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.     

Noninformative priors for the between-group variance in the unbalanced one-way random effects model with heterogeneous error variances

For the unbalanced one-way random effects model with heterogeneous error variances, we propose the non-informative priors for the between-group variance and develop the first- and second-order matching priors. It turns out that the second-order matching priors do not exist and the reference prior and Jeffreys prior do not satisfy a first-order matching criterion. We also show that the first-order matching prior meets the frequentist target coverage probabilities much better than the Jeffreys prior and reference prior through simulation study, and the Bayesian credible intervals based on the matching prior and reference prior give shorter intervals than the existing confidence intervals by examples.     

Leader negative feedback-seeking and leader effectiveness in leader-subordinate relationships: The paradoxical role of subordinate expertise

From a motivational perspective of feedback-seeking behavior, we examined the mediating role of leaders' negative feedback-seeking from subordinates in the relationship between the quality of leader-member exchange (LMX) and subordinates' evaluation of leader effectiveness, along with the moderating role of subordinate expertise in the mediated relationship. Using 151 unique matched sets of leader and subordinate reports obtained from 5 large Korean companies, we found that the positive relationship between LMX and leader effectiveness was mediated by leaders' negative feedback-seeking. Additionally, the positive relationship between LMX and leader negative feedback-seeking was stronger when perceived subordinate expertise was lower. Lastly, the indirect effect of LMX on leader effectiveness through leader negative feedback-seeking was stronger when perceived subordinate expertise was lower. These findings were obtained after controlling for leaders' power distance and goal orientations that might influence their motives to seek or avoid feedback. Theoretical and practical implications are discussed.     

How School Contexts Shape the Relations Among Adolescents’ Beliefs,Peer Victimization,and Depressive Symptoms

The present research examined how school contexts shape the extent to which beliefs about the potential for change (implicit theories) interact with social adversity to predict depressive symptoms. A preregistered multilevel regression analysis using data from 6,237 ninth‐grade adolescents in 25 U.S. high schools showed a three‐way interaction: Implicit theories moderated the associations between victimization and depressive symptoms only in schools with high levels of school‐level victimization, but not in schools with low victimization levels. In high‐victimization schools, adolescents who believed that people cannot change (an entity theory of personality) were more depressed when they were victimized more frequently. Thus, the mental health correlates of adolescents’ implicit theories depend on both personal experiences and the norms in the context.     

Diasporic kinship hegemonies and transnational continuities in the Hmong diaspora

ABSTRACT

Although hegemony has been understood as the property of nation-states and the ruling classes, this paper explores cultural hegemonies among diasporic peoples by examining the pervasive compliance of Hmong living in Laos and the United States with the principles of their kinship system. Since these kinship rules are inculcated through parental education from an early age and are seen as essential for maintaining the cohesion of their dispersed diasporic community in the absence of a territorial ancestral homeland, they have become culturally engrained and taken-for-granted by Hmong through their voluntary consent and no longer have to be enforced by overt power and coercive means. However, like all hegemonies, the Hmong kinship system may also confront increasing challenges and contestation as it is enacted in the different nation-states where Hmong reside, and may eventually become an ideology that needs to be actively enforced and imposed by the direct use of power.     

DESPERATE TIMES CALL FOR DESPERATE MEASURES: GOVERNMENT SPENDING MULTIPLIERS IN HARD TIMES

We investigate state-dependent effects of fiscal multipliers and allow for endogenous sample splitting to determine whether the U.S. economy is in a slack state. When the endogenized slack state is estimated as the period of the unemployment rate higher than about 12%, the estimated cumulative multipliers are significantly larger during slack periods than nonslack periods and are above unity. We also examine the possibility of time-varying regimes of slackness and find that our empirical results are robust under a more flexible framework. Our estimation results point out the importance of the heterogenous effects of fiscal policy and shed light on the prospect of fiscal policy in response to economic shocks from the current COVID-19 pandemic. (JEL C32, E62, H20, H62)     

Pressure to Attend Therapy,Dyadic Adjustment,and Adverse Childhood Experiences: Direct and Indirect Effects on the Therapeutic Alliance in Couples Therapy

In this study we examine the role that pressure to attend therapy, dyadic adjustment, and adverse childhood experiences (ACEs) play in developing the therapeutic alliance. A total of 351 couples received treatment as usual at three family therapy training clinics. Participants rated predictor variables at intake and alliance at the fourth session. Results of a path analysis indicate that each partner's dyadic adjustment is directly associated with the quality of her or his own alliance. In addition, when male partners report more ACEs and pressure to attend treatment, their own alliance scores decrease. Additionally, when one partner reports feeling pressure to attend therapy, the other partner's alliance decreases. Finally, for males, there is an indirect effect of dyadic adjustment on alliance through pressure to attend therapy. These results suggest that clinicians should routinely assess relationship adjustment, how pressured each partner is feeling to attend treatment, and ACEs; as these may impact alliance quality.     

An Introduction and Illustration of Bayesian Modeling in Couple and Family Therapy Research

Bayesian modeling is becoming increasing popular as a method for data analyses in the social sciences and can move couple, marriage, and family therapy (C/MFT) research forward. Bayesian modeling helps researchers better understand the uncertainty of findings and incorporate previous research into analyses. Other benefits of Bayesian modeling are the straightforward interpretation of findings, high-quality inferences even with small samples (in combination with an informative prior), and the ability to work with complex data structures (observations nested in relationships and time points) which are common in C/MFT research. This article introduces the benefits of Bayesian modeling and provides an example of an Actor–Partner Interdependence Model using R. Information on how to conduct the same analyses using Stata and MPlus is provided in the Supplemental Information.     

Toward General Principles for Resilience Engineering

Maintaining the performance of infrastructure-dependent systems in the face of surprises and unknowable risks is a grand challenge. Addressing this issue requires a better understanding of enabling conditions or principles that promote system resilience in a universal way. In this study, a set of such principles is interpreted as a group of interrelated conditions or organizational qualities that, taken together, engender system resilience. The field of resilience engineering identifies basic system or organizational qualities (e.g., abilities for learning) that are associated with enhanced general resilience and has packaged them into a set of principles that should be fostered. However, supporting conditions that give rise to such first-order system qualities remain elusive in the field. An integrative understanding of how such conditions co-occur and fit together to bring about resilience, therefore, has been less clear. This article contributes to addressing this gap by identifying a potentially more comprehensive set of principles for building general resilience in infrastructure-dependent systems. In approaching this aim, we organize scattered notions from across the literature. To reflect the partly self-organizing nature of infrastructure-dependent systems, we compare and synthesize two lines of research on resilience: resilience engineering and social-ecological system resilience. Although some of the principles discussed within the two fields overlap, there are some nuanced differences. By comparing and synthesizing the knowledge developed in them, we recommend an updated set of resilience-enhancing principles for infrastructure-dependent systems. In addition to proposing an expanded list of principles, we illustrate how these principles can co-occur and their interdependencies.     

Mobile use,personal values,and connectedness with civic life

This study aims to examine whether and how mobile communication enables citizens to translate their value orientations into their connectedness to the civic life. Specifically, we probe the indirect process in which different types of personal values predict key dimensions of engagement with civic affairs through patterns of mobile phone use. We show that individualism is indirectly associated with engagement with civic affairs through informational mobile use, whereas the link between collectivism and community involvement is positively intervened by relational mobile use. Additionally, socio-tropic empathy yields indirect relationships with civic engagement through informational mobile use. Implications of these findings are discussed.