59 research outputs found
Real-time dynamic modelling for the design of a cluster-randomized phase 3 Ebola vaccine trial in Sierra Leone.
BACKGROUND: Declining incidence and spatial heterogeneity complicated the design of phase 3 Ebola vaccine trials during the tail of the 2013-16 Ebola virus disease (EVD) epidemic in West Africa. Mathematical models can provide forecasts of expected incidence through time and can account for both vaccine efficacy in participants and effectiveness in populations. Determining expected disease incidence was critical to calculating power and determining trial sample size. METHODS: In real-time, we fitted, forecasted, and simulated a proposed phase 3 cluster-randomized vaccine trial for a prime-boost EVD vaccine in three candidate regions in Sierra Leone. The aim was to forecast trial feasibility in these areas through time and guide study design planning. RESULTS: EVD incidence was highly variable during the epidemic, especially in the declining phase. Delays in trial start date were expected to greatly reduce the ability to discern an effect, particularly as a trial with an effective vaccine would cause the epidemic to go extinct more quickly in the vaccine arm. Real-time updates of the model allowed decision-makers to determine how trial feasibility changed with time. CONCLUSIONS: This analysis was useful for vaccine trial planning because we simulated effectiveness as well as efficacy, which is possible with a dynamic transmission model. It contributed to decisions on choice of trial location and feasibility of the trial. Transmission models should be utilised as early as possible in the design process to provide mechanistic estimates of expected incidence, with which decisions about sample size, location, timing, and feasibility can be determined
Robust Henderson III estimators of variance components in the nested error model
Common methods for estimating variance components in Linear Mixed Models include Maximum Likelihood (ML) and Restricted Maximum Likelihood (REML). These methods are based on the strong assumption of multivariate normal distribution and it is well know that they are very sensitive to outlying observations with respect to any of the random components. Several robust altematives of these methods have been proposed (e.g. Fellner 1986, Richardson and Welsh 1995). In this work we present several robust alternatives based on the Henderson method III which do not rely on the normality assumption and provide explicit solutions for the variance components estimators. These estimators can later be used to derive robust estimators of regression coefficients. Finally, we describe an application of this procedure to small area estimation, in which the main target is the estimation of the means of areas or domains when the within-area sample sizes are small
Signature Movements Lead to Efficient Search for Threatening Actions
The ability to find and evade fighting persons in a crowd is potentially life-saving. To investigate how the visual system processes threatening actions, we employed a visual search paradigm with threatening boxer targets among emotionally-neutral walker distractors, and vice versa. We found that a boxer popped out for both intact and scrambled actions, whereas walkers did not. A reverse correlation analysis revealed that observers' responses clustered around the time of the “punch", a signature movement of boxing actions, but not around specific movements of the walker. These findings support the existence of a detector for signature movements in action perception. This detector helps in rapidly detecting aggressive behavior in a crowd, potentially through an expedited (sub)cortical threat-detection mechanism
Visual adaptation enhances action sound discrimination
Prolonged exposure, or adaptation, to a stimulus in one modality can bias, but also enhance, perception of a subsequent stimulus presented within the same modality. However, recent research has also found that adaptation in one modality can bias perception in another modality. Here we show a novel crossmodal adaptation effect, where adaptation to a visual stimulus enhances subsequent auditory perception. We found that when compared to no adaptation, prior adaptation to visual, auditory or audiovisual hand actions enhanced discrimination between two subsequently presented hand action sounds. Discrimination was most enhanced when the visual action ‘matched’ the auditory action. In addition, prior adaptation to a visual, auditory or audiovisual action caused subsequent ambiguous action sounds to be perceived as less like the adaptor. In contrast, these crossmodal action aftereffects were not generated by adaptation to the names of actions. Enhanced crossmodal discrimination and crossmodal perceptual aftereffects may result from separate mechanisms operating in audiovisual action sensitive neurons within perceptual systems. Adaptation induced crossmodal enhancements cannot be explained by post-perceptual responses or decisions. More generally, these results together indicate that adaptation is a ubiquitous mechanism for optimizing perceptual processing of multisensory stimuli
Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women
BACKGROUND
The incidence of human immunodeficiency virus (HIV) infection remains high
among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended
use of a vaginal ring containing dapivirine for the prevention of HIV infection
in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities
in South Africa and Uganda.
METHODS
In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly
assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg
of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks
for up to 24 months. The primary efficacy end point was the rate of HIV type 1
(HIV-1) seroconversion.
RESULTS
A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion
during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years),
as compared with 56 in the placebo group who underwent HIV-1 seroconversion
during 917 person-years of follow-up (6.1 seroconversions per 100 person-years).
The incidence of HIV-1 infection was 31% lower in the dapivirine group than in
the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P = 0.04). There was no significant difference in efficacy of the dapivirine ring
among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI,
0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45
to 1.60; P = 0.43 for treatment-by-age interaction). Among participants with HIV-1
infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were
detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56
(16.1%) in the placebo group. Serious adverse events occurred more often in the
dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]).
However, no clear pattern was identified.
CONCLUSIONS
Among women in sub-Saharan Africa, the dapivirine ring was not associated with
any safety concerns and was associated with a rate of acquisition of HIV-1 infection
that was lower than the rate with placebo.Supported by the International Partnership for Microbicides
(a not-for-profit product-development partnership), which receives
support from the Bill and Melinda Gates Foundation,
Irish Aid, the Ministry of Foreign Affairs of Denmark, the Ministry
of Foreign Affairs of the Netherlands, the Norwegian
Agency for Development Cooperation, the U.K. Department for
International Development, the American people through the
U.S. Agency for International Development, and the President’s
Emergency Plan for AIDS Relief.http://www.nejm.org2017-06-01am2017Family Medicin
Estimating reliability and generalizability from hierarchical biomedical data
It is shown how hierarchical biomedical data, such as coming from longitudinal clinical trials, meta-analyses, or a combination of both, can be used to provide evidence for quantitative strength of reliability, agreement, generalizability, and related measures that derive from association concepts. When responses are of a continuous, Gaussian type, the linear mixed model is shown to be a versatile framework. At the same time, the framework is embedded in the generalized linear mixed models, such that non-Gaussian, e.g., binary, outcomes can be studied as well. Similarities and, above all, important differences are studied. All developments are exemplified using clinical studies in schizophrenia, with focus on the endpoints Clinician's Global Impression (CGI) or Positive and Negative Syndrome Scale (PANSS).status: publishe
Generalized reliability estimation using repeated measurements
Reliability can be studied in a generalized way using repeated measurements. Linear mixed models are used to derive generalized test-retest reliability measures. The method allows for repeated measures with a different mean structure due to correction for covariate effects. Furthermore, different variance-covariance structures between measurements can be implemented. When the variance structure reduces to a random intercept (compound symmetry), classical methods are recovered. With more complex variance structures (e.g. including random slopes of time and/or serial correlation), time-dependent reliability functions are obtained. The effect of time lag between measurements on reliability estimates can be evaluated. The methodology is applied to a psychiatric scale for schizophrenia.status: publishe
Marginal correlation from logit- and probit-data-normal models for hierarchical binary data
© 2014 Taylor & Francis Group, LLC. In hierarchical data settings, be it of a longitudinal, spatial, multi-level, clustered, or otherwise repeated nature, often the association between repeated measurements attracts at least part of the scientific interest. Quantifying the association frequently takes the form of a correlation function, including but not limited to intraclass correlation. Vangeneugden et al. (2010) derived approximate correlation functions for longitudinal sequences of general data type, Gaussian and non-Gaussian, based on generalized linear mixed-effects models. Here, we consider the extended model family proposed by Molenberghs et al. (2010). This family flexibly accommodates data hierarchies, intra-sequence correlation, and overdispersion. The family allows for closed-form means, variance functions, and correlation function, for a variety of outcome types and link functions. Unfortunately, for binary data with logit link, closed forms cannot be obtained. This is in contrast with the probit link, for which such closed forms can be derived. It is therefore that we concentrate on the probit case. It is of interest, not only in its own right, but also as an instrument to approximate the logit case, thanks to the well-known probit-logit conversion. Next to the general situation, some important special cases such as exchangeable clustered outcomes receive attention because they produce insightful expressions. The closed-form expressions are contrasted with the generic approximate expressions of Vangeneugden et al. (2010) and with approximations derived for the so-called logistic-beta-normal combined model. A simulation study explores performance of the method proposed. Data from a schizophrenia trial are analyzed and correlation functions derived.peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope.
aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=lsta20status: publishe
- …