Assessing methods for dealing with treatment crossover in clinical trials: A follow-up simulation study

Background: Treatment switching commonly occurs in clinical trials of novel interventions, particularly in the advanced or metastatic cancer setting, which causes important problems for health technology assessment. Previous research has demonstrated which adjustment methods are suitable in specific scenarios, but scenarios considered have been limited. Objectives: We aimed to assess statistical approaches for adjusting survival estimates in the presence of treatment switching in order to determine which methods are most appropriate in a new range of realistic scenarios, building upon previous research. In particular we consider smaller sample sizes, reduced switching proportions, increased levels of censoring, and alternative data generating models. Methods: We conducted a simulation study to assess the bias, mean squared error and coverage associated with alternative switching adjustment methods across a wide range of realistic scenarios. Results: Our results generally supported those found in previous research, but the novel scenarios considered meant that we could make conclusions based upon a more robust evidence base. Simple methods such as censoring or excluding patients that switch again resulted in high levels of bias. More complex randomisation-based methods (e.g. Rank Preserving Structural Failure Time Models (RPSFTM)) were unbiased when the “common treatment effect” held. Observational-based methods (e.g. inverse probability of censoring weights (IPCW)) coped better with time-dependent treatment effects but are heavily data reliant, and generally led to higher levels of bias in our simulations. Novel “two stage” methods produced relatively low bias across all simulated scenarios. All methods generally produced higher bias when the simulated sample size was smaller and when the censoring proportion was higher. All methods generally produced lower bias when switching proportions were lower. We find that the size of the treatment effect in terms of an acceleration factor has an important bearing on the levels of bias associated with the adjustment methods. Conclusions: Randomisation-based methods can accurately adjust for treatment switching when the treatment effect received by patients that switch is the same as that received by patients randomised to the experimental group. When this is not the case observational-based methods or simple twostage methods should be considered, although the IPCW is prone to substantial bias when the proportion of patients that switch is greater than approximately 90%. Simple methods such as censoring or excluding patients that switch should not be used

Neutron background in large-scale xenon detectors for dark matter searches

Simulations of the neutron background for future large-scale particle dark matter detectors are presented. Neutrons were generated in rock and detector elements via spontaneous fission and (alpha,n) reactions, and by cosmic-ray muons. The simulation techniques and results are discussed in the context of the expected sensitivity of a generic liquid xenon dark matter detector. Methods of neutron background suppression are investigated. A sensitivity of $10^{-9}-10^{-10}$ pb to WIMP-nucleon interactions can be achieved by a tonne-scale detector.Comment: 35 pages, 13 figures, 2 tables, accepted for publication in Astroparticle Physic

Scaling violations: Connections between elastic and inelastic hadron scattering in a geometrical approach

Starting from a short range expansion of the inelastic overlap function, capable of describing quite well the elastic pp and $\bar{p}p$ scattering data, we obtain extensions to the inelastic channel, through unitarity and an impact parameter approach. Based on geometrical arguments we infer some characteristics of the elementary hadronic process and this allows an excellent description of the inclusive multiplicity distributions in $pp$ and $\bar{p}p$ collisions. With this approach we quantitatively correlate the violations of both geometrical and KNO scaling in an analytical way. The physical picture from both channels is that the geometrical evolution of the hadronic constituents is principally reponsible for the energy dependence of the physical quantities rather than the dynamical (elementary) interaction itself.Comment: 16 pages, aps-revtex, 11 figure

Interoperable atlases of the human brain

International audienceThe last two decades have seen an unprecedented development of human brain mapping approaches at various spatial and temporal scales. Together, these have provided a large fundus of information on many different as-pects of the human brain including micro-and macrostructural segregation, regional specialization of function, connectivity, and temporal dynamics. Atlases are central in order to integrate such diverse information in a topo-graphically meaningful way. It is noteworthy, that the brain mapping field has been developed along several major lines such as structure vs. function, postmortem vs. in vivo, individual features of the brain vs. population-based aspects, or slow vs. fast dynamics. In order to understand human brain organization, however, it seems inevitable that these different lines are integrated and combined into a multimodal human brain model. To this aim, we held a workshop to determine the constraints of a multi-modal human brain model that are needed to enable (i) an integration of different spatial and temporal scales and data modalities into a common reference system, and (ii) efficient data exchange and analysis. As detailed in this report, to arrive at fully interoperable atlases of the human brain will still require much work at the frontiers of data acquisition, analysis, and represen-tation. Among them, the latter may provide the most challenging task, in particular when it comes to representing features of vastly different scales of space, time and abstraction. The potential benefits of such endeavor, however, clearly outweigh the problems, as only such kind of multi-modal human brain atlas may provide a starting point from which the complex relationships between structure, function, and connectivity may be explored

Ethnic and gender differences in applicants' decision-making processes: An application of the theory of reasoned action

Contains fulltext : 54483.pdf (publisher's version ) (Closed access)11 p

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis

Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.info:eu-repo/semantics/publishedVersio

Toward a Multifaceted Heuristic of Digital Reading to Inform Assessment, Research, Practice, and Policy

In this commentary, the author explores the tension between almost 30 years of work that has embraced increasingly complex conceptions of digital reading and recent studies that risk oversimplifying digital reading as a singular entity analogous with reading text on a screen. The author begins by tracing a line of theoretical and empirical work that both informs and complicates our understanding of digital literacy and, more specifically, digital reading. Then, a heuristic is proposed to systematically organize, label, and define a multifaceted set of increasingly complex terms, concepts, and practices that characterize the spectrum of digital reading experiences. Research that informs this heuristic is used to illustrate how more precision in defining digital reading can promote greater clarity across research methods and advance a more systematic study of promising digital reading practices. Finally, the author discusses implications for assessment, research, practice, and policy