Survival extrapolation in the presence of cause specific hazards.

Health economic evaluations require estimates of expected survival from patients receiving different interventions, often over a lifetime. However, data on the patients of interest are typically only available for a much shorter follow-up time, from randomised trials or cohorts. Previous work showed how to use general population mortality to improve extrapolations of the short-term data, assuming a constant additive or multiplicative effect on the hazards for all-cause mortality for study patients relative to the general population. A more plausible assumption may be a constant effect on the hazard for the specific cause of death targeted by the treatments. To address this problem, we use independent parametric survival models for cause-specific mortality among the general population. Because causes of death are unobserved for the patients of interest, a polyhazard model is used to express their all-cause mortality as a sum of latent cause-specific hazards. Assuming proportional cause-specific hazards between the general and study populations then allows us to extrapolate mortality of the patients of interest to the long term. A Bayesian framework is used to jointly model all sources of data. By simulation, we show that ignoring cause-specific hazards leads to biased estimates of mean survival when the proportion of deaths due to the cause of interest changes through time. The methods are applied to an evaluation of implantable cardioverter defibrillators for the prevention of sudden cardiac death among patients with cardiac arrhythmia. After accounting for cause-specific mortality, substantial differences are seen in estimates of life years gained from implantable cardioverter defibrillators

Racial/Ethnic Differences in Bone Mineral Density of Young Adults

An estimated 1.5 million people suffer a bone disease-related fracture every year. Most work investigating bone mineral density (BMD) focuses on post-menopausal females but a report from the Surgeon General in 2004 stated that of particular concern are men, racial and ethnic minorities, poor individuals, individuals with disabilities, and individuals living in rural areas. The purpose of this study was to examine the racial/ethnic differences in bone mineral density of young adults and to investigate any correlations with variables suggested to influence BMD. BMD was assessed at a younger age than most studies based on the assumption that osteoporosis is a pediatric disorder that manifests in old age. Whole-body BMD, percent body fat (BF), fat mass (FM), and lean mass (LM) of 103 college-aged Blacks, Whites, and Hispanics (18 – 34 years of age) were measured using a Lunar Prodigy Dual Energy X-ray Absorptiometry (DEXA). Blacks and Whites were taller than Hispanics. Blacks had higher BMD than Whites and Hispanics. Blacks and Whites had higher t-scores than Hispanics. Weight and LM correlated with BMD for all three groups. Height correlated with BMD for Blacks only. FM correlated with BMD for Hispanics only. In conclusion, BMD is suggested to be higher in Blacks than Whites and Hispanics. LM is suggested to be an important component of bone health. It is important to stress resistance training for building and maintaining bone health throughout life

Calibration of complex models through Bayesian evidence synthesis: a demonstration and tutorial.

Decision-analytic models must often be informed using data that are only indirectly related to the main model parameters. The authors outline how to implement a Bayesian synthesis of diverse sources of evidence to calibrate the parameters of a complex model. A graphical model is built to represent how observed data are generated from statistical models with unknown parameters and how those parameters are related to quantities of interest for decision making. This forms the basis of an algorithm to estimate a posterior probability distribution, which represents the updated state of evidence for all unknowns given all data and prior beliefs. This process calibrates the quantities of interest against data and, at the same time, propagates all parameter uncertainties to the results used for decision making. To illustrate these methods, the authors demonstrate how a previously developed Markov model for the progression of human papillomavirus (HPV-16) infection was rebuilt in a Bayesian framework. Transition probabilities between states of disease severity are inferred indirectly from cross-sectional observations of prevalence of HPV-16 and HPV-16-related disease by age, cervical cancer incidence, and other published information. Previously, a discrete collection of plausible scenarios was identified but with no further indication of which of these are more plausible. Instead, the authors derive a Bayesian posterior distribution, in which scenarios are implicitly weighted according to how well they are supported by the data. In particular, we emphasize the appropriate choice of prior distributions and checking and comparison of fitted models

Cost-effectiveness of initial stress cardiovascular MR, stress SPECT or stress echocardiography as a gate-keeper test, compared with upfront invasive coronary angiography in the investigation and management of patients with stable chest pain: Mid-term outcomes from the CECaT randomised controlled trial

Objectives: To compare outcomes and cost-effectiveness of various initial imaging strategies in the management of stable chest pain in a long-term prospective randomised trial. Setting: Regional cardiothoracic referral centre in the east of England. Participants: 898 patients (69% man) entered the study with 869 alive at 2 years of follow-up. Patients were included if they presented for assessment of stable chest pain with a positive exercise test and no prior history of ischaemic heart disease. Exclusion criteria were recent infarction, unstable symptoms or any contraindication to stress MRI. Primary outcome measures: The primary outcomes of this follow-up study were survival up to a minimum of 2 years post-treatment, quality-adjusted survival and cost-utility of each strategy. Results: 898 patients were randomised. Compared with angiography, mortality was marginally higher in the groups randomised to cardiac MR (HR 2.6, 95% CI 1.1 to 6.2), but similar in the single photon emission CT-methoxyisobutylisonitrile (SPECT-MIBI; HR 1.0, 95% CI 0.4 to 2.9) and ECHO groups (HR 1.6, 95% CI 0.6 to 4.0). Although SPECT-MIBI was marginally superior to other non-invasive tests there were no other significant differences between the groups in mortality, quality-adjusted survival or costs. Conclusions: Non-invasive cardiac imaging can be used safely as the initial diagnostic test to diagnose coronary artery disease without adverse effects on patient outcomes or increased costs, relative to angiography. These results should be interpreted in the context of recent advances in imaging technology. Trial registration: ISRCTN 47108462, UKCRN 3696

Data Management Plans: Stages, Components, and Activities

Data management strategies have become increasingly important as new computer technologies allow for larger and more complex data sets to be analyzed easily. As a consequence, data management has become a specialty requiring specific skills and knowledge. Many new investigators have no formal training in management of data sets. This paper describes common basic strategies critical to the management of data as applied to a data set from a longitudinal study. The stages of data management are identified. Moreover, key components and strategies, at each stage are described

Patterns of Risk of Depressive Symptoms Among HIV-Positive Women in the Southeastern United States

Depressive symptoms are a common response to HIV disease, and women appear to be at particularly high risk. The authors report results from a crosssectional analysis of data collected from 280 rural women with HIV/AIDS in the Southeastern United States aimed at identifying risk factors of depressive symptoms. Stress theory provided a framework for identification of potential risk factors. Descriptive statistics, measures of association, and regression analyses were used to systematically identify patterns of risk. The final regression model included 22 factors that accounted for 69% of the variance in depressive symptoms. The majority of variance in depressive symptoms was accounted for by only six variables: the frequency of HIV symptoms, recent experiences of sadness/hopelessness, the availability of social support, and the use of three coping strategies: living positively with HIV, isolation/withdrawal, and denial/avoidance. The results suggest a number of intervention strategies for use with rural women with HIV/AIDS

High-resolution temporal profiling of transcripts during Arabidopsis leaf senescence reveals a distinct chronology of processes and regulation

Leaf senescence is an essential developmental process that impacts dramatically on crop yields and involves altered regulation of thousands of genes and many metabolic and signaling pathways, resulting in major changes in the leaf. The regulation of senescence is complex, and although senescence regulatory genes have been characterized, there is little information on how these function in the global control of the process. We used microarray analysis to obtain a highresolution time-course profile of gene expression during development of a single leaf over a 3-week period to senescence. A complex experimental design approach and a combination of methods were used to extract high-quality replicated data and to identify differentially expressed genes. The multiple time points enable the use of highly informative clustering to reveal distinct time points at which signaling and metabolic pathways change. Analysis of motif enrichment, as well as comparison of transcription factor (TF) families showing altered expression over the time course, identify clear groups of TFs active at different stages of leaf development and senescence. These data enable connection of metabolic processes, signaling pathways, and specific TF activity, which will underpin the development of network models to elucidate the process of senescence

Theoretical Study of Cubic Structures Based on Fullerene Carbon Clusters: C28_{28}C and (C28)2_{28})_{2}

We study a new hypothetical form of solid carbon \csc, with a unit cell which is composed of the \cs \ fullerene cluster and an additional single carbon atom arranged in the zincblende structure. Using {\it ab initio} calculations, we show that this new form of solid carbon has lower energy than hyperdiamond, the recently proposed form composed of \cs \ units in the diamond structure. To understand the bonding character of of these cluster-based solids, we analyze the electronic structure of \csc \ and of hyperdiamond and compare them to the electronic states of crystalline cubic diamond.Comment: 15 pages, latex, no figure