Inference and Decision Making for 21st-Century Drug Development and Approval

ABSTRACT

The cost and time of pharmaceutical drug development continue to grow at rates that many say are unsustainable. These trends have enormous impact on what treatments get to patients, when they get them and how they are used. The statistical framework for supporting decisions in regulated clinical development of new medicines has followed a traditional path of frequentist methodology. Trials using hypothesis tests of “no treatment effect” are done routinely, and the p-value < 0.05 is often the determinant of what constitutes a “successful” trial. Many drugs fail in clinical development, adding to the cost of new medicines, and some evidence points blame at the deficiencies of the frequentist paradigm. An unknown number effective medicines may have been abandoned because trials were declared “unsuccessful” due to a p-value exceeding 0.05. Recently, the Bayesian paradigm has shown utility in the clinical drug development process for its probability-based inference. We argue for a Bayesian approach that employs data from other trials as a “prior” for Phase 3 trials so that synthesized evidence across trials can be utilized to compute probability statements that are valuable for understanding the magnitude of treatment effect. Such a Bayesian paradigm provides a promising framework for improving statistical inference and regulatory decision making.     

自杀和生命的意义——来自脑科学研究的解读

生命本身是一个随机事件，并不具有高尚的意义。进化的结果使人类可通过工作、家庭和人际关系等给予自己的生命以意义感。当我们的生活方式使脑内奖赏系统获得刺激，就会带来生命具有意义的感受，这种感受给人带来更好的生存机会。生存的欲望是一切生物体最具特征的属性，一些精神疾病患者缺乏这种欲望。自杀主要发生于精神疾病患者，它并非是基于自由意志的行为。抗精神病治疗和适当的社会交往可以预防自杀。由于不同个体有着不同的大脑，人们的生活方式就应该去适应各自大脑的特征。只要人们的生活方式不对他人造成过多的伤害，政府就应该允许和保护人们自由地按照各自的方式生活。     

Measures of Multigroup Segregation

In this paper we derive and evaluate measures of multigroup segregation. After describing four ways to conceptualize the measurement of multigroup segregation—as the disproportionality in group (e.g., race) proportions across organizational units (e.g., schools or census tracts), as the strength of association between nominal variables indexing group and organizational unit membership, as the ratio of between–unit diversity to total diversity, and as the weighted average of two–group segregation indices—we derive six multigroup segregation indices: a dissimilarity index (D), a Gini index (G), an information theory index (H), a squared coefficient of variation index (C), a relative diversity index (R), and a normalized exposure index (P). We evaluate these six indices against a set of seven desirable properties of segregation indices. We conclude that the information theory index H is the most conceptually and mathematically satisfactory index, since it alone obeys the principle of transfers in the multigroup case. Moreover, H is the only multigroup index that can be decomposed into a sum of between– and within–group components.     

GENDER AND RACE PATTERNS IN THE PATHWAYS FROM SPORTS PARTICIPATION TO SELF-ESTEEM

Athletics is the most prominent extracurricular activity in U.S. secondary schools in terms of student participation and school budgets. The latter is often justified on the grounds that healthy bodies produce healthy minds, that school sports boost school spirit, and that participation in school-based sports increases students' self-esteem. In this article we examine the interrelationships among participation in a school-based sport and the benefits assumed to be associated with it. Specifically, we test a model that postulates that school spirit, operationalized as attachment to school, and healthy bodies, operationalized as a sense of physical well-being, mediate the relationship between school sports and self-esteem. Data from the National Longitudinal Study of Adolescent Health on Caucasian and African American girls and boys were employed to test the model. School attachment and physical well-being absorbed the statistical effect of participating in a sport for all four gender-by-race groups. Among Caucasian girls a negative residual effect of sports participation was observed, which suggests that sports participation encapsulates multiple effects with contradictory influences. For African American girls school attachment by itself was not a significant mediator of the effect of sports participation on self-esteem. For all groups a sense of physical well-being was the more powerful mediator.     

Peer Crowd Affiliation and Internalizing Distress in Childhood and Adolescence: A Longitudinal Follow‐Back Study

Concurrent and longitudinal associations between peer crowd affiliation and internalized distress were examined in a sample of 246 youth (148 girls, 98 boys). Children completed measures of depression, social anxiety, loneliness, and self‐esteem when they were in grades 4 to 6 (Time 1), and again 6 years later during adolescence (grades 10 – 12; Time 2). At Time 2, adolescents also reported their self‐concept and their identification with reputation‐based peer crowds, including Populars, Jocks, Brains, Burnouts, Non‐Conformists, and None/Average crowds. Results indicated that adolescents' report of peer crowd affiliation was concurrently associated with self‐concept and levels of internalizing distress. Follow‐back analyses of internalizing trajectories revealed that Populars/Jocks had experienced significant declines in internalizing distress across development, whereas Brains exhibited some increases in internalizing distress between childhood and adolescence.     

THE EAST END, THE WEST END, AND KING'S CROSS: ON CLUSTERING IN THE FOUR-PLAYER HOTELLING GAME

We study experimentally a standard four-player Hotelling location game with a uniform density of consumers and inelastic demand. The pure strategy Nash equilibrium configuration consists of two firms located at one quarter of the "linear city," and the other two at three quarters. We do not observe convergence to such an equilibrium. In our experimental data we find three clusters. Besides the direct proximity of the two equilibrium locations, this concerns the focal midpoint. Moreover, we observe that whereas this midpoint appears to become more notable over time, other focal points fade away. We explain how these observations are related to best-response dynamics, and to the fact that the players rely on best-responses in particular when they are close to the equilibrium configuration.     

Media Publicity and the Voluntary Sector: The Case of Nonprofit Organizations in New York City

Media publicity is an important resource for contemporary voluntary associations, but very little is actually known about the resources and organizational characteristics that are most important for getting media attention. To address this question, we collected and analyzed data on the organizational attributes and news publicity of 739 nonprofit organizations in New York City. We find that an organization's income, paid staff, membership size, and library resources are significantly related to getting media publicity, whereas the number of chapter affiliations is inversely related to publicity. Association type is also a significant factor that influences an organization's ability to get publicity. We discuss the implications that these findings have for current debates about advocacy and civic engagement in the nonprofit sector.     

Fire and restoration of the largest urban forest of the world in Rio de Janeiro City,Brazil

National Park of Tijuca in Rio de Janeiro (Brazil) is about 3,300 ha and considered the largest urban forest in the world. Its floristic composition is typical of Atlantic Rain Forest. The reserve is being altered because of fire occurrences and urban expansion. This study identified locations and causes of forest fires, and makes management recommendations to restore damaged areas. From 1991 to 2000, forest firefighters recorded an average of 75-fire occurrences/year. Identified causes included hot air balloons (24%), intentional (24%), rubbish burning (21%) and religious practices (17%). Primary fuels included invasive grasses and ferns. Although hot air balloons destroyed larger areas of forest in each occurrence, a greater number of fires started in the invasive vegetation along roads that bisect the forest. In response to recurrent forests, invasive vegetation has spread gradually into the forest increasing forest degradation. To decrease fire damage, sites with high fire frequencies and density of invasive vegetation were planted with less flammable species. Results indicate that fire frequency decreased and density of invasive vegetation declined. This approach appears to prevent fire incidence, reduce the need for fire fighting, and preserve existing biodiversity.