Development of an economic evaluation of diagnostic strategies: the case of monogenic diabetes.

notes: PMCID: PMC3657677types: Journal ArticleThis is a freely-available open access publication. Please cite the published version which is available via the DOI link in this recordTo describe the development process for defining an appropriate model structure for the economic evaluation of test-treatment strategies for patients with monogenic diabetes (caused by mutations in the GCK, HNF1A or HNF4A genes).Health Innovation Challenge FundWellcome TrustDepartment of Healt

Evidence used in model-based economic evaluations for evaluating pharmacogenetic and pharmacogenomic tests: a systematic review protocol

This is the final version of the article. Available from BMJ Publishing Grou via the DOI in this record.INTRODUCTION: Decision models can be used to conduct economic evaluations of new pharmacogenetic and pharmacogenomic tests to ensure they offer value for money to healthcare systems. These models require a great deal of evidence, yet research suggests the evidence used is diverse and of uncertain quality. By conducting a systematic review, we aim to investigate the test-related evidence used to inform decision models developed for the economic evaluation of genetic tests. METHODS AND ANALYSIS: We will search electronic databases including MEDLINE, EMBASE and NHS EEDs to identify model-based economic evaluations of pharmacogenetic and pharmacogenomic tests. The search will not be limited by language or date. Title and abstract screening will be conducted independently by 2 reviewers, with screening of full texts and data extraction conducted by 1 reviewer, and checked by another. Characteristics of the decision problem, the decision model and the test evidence used to inform the model will be extracted. Specifically, we will identify the reported evidence sources for the test-related evidence used, describe the study design and how the evidence was identified. A checklist developed specifically for decision analytic models will be used to critically appraise the models described in these studies. Variations in the test evidence used in the decision models will be explored across the included studies, and we will identify gaps in the evidence in terms of both quantity and quality. DISSEMINATION: The findings of this work will be disseminated via a peer-reviewed journal publication and at national and international conferences.JLP is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula and CC is funded by an NIHR Health Technology Assessment Grant (RNC-023-09)

Liver Allograft: Its Use in Chronic Active Hepatitis with Macronodular Cirrhosis, Hepatitis B Surface Antigen

A patient suffering from chronic active hepatitis with macronodular cirrhosis, positive for hepatitis B surface antigen (HBsAg), was treated with an orthotopic liver allograft. The HBs antigenemia, as measured with several precipitation tests and by complement fixation, became negative after transplantation and remained so for about 2½ months. During the interval, very low titers of the antigen were detectable by radioimmunoassay. At about three months after transplantation, she had an attack of acute hepatitis, at which time HBsAg became detectable by all tests. She recovered, but progressive liver disease developed during the remaining 1½ years of her life. She died of disseminated nocardiosis and candidiasis with deteriorating hepatic function. The homograft at autopsy showed no evidence of rejection, but was the site of chronic active liver disease, although of a different pathologic pattern than that affecting her native liver. The differences in histology may reflect the influence of chronic immunosuppression on the features of chronic active hepatitis. © 1979, American Medical Association. All rights reserved

Optimal leverage from non-ergodicity

In modern portfolio theory, the balancing of expected returns on investments against uncertainties in those returns is aided by the use of utility functions. The Kelly criterion offers another approach, rooted in information theory, that always implies logarithmic utility. The two approaches seem incompatible, too loosely or too tightly constraining investors' risk preferences, from their respective perspectives. The conflict can be understood on the basis that the multiplicative models used in both approaches are non-ergodic which leads to ensemble-average returns differing from time-average returns in single realizations. The classic treatments, from the very beginning of probability theory, use ensemble-averages, whereas the Kelly-result is obtained by considering time-averages. Maximizing the time-average growth rates for an investment defines an optimal leverage, whereas growth rates derived from ensemble-average returns depend linearly on leverage. The latter measure can thus incentivize investors to maximize leverage, which is detrimental to time-average growth and overall market stability. The Sharpe ratio is insensitive to leverage. Its relation to optimal leverage is discussed. A better understanding of the significance of time-irreversibility and non-ergodicity and the resulting bounds on leverage may help policy makers in reshaping financial risk controls.Comment: 17 pages, 3 figures. Updated figures and extended discussion of ergodicit

Ionised gas kinematics in bipolar H II regions

Stellar feedback plays a fundamental role in shaping the evolution of galaxies. Here we explore the use of ionised gas kinematics in young, bipolar H II regions as a probe of early feedback in these star-forming environments. We have undertaken a multiwavelength study of a young, bipolar H II region in the Galactic disc, G$316.81-0.06$, which lies at the centre of a massive ($\sim10^3$ M$_{\odot}$) infrared-dark cloud filament. It is still accreting molecular gas as well as driving a $\sim 0.2$ pc ionised gas outflow perpendicular to the filament. Intriguingly, we observe a large velocity gradient ($47.81 \pm 3.21$ km s$^{-1}$ pc$^{-1}$) across the ionised gas in a direction perpendicular to the outflow. This kinematic signature of the ionised gas shows a reasonable correspondence with the simulations of young H II regions. Based on a qualitative comparison between our observations and these simulations, we put forward a possible explanation for the velocity gradients observed in G$316.81-0.06$. If the velocity gradient perpendicular to the outflow is caused by rotation of the ionised gas, then we infer that this rotation is a direct result of the initial net angular momentum in the natal molecular cloud. If this explanation is correct, this kinematic signature should be common in other young (bipolar) H II regions. We suggest that further quantitative analysis of the ionised gas kinematics of young H II regions, combined with additional simulations, should improve our understanding of feedback at these early stages

Assessment of regression-based methods to adjust for publication bias through a comprehensive simulation study

<p>Abstract</p> <p>Background</p> <p>In meta-analysis, the presence of funnel plot asymmetry is attributed to publication or other small-study effects, which causes larger effects to be observed in the smaller studies. This issue potentially mean inappropriate conclusions are drawn from a meta-analysis. If meta-analysis is to be used to inform decision-making, a reliable way to adjust pooled estimates for potential funnel plot asymmetry is required.</p> <p>Methods</p> <p>A comprehensive simulation study is presented to assess the performance of different adjustment methods including the novel application of several regression-based methods (which are commonly applied to detect publication bias rather than adjust for it) and the popular Trim & Fill algorithm. Meta-analyses with binary outcomes, analysed on the log odds ratio scale, were simulated by considering scenarios with and without i) publication bias and; ii) heterogeneity. Publication bias was induced through two underlying mechanisms assuming the probability of publication depends on i) the study effect size; or ii) the p-value.</p> <p>Results</p> <p>The performance of all methods tended to worsen as unexplained heterogeneity increased and the number of studies in the meta-analysis decreased. Applying the methods conditional on an initial test for the presence of funnel plot asymmetry generally provided poorer performance than the unconditional use of the adjustment method. Several of the regression based methods consistently outperformed the Trim & Fill estimators.</p> <p>Conclusion</p> <p>Regression-based adjustments for publication bias and other small study effects are easy to conduct and outperformed more established methods over a wide range of simulation scenarios.</p

The role of statins in prevention and treatment of community acquired pneumonia: a systematic review and meta-analysis.

BACKGROUND: Emerging epidemiological evidence suggests that statins may reduce the risk of community-acquired pneumonia (CAP) and its complications. PURPOSE: Performed a systematic review to address the role of statins in the prevention or treatment of CAP. DATA SOURCE: Ovid MEDLINE, Cochrane, EMBASE, ISI Web of Science, and Scopus from inception through December 2011 were searched for randomized clinical trials, cohort and case-control studies. STUDY SELECTION: Two authors independently reviewed studies that examined the role of statins in CAP. DATA EXTRACTION: Data about study characteristics, adjusted effect-estimates and quality characteristics was extracted. DATA SYNTHESIS: Eighteen studies corresponding to 21 effect-estimates (eight and 13 of which addressed the preventive and therapeutic roles of statins, respectively) were included. All studies were of good methodological quality. Random-effects meta-analyses of adjusted effect-estimates were used. Statins were associated with a lower risk of CAP, 0.84 (95% CI, 0.74-0.95), I(2) = 90.5% and a lower short-term mortality in patients with CAP, 0.68 (95% CI, 0.59-0.78), I(2) = 75.7%. Meta-regression did not identify sources of heterogeneity. A funnel plot suggested publication bias in the treatment group, which was adjusted by a novel regression method with a resultant effect-estimate of 0.85 (95% CI, 0.77-0.93). Sensitivity analyses using the rule-out approach showed that it is unlikely that the results were due to an unmeasured confounder. CONCLUSIONS: Our meta-analysis reveals a beneficial role of statins for the risk of development and mortality associated with CAP. However, the results constitute very low quality evidence as per the GRADE framework due to observational study design, heterogeneity and publication bias

Application and investigation of a bound for outcome reporting bias

BACKGROUND: Direct empirical evidence for the existence of outcome reporting bias is accumulating and this source of bias is recognised as a potential threat to the validity of meta-analysis of randomised clinical trials. METHODS: A method for calculating the maximum bias in a meta-analysis due to publication bias is adapted for the setting where within-study selective non-reporting of outcomes is suspected, and compared to the alternative approach of missing data imputation. The properties of both methods are investigated in realistic small sample situations. RESULTS: The results suggest that the adapted Copas and Jackson approach is the preferred method for reviewers to apply as an initial assessment of robustness to within-study selective non-reporting. CONCLUSION: The Copas and Jackson approach is a useful method for systematic reviewers to apply to assess robustness to outcome reporting bias

Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS