Cluster randomized trials: Another problem for cost-effectiveness ratios

Objectives: This work has investigated under what conditions cost-effectiveness data from a cluster randomized trial (CRT) are suitable for analysis using a cluster-adjusted nonparametric bootstrap. The bootstrap's main advantages are in dealing with skewed data and its ability to take correlations between costs and effects into account. However, there are known theoretical problems with a commonly used cluster bootstrap procedure, and the practical implications of these require investigation. Methods: Simulations were used to estimate the coverage of confidence intervals around incremental cost-effectiveness ratios from CRTs using two bootstrap methods. Results: The bootstrap gave excessively narrow confidence intervals, but there was evidence to suggest that, when the number of clusters per treatment arm exceeded 24, it might give acceptable results. The method that resampled individuals as well as clusters did not perform well when cost and effectiveness data were correlated. Conclusions: If economic data from such trials are to be analyzed adequately, then there is a need for further investigations of more complex bootstrap procedures. Similarly, further research is required on methods such as the net benefit approach. Copyright © 2005 Cambridge University Press

Design, analysis and presentation of factorial randomised controlled trials

BackgroundThe evaluation of more than one intervention in the same randomised controlled trial can be achieved using a parallel group design. However this requires increased sample size and can be inefficient, especially if there is also interest in considering combinations of the interventions. An alternative may be a factorial trial, where for two interventions participants are allocated to receive neither intervention, one or the other, or both. Factorial trials require special considerations, however, particularly at the design and analysis stages.DiscussionUsing a 2 × 2 factorial trial as an example, we present a number of issues that should be considered when planning a factorial trial. The main design issue is that of sample size. Factorial trials are most often powered to detect the main effects of interventions, since adequate power to detect plausible interactions requires greatly increased sample sizes. The main analytical issues relate to the investigation of main effects and the interaction between the interventions in appropriate regression models. Presentation of results should reflect the analytical strategy with an emphasis on the principal research questions. We also give an example of how baseline and follow-up data should be presented. Lastly, we discuss the implications of the design, analytical and presentational issues covered.SummaryDifficulties in interpreting the results of factorial trials if an influential interaction is observed is the cost of the potential for efficient, simultaneous consideration of two or more interventions. Factorial trials can in principle be designed to have adequate power to detect realistic interactions, and in any case they are the only design that allows such effects to be investigated

Contributions of anterior cingulate cortex and basolateral amygdala to decision confidence and learning under uncertainty.

The subjective sense of certainty, or confidence, in ambiguous sensory cues can alter the interpretation of reward feedback and facilitate learning. We trained rats to report the orientation of ambiguous visual stimuli according to a spatial stimulus-response rule that must be learned. Following choice, rats could wait a self-timed delay for reward or initiate a new trial. Waiting times increase with discrimination accuracy, demonstrating that this measure can be used as a proxy for confidence. Chemogenetic silencing of BLA shortens waiting times overall whereas ACC inhibition renders waiting times insensitive to confidence-modulating attributes of visual stimuli, suggesting contribution of ACC but not BLA to confidence computations. Subsequent reversal learning is enhanced by confidence. Both ACC and BLA inhibition block this enhancement but via differential adjustments in learning strategies and consistent use of learned rules. Altogether, we demonstrate dissociable roles for ACC and BLA in transmitting confidence and learning under uncertainty

Clinical features of colorectal cancer before diagnosis: a population-based case-control study

This is the final version of the article. Available from the publisher via the DOI in this record.Most colorectal cancers are diagnosed after the onset of symptoms. However, the risk of colorectal cancer posed by particular symptoms is largely unknown, especially in unselected populations like primary care. This was a population-based case-control study in all 21 general practices in Exeter, Devon, UK, aiming to identify and quantify the prediagnostic features of colorectal cancer. In total, 349 patients with colorectal cancer, aged 40 years or more, and 1744 controls, matched by age, sex and general practice, were studied. The full medical record for 2 years before diagnosis was coded using the International Classification of Primary Care-2. We calculated odds ratios for variables independently associated with cancer, using multivariable conditional logistic regressions, and then calculated the positive predictive values of these variables, both individually and in combination. In total, 10 features were associated with colorectal cancer before diagnosis. The positive predictive values (95% confidence interval) of these were rectal bleeding 2.4% (1.9, 3.2); weight loss 1.2% (0.91, 1.6); abdominal pain 1.1% (0.86, 1.3); diarrhoea 0.94% (0.73, 1.1); constipation 0.42% (0.34, 0.52); abnormal rectal examination 4.0% (2.4, 7.4); abdominal tenderness 1.1% (0.77, 1.5); haemoglobin 10 mmol l(-1) 0.78% (0.51, 1.1): all P < 0.001. Earlier diagnosis of colorectal cancer may be possible using the predictive values for single or multiple symptoms, physical signs or test results.Project funding from the Department of Health. The funding source had no role in study design, data collection, analysis or writing of the report. All authors had full access to all data, and take final responsibility for publication. WH was funded through his research practice (Barnfield Hill, Exeter) and RCGP/BUPA and NHS Fellowships. The views expressed in the publication are those of the authors and not necessarily those of the Department of Health. We wish to thank all 21 general practices in Exeter, the Dendrite personnel, and the Patients and Practitioners Service Authority, without which this project would not have been successful

Risk of ovarian cancer in women with symptoms in primary care: population based case-control study.

addresses: NIHR School for Primary Care Research, Department of Community Based Medicine, University of Bristol, Bristol BS8 2AA, UK. [email protected]: PMCID: PMC2731836types: Journal Article; Multicenter Study; Research Support, Non-U.S. Gov'tCopyright © 2009 by the BMJ Publishing Group Ltd. This articles was first published in: BMJ, 2009, Vol. 339, pp. b2998 -To identify and quantify symptoms of ovarian cancer in women in primary care