Estimating the Expected Value of Partial Perfect Information in Health Economic Evaluations using Integrated Nested Laplace Approximation

The Expected Value of Perfect Partial Information (EVPPI) is a decision-theoretic measure of the "cost" of parametric uncertainty in decision making used principally in health economic decision making. Despite this decision-theoretic grounding, the uptake of EVPPI calculations in practice has been slow. This is in part due to the prohibitive computational time required to estimate the EVPPI via Monte Carlo simulations. However, recent developments have demonstrated that the EVPPI can be estimated by non-parametric regression methods, which have significantly decreased the computation time required to approximate the EVPPI. Under certain circumstances, high-dimensional Gaussian Process regression is suggested, but this can still be prohibitively expensive. Applying fast computation methods developed in spatial statistics using Integrated Nested Laplace Approximations (INLA) and projecting from a high-dimensional into a low-dimensional input space allows us to decrease the computation time for fitting these high-dimensional Gaussian Processes, often substantially. We demonstrate that the EVPPI calculated using our method for Gaussian Process regression is in line with the standard Gaussian Process regression method and that despite the apparent methodological complexity of this new method, R functions are available in the package BCEA to implement it simply and efficiently

High-Dimensional Inference with the generalized Hopfield Model: Principal Component Analysis and Corrections

We consider the problem of inferring the interactions between a set of N binary variables from the knowledge of their frequencies and pairwise correlations. The inference framework is based on the Hopfield model, a special case of the Ising model where the interaction matrix is defined through a set of patterns in the variable space, and is of rank much smaller than N. We show that Maximum Lik elihood inference is deeply related to Principal Component Analysis when the amp litude of the pattern components, xi, is negligible compared to N^1/2. Using techniques from statistical mechanics, we calculate the corrections to the patterns to the first order in xi/N^1/2. We stress that it is important to generalize the Hopfield model and include both attractive and repulsive patterns, to correctly infer networks with sparse and strong interactions. We present a simple geometrical criterion to decide how many attractive and repulsive patterns should be considered as a function of the sampling noise. We moreover discuss how many sampled configurations are required for a good inference, as a function of the system size, N and of the amplitude, xi. The inference approach is illustrated on synthetic and biological data.Comment: Physical Review E: Statistical, Nonlinear, and Soft Matter Physics (2011) to appea

Extensive telomere repeat arrays in mouse are hypervariable

In this study we have analysed mouse telomeres by Pulsed Field Gel Electrophoresis (PFGE). A number of specific restriction fragments hybridising to a (TTA-GGG)4 probe in the size range 50-150kb can be detected. These fragments are devoid of sites for most restriction enzymes suggesting that they comprise simple repeats; we argue that most of these are likely to be (TTAGGG)n. Each discrete fragment corresponds to the telomere of an individual chromosome and segregates as a Mendelian character. However, new size variants are being generated in the germ line at very high rates such that inbred mice are heterozygous at all telomeres analysable. In addition we show that specific small (approximately 4-12kb) fragments can be cleaved within some terminal arrays by the restriction enzyme MnII which recognises 5'(N7)GAGG3'. Like the complete telomere-repeat arrays (TRA's) these fragments form new variants at high rates and possibly by the same process. We speculate on the mechanisms that may be involved

Discovery of molecular subtypes in leiomyosarcoma through integrative molecular profiling.

Leiomyosarcoma (LMS) is a soft tissue tumor with a significant degree of morphologic and molecular heterogeneity. We used integrative molecular profiling to discover and characterize molecular subtypes of LMS. Gene expression profiling was performed on 51 LMS samples. Unsupervised clustering showed three reproducible LMS clusters. Array comparative genomic hybridization (aCGH) was performed on 20 LMS samples and showed that the molecular subtypes defined by gene expression showed distinct genomic changes. Tumors from the muscle-enriched cluster showed significantly increased copy number changes (P=0.04). A majority of the muscle-enriched cases showed loss at 16q24, which contains Fanconi anemia, complementation group A, known to have an important role in DNA repair, and loss at 1p36, which contains PRDM16, of which loss promotes muscle differentiation. Immunohistochemistry (IHC) was performed on LMS tissue microarrays (n=377) for five markers with high levels of messenger RNA in the muscle-enriched cluster (ACTG2, CASQ2, SLMAP, CFL2 and MYLK) and showed significantly correlated expression of the five proteins (all pairwise P<0.005). Expression of the five markers was associated with improved disease-specific survival in a multivariate Cox regression analysis (P<0.04). In this analysis that combined gene expression profiling, aCGH and IHC, we characterized distinct molecular LMS subtypes, provided insight into their pathogenesis, and identified prognostic biomarkers

Exposure of individual harbour seals (Phoca vitulina) and waters surrounding protected habitats to acoustic deterrent noise from aquaculture

This work was funded by the European Social Fund and Scottish Funding Council as part of Developing Scotland's Workforce in the Scotland 2014–2020 European Structural and Investment Fund Programme. NDM and AF were funded by the Centre for Environment, Fisheries and Aquaculture Science (Cefas). Funding for the seal tagging was provided by the Scottish Government to the Sea Mammal Research Unit (SMRU) as part of the Marine Mammal Scientific Support Program MMSS/002/15, with additional resources from the Natural Environment Research Council (grant numbers NE/J004251/1 and SMRU1001).1. Pinniped depredation at aquaculture sites is a globally recognized problem. To mitigate depredation, the aquaculture sector uses acoustic deterrent devices (ADDs) as a non-lethal alternative to shooting pinnipeds interacting with caged finfish. However, it is unclear whether sound emissions from ADDs have the potential to also impact non-target pinnipeds at spatial scales relevant to populations. 2. Global Positioning System (GPS) tracking data from seven harbour seals tagged in a non-aquaculture context, on the west coast of Scotland, in 2017 were combined with modelled maps of ADD noise to quantify sound exposure and estimate the potential for auditory impairment. The acoustic model applied an energy flux approach across the main frequency range of ADDs (2–40 kHz). Predictions of temporary and permanent auditory threshold shifts were made using seal location data and published noise exposure criteria. The acoustic exposure of waters (10-km buffers) surrounding protected habitats (i.e. designated haul outs and Special Areas of Conservation (SACs)) on the west coast of Scotland was also assessed. 3. All tagged seals and waters surrounding 51 of 56 protected sites were predicted to be exposed to ADD noise exceeding median ambient sound levels. Temporary auditory impairment was predicted to occur in one of the seven tagged harbour seals and across 1.7% of waters surrounding protected habitats over a 24-hour period, when assuming a 100% ADD duty cycle. 4. Although the predicted risk of auditory impairment appears to be relatively low, these findings suggest that harbour seals inhabiting inshore waters off western Scotland are routinely exposed to ADD noise that exceeds median ambient sound levels. This chronic exposure risks negative consequences for individual harbour seals among the wider population in this region. The use of ADDs to mitigate pinniped depredation should be carefully considered to reduce unintended habitat-wide impacts on non-target species, including pinnipeds that are not specifically interacting with aquaculture.Publisher PDFPeer reviewe

Fast stable direct fitting and smoothness selection for Generalized Additive Models

Existing computationally efficient methods for penalized likelihood GAM fitting employ iterative smoothness selection on working linear models (or working mixed models). Such schemes fail to converge for a non-negligible proportion of models, with failure being particularly frequent in the presence of concurvity. If smoothness selection is performed by optimizing `whole model' criteria these problems disappear, but until now attempts to do this have employed finite difference based optimization schemes which are computationally inefficient, and can suffer from false convergence. This paper develops the first computationally efficient method for direct GAM smoothness selection. It is highly stable, but by careful structuring achieves a computational efficiency that leads, in simulations, to lower mean computation times than the schemes based on working-model smoothness selection. The method also offers a reliable way of fitting generalized additive mixed models

The similarity of the effect of carbohydrase or prebiotic supplementation in broilers aged 21 days, fed mixed cereal diets and challenged with coccidiosis infection

The aim of this study was to investigate the effect on growth performance and nutrient utilisation when supplementing diets deficient in energy and protein with carbohydrase enzymes or xylo-oligosaccharide in broilers challenged with coccidia. 960 Ross 308 broilers were used in this 21-day study. The treatments were arranged into a 2×4 factorial with 2 challenge states (challenged and non-challenged) and 4 different additive types (control, xylanase alone, xylanase and β-glucanase mixture and xylo-oligosaccharide). On day 14, the challenged group received 12× the recommended dose of coccidiosis vaccine while the non-challenged group received a sham treatment of water only. The birds and feed were weighed on days 0, 14 and 21. On day 21, two birds per pen were euthanized, the caeca were removed and the contents collected for short chain fatty acid analysis. Six more birds per pen were euthanized and ileal digesta were collected and pooled per pen for nutrient digestibility analysis. Feed intake was greater (P < 0.05) on days 14 and 21 when xylo-oligosaccharide was included in the diet compared to the xylanase and β-glucanase mixture in birds challenged with coccidiosis. Including xylo-oligosaccharide in the diet improved (P < 0.05) the digestibility of nitrogen and supplementing diets with the xylanase and β-glucanase mixture improved (P < 0.05) the digestibility of several amino acids. The concentration of arabinose and xylose was (P < 0.001) greater when broiler diets were supplemented with carbohydrase enzymes or xylo-oligosaccharide compared to the control. Although there was an increase in short chain fatty acid production due to the addition of carbohydrase enzymes or xylo-oligosaccharide, there was no additive effect on the %G+C profile of caecal bacteria however there was a negative effect of coccidiosis. In conclusion, the similarity in the response to carbohydrase enzymes or xylo-oligosaccharide supplementation illustrates that the hydrolysis products from carbohydrase activity may have prebiotic like effects

The effect of carbohydrases or prebiotic oligosaccharides on growth performance, nutrient utilisation and the development of the small intestine and immune organs in broilers fed nutrient-adequate diets based on either wheat or barley

BACKGROUND: Non‐starch polysaccharides are large complex molecules and are found in cereal grains. This study was conducted to investigate the effect of carbohydrase enzymes or prebiotic oligosaccharides on growth performance, nutrient utilisation and weight of organs associated with the immune system in broilers fed wheat‐ or barley‐based diets. RESULTS: In wheat‐based diets, feed intake was lower (P < 0.05) following xylo‐oligosaccharide supplementation, whereas in barley‐based diets feed intake was greater (P < 0.05) following β‐glucanase supplementation. Gross energy digestibility was improved (P < 0.01) when either level of xylanase was added to wheat diets. Ileal digestible energy was greater (P < 0.01) in wheat diets including an additive compared with the control diet. In wheat diets, bursa weight was lower (P < 0.05) following xylo‐oligosaccharide supplementation compared with the control treatment. CONCLUSIONS: The current study showed that supplemented carbohydrases or prebiotic oligosaccharides could alter the development of immune organs or small intestine without any significant effect on growth performance in broilers receiving nutrient‐adequate diets