Identifying the most successful dose (MSD) in dose-finding studies in cancer

For a dose finding study in cancer, the most successful dose (MSD), among a group of available doses, is that dose at which the overall success rate is the highest. This rate is the product of the rate of seeing non-toxicities together with the rate of tumor response. A successful dose finding trial in this context is one where we manage to identify the MSD in an efficient manner. In practice we may also need to consider algorithms for identifying the MSD which can incorporate certain restrictions, the most common restriction maintaining the estimated toxicity rate alone below some maximum rate. In this case the MSD may correspond to a different level than that for the unconstrained MSD and, in providing a final recommendation, it is important to underline that it is subject to the given constraint. We work with the approach described in O'Quigley et al. [Biometrics 2001; 57(4):1018-1029]. The focus of that work was dose finding in HIV where both information on toxicity and efficacy were almost immediately available. Recent cancer studies are beginning to fall under this same heading where, as before, toxicity can be quickly evaluated and, in addition, we can rely on biological markers or other measures of tumor response. Mindful of the particular context of cancer, our purpose here is to consider the methodology developed by O'Quigley et al. and its practical implementation. We also carry out a study on the doubly under-parameterized model, developed by O'Quigley et al. but not     

Bayesian sample size determination for phase IIA clinical trials using historical data and semi‐parametric prior's elicitation

The Simon's two‐stage design is the most commonly applied among multi‐stage designs in phase IIA clinical trials. It combines the sample sizes at the two stages in order to minimize either the expected or the maximum sample size. When the uncertainty about pre‐trial beliefs on the expected or desired response rate is high, a Bayesian alternative should be considered since it allows to deal with the entire distribution of the parameter of interest in a more natural way. In this setting, a crucial issue is how to construct a distribution from the available summaries to use as a clinical prior in a Bayesian design. In this work, we explore the Bayesian counterparts of the Simon's two‐stage design based on the predictive version of the single threshold design. This design requires specifying two prior distributions: the analysis prior, which is used to compute the posterior probabilities, and the design prior, which is employed to obtain the prior predictive distribution. While the usual approach is to build beta priors for carrying out a conjugate analysis, we derived both the analysis and the design distributions through linear combinations of B‐splines. The motivating example is the planning of the phase IIA two‐stage trial on anti‐HER2 DNA vaccine in breast cancer, where initial beliefs formed from elicited experts' opinions and historical data showed a high level of uncertainty. In a sample size determination problem, the impact of different priors is evaluated.     

On the complexity of achieving proportional representation

We demonstrate that winner selection in two prominent proportional representation voting systems is a computationally intractable problem—implying that these systems are impractical when the assembly is large. On a different note, in settings where the size of the assembly is constant, we show that the problem can be solved in polynomial time.     

Legible lesbian lines: The bilingual poetry of Irena Klepfisz

Abstract

This article focuses on the poetry of Jewish lesbian poet Irena Klepfisz, written in New York starting in the 1970s. While drawing on the tradition of Yiddish women’s poetry from the first half of the twentieth century, both as scholar and poet, Klepfisz also creates a brand new, bilingual, Yiddish-English poetic mode. By mobilizing both Yiddish and English to voice her poetic and political concerns, Klepfisz stages the English/Yiddish encounter as a site where dominant norms in both languages can be challenged and new possibilities emerge. Exploring both her turn to the past and her bilingual poetry, this article reveals how Klepfisz puts her politics and scholarship to poetic practice and suggests that Klepfisz offers a model of queer translation that undoes the borders between past and present, English and Yiddish, creating a unique mode of Jewish lesbian reclamation and invention.     

A Bayesian dose‐finding design for drug combination clinical trials based on the logistic model

In early phase dose‐finding cancer studies, the objective is to determine the maximum tolerated dose, defined as the highest dose with an acceptable dose‐limiting toxicity rate. Finding this dose for drug‐combination trials is complicated because of drug–drug interactions, and many trial designs have been proposed to address this issue. These designs rely on complicated statistical models that typically are not familiar to clinicians, and are rarely used in practice. The aim of this paper is to propose a Bayesian dose‐finding design for drug combination trials based on standard logistic regression. Under the proposed design, we continuously update the posterior estimates of the model parameters to make the decisions of dose assignment and early stopping. Simulation studies show that the proposed design is competitive and outperforms some existing designs. We also extend our design to handle delayed toxicities. Copyright © 2014 John Wiley & Sons, Ltd.     

The Role of Dissociation in Self-Injurious Behavior among Female Adolescents Who Were Sexually Abused

The study aimed to examine the role of dissociation (persistent versus peritraumatic) in self-injurious behavior among at-risk Israeli female adolescents. In addition, the relationship between childhood sexual abuse, depression, dissociation, and potency was investigated. A convenience sample of 93 female adolescents aged 12 years to 18 years were recruited from institutions for at-risk adolescent girls in Israel. Participants were administered an anonymous self-report questionnaire that included six measures: Demographics, Dissociative Experiences Scale, Center for Epidemiologic Studies Depression Scale, the Peritraumatic Dissociative Experiences Questionnaire, the Traumatic Events Questionnaire, and the Potency Scale. Results indicated that childhood sexual abuse increases the risk for self-injurious behavior more than threefold. Higher levels of persistent dissociation were found among girls who reported child sexual abuse compared to those who did not. Self-injurious behavior was predicted by persistent dissociation. Girls who engaged in self-injurious behavior had lower potency and higher depression levels, regardless of childhood sexual abuse history.     

Approaches to sample size calculation for clinical trials in rare diseases

We discuss 3 alternative approaches to sample size calculation: traditional sample size calculation based on power to show a statistically significant effect, sample size calculation based on assurance, and sample size based on a decision‐theoretic approach. These approaches are compared head‐to‐head for clinical trial situations in rare diseases. Specifically, we consider 3 case studies of rare diseases (Lyell disease, adult‐onset Still disease, and cystic fibrosis) with the aim to plan the sample size for an upcoming clinical trial. We outline in detail the reasonable choice of parameters for these approaches for each of the 3 case studies and calculate sample sizes. We stress that the influence of the input parameters needs to be investigated in all approaches and recommend investigating different sample size approaches before deciding finally on the trial size. Highly influencing for the sample size are choice of treatment effect parameter in all approaches and the parameter for the additional cost of the new treatment in the decision‐theoretic approach. These should therefore be discussed extensively.     

“The risk of age”? Early detection test,prostate cancer and practices of self

Drawing on Rose and Novas’s concept of “biological citizenship” and Michel Foucault's "practices of self", this paper reflects on how men become agents of their own therapeutic regimens, and yet internalise messages of risk and practices of self within early detection of prostate cancer discourses in the late 20th century. In doing so, it traces the ways in which concepts of age, gender and risk converge at the problematic site of prostate cancer and preventative health strategies, both of the state and the medical profession. Analysing how insecurities have simultaneously resulted in over-promoting and over-diagnosing risk, thereby blurring the lines between normal and pathological states of health and aging, the paper finishes with a critical discussion on how men have adopted self-surveying and attuned themselves to risk discourses. Suggestions are made for future research on comparative gender studies on embodied concepts of self and cancer screening and the relation between differential aging, risk management and the concept of the body.     

News‐Media and Terrorism: Changing Relationship,Changing Definitions

This article discusses two aspects that are important for understanding the relationship between Western news media and terrorism: the changing representation of terrorists and terrorist attacks in the media and, with it, the changing definition of terrorism. By calling attention to evolving news media practices in times of terrorism, I argue that advanced communication technologies and the emergence of global media ecology since the 1990s has made terrorism more visible in both national and international media landscapes. One result is that the more the news media expose terrorism to global audiences via the “front door,” the more controversial the use of the terms “terrorism” and “terrorist” become in social, political, and scholarly discourses. The paper addresses the evolving journalistic practices and their consequences as documented in previous studies on media reporting of terrorism in several national contexts, mostly the UK, the United States, and Israel.     

Exact and heuristic methods for a class of selective newsvendor problems with normally distributed demands

In this paper we study a class of selective newsvendor problems, where a decision maker has a set of raw materials each of which can be customized shortly before satisfying demand. The goal is then to select which subset of customizations maximizes expected profit. We show that certain multi-period and multi-product selective newsvendor problems fall within our problem class. Under the assumption that the demands are independent and normally, but not necessarily identically, distributed we show that some problem instances from our class can be solved efficiently using an attractive sorting property that was also established in the literature for some related problems. For our general model we use the KKT conditions to develop an exact algorithm that is efficient in the number of raw materials. In addition, we develop a class of heuristic algorithms. In a numerical study, we compare the performance of the algorithms, and the heuristics are shown to have excellent performance and running times as compared to available commercial solvers.