Power calculations using exact data simulation: A useful tool for genetic study designs.

Statistical power calculations constitute an essential first step in the planning of scientific studies. If sufficient summary statistics are available, power calculations are in principle straightforward and computationally light. In designs, which comprise distinct groups (e.g., MZ & DZ twins), sufficient statistics can be calculated within each group, and analyzed in a multi-group model. However, when the number of possible groups is prohibitively large (say, in the hundreds), power calculations on the basis of the summary statistics become impractical. In that case, researchers may resort to Monte Carlo based power studies, which involve the simulation of hundreds or thousands of replicate samples for each specified set of population parameters. Here we present exact data simulation as a third method of power calculation. Exact data simulation involves a transformation of raw data so that the data fit the hypothesized model exactly. As in power calculation with summary statistics, exact data simulation is computationally light, while the number of groups in the analysis has little bearing on the practicality of the method. The method is applied to three genetic designs for illustrative purposes

Smoking and health-related quality of life in English general population: Implications for economic evaluations

Copyright @ 2012 Vogl et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.Background: Little is known as to how health-related quality of life (HRQoL) when measured by generic instruments such as EQ-5D differ across smokers, ex-smokers and never-smokers in the general population; whether the overall pattern of this difference remain consistent in each domain of HRQoL; and what implications this variation, if any, would have for economic evaluations of tobacco control interventions. Methods: Using the 2006 round of Health Survey for England data (n = 13,241), this paper aims to examine the impact of smoking status on health-related quality of life in English population. Depending upon the nature of the EQ-5D data (i.e. tariff or domains), linear or logistic regression models were fitted to control for biology, clinical conditions, socio-economic background and lifestyle factors that an individual may have regardless of their smoking status. Age- and gender-specific predicted values according to smoking status are offered as the potential 'utility' values to be used in future economic evaluation models. Results: The observed difference of 0.1100 in EQ-5D scores between never-smokers (0.8839) and heavy-smokers (0.7739) reduced to 0.0516 after adjusting for biological, clinical, lifestyle and socioeconomic conditions. Heavy-smokers, when compared with never-smokers, were significantly more likely to report some/severe problems in all five domains - mobility (67%), self-care (70%), usual activity (42%), pain/discomfort (46%) and anxiety/depression (86%) -. 'Utility' values by age and gender for each category of smoking are provided to be used in the future economic evaluations. Conclusion: Smoking is significantly and negatively associated with health-related quality of life in English general population and the magnitude of this association is determined by the number of cigarettes smoked. The varying degree of this association, captured through instruments such as EQ-5D, may need to be fed into the design of future economic evaluations where the intervention being evaluated affects (e.g. tobacco control) or is affected (e.g. treatment for lung cancer) by individual's (or patients') smoking status

Simvastatin for patients with Acute Respiratory Distress Syndrome: long term outcomes and cost-effectiveness from a randomised controlled trial

Background: Simvastatin therapy for patients with ARDS has been shown to be safe and associated with minimal adverse effects, but it does not improve clinical outcomes. The aim of this research was to report on mortality and cost-effectiveness of simvastatin in patients with ARDS at 12 months. Methods: A cost-utility analysis alongside a multicentre, double-blind, randomised controlled trial carried out in the UK and Ireland. Five hundred and forty intubated and mechanically ventilated patients with acute respiratory distress syndrome were randomly assigned (1:1) to receive once-daily simvastatin (at a dose of 80 mg) or identical placebo tablets enterally for up to 28 days. Results: Mortality was lower in the simvastatin group (31.8%; 95% CI 26.1, 37.5) compared to the placebo group (37.3%; 95% CI 31.6, 43.0) at 12 months although this was not significant. Simvastatin was associated with statistically significant QALY gain (incremental QALYs 0.064, 95% CI 0.002, 0.127) compared to placebo. Simvastatin was also less costly (incremental total costs –£3601, 95% CI –8061, 859). At a willingness-to-pay threshold of £20,000 per QALY the probability of simvastatin being cost-effective was 99%. Sensitivity analyses indicated that the results were robust to changes in methodological assumptions with the probability of cost-effectiveness never dropping below 90%. Conclusion: Simvastatin was found to be cost-effective for the treatment of ARDS, being associated with both a significant QALY gain and a cost saving. There was no significant reduction in mortality at 12 months

A study to explore if dentists’ anxiety affects their clinical decision-making

Aims To develop a measure of dentists’ anxiety in clinical situations; to establish if dentists’ anxiety in clinical situations affected their self-reported clinical decision-making; to establish if occupational stress, as demonstrated by burnout, is associated with anxiety in clinical situations and clinical decision-making; and to explore the relationship between decision-making style and the clinical decisions which are influenced by anxiety. Design Cross-sectional study. Setting Primary Dental Care. Subjects and methods A questionnaire battery [Maslach Burnout Inventory, measuring burnout; Melbourne Decision Making Questionnaire, measuring decision-making style; Dealing with Uncertainty Questionnaire (DUQ), measuring coping with diagnostic uncertainty; and a newly designed Dentists’ Anxieties in Clinical Situations Scale, measuring dentists’ anxiety (DACSS-R) and change of treatment (DACSS-C)] was distributed to dentists practicing in Nottinghamshire and Lincolnshire. Demographic data were collected and dentists gave examples of anxiety-provoking situations and their responses to them. Main outcome measure Respondents’ self-reported anxiety in various clinical situations on a 11-point Likert Scale (DACSS-R) and self-reported changes in clinical procedures (Yes/No; DACSS-C). The DACSS was validated using multiple t-tests and a principal component analysis. Differences in DACSS-R ratings and burnout, decision-making and dealing with uncertainty were explored using Pearson correlations and multiple regression analysis. Qualitative data was subject to a thematic analysis. Results The DACSS-R revealed a four-factor structure and had high internal reliability (Cronbach’s α = 0.94). Those with higher DACSS-R scores of anxiety were more likely to report changes in clinical procedures (DACSS-C scores). DACSS-R scores were associated with decision-making self-esteem and style as measured by the MDMQ and all burnout subscales, though not with scores on the DUQ scale. Conclusion Dentists’ anxiety in clinical situations does affect the way that dentists work clinically, as assessed using the newly designed and validated DACSS. This anxiety is associated with measures of burnout and decision-making style with implications for training packages for dentists

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Stochastic Bundle Adjustment for Efficient and Scalable 3D Reconstruction

Current bundle adjustment solvers such as the Levenberg-Marquardt (LM) algorithm are limited by the bottleneck in solving the Reduced Camera System (RCS) whose dimension is proportional to the camera number. When the problem is scaled up, this step is neither efficient in computation nor manageable for a single compute node. In this work, we propose a stochastic bundle adjustment algorithm which seeks to decompose the RCS approximately inside the LM iterations to improve the efficiency and scalability. It first reformulates the quadratic programming problem of an LM iteration based on the clustering of the visibility graph by introducing the equality constraints across clusters. Then, we propose to relax it into a chance constrained problem and solve it through sampled convex program. The relaxation is intended to eliminate the interdependence between clusters embodied by the constraints, so that a large RCS can be decomposed into independent linear sub-problems. Numerical experiments on unordered Internet image sets and sequential SLAM image sets, as well as distributed experiments on large-scale datasets, have demonstrated the high efficiency and scalability of the proposed approach. Codes are released at https://github.com/zlthinker/STBA.Comment: Accepted by ECCV 202

Unitarity and the Holographic S-Matrix

The bulk S-Matrix can be given a non-perturbative definition in terms of the flat space limit of AdS/CFT. We show that the unitarity of the S-Matrix, ie the optical theorem, can be derived by studying the behavior of the OPE and the conformal block decomposition in the flat space limit. When applied to perturbation theory in AdS, this gives a holographic derivation of the cutting rules for Feynman diagrams. To demonstrate these facts we introduce some new techniques for the analysis of conformal field theories. Chief among these is a method for conglomerating local primary operators to extract the contribution of an individual primary in their OPE. This provides a method for isolating the contribution of specific conformal blocks which we use to prove an important relation between certain conformal block coefficients and anomalous dimensions. These techniques make essential use of the simplifications that occur when CFT correlators are expressed in terms of a Mellin amplitude.Comment: 33+12 pages, 6 figures; v2: typos corrected, some clarifications adde

Influence of O6-benzylguanine on the anti-tumour activity and normal tissue toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea and molecular combinations of 5-fluorouracil and 2-chloroethyl-1-nitrosourea in mice

Previous studies have demonstrated that novel molecular combinations of 5-fluorouracil (5FU) and 2-chloroethyl-1-nitrosourea (CNU) have good preclinical activity and may exert less myelotoxicity than the clinically used nitrosoureas such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This study examined the effect of O6-alkylguanine-DNA-alkyltransferase (ATase) depletion by the pseudosubstrate O6-benzylguanine (BG) on the anti-tumour activity and normal tissue toxicity in mice of three such molecular combinations, in comparison with BCNU. When used as single agents at their maximum tolerated dose, all three novel compounds produced a significant growth retardation of BCNU-resistant murine colon and human breast xenografts. This in vivo anti-tumour effect was potentiated by BG, but was accompanied by severe myelotoxicity as judged by spleen colony forming assays. However, while tumour resistance to BCNU was overcome using BG, this was at the expense of enhanced bone marrow, gut and liver toxicity. Therefore, although this ATase-depletion approach resulted in improved anti-tumour activity for all three 5-FU:CNU molecular combinations, the potentiated toxicities in already dose-limiting tissues indicate that these types of agents offer no therapeutic advantage over BCNU when they are used together with BG. © 1999 Cancer Research Campaig

Analyticity and the Holographic S-Matrix

We derive a simple relation between the Mellin amplitude for AdS/CFT correlation functions and the bulk S-Matrix in the flat spacetime limit, proving a conjecture of Penedones. As a consequence of the Operator Product Expansion, the Mellin amplitude for any unitary CFT must be a meromorphic function with simple poles on the real axis. This provides a powerful and suggestive handle on the locality vis-a-vis analyticity properties of the S-Matrix. We begin to explore analyticity by showing how the familiar poles and branch cuts of scattering amplitudes arise from the holographic description. For this purpose we compute examples of Mellin amplitudes corresponding to 1-loop and 2-loop Witten diagrams in AdS. We also examine the flat spacetime limit of conformal blocks, implicitly relating the S-Matrix program to the Bootstrap program for CFTs. We use this connection to show how the existence of small black holes in AdS leads to a universal prediction for the conformal block decomposition of the dual CFT.Comment: 28+15 pages, 7 figures; v2: typos correcte

A phase I study of extended dosing with lomeguatrib with temozolomide in patients with advanced melanoma

Lomeguatrib, an O6-methylguanine-DNA methyltransferase inactivator, was evaluated in an extended dosing regimen with temozolomide, designed according to pharmacodynamic data from previous studies. Patients with unresectable stage 3 or 4 cutaneous or unknown primary melanoma metastases were treated with lomeguatrib 40 mg, b.i.d. for 10 or 14 days and temozolomide 75–100 mg m−2 on days 1–5. Drugs were administered orally with cycles repeated every 28 days, for up to six cycles. A total of 32 patients were recruited to the study. Lomeguatrib for 10 days with temozolomide 75 mg m−2 was established as the optimal extended lomeguatrib dosing schedule, with haematological toxicity being dose limiting. There were two partial responses to treatment giving an overall response rate of 6.25%. Extending lomeguatrib administration beyond that of temozolomide requires a reduced dose of the latter agent. Only limited clinical activity was seen, suggesting no advantage for this regimen over conventional temozolomide administration in the treatment of melanoma