Interacting Multiple Try Algorithms with Different Proposal Distributions

We propose a new class of interacting Markov chain Monte Carlo (MCMC) algorithms designed for increasing the efficiency of a modified multiple-try Metropolis (MTM) algorithm. The extension with respect to the existing MCMC literature is twofold. The sampler proposed extends the basic MTM algorithm by allowing different proposal distributions in the multiple-try generation step. We exploit the structure of the MTM algorithm with different proposal distributions to naturally introduce an interacting MTM mechanism (IMTM) that expands the class of population Monte Carlo methods. We show the validity of the algorithm and discuss the choice of the selection weights and of the different proposals. We provide numerical studies which show that the new algorithm can perform better than the basic MTM algorithm and that the interaction mechanism allows the IMTM to efficiently explore the state space

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias

Efficacy of a novel perfluorocarbon-based intrapulmonary drug delivery system

Introduction: We sought to determine the efficacy of a novel intrapulmonary perfluorocarbon (PFC) based antibiotic delivery system in a rat model of pneumococcal pneumonia. Methods: Wistar rats (400-500 g) were inoculated with 8x10' type 3 pneumococcus via direct intratracheal (IT) injection. Twenty-four h after inoculation, rats received no treatment (control, n=15), 10 mg IM ampicillin (AMP, n =10), 10 ml lavage with an AMP containing (1 mg/ml) microparticulate dispersion in PFC (AMPPFC; Alliance Pharmaceutical Corp.; n=ll). Animals were monitored daily for survival for 10 days. AMP concentrations, were determined in serum and lung homogenates using a bioassay. The log-rank test with Bonferroni's correction was used to determine differences in mortality among groups. The null hypothesis was rejected for a critical p&lt;0.017. Results: Mortality was significantly higher in controls than AMPPFC (100% vs 18%, p &lt; 0.017). There was a trend favoring treatment with AMPPFC compared to AMP (18% vs 70% mortality, p&lt;0.019). The table shows serum and lung antibiotic concentrations (n=2) Time (h) AMP (jig/ml) AMPPFC Qig/ml) Serum Lung Serum Lung 1 15 2 15 500 2 1 1 2 120 3 0 0 1 60 4 0 0 2 50 8 0 0 0 15 24 0 0 0 10 48 0 0 0 3 72 0 0 0 2 Conclusions: PFC-based IT antibiotic microparticulate formüations may be more effect than systemic antibiotic therapy alone in the treatment of severe pneumonia