Advantages of Bayesian monitoring methods in deciding whether and when to stop a clinical trial: an example of a neonatal cooling trial.

BackgroundDecisions to stop randomized trials are often based on traditional P value thresholds and are often unconvincing to clinicians. To familiarize clinical investigators with the application and advantages of Bayesian monitoring methods, we illustrate the steps of Bayesian interim analysis using a recent major trial that was stopped based on frequentist analysis of safety and futility.MethodsWe conducted Bayesian reanalysis of a factorial trial in newborn infants with hypoxic-ischemic encephalopathy that was designed to investigate whether outcomes would be improved by deeper (32 °C) or longer cooling (120 h), as compared with those achieved by standard whole body cooling (33.5 °C for 72 h). Using prior trial data, we developed neutral and enthusiastic prior probabilities for the effect on predischarge mortality, defined stopping guidelines for a clinically meaningful effect, and derived posterior probabilities for predischarge mortality.ResultsBayesian relative risk estimates for predischarge mortality were closer to 1.0 than were frequentist estimates. Posterior probabilities suggested increased predischarge mortality (relative risk > 1.0) for the three intervention groups; two crossed the Bayesian futility threshold.ConclusionsBayesian analysis incorporating previous trial results and different pre-existing opinions can help interpret accruing data and facilitate informed stopping decisions that are likely to be meaningful and convincing to clinicians, meta-analysts, and guideline developers.Trial registrationClinicalTrials.gov NCT01192776 . Registered on 31 August 2010

The Rise of Massive Red Galaxies: the color-magnitude and color-stellar mass diagrams for z < ~2 from the MUltiwavelength Survey by Yale-Chile (MUSYC)

We present the color-magnitude and color-stellar mass diagrams for galaxies with z_phot < ~2, based on a K < 22 (AB) catalog of the Extended Chandra Deep Field South (ECDFS) from the MUltiwavelength Survey by Yale-Chile (MUSYC). Our main sample of 7840 galaxies contains 1297 M_* > 10^11 M_Sol galaxies in the range 0.2 < z_phot < 1.8. We show empirically that this catalog is approximately complete for M_* > 10^11 M_Sol galaxies for z_phot < 1.8. For this mass-limited sample, we show that the locus of the red sequence color-stellar mass relation evolves as Del(u-r) ~ (-0.44+/-0.02) z_phot for z_phot ~1.3, however, we are no longer able to reliably distinguish red and blue subpopulations from the observed color distribution; we show that this would require much deeper near infrared data. At 1.5 < z_phot 10^11 M_Sol galaxies is ~50% of the local value, with a red fraction of ~33%. Making a parametric fit to the observed evolution, we find n_tot(z) ~ (1+z_phot)^(-0.52+/-0.12(+/-0.20)). We find stronger evolution in the red fraction: f_red(z) ~ (1+z_phot)^(-1.17+/-0.18(+/-0.21)). Through a series of sensitivity analyses, we show that the most important sources of systematic error are: 1. systematic differences in the analysis of the z~0 and z>>0 samples; 2. systematic effects associated with details of the photometric redshift calculation; and 3. uncertainties in the photometric calibration. With this in mind, we show that our results based on photometric redshifts are consistent with a completely independent analysis which does not require redshift information for individual galaxies. Our results suggest that, at most, 1/5 of local red sequence galaxies with M_* >10^11 M_Sol were already in place at z ~ 2.Comment: Accepted for publication in ApJ. 31 pages in emulateapj format; 18 figues (14 in main text). Additional online data available through http://www.strw.leidenuniv.nl/~ent

Great Circle tidal streams: evidence for a nearly spherical massive dark halo around the Milky Way

An all high-latitude sky survey for cool carbon giant stars in the Galactic halo has revealed 75 such stars, of which the majority are new detections. Of these, more than half are clustered on a Great Circle on the sky which intersects the center of Sagittarius dwarf galaxy (Sgr) and is parallel to its proper motion vector, while many of the remainder are outlying Magellanic Cloud C-stars. A pole-count analysis of the carbon star distribution clearly indicates that the Great Circle stream we have isolated is statistically significant, being a 5-6 sigma over-density. These two arguments strongly support our conclusion that a large fraction of the Halo carbon stars originated in Sgr. The stream orbits the Galaxy between the present location of Sgr, 16 kpc from the Galactic center, and the most distant stream carbon star, at ~60 kpc. It follows neither a polar nor a Galactic plane orbit, so that a large range in both Galactic R and z distances are probed. That the stream is observed as a Great Circle indicates that the Galaxy does not exert a significant torque upon the stream, so the Galactic potential must be nearly spherical in the regions probed by the stream. We present N-body experiments simulating this disruption process as a function of the distribution of mass in the Galactic halo. A likelihood analysis shows that, in the Galactocentric distance range 16 kpc < R < 60 kpc, the dark halo is most likely almost spherical. We rule out, at high confidence levels, the possibility that the Halo is significantly oblate, with isodensity contours of aspect q_m < 0.7. This result is quite unexpected and contests currently popular galaxy formation models. (Abridged)Comment: 26 pages, 13 figures (6 in color, 8 chunky due to PS compression), minor revisions, accepted by Ap

Cost analysis of noninvasive blood-based microRNA testing versus CT scans for follow-up in patients with testicular germ-cell tumors

BACKGROUND: Our group has developed a noninvasive blood-based microRNA (miRNA) test for improving diagnosis, disease monitoring, and relapse detection in malignant testicular germ-cell tumors (TGCTs). Performance analysis suggests the test is likely to have comparable sensitivity and specificity in detecting TGCT as computed tomography (CT), thus reducing the need for serial CT scans for follow-up monitoring, with associated reductions in cumulative radiation burden and second cancer risk. To facilitate clinical adoption, we undertook a cost analysis to identify the budget impact of replacing CT scans with miRNA testing within health care systems. METHODS: The TGCT aftercare pathway was mapped out using National Comprehensive Cancer Network guidelines. A Markov model was built to simulate the impact of the miRNA test on TGCT aftercare costs. Incidence, treatment probabilities, relapse rate, and death rate data were collected from published studies to populate the model. RESULTS: Applying our model to the US health care system, the miRNA test has the potential to save up to $69 million per year in aftercare expenses related to TGCT treatment, with exact savings depending on the adoption rate and test price. CONCLUSION: This analysis demonstrates the potential positive budget impact of adopting miRNA testing in place of CT scans in the clinical management of TGCTs