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Concept: Nuisance parameter


Background Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. Methods We conducted this trial of two targeted temperature interventions at 38 children’s hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. Results A total of 295 patients underwent randomization. Among the 260 patients with data that could be could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. Conclusions In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH number, NCT00878644 .).

Concepts: Blood, Heart, Cardiac arrest, Asystole, Therapeutic hypothermia, Nuisance parameter, Coma, Drowning


Clinical trials often use paired binomial data as their clinical endpoint. The confidence interval is frequently used to estimate the treatment performance. Tang et al. (2009) have proposed exact and approximate unconditional methods for constructing a confidence interval in the presence of incomplete paired binary data. The approach proposed by Tang et al. can be overly conservative with large expected confidence interval width (ECIW) in some situations. We propose a profile likelihood-based method with a Jeffreys' prior correction to construct the confidence interval. This approach generates confidence interval with a much better coverage probability and shorter ECIWs. The performances of the method along with the corrections are demonstrated through extensive simulation. Finally, three real world data sets are analyzed by all the methods. Statistical Analysis System (SAS) codes to execute the profile likelihood-based methods are also presented. Copyright © 2013 John Wiley & Sons, Ltd.

Concepts: Statistics, Estimator, Probability theory, Confidence interval, Normal distribution, Statistical inference, Nuisance parameter, Binomial proportion confidence interval


Physiologically based pharmacokinetic (PBPK) models provide a framework useful for generating credible human pharmacokinetic predictions from data available at the earliest, preclinical stages of pharmaceutical research. With this approach, the pharmacokinetic implications of in vitro data are contextualized via scaling according to independent physiological information. However, in many cases these models also require model-based estimation of additional empirical scaling factors (SFs) in order to accurately recapitulate known human pharmacokinetic behavior. While this practice clearly improves data characterization, the introduction of empirically derived SFs may belie the extrapolative power commonly attributed to PBPK. This is particularly true when such SFs are compound dependent and/or when there are issues with regard to identifiability. As such, when empirically-derived SFs are necessary, a critical evaluation of parameter estimation and model structure are prudent. In this study, we applied a global optimization method to support model-based estimation of a single set of empirical SFs from intravenous clinical data on seven OATP substrates within the context of a previously published PBPK model as well as a revised PBPK model. The revised model with experimentally measured unbound fraction in liver, permeability between liver compartments, and permeability limited distribution to selected tissues improved data characterization. We utilized large-sample approximation and resampling approaches to estimate confidence intervals for the revised model in support of forward predictions that reflect the derived uncertainty. This work illustrates an objective approach to estimating empirically-derived SFs, systematically refining PBPK model performance and conveying the associated confidence in subsequent forward predictions.

Concepts: Scientific method, Statistics, Estimator, Science, Approximation, Estimation, Statistical inference, Nuisance parameter


The UK is a global leader in stop-smoking support-providing free behavioral support and cessation medication via stop smoking services (SSS) without charge to smokers. This study aimed to explore the client and service characteristics associated with abstinence 52 weeks after quitting. A prospective cohort study of 3057 SSS clients in nine different areas of England who began their quit attempt between March 2012 and March 2013 was conducted. Important determinants of long-term quitting were assessed through quit rates and multivariable logistic regression. Our results showed that the overall weighted carbon monoxide validated quit rate for clients at 52 weeks was 7.7% (95% confidence interval (CI) 6.6-9.0). The clients of advisors, whose main role was providing stop-smoking support, were more likely to quit long-term than advisors who had a generalist role in pharmacies or general practices (odds ratio (OR) 2.3 (95% CI 1.2-4.6)). Clients were more likely to achieve abstinence through group support than one-to-one support (OR 3.4 (95% CI 1.7-6.7)). Overall, one in thirteen people who set a quit date with the National Health Service (NHS) Stop-Smoking Service maintain abstinence for a year. Improving abstinence is likely to require a greater emphasis on providing specialist smoking cessation support. Results from this study suggest that over 18,000 premature deaths were prevented through longer-term smoking cessation achieved by smokers who accessed SSS in England from March 2012 to April 2013, but outcomes varied by client characteristic and the type of support provided.

Concepts: Logit, Relative risk, Smoking, Nicotine, Smoking cessation, Carbon monoxide, National Health Service, Nuisance parameter


Previous studies suggested that early pregnancy exposure to specific oral decongestants increases the risks of several birth defects. Using January 1993-January 2010 data from the Slone Epidemiology Center Birth Defects Study, we tested those hypotheses among 12,734 infants with malformations (cases) and 7,606 nonmalformed control infants in the United States and Canada. Adjusted odds ratios and 95% confidence intervals were estimated for specific birth defects, with controlling for potential confounders. Findings did not replicate several hypotheses but did support 3 previously reported associations: phenylephrine and endocardial cushion defect (odds ratio = 8.0; 95% confidence interval: 2.5, 25.3; 4 exposed cases), phenylpropanolamine and ear defects (odds ratio = 7.8; 95% confidence interval: 2.2, 27.2; 4 exposed cases), and phenylpropanolamine and pyloric stenosis (odds ratio = 3.2; 95% confidence interval: 1.1, 8.8; 6 exposed cases). Hypothesis-generating analyses involving multiple comparisons identified a small number of associations with oral and intranasal decongestants. Accumulating evidence supports associations between first-trimester use of specific oral and possibly intranasal decongestants and the risk of some infrequent specific birth defects.

Concepts: Statistics, Odds ratio, Interval finite element, Confidence interval, Statistical terminology, Odds, Nuisance parameter, Decongestant


Unfavorable work characteristics, such as low job control and too high or too low job demands, have been suggested to increase the likelihood of physical inactivity during leisure time, but this has not been verified in large-scale studies. The authors combined individual-level data from 14 European cohort studies (baseline years from 1985-1988 to 2006-2008) to examine the association between unfavorable work characteristics and leisure-time physical inactivity in a total of 170,162 employees (50% women; mean age, 43.5 years). Of these employees, 56,735 were reexamined after 2-9 years. In cross-sectional analyses, the odds for physical inactivity were 26% higher (odds ratio = 1.26, 95% confidence interval: 1.15, 1.38) for employees with high-strain jobs (low control/high demands) and 21% higher (odds ratio = 1.21, 95% confidence interval: 1.11, 1.31) for those with passive jobs (low control/low demands) compared with employees in low-strain jobs (high control/low demands). In prospective analyses restricted to physically active participants, the odds of becoming physically inactive during follow-up were 21% and 20% higher for those with high-strain (odds ratio = 1.21, 95% confidence interval: 1.11, 1.32) and passive (odds ratio = 1.20, 95% confidence interval: 1.11, 1.30) jobs at baseline. These data suggest that unfavorable work characteristics may have a spillover effect on leisure-time physical activity.

Concepts: Epidemiology, Statistics, Obesity, Overweight, Interval finite element, Effect size, Statistical terminology, Nuisance parameter


Purpose in life has been linked with better health (mental and physical) and health behaviors, but its link with patterns of health care use are understudied. We hypothesized that people with higher purpose would be more proactive in taking care of their health, as indicated by a higher likelihood of using preventive health care services. We also hypothesized that people with higher purpose would spend fewer nights in the hospital. Participants (n = 7,168) were drawn from the Health and Retirement Study, a nationally representative panel study of American adults over the age of 50, and tracked for 6 y. After adjusting for sociodemographic factors, each unit increase in purpose (on a six-point scale) was associated with a higher likelihood that people would obtain a cholesterol test [odds ratio (OR) = 1.18, 95% confidence interval (CI) = 1.08-1.29] or colonoscopy (OR = 1.06, 95% CI = 0.99-1.14). Furthermore, females were more likely to receive a mammogram/X-ray (OR = 1.27, 95% CI = 1.16-1.39) or pap smear (OR = 1.16, 95% CI = 1.06-1.28), and males were more likely to receive a prostate examination (OR = 1.31, 95% CI = 1.18-1.45). Each unit increase in purpose was also associated with 17% fewer nights spent in the hospital (rate ratio = 0.83, 95% CI = 0.77-0.89). An increasing number of randomized controlled trials show that purpose in life can be raised. Therefore, with additional research, findings from this study may inform the development of new strategies that increase the use of preventive health care services, offset the burden of rising health care costs, and enhance the quality of life among people moving into the ranks of our aging society.

Concepts: Health care, Public health, Epidemiology, Clinical trial, Randomized controlled trial, Meaning of life, Gross domestic product, Nuisance parameter


Several studies have been conducted with mixed results since our initial report of increased Parkinson’s disease risk in individuals with red hair and/or red hair-associated p.R151C variant of the MC1R gene, both of which confer high melanoma risk. We performed a meta-analysis of six publications on red hair, MC1R, and Parkinson’s disease. We found that red hair (pooled odds ratios = 1.68, 95% confidence intervals: 1.07, 2.64) and p.R151C (pooled odds ratios = 1.10, 95% confidence intervals: 1.00, 1.21), but not p.R160W, were associated with greater risk for Parkinson’s disease. Our results support potential roles of pigmentation and its key regulator MC1R in the pathogenesis of Parkinson’s disease.

Concepts: Epidemiology, Parkinson's disease, Melanin, Confidence interval, Nuisance parameter, Variant type


Presentation of confidence intervals alongside information about treatment effects can support informed treatment choices in people with multiple sclerosis. We aimed to develop and pilot-test different written patient information materials explaining confidence intervals in people with relapsing-remitting multiple sclerosis. Further, a questionnaire on comprehension of confidence intervals was developed and piloted.

Concepts: Scientific method, Randomized controlled trial, Evaluation methods, Multiple sclerosis, Nuisance parameter, Human Development Index, Development


We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (N=662) or follicular lymphoma grade 3b (N=21) in first complete remission. Patients were randomised for rituximab maintenance (N=338) or observation (N=345). At a median follow-up of 45 months, event-free survival (primary endpoint) at 3 years was 80.4% for rituximab maintenance vs. 76.5% for observation. This difference was not significant for the intent to treat population (Likelihood ratio p=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; p=0.1433). The secondary endpoint progression-free survival was also not met for the whole population (Likelihood ratio p=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (Hazard ratio: 0.62; 95% confidence interval 0.43-0.90; p=0.0120). Overall survival remained unchanged (92.0 vs. 90.3%). In subgroup analysis male patients benefitted from rituximab maintenance regarding event-free survival (84.1% vs. 74.4%) (Hazard ratio: 0.58; 95% confidence interval 0.36-0.94; p=0.0267) and progression-free survival (89.0% vs. 77.6%) (Hazard ratio: 0.45; 95% confidence interval 0.25-0.79; p=0.0058). Women had more grade ¾ adverse events (p=0.0297) and infections (p=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-Non Hodgkin lymphoma. The significantly better outcome of men warrant further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and as #NCT00400478.

Concepts: Types of cancer, Hematology, Lymphoma, Hodgkin's lymphoma, Diffuse large B cell lymphoma, Nuisance parameter, Follicular lymphoma, B-cell lymphoma