Dose Selection Balancing Efficacy and Toxicity Using Bayesian Model Averaging

Successful pharmaceutical drug development requires finding correct doses that provide an optimum balance between efficacy and toxicity. Competing responses to dose such as efficacy and toxicity often will increase with dose, and it is important to identify a range of doses to provide an acceptable efficacy response (minimum effective dose) while not causing unacceptable intolerance or toxicity (maximum tolerated dose). How this should be done is not self-evident. Relating efficacy to dose conditionally on possible toxicity may be problematic because whether toxicity occurs will not be known when a dose for a patient needs to be chosen. Copula models provide an appealing approach for incorporating an efficacy-toxicity association when the functional forms of the efficacy and toxicity dose-response models are known but may be less appealing in practice when the functional forms of the dose-response models and the particular copula association model are unknown. This paper explores the use of the BMA-Mod Bayesian model averaging framework that accommodates efficacy and toxicity responses to provide a statistically valid, distributionally flexible, and operationally practical model-agnostic strategy for predicting efficacy and toxicity outcomes both in terms of expected responses and in terms of predictions for individual patients. The performance of the approach is evaluated via simulation when efficacy and toxicity outcomes are considered marginally, when they are associated via gaussian and Archimedean copulas, and when they are expressed in terms of clinically meaningful categories. In all cases, the BMA-Mod strategy identified consistent ranges of acceptable doses.Comment: 23 pages, 14 figures. R code, annotated session log, and datasets available from [email protected]

A New WIMP Population in the Solar System and New Signals for Dark-Matter Detectors

We describe in detail how perturbations due to the planets can cause a sub-population of WIMPs captured by scattering in surface layers of the Sun to evolve to have orbits which no longer intersect the Sun. We argue that such WIMPs, if their orbit has a semi-major axis less than 1/2 of Jupiter's, can persist in the solar system for cosmological timescales. This leads to a new, previously unanticipated WIMP population intersecting the Earth's orbit. The WIMP-nucleon cross sections required for this population to be significant are precisely those in the range predicted for SUSY dark matter, lying near the present limits obtained by direct underground dark matter searches using cyrogenic detectors. Thus, if a WIMP signal is observed in the next generation of detectors, a potentially measurable signal due to this new population must exist. This signal, lying in the keV range for Germanium detectors, would be complementary to that of galactic halo WIMPs. A comparison of event rates, anisotropies, and annual modulations would not only yield additional confirmation that any claimed signal is indeed WIMP-based, but would also allow one to gain information on the nature of the underlying dark matter model.Comment: Revtex, 37 pages including 6 figures, accepted by Phys. Rev D. (version to be published, including changes made in response to referees reports

Slowing and cooling molecules and neutral atoms by time-varying electric field gradients

A method of slowing, accelerating, cooling, and bunching molecules and neutral atoms using time-varying electric field gradients is demonstrated with cesium atoms in a fountain. The effects are measured and found to be in agreement with calculation. Time-varying electric field gradient slowing and cooling is applicable to atoms that have large dipole polarizabilities, including atoms that are not amenable to laser slowing and cooling, to Rydberg atoms, and to molecules, especially polar molecules with large electric dipole moments. The possible applications of this method include slowing and cooling thermal beams of atoms and molecules, launching cold atoms from a trap into a fountain, and measuring atomic dipole polarizabilities.Comment: 13 pages, 10 figures. Scheduled for publication in Nov. 1 Phys. Rev.

The Lyman-alpha glow of gas falling into the dark matter halo of a z=3 galaxy

Quasars are the visible signatures of super-massive black holes in the centres of distant galaxies. It has been suggested that quasars are formed during ``major merger events'' when two massive galaxies collide and merge, leading to the prediction that quasars should be found in the centres of the regions of largest overdensity in the early Universe. In dark matter (DM)-dominated models of the early Universe, massive DM halos are predicted to attract the surrounding gas, which falls towards its centre. The neutral gas is not detectable in emission by itself, but gas falling into the ionizing cone of such a quasar will glow in the Lyman-alpha line of hydrogen, effectively imaging the DM halo. Here we present a Lyman-alpha image of a DM halo at redshift 3, along with a two-dimensional spectrum of the gaseous halo. Our observations are best understood in the context of the standard model for DM halos; we infer a mass of (2-7) x 10^12 solar masses (Msun) for the halo.Comment: 4 pages, 4 figures. Published as a Letter to Nature in the August 26, 2004 issue; see accompanying News and Views article by Z. Haiman in the same issu

Neutrinos produced by ultrahigh-energy photons at high red shift

Some of the proposed explanations for the origin of ultrahigh-energy cosmic rays invoke new sources of energetic photons (e.g., topological defects, relic particles, etc.). At high red shift, when the cosmic microwave background has a higher temperature but the radio background is low, the ultrahigh-energy photons can generate neutrinos through pair-production of muons and pions. Neutrinos produced at high red shift by slowly evolving sources can be detected. Rapidly evolving sources of photons can be ruled out based on the existing upper limit on the neutrino flux.Comment: 4 pages, revtex; to appear in Phys. Rev. Let

Gamma-Ray Bursts and Magnetars as Possible Sources of Ultra High Energy Cosmic Rays: Correlation of Cosmic Ray Event Positions with IRAS Galaxies

We use the two-dimensional Kolmogorov-Smirnov (KS) test to study the correlation between the 60 cosmic ray events above 4x10^19 eV from the AGASA experiment and the positions of infrared luminous galaxies from the IRAS PSCz catalog. These galaxies are expected to be hosts to gamma ray bursts (GRB) and magnetars, both of which are associated with core collapse supernovae and have been proposed as possible acceleration sites for ultra high energy cosmic rays. We find consistency between the models and the AGASA events to have been drawn from the same underlying distribution of positions on the sky with KS probabilities ~50%. Application of the same test to the 11 highest AGASA events above 10^20 eV, however, yields a KS probability of < 0.5%, rejecting the models at >99.5% significance level. Taken at face value, these highest energy results suggest that the existing cosmic ray events above 10^20 eV do not owe their origin to long burst GRBs, rapidly rotating magnetars, or any other events associated with core collapse supernovae. The larger data set expected from the AUGER experiment will test whether this conclusion is real or is a statistical fluke that we estimate to be at the 2 sigma level.Comment: 15 pages, 4 figures. Final Version to be published in Phys. Rev.

A tutorial on pilot studies: the what, why and how

Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format

Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.

We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions

Extragalactic Background Light Inferred from AEGIS Galaxy SED-type Fractions

The extragalactic background light (EBL) is of fundamental importance both for understanding the entire process of galaxy evolution and for gamma-ray astronomy, but the overall spectrum of the EBL between 0.1-1000 microns has never been determined directly from galaxy spectral energy distribution (SED) observations over a wide redshift range. The evolving, overall spectrum of the EBL is derived here utilizing a novel method based on observations only. This is achieved from the observed evolution of the rest-frame K-band galaxy luminosity function up to redshift 4 (Cirasuolo et al. 2010), combined with a determination of galaxy SED-type fractions. These are based on fitting SWIRE templates to a multiwavelength sample of about 6000 galaxies in the redshift range from 0.2 to 1 from the All-wavelength Extended Groth Strip International Survey (AEGIS). The changing fractions of quiescent galaxies, star-forming galaxies, starburst galaxies and AGN galaxies in that redshift range are estimated, and two alternative extrapolations of SED-types to higher redshifts are considered. This allows calculation of the evolution of the luminosity densities from the UV to the IR, the evolving star formation rate density of the universe, the evolving contribution to the bolometric EBL from the different galaxy populations including AGN galaxies and the buildup of the EBL. Our EBL calculations are compared with those from a semi-analytic model, from another observationally-based model and observational data. The EBL uncertainties in our modeling based directly on the data are quantified, and their consequences for attenuation of very high energy gamma-rays due to pair production on the EBL are discussed. It is concluded that the EBL is well constrained from the UV to the mid-IR, but independent efforts from infrared and gamma-ray astronomy are needed in order to reduce the uncertainties in the far-IR.Comment: 25 pages, 18 figures, 4 tables; accepted for publication in MNRAS on September 3, 2010. Online material available at http://side.iaa.es/EB

The fruits of collaboration in a multidisciplinary field

Collaboration between researchers and between research organizations is generally considered a desirable course of action, in particular by some funding bodies. However, collaboration within a multidisciplinary community, such as the Computer–Human Interaction (CHI) community, can be challenging. We performed a bibliometric analysis of the CHI conference proceedings to determine if papers that have authors from different organization or countries receive more citations than papers that are authored by members of the same organization. There was no significant difference between these three groups, indicating that there is no advantage for collaboration in terms of citation frequency. Furthermore, we tested if papers written by authors from different organizations or countries receive more best paper awards or at least award nominations. Papers from only one organization received significantly fewer nominations than collaborative papers