Development of predictive signatures for treatment selection in precision medicine with survival outcomes

For survival endpoints in subgroup selection, a score conversion model is often used to convert the set of biomarkers for each patient into a univariate score and using the median of the univariate scores to divide the patients into biomarker‐positive and biomarker‐negative subgroups. However, this may lead to bias in patient subgroup identification regarding the 2 issues: (1) treatment is equally effective for all patients and/or there is no subgroup difference; (2) the median value of the univariate scores as a cutoff may be inappropriate if the sizes of the 2 subgroups are differ substantially. We utilize a univariate composite score method to convert the set of patient's candidate biomarkers to a univariate response score. We propose applying the likelihood ratio test (LRT) to assess homogeneity of the sampled patients to address the first issue. In the context of identification of the subgroup of responders in adaptive design to demonstrate improvement of treatment efficacy (adaptive power), we suggest that subgroup selection is carried out if the LRT is significant. For the second issue, we utilize a likelihood‐based change‐point algorithm to find an optimal cutoff. Our simulation study shows that type I error generally is controlled, while the overall adaptive power to detect treatment effects sacrifices approximately 4.5% for the simulation designs considered by performing the LRT; furthermore, the change‐point algorithm outperforms the median cutoff considerably when the subgroup sizes differ substantially.     

Response‐adaptive designs for binary responses: How to offer patient benefit while being robust to time trends?

Response‐adaptive randomisation (RAR) can considerably improve the chances of a successful treatment outcome for patients in a clinical trial by skewing the allocation probability towards better performing treatments as data accumulates. There is considerable interest in using RAR designs in drug development for rare diseases, where traditional designs are not either feasible or ethically questionable. In this paper, we discuss and address a major criticism levelled at RAR: namely, type I error inflation due to an unknown time trend over the course of the trial. The most common cause of this phenomenon is changes in the characteristics of recruited patients—referred to as patient drift. This is a realistic concern for clinical trials in rare diseases due to their lengthly accrual rate. We compute the type I error inflation as a function of the time trend magnitude to determine in which contexts the problem is most exacerbated. We then assess the ability of different correction methods to preserve type I error in these contexts and their performance in terms of other operating characteristics, including patient benefit and power. We make recommendations as to which correction methods are most suitable in the rare disease context for several RAR rules, differentiating between the 2‐armed and the multi‐armed case. We further propose a RAR design for multi‐armed clinical trials, which is computationally efficient and robust to several time trends considered.     

Deep Uncertainties in Sea-Level Rise and Storm Surge Projections: Implications for Coastal Flood Risk Management

Sea levels are rising in many areas around the world, posing risks to coastal communities and infrastructures. Strategies for managing these flood risks present decision challenges that require a combination of geophysical, economic, and infrastructure models. Previous studies have broken important new ground on the considerable tensions between the costs of upgrading infrastructure and the damages that could result from extreme flood events. However, many risk-based adaptation strategies remain silent on certain potentially important uncertainties, as well as the tradeoffs between competing objectives. Here, we implement and improve on a classic decision-analytical model (Van Dantzig 1956) to: (i) capture tradeoffs across conflicting stakeholder objectives, (ii) demonstrate the consequences of structural uncertainties in the sea-level rise and storm surge models, and (iii) identify the parametric uncertainties that most strongly influence each objective using global sensitivity analysis. We find that the flood adaptation model produces potentially myopic solutions when formulated using traditional mean-centric decision theory. Moving from a single-objective problem formulation to one with multiobjective tradeoffs dramatically expands the decision space, and highlights the need for compromise solutions to address stakeholder preferences. We find deep structural uncertainties that have large effects on the model outcome, with the storm surge parameters accounting for the greatest impacts. Global sensitivity analysis effectively identifies important parameter interactions that local methods overlook, and that could have critical implications for flood adaptation strategies.     

Ethnographies of Volunteering: Providing Nuance to the Links Between Volunteering and Development

VOLUNTAS: International Journal of Voluntary and Nonprofit Organizations - This paper explores how ethnographic approaches to third sector and nonprofit studies allow for context-based...     

Men,masculinities, and gender-based violence: The broadening scope of recent research

Men's relationships to gender-based violence (GBV) have long been an area of sociological inquiry, but until recently men have primarily been framed as perpetrators of violence against women. More recently, research on men and GBV has broadened to include studying men as victims/survivors, as investigators and law enforcement officers, as passive or active bystanders, and as allies in working to address this social problem. We review this research in an effort to bridge these divergent bodies of work; we identify methodological trends and gaps in existing research, make recommendations for improved theoretical and methodological robustness, and suggest that research perspectives on men and GBV have shifted over time as wider understandings of gender and masculinities become more hopeful and more inclusive. While we see optimism and promise in new directions of GBV research, we urge ongoing research to retain the wisdoms and critical perspectives that marked the beginnings of GBV inquiry.     

Exploring the link between integrated leadership and public sector performance

This study develops the concept of integrated leadership in the public sector. Integrated leadership is conceived as the combination of five leadership roles that are performed collectively by employees and managers at different levels of the hierarchy. The leadership roles are task-, relations-, change-, diversity-, and integrity-oriented leadership. Using data from the Federal Human Capital Survey and Program Assessment Rating Tool, we analyze the relationship between integrated leadership and federal program performance. The findings from the empirical analysis indicate that integrated leadership has a positive and sizeable effect on the performance of federal sub-agencies. The study concludes with a discussion of the implications of the findings and limitations of the study.     

On sequential closed testing dose groups with a control

Methods for a sequential test of a dose-response effect in pre-clinical studies are investigated. The objective of the test procedure is to compare several dose groups with a zero-dose control. The sequential testing is conducted within a closed family of one-sided tests. The procedures investigated are based on a monotonicity assumption. These closed procedures strongly control the familywise error rate while providing information about the shape of the dose-responce relationship. Performance of sequential testing procedures are compared via a Monte Carlo simulation study. We illustrae the procedures by application to a real data set.