Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation

Children represent a large underserved population of “therapeutic orphans,” as an estimated 80% of children are treated off‐label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or “borrowing”) of information across disparate sources, such as the adult and pediatric data. In this paper, authored by the pediatric subteam of the Drug Information Association Bayesian Scientific Working Group and Adaptive Design Working Group, we develop, illustrate, and provide suggestions on Bayesian statistical methods that could be used to design improved pediatric development programs that use all available information in the most efficient manner. A variety of relevant Bayesian approaches are described, several of which are illustrated through 2 case studies: extrapolating adult efficacy data to expand the labeling for Remicade to include pediatric ulcerative colitis and extrapolating adult exposure‐response information for antiepileptic drugs to pediatrics.     

Community-Based Design Research: Learning Across Generations and Strategic Transformations of Institutional Relations Toward Axiological Innovations

The socio-ecological challenges facing communities in the 21st century are building towards a critical conjuncture of history, culture, power, and profound inequity. Scholars working in the service of social transformation and improving the wellbeing of communities are calling for creative, deliberate, and consequential interventions. Tharp & O’Donnell (this issue) call for increased engagement between Cultural-Community Psychology and Cultural-Historical Activity Theory to lead this kind of call. Drawing from our experiences in community based design research, we argue for cultivating axiological innovations in research and interventions. We explore three examples including: critical historicity, inter-generational learning, and strategic transformations of institutional relations.     

论高海拔地区人类生殖能力的研究:回应霍夫

霍夫的评论表明,那些叙述高海拔缺氧影响人类生育力和生殖能力的文献中弥漫着方法论和概念的迷雾.我们去年的文章主题也谈到了这一点(见<美国人类学家>85:28-49,1983).我们的论文尽力阐述了喜马拉雅山脉的高海拔地区,藏语族群中普遍存在的不同生育力水平,是与某些文献的报道一致的.     

Partnership Instability and Child Well‐Being

We use data from three waves of the Fragile Families Study (N= 2,111) to examine the prevalence and effects of mothers’ partnership changes between birth and age 3 on children’s behavior. We find that children born to unmarried and minority parents experience significantly more partnership changes than children born to parents who are married or White. Each transition is associated with a modest increase in behavioral problems, but a significant number of children experience 3 or more transitions. The association between instability and behavior is mediated by maternal stress and lower quality mothering. The findings imply that policies aimed at reducing maternal stress and partnership instability may improve child well‐being.     

Perceived Equity in the Gendered Division of Household Labor

Despite huge imbalances in the division of housework between women and men, previous studies have found perceptions of equity on the part of women to be much more frequent than feelings of injustice. Taking a comparative perspective on the basis of International Social Survey Program (ISSP) 2002 data (N = 8,556), we find that, on the individual level, the explanatory frameworks that have been found to influence the actual inequality of household division of labor (time availability, resource dependence, and gender ideology) contribute to the explanation of perceptions of equity, in that they interact with the inequality of the household division of labor. On the country level, the gender‐wage ratio and the average level of inequality are important predictors.     

Structural influences on the relationship between objective and subjective indicators of economic well-being

The study investigated the relationship between objective and subjective indicators of economic well-being within different age, race, and sex groups over time. Stratification theory and an accommodation hypothesis were used to predict differential subjective responses to objective conditions within subgroups. Findings supported the hypothesis that the relationship would be weakest among the oldest age group compared to other age groups. Support was found for the hypothesis that predicted smaller coefficients among subgroups characterized as older, female, and nonwhite. Relationships were found to remain stable within all subgroups over time.     

Random regression models for human immunodeficiency virus ribonucleic acid data subject to left censoring and informative drop-outs

Objectives in many longitudinal studies of individuals infected with the human immunodeficiency virus (HIV) include the estimation of population average trajectories of HIV ribonucleic acid (RNA) over time and tests for differences in trajectory across subgroups. Special features that are often inherent in the underlying data include a tendency for some HIV RNA levels to be below an assay detection limit, and for individuals with high initial levels or high ranges of change to drop out of the study early because of illness or death. We develop a likelihood for the observed data that incorporates both of these features. Informative drop-outs are handled by means of an approach previously published by Schluchter. Using data from the HIV Epidemiology Research Study, we implement a maximum likelihood procedure to estimate initial HIV RNA levels and slopes within a population, compare these parameters across subgroups of HIV-infected women and illustrate the importance of appropriate treatment of left censoring and informative drop-outs. We also assess model assumptions and consider the prediction of random intercepts and slopes in this setting. The results suggest that marked bias in estimates of fixed effects, variance components and standard errors in the analysis of HIV RNA data might be avoided by the use of methods like those illustrated.     

Managing Contradiction: Stockholder and Stakeholder Views of the Firm as Paradoxical Opportunity

Stockholder and stakeholder perspectives have been positioned in the literature as being in tension, and thus a potential source of innovation and change. However, researchers have overlooked a systematic examination of this presumption in theory and in practice. This study explores the ways that stockholder and stakeholder assumptions are presented by theorists and compares these with expressions of stockholder and stakeholder perspectives used by firms in practice. We argue that theoretical entrenchment dichotomizing these perspectives has disrupted the ability of researchers to leverage this tension. While scholarship remains trapped in a vicious cycle, we also argue that firms in practice express only the acceptance dimension of a virtuous cycle. Our empirical research demonstrates that firms accept and accommodate the paradoxical tension between managing for stockholders versus balancing the interests of stakeholders. This is evidenced by strategies we identify as book‐ending, cadence, continuous and simultaneous co‐mingling, and hybridization. We find that in practice these tensions are more integrated whereas in theory they are treated as more distinct and, often, in conflict. We suggest ways in which both scholarship and practice can better leverage tension as paradoxical opportunity.     

Institutionalizing Counter‐Memories of the U.S. Civil Rights Movement: The National Civil Rights Museum and an Application of the Interest‐Convergence Principle

During the post–Reconstruction era in the United States, white southerners marked the cultural landscape with monuments and memorials honoring the Confederate cause and its heroes. These racialized symbols enjoyed an undisputed claim to public squares and parks throughout the South. It was not until the late twentieth century that commemorations to the black freedom struggle were publicly supported. This analysis examines the institutionalization of counter‐memories of the civil rights movement in Memphis, Tennessee at the Lorraine Motel, the site of the assassination of Reverend Dr. Martin Luther King, Jr. The author draws on collective memory, cultural trauma, and social movements research as well as critical race theory to explain the creation of the National Civil Rights Museum. Using primary and secondary data sources the author examines how social memory agents, a changing political culture, and the passage of time mediated the cultural trauma of King's assassination and influenced the institutionalization of oppositional collective memories. Relying on Derrick Bell's interest‐convergence principle, the author concludes that the creation of this major memorial museum was a result of the convergence of white and black interests, specifically the economic and political interests of white elites and the cultural and political interests of black symbolic entrepreneurs.     

Reanalysis of the DEMS Nested Case‐Control Study of Lung Cancer and Diesel Exhaust: Suitability for Quantitative Risk Assessment

The International Agency for Research on Cancer (IARC) in 2012 upgraded its hazard characterization of diesel engine exhaust (DEE) to “carcinogenic to humans.” The Diesel Exhaust in Miners Study (DEMS) cohort and nested case‐control studies of lung cancer mortality in eight U.S. nonmetal mines were influential in IARC's determination. We conducted a reanalysis of the DEMS case‐control data to evaluate its suitability for quantitative risk assessment (QRA). Our reanalysis used conditional logistic regression and adjusted for cigarette smoking in a manner similar to the original DEMS analysis. However, we included additional estimates of DEE exposure and adjustment for radon exposure. In addition to applying three DEE exposure estimates developed by DEMS, we applied six alternative estimates. Without adjusting for radon, our results were similar to those in the original DEMS analysis: all but one of the nine DEE exposure estimates showed evidence of an association between DEE exposure and lung cancer mortality, with trend slopes differing only by about a factor of two. When exposure to radon was adjusted, the evidence for a DEE effect was greatly diminished, but was still present in some analyses that utilized the three original DEMS DEE exposure estimates. A DEE effect was not observed when the six alternative DEE exposure estimates were utilized and radon was adjusted. No consistent evidence of a DEE effect was found among miners who worked only underground. This article highlights some issues that should be addressed in any use of the DEMS data in developing a QRA for DEE.