Re-randomization tests as sensitivity analyses to confirm immunological noninferiority of an investigational vaccine: Case study

Here we present as case study how re-randomization tests were performed in two randomized, controlled clinical trials as sensitivity analyses, as recommended by the United States Food and Drug Administration in the context of adaptive randomization. This was done to confirm primary conclusions on immunological noninferiority of an investigational new fully liquid presentation of a quadrivalent cross-reacting material conjugate meningococcal vaccine (MenACWY-CRM), over its licensed lyophilized/liquid presentation. In two phase 2b studies (Study #1: NCT03652610; Study #2: NCT03433482), noninferiority of the fully liquid presentation of MenACWY-CRM to the licensed presentation was assessed and demonstrated for immune responses against meningococcal serogroup A (MenA), the only vaccine component modified from lyophilized to liquid in the new presentation. The original vaccine assignment algorithm, with a minimization procedure accounting for center or center within age strata, was used to re-randomize participants belonging to the fully liquid and licensed vaccine groups while keeping antibody responses, covariates and entry order as observed. Test statistics under re-randomization were generated according to the ANCOVA model used in the primary analysis. To confirm immunological noninferiority following re-randomization, the corresponding p-values had to be <0.025. For both studies and all primary objective evaluations, the re-randomization p-values were well below 0.025 (0.0004 for Study #1; 0.0001 for the two co-primary endpoints in Study #2). Re-randomization tests performed to comply with a regulatory request confirmed the primary conclusions of immunological noninferiority for the MenA of the fully liquid compared to the licensed vaccine presentation.     

The Redistributive Effects of the Tax Wedge in Italy

Abstract. This paper presents an original data set of microdata on the tax wedge in Italy, obtained by using the microsimulation model ITAXMOD, developed at ISPE (Institute for Studies on Economic Planning). These data are used to measure the components of the tax wedge and their burden on the total cost of labour at the individual level. The results have been aggregated across income brackets, socio-economic groups and sectors of employment. These data are the necessary preliminary input for any redistributive analysis and in addition they make the available data for Italy comparable with those of other countries. Scant attention has been paid up to now to the redistributive aspects of the tax wedge, since most analyses are based on the income of the “average production worker” which is far from an ideal standard for comparison. The computation of the tax wedge for different brackets of total labour cost has been explored in two ways. The first is related to the differing weights of the components of the tax wedge on cost of labour and no particular hypothesis has been made about the incidence of these components. The results show that the burden of personal income taxation and of social security contributions is very high even for wage-earners in the lowest brackets (in 1992, the estimated tax wedge is more than 44% of total labour cost even in the second decile of the labour cost). That might discourage both labour supply and labour demand across the entire spectrum of deciles of cost of labour. The second line of research studies the incidence of personal income taxes and employees' social security contributions on gross earnings, under the maintained hypothesis that these two components of the tax wedge are shouldered by the employees.     

The distinction between provoked and unprovoked aggression in toddlerhood,and associations with empathy-related processes

Physical aggression in toddlerhood has received considerable attention in the past 20 years. The underlying theme has been that toddlers behave aggressively due to not yet being able to regulate their frustration. However, there is some evidence to suggest that early aggression can occur for other reasons. In this study, we tested the distinction between provoked and unprovoked aggression in toddlerhood, and examined whether different empathy-related processes would show unique associations with each type of aggression. Participants were 200 mothers of children aged 15–21 months (M_age = 18.32 months, SD = 1.75) who completed measures of provoked and unprovoked aggression, and empathy-related processes. We found that the two-factor aggression model fit the data well. In addition, when controlling for the overlap between other-oriented empathy and personal distress, other-oriented empathy demonstrated a negative association with unprovoked aggression, and personal distress showed a positive link with provoked aggression. Our findings underscore the importance of studying early physical aggression in a more nuanced way to better understand different functions it may serve in toddlerhood.     

Aggression in toddlers: Associations with temper loss and parent-child conflict

Using a normative US sample of 477 mothers of 6- to 24- month-old children, we explored the relations among toddlers’ physical aggression, child temper loss, and parent-child conflict to gain a better understanding of how aggression develops from infancy to toddlerhood. An inventory of specific aggressive acts was subject to factor analysis to test whether the acts clustered as hypothesized. Consistent with our hypothesis, confirmatory factor analyses supported the distinction between the two types of aggression, directed and exploratory physical aggression. Although the two types were correlated, they showed differential associations with temper loss and parent-child conflict consistent with theory. Directed aggression had a relatively stronger relation with child defiance and temper loss than did exploratory aggression. Moreover, the association between directed aggression and defiance was stronger for older children. The findings from this cross-sectional study provide preliminary support for two forms of early aggression that may differ in trajectory and context.     

QUALITATIVE VARIABLE DISCRIMINANT ANALYSIS AND ITS USE IN PRODUCT VERSION SELECTION

The purpose of this article is to illustrate the use of multiple discriminant analysis in those cases in which all discriminating variables are qualitative. The authors will show that an appropriate qualitative variable discriminant analysis model is a reformulation of the Bayesian decision theoretic model. Rules for the use of multiple discriminant analysis also are suggested for the cases in which some variables are qualitative and some are measurable on at least an interval scale. The qualitative variable discriminant analysis model is illustrated as an appropriate device for selecting a product version that will minimize a manufacturer's risk of product introduction.