Estimates of subgroup treatment effects in overall nonsignificant trials: To what extent should we believe in them?

In drug development, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population but appears to be beneficial in a relevant subgroup. In case the subgroup of interest was not part of a confirmatory testing strategy, the inflation of the overall type I error is substantial and therefore such a subgroup analysis finding can only be seen as exploratory at best. To support such exploratory findings, an appropriate replication of the subgroup finding should be undertaken in a new trial. We should, however, be reasonably confident in the observed treatment effect size to be able to use this estimate in a replication trial in the subpopulation of interest. We were therefore interested in evaluating the bias of the estimate of the subgroup treatment effect, after selection based on significance for the subgroup in an overall “failed” trial. Different scenarios, involving continuous as well as dichotomous outcomes, were investigated via simulation studies. It is shown that the bias associated with subgroup findings in overall nonsignificant clinical trials is on average large and varies substantially across plausible scenarios. This renders the subgroup treatment estimate from the original trial of limited value to design the replication trial. An empirical Bayesian shrinkage method is suggested to minimize this overestimation. The proposed estimator appears to offer either a good or a conservative correction to the observed subgroup treatment effect hence provides a more reliable subgroup treatment effect estimate for adequate planning of future studies.     

Improving the Efficacy of Administrative Data for Evaluation of Holistic Defense

A college of social work developed a partnership with a state commission on indigent defense to examine existing data-collection procedures, potential case outcomes, and practical implications of implementing holistic defense programs. The holistic defense model responds to the complex challenges of justice-system-involved defendants by providing social services in public defense offices. Using chi-square and logistic regression analyses of administrative data for a sample of 15,994 public defendants from a single judicial circuit, this research study examined case outcomes before and after implementation of a holistic defense program. Results were mixed regarding effectiveness of holistic defense in mitigating the effect of justice involvement for indigent defendants. Implementation of holistic defense was associated with a decrease in case dismissals. However, defendants receiving holistic representation were less likely to be indicted than defendants prior to program implementation. Once indicted, there were no changes in levels of diversions, and more defendants were held on bond, convicted as guilty, and incarcerated. After program implementation, fewer defendants were sentenced to alternatives to incarceration; more defendants were sentenced to time served, avoiding further incarcerative penalty. These findings suggested the need for further research to determine whether holistic defense practices are producing desired legal and social service outcomes.     

THE USE OF AGGREGATE DATA TO ESTIMATE GOMPERTZ‐TYPE OLD‐AGE MORTALITY IN HETEROGENEOUS POPULATIONS

We consider two related aspects of the study of old‐age mortality. One is the estimation of a parameterized hazard function from grouped data, and the other is its possible deceleration at extreme old age owing to heterogeneity described by a mixture of distinct sub‐populations. The first is treated by half of a logistic transform, which is known to be free of discretization bias at older ages, and also preserves the increasing slope of the log hazard in the Gompertz case. It is assumed that data are available in the form published by official statistical agencies, that is, as aggregated frequencies in discrete time. Local polynomial modelling and weighted least squares are applied to cause‐of‐death mortality counts. The second, related, problem is to discover what conditions are necessary for population mortality to exhibit deceleration for a mixture of Gompertz sub‐populations. The general problem remains open but, in the case of three groups, we demonstrate that heterogeneity may be such that it is possible for a population to show decelerating mortality and then return to a Gompertz‐like increase at a later age. This implies that there are situations, depending on the extent of heterogeneity, in which there is at least one age interval in which the hazard function decreases before increasing again.     

Comment: there may be compositional effects,but they do not work that way*

This analysis joins the debate on how declines in marriage have shifted the composition of the unmarried and married populations in the United States, and how compositional shifts have affected nonmarital birth rates. Gray, Stockard, and Stone (2006) presented one model for compositional effects that Ermisch (2009) challenged with alternative statistical tests. I propose an alternative model for compositional shifts based not on theory but on observed marriage and fertility patterns. The results from this alternative model are consistent with Ermisch’s findings yet support Gray et al.’s general case that compositional effects have had an important infiuence on nonmarital birth rates.     

The Life Course,Cohort Dynamics,and International Differences in Aging Trajectories

In recent years, population health research has focused on understanding the determinants of later-life health. Two strands of that work have focused on (1) international comparisons of later-life health and (2) assessing the early-life origins of disease and disability and the importance of life course processes. However, the less frequently examined intersection of these approaches remains an important frontier. The present study contributes to the integration of these approaches. We use the Health and Retirement Study family of data sets and a cohort dynamic approach to compare functional health trajectories across 12 high-income countries and to examine the role of life course processes and cohort dynamics in contributing to variation in those trajectories. We find substantial international variation in functional health trajectories and an important role of cohort dynamics in generating that variation, with younger cohorts often less healthy at comparable ages than the older cohorts they are replacing. We further find evidence of heterogeneous effects of life course processes on health trajectories. The results have important implications for future trends in morbidity and mortality as well as public policy.     

Seeking Clarity and Confidence in the Divorce Decision-Making Process

There is a well-established literature dedicated to why couples divorce, transitions associated with divorce, and the impact of divorce on families. However, little is known about the divorce decision-making process. We conducted in-depth interviews with individuals who have recently considered divorce (n = 30) and asked specifically about the roles of 2 concepts in their decision-making process: clarity and confidence. Three major themes emerged from the data: (a) Clarity about a decision to divorce or stay married is desired, it fluctuates, and takes time to find; (b) pivotal moments can bring clarity; and (c) confidence (in the final decision) is desired. Clinical implications and directions for future research are discussed.     

Keep the hope alive: young Indonesian musicians’ views of the future

Using ethnographic and interview data, this article explores hopes for the future of young Indonesian musicians. The young people are seen to consider their future trajectories in multiple, hierarchical music fields. The article also takes into account the ontological insecurity of jobs as a professional musician, arguing that there is continuous reproduction of a doxa, namely ‘survival of the fittest’ in Indonesia. Yet despite abundant risks to livelihoods, young Indonesian musicians expressed optimistic views about the future. The analysis of data below bridges the gap between the traditionally separate youth studies fields of youth transitions and youth cultures. Our interpretation critically contextualises the dialogue between these two fields based on the experiences of young Indonesian musicians as a part of the Global South.     

Functional analysis of high-content high-throughput imaging data

High-content automated imaging platforms allow the multiplexing of several targets simultaneously to generate multi-parametric single-cell data sets over extended periods of time. Typically, standard simple measures such as mean value of all cells at every time point are calculated to summarize the temporal process, resulting in loss of time dynamics of the single cells. Multiple experiments are performed but observation time points are not necessarily identical, leading to difficulties when integrating summary measures from different experiments. We used functional data analysis to analyze continuous curve data, where the temporal process of a response variable for each single cell can be described using a smooth curve. This allows analyses to be performed on continuous functions, rather than on original discrete data points. Functional regression models were applied to determine common temporal characteristics of a set of single cell curves and random effects were employed in the models to explain variation between experiments. The aim of the multiplexing approach is to simultaneously analyze the effect of a large number of compounds in comparison to control to discriminate between their mode of action. Functional principal component analysis based on T-statistic curves for pairwise comparison to control was used to study time-dependent compound effects.