Parallel hierarchical sampling:a general-purpose class of multiple-chains MCMC algorithms

This paper introduces the Parallel Hierarchical Sampler (PHS), a class of Markov chain Monte Carlo algorithms using several interacting chains having the same target distribution but different mixing properties. Unlike any single-chain MCMC algorithm, upon reaching stationarity one of the PHS chains, which we call the “mother” chain, attains exact Monte Carlo sampling of the target distribution of interest. We empirically show that this translates in a dramatic improvement in the sampler’s performance with respect to single-chain MCMC algorithms. Convergence of the PHS joint transition kernel is proved and its relationships with single-chain samplers, Parallel Tempering (PT) and variable augmentation algorithms are discussed. We then provide two illustrative examples comparing the accuracy of PHS with

A Conservative Approach to Leveraging External Evidence for Effective Clinical Trial Design

Prior probabilities of clinical hypotheses are not systematically used for clinical trial design yet, due to a concern that poor priors may lead to poor decisions. To address this concern, a conservative approach to Bayesian trial design is illustrated here, requiring that the operational characteristics of the primary trial outcome are stronger than the prior. This approach is complementary to current Bayesian design methods, in that it insures against prior-data conflict by defining a sample size commensurate to a discrete design prior. This approach is ethical, in that it requires designs appropriate to achieving pre-specified levels of clinical equipoise imbalance. Practical examples are discussed, illustrating design of trials with binary or time to event endpoints. Moderate increases in phase II study sample size are shown to deliver strong levels of overall evidence for go/no-go clinical development decisions. Levels of negative evidence provided by group sequential confirmatory designs are found negligible, highlighting the importance of complementing efficacy boundaries with non-binding futility criteria.Comment: 13 pages, 3 color figures, 4 table

Microbiome yarns : microbiomology of curly and straight hair

Non peer reviewe

Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage

AbstractBackground4CMenB (Bexsero), a vaccine developed against invasive meningococcal disease caused by capsular group B strains (MenB), was recently licensed for use by the European Medicines Agency. Assessment of 4CMenB strain coverage in specific epidemiologic settings is of primary importance to predict vaccination impact on the burden of disease. The Meningococcal Antigen Typing System (MATS) was developed to predict 4CMenB strain coverage, using serum bactericidal antibody assay with human complement (hSBA) data from a diverse panel of strains not representative of any specific epidemiology.ObjectiveTo experimentally validate the accuracy of MATS-based predictions against strains representative of a specific epidemiologic setting.Methods and resultsWe used a stratified sampling method to identify a representative sample from all MenB disease isolates collected from England and Wales in 2007–2008, tested the strains in the hSBA assay with pooled sera from infant and adolescent vaccinees, and compared these results with MATS. MATS predictions and hSBA results were significantly associated (P=0.022). MATS predicted coverage of 70% (95% CI, 55–85%) was largely confirmed by 88% killing in the hSBA (95% CI, 72–95%). MATS had 78% accuracy and 96% positive predictive value against hSBA.ConclusionMATS is a conservative predictor of strain coverage by the 4CMenB vaccine in infants and adolescents

Retrospective Identification of a Broad IgG Repertoire Differentiating Patients With S. aureus Skin and Soft Tissue Infections From Controls

Background: Although the relevance of humoral immunity for protection against S. aureus skin and soft tissue infections (SSTIs) has been suggested by several animal and human studies, the question of which human antibodies may be protective has so far impeded the development of a safe and effective vaccine. Because most adults have developed certain anti-S. aureus antibodies due to S. aureus colonization or infection, we hypothesized that the titers of antibodies to S. aureus in uninfected controls would differ from those in infected patients and would also differ in infected patients from the time of acute infection to a 40-day convalescent serum.Methods: To test these hypotheses, we measured human antibody levels against a panel of 134 unique antigens comprising the S. aureus surfome and secretome in subjects with active culture-confirmed S. aureus SSTIs (cases) and in controls with no infection, using a novel S. aureus protein microarray.Results: Most S. aureus SSTI patients (n = 60) and controls (n = 142) had antibodies to many of the tested S. aureus antigens. Univariate analysis showed statistically weak differences in the IgG levels to some antigens in the SSTI patient (case) sera compared with controls. Antibody levels to most tested antigens did not increase comparing acute with 40-day serum. Multiple logistic regression identified a rich subset of antigens that, by their antibody levels, together correctly differentiated all cases from all controls.Conclusions: Antibodies directed against S. aureus antigens were present both in patients with S. aureus SSTIs and in uninfected control patients. We found that SSTI patients and controls could be distinguished only based on differences in antibody levels to many staphylococcal surface and secreted antigens. Our results demonstrate that in the studied population, the levels of anti-S. aureus antibodies appear largely fixed, suggesting that there may be some level of unresponsiveness to natural infection

Association analysis of ACE and ACTN3 in Elite Caucasian and East Asian Swimmers

PURPOSE: Polymorphic variation in the angiotensin-converting enzyme (ACE) and alpha-actinin-3 (ACTN3) genes has been reported to be associated with endurance and/or power-related human performance. Our aim was to investigate whether polymorphisms in ACE and ACTN3 are associated with elite swimmer status in Caucasian and East Asian populations. METHODS: ACE I/D and ACTN3 R577X genotyping was carried out for 200 elite Caucasian swimmers from European, Commonwealth, Russian and American cohorts (short and middle distance, SMD ≤ 400 m, n = 130; long distance, LD greater than 400 m, n = 70) and 326 elite Japanese and Taiwanese swimmers (short distance, SD ≤ 100 m, n = 166; middle distance, MD: 200 - 400 m, n = 160). Genetic associations were evaluated by logistic regression and other tests accommodating multiple testing adjustment. RESULTS: ACE I/D was associated with swimmer status in Caucasians, with the D-allele being overrepresented in SMD swimmers under both additive and I-allele dominant models (permutation test p = 0.003 and p = 0.0005, respectively). ACE I/D was also associated with swimmer status in East Asians. In this group, however, the I-allele was overrepresented in the SD swimmer group (permutation test p = 0.041 and p = 0.0098 under the additive and the D-allele-dominant models, respectively). ACTN3 R577X was not significantly associated with swimmer status in either Caucasians or East Asians. CONCLUSIONS: ACE I/D associations were observed in these elite swimmer cohorts, with different risk alleles responsible for the associations in swimmers of different ethnicities. The functional ACTN3 R577X polymorphism did not show any significant association with elite swimmer status, despite numerous previous reports of associations with 'power/sprint' performance in other sports.Additional co-authors: Jason Gulbin, Viktor A. Rogozkin, Ildus I. Ahmetov, Nan Yang, Kathryn N. North, Saraslanidis Ploutarhos, Hugh E. Montgomery, Mark E.S. Bailey, and Yannis P. Pitsiladi

Beta-Stacy survival regression models

This paper introduces a class of survival models for discrete time-to-event data with random right censoring. Flexible distributions for the survival times are constructed by modelling the random survival functions as discrete-time beta-Stacy processes (DBS) and by introducing the regression effects via their prior means. Identifiability is attained by defining the DBS precision parameters as appropriate functions of the regression coefficients. By the conjugacy of the beta-Stacy process with respect to random right censoring, marginal posterior inferences for all model parameters can be efficiently approximated using the standard Gibbs sampler. The latter also yields a Monte Carlo approximation for the predictive distributions of the survival probabilities for future covariate profiles. We provide three clinical applications of the DBS survival regression framework comparing its estimates with those of parametric, semiparametric and non-parametric survival models

Isoseparation and robustness in finite parameter Bayesian inference

Under a new family of separations the distance between two posterior densities is the same as the distance between their prior densities whatever the observed likelihood when that likelihood is strictly positive. Local versions of such separations form the basis of a weak topology having close links to the Euclidean metric on the natural parameters of two exponential family densities. Using these local separation measures it is shown that when the tails of the approximating density have appropriate properties, the variation distance between an approximating posterior density to a genuine density can be bounded explicitly. These bounds apply irrespective of whether the prior densities are grossly misspecified with respect to variation distance and irrespective of the form or the validity of the observed likelihood