Imputation of a true endpoint from a surrogate: application to a cluster randomized controlled trial with partial information on the true endpoint

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background The Anglia Menorrhagia Education Study (AMES) is a randomized controlled trial testing the effectiveness of an education package applied to general practices. Binary data are available from two sources; general practitioner reported referrals to hospital, and referrals to hospital determined by independent audit of the general practices. The former may be regarded as a surrogate for the latter, which is regarded as the true endpoint. Data are only available for the true end point on a sub set of the practices, but there are surrogate data for almost all of the audited practices and for most of the remaining practices. Methods The aim of this paper was to estimate the treatment effect using data from every practice in the study. Where the true endpoint was not available, it was estimated by three approaches, a regression method, multiple imputation and a full likelihood model. Results Including the surrogate data in the analysis yielded an estimate of the treatment effect which was more precise than an estimate gained from using the true end point data alone. Conclusions The full likelihood method provides a new imputation tool at the disposal of trials with surrogate data.Published versio

A Maximum Entropy Method of Obtaining Thermodynamic Properties from Quantum Monte Carlo Simulations

We describe a novel method to obtain thermodynamic properties of quantum systems using Baysian Inference -- Maximum Entropy techniques. The method is applicable to energy values sampled at a discrete set of temperatures from Quantum Monte Carlo Simulations. The internal energy and the specific heat of the system are easily obtained as are errorbars on these quantities. The entropy and the free energy are also obtainable. No assumptions as to the specific functional form of the energy are made. The use of a priori information, such as a sum rule on the entropy, is built into the method. As a non-trivial example of the method, we obtain the specific heat of the three-dimensional Periodic Anderson Model.Comment: 8 pages, 3 figure

Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial.

A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women). D-4F was safe and well-tolerated. Mean ± SD plasma D-4F area under the curve (AUC, 0-8h) was 6.9 ± 5.7 ng/mL*h (100 mg), 22.7 ± 19.6 ng/mL*h (300 mg), and 104.0 ± 60.9 ng/mL*h (500 mg) among men, higher among women. Whereas placebo dropped HDL inflammatory index (HII) 28% 8 h postdose (range, 1.25-0.86), 300-500 mg D-4F effectively halved HII: 1.35-0.57 and 1.22-0.63, respectively (P \u3c 0.03 vs. placebo). Oral D-4F peptide dose predicted HII suppression, whereas plasma D-4F exposure was dissociated, suggesting plasma penetration is unnecessary. In conclusion, oral D-4F dosing rendered HDL less inflammatory, affirming oral D-4F as a potential therapy to improve HDL function

Wideband dual sphere detector of gravitational waves

We present the concept of a sensitive AND broadband resonant mass gravitational wave detector. A massive sphere is suspended inside a second hollow one. Short, high-finesse Fabry-Perot optical cavities read out the differential displacements of the two spheres as their quadrupole modes are excited. At cryogenic temperatures one approaches the Standard Quantum Limit for broadband operation with reasonable choices for the cavity finesses and the intracavity light power. A molybdenum detector of overall size of 2 m, would reach spectral strain sensitivities of 2x10^-23/Sqrt{Hz} between 1000 Hz and 3000 Hz.Comment: 4 pages, 3 figures. Changed content. To appear in Phys. Rev. Let

On the over-concentration problem of strong lensing clusters

Lambda cold dark matter paradigm predicts that galaxy clusters follow an universal mass density profile and fit a well defined mass-concentration relation, with lensing clusters being preferentially triaxial haloes elongated along the line of sight. Oddly, recent strong and weak lensing analyses of clusters with a large Einstein radius suggested those haloes to be highly over-concentrated. Here, we investigate what intrinsic shape and orientation an halo should have to account for both theoretical predictions and observations. We considered a sample of 10 strong lensing clusters. We first measured their elongation assuming a given mass-concentration relation. Then, for each cluster we found the intrinsic shape and orientation which are compatible with the inferred elongation and the measured projected ellipticity. We distinguished two groups. The first one (nearly one half) seems to be composed of outliers of the mass-concentration relation, which they would fit only if they were characterised by a filamentary structure extremely elongated along the line of sight, that is not plausible considering standard scenarios of structure formations. The second sample supports expectations of N-body simulations which prefer mildly triaxial lensing clusters with a strong orientation bias.Comment: 11 pages, 8 figures, in press on MNRA

Coping strategies and self-esteem in the high-risk offspring of bipolar parents.

Objectives: This study investigated whether there were differences in coping strategies and self-esteem between offspring of parents with bipolar disorder (high-risk) and offspring of unaffected parents (control), and whether these psychological factors predicted the onset and recurrence of mood episodes. Methods: High-risk and control offspring were followed longitudinally as part of the Flourish Canadian high-risk bipolar offspring cohort study. Offspring were clinically assessed annually by a psychiatrist using semi-structured interviews and completed a measure of coping strategies and self-esteem. Results: In high-risk offspring, avoidant coping strategies significantly increased the hazard of a new onset Diagnostic and Statistical Manual of Mental Disorders, 4th Edition twice revised mood episode or recurrence (hazard ratio: 1.89, p = 0.04), while higher self-esteem significantly decreased this hazard (hazard ratio: 2.50, p < 0.01). Self-esteem and avoidant coping significantly interacted with one another (p < 0.05), where the risk of a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition twice revised new onset mood episode or recurrence was only significantly increased among high-risk offspring with both high avoidant coping and low self-esteem. Conclusion: A reduction of avoidant coping strategies in response to stress and improvement of self-esteem may be useful intervention targets for preventing the new onset or recurrence of a clinically significant mood disorder among individuals at high familial risk

Comparison of an X-ray selected sample of massive lensing clusters with the MareNostrum Universe LCDM simulation

A long-standing problem of strong lensing by galaxy clusters regards the observed high rate of giant gravitational arcs as compared to the predictions in the framework of the "standard" cosmological model. Recently, few other inconsistencies between theoretical expectations and observations have been claimed which regard the large size of the Einstein rings and the high concentrations of few clusters with strong lensing features. All of these problems consistently indicate that observed galaxy clusters may be gravitational lenses stronger than expected. We use clusters extracted from the MareNostrum Universe to build up mock catalogs of galaxy clusters selected through their X-ray flux. We use these objects to estimate the probability distributions of lensing cross sections, Einstein rings, and concentrations for the sample of 12 MACS clusters at $z>0.5$ presented in Ebeling et al. (2007) and discussed in Zitrin et al. (2010). We find that simulated clusters produce $\sim 50$ less arcs than observed clusters do. The medians of the distributions of the Einstein ring sizes differ by $\sim 25$ between simulations and observations. We estimate that, due to cluster triaxiality and orientation biases affecting the lenses with the largest cross sections, the concentrations of the individual MACS clusters inferred from the lensing analysis should be up to a factor of $\sim 2$ larger than expected from the $\Lambda$CDM model. The arc statistics, the Einstein ring, and the concentration problems in strong lensing clusters are mitigated but not solved on the basis of our analysis. Nevertheless, due to the lack of redshifts for most of the multiple image systems used for modeling the MACS clusters, the results of this work will need to be verified with additional data. The upcoming CLASH program will provide an ideal sample for extending our comparison (abridged).Comment: 11 pages, 9 figures, accepted for publication on A&

Pairing, Charge, and Spin Correlations in the Three-Band Hubbard Model

Using the Constrained Path Monte Carlo (CPMC) method, we simulated the two-dimensional, three-band Hubbard model to study pairing, charge, and spin correlations as a function of electron and hole doping and the Coulomb repulsion $V_{pd}$ between charges on neighboring Cu and O lattice sites. As a function of distance, both the $d_{x^2 - y^2}$-wave and extended s-wave pairing correlations decayed quickly. In the charge-transfer regime, increasing $V_{pd}$ decreased the long-range part of the correlation functions in both channels, while in the mixed-valent regime, it increased the long-range part of the s-wave behavior but decreased that of the d-wave behavior. Still the d-wave behavior dominated. At a given doping, increasing $V_{pd}$ increased the spin-spin correlations in the charge-transfer regime but decreased them in the mixed-valent regime. Also increasing $V_{pd}$ suppressed the charge-charge correlations between neighboring Cu and O sites. Electron and hole doping away from half-filling was accompanied by a rapid suppression of anti-ferromagnetic correlations.Comment: Revtex, 8 pages with 15 figure

A systematic variation of the stellar initial mass function in early-type galaxies

Much of our knowledge of galaxies comes from analysing the radiation emitted by their stars. It depends on the stellar initial mass function (IMF) describing the distribution of stellar masses when the population formed. Consequently knowledge of the IMF is critical to virtually every aspect of galaxy evolution. More than half a century after the first IMF determination, no consensus has emerged on whether it is universal in different galaxies. Previous studies indicated that the IMF and the dark matter fraction in galaxy centres cannot be both universal, but they could not break the degeneracy between the two effects. Only recently indications were found that massive elliptical galaxies may not have the same IMF as our Milky Way. Here we report unambiguous evidence for a strong systematic variation of the IMF in early-type galaxies as a function of their stellar mass-to-light ratio, producing differences up to a factor of three in mass. This was inferred from detailed dynamical models of the two-dimensional stellar kinematics for the large Atlas3D representative sample of nearby early-type galaxies spanning two orders of magnitude in stellar mass. Our finding indicates that the IMF depends intimately on a galaxy's formation history.Comment: 4 pages, 2 figures, LaTeX. Accepted for publication as a Nature Letter. More information about our Atlas3D project is available at http://purl.org/atlas3

Multicomponent analysis of the tumour microenvironment reveals low CD8 T cell number, low stromal caveolin-1 and high tenascin-C and their combination as significant prognostic markers in non-small cell lung cancer

The complex interplay of the tumour microenvironment (TME) and its role in disease progression and response to therapy is poorly understood. The majority of studies to date focus on individual components or molecules within the TME and so lack the power correlative analysis. Here we have performed a multi-parameter analysis of the TME in 62 resectable non-small cell lung cancer (NSCLC) specimens detailing number and location of immune infiltrate, assessing markers of cancer-associated fibroblasts, caveolin-1 and tenascin-C, and correlating with clinicopathological details, as well as markers of disease progression such as epithelial-to-mesenchymal transition (EMT). The influence of individual parameters on overall survival was determined in univariate and multivariate analysis and the combination of risk factors and interplay between components analysed. Low numbers of CD8 T cells, low stromal levels of caveolin-1 or high levels of tenascin-C were significant prognostic markers of decreased overall survival in both univariate and multivariate analysis. Patients with two or more risk factors had dramatically reduced overall survival and those with all three a median survival of just 7.5 months. In addition, low levels of tumour E-cadherin correlated with reduced immune infiltrate into the tumour nests, possibly linking EMT to the avoidance of CD8 T cell control. The multicomponent approach has allowed identification of the dominant influences on overall survival, and exploration of the interplay between different components of the TME in NSCLC