiparametric expectile regression estimate. Therefore confidence intervals for expectiles based on an asymptotic normal distribution are introduced. Their properties are investigated by a simulation study and compared to a boostrap-based gold standard method. Finally the introduced confidence intervals help to evaluate a geoadditive expectile regression model on childhood malnutrition data from India.