Though facing complex challenges, America’s foreign policy strategy must remain a continual work in progress

America today faces a number of complex foreign policy challenges, with few obvious routes towards their successful resolution. In light of this complexity, many may yearn for the clarity of the Cold War, but Daniel J. Sargent warns against this. He writes that the Cold War policy of containment was no roadmap for policy, and that within its relatively loose outlook policymakers improvised and adapted, and pursued diverse agendas. In contemporary foreign policy, strategists must also acknowledge the potential need to change quickly, and the validity of alternative perspectives on the world

All-Comers versus Enrichment Design Strategy in Phase II Trials

Abstract:Designs for biomarker validation have been proposed and used in the phase III oncology clinical trial setting. Broadly, these designs follow either an enrichment (i.e., targeted) strategy or an all-comers (i.e., unselected) strategy. An enrichment design screens patients for the presence or absence of a marker or a panel of markers and then only includes patients who either have or do not have a certain marker characteristic or profile. In contrast, all patients meeting the eligibility criteria (regardless of a particular biomarker status) are entered into an all-comers design. The strength of the preliminary evidence, the prevalence of the marker, the reproducibility and validity of the assay, and the feasibility of real-time marker assessment play a major role in the choice of the design. In this report, we discuss the parameters under which the enrichment or an all-comers design strategy would be appropriate for phase II trials

Randomized Phase II Trials: Time for a New Era in Clinical Trial Design

AbstractThe classic single-arm oncology phase II trial designs for evaluating an experimental regimen/agent are limited by multiple sources of bias arising from the inability to separate trial effects (such as patient selection, trial eligibility, imaging techniques and assessment schedule, and treatment locations) from treatment effect on clinical outcomes. Changes in patient population based on biologic subsetting, newer imaging technologies, the use of alternative end points, constrained resources, and the multitude of promising therapies for a given disease make randomized phase II designs, with a concurrent control arm where necessary, attractive. In this brief report, we discuss the salient features of the randomized designs for phase II trials, which when properly applied under the constraints of their underlying inference framework can assure optimal use of limited phase III financial and patient resources

Genomic advances and their impact on clinical trial design

Medical treatment for patients has historically been based on two primary elements: the expected outcome for the patient, and the ability of treatment to improve the expected outcome. The advance in genomic technologies has the potential to change this paradigm and add substantial value to current medical practice by providing an integrated approach to guide patient-specific treatment selection using the genetic make-up of the disease and the genotype of the patient. Specifically, genomic signatures can aid in patient stratification (risk assessment), treatment response identification (surrogate markers), and/or in differential diagnosis (identifying who is likely to respond to which drug(s)). Several critical issues, including scientific rationale, clinical trial design, marker assessment methods, cost and feasibility have to be carefully considered in the validation of biomarkers through clinical research before they can be routinely integrated into clinical practice. Here, we highlight the impact of genomic advances on various aspects of clinical trial design

Keck Echellette Spectrograph and Imager Observations of Metal-poor Damped Lyα Systems

We present the first results from a survey of SDSS quasars selected for strong H I damped Lyα (DLA) absorption with corresponding low equivalent width absorption from strong low-ion transitions (e.g., C II λ1334 and Si II λ1260). These metal-poor DLA candidates were selected from the SDSS fifth release quasar spectroscopic database, and comprise a large new sample for probing low-metallicity galaxies. Medium-resolution echellette spectra from the Keck Echellette Spectrograph and Imager spectrograph for an initial sample of 35 systems were obtained to explore the metal-poor tail of the DLA distribution and to investigate the nucleosynthetic patterns at these metallicities. We have estimated saturation corrections for the moderately underresolved spectra, and systems with very narrow Doppler parameters (b ≤ 5 km s^(–1)) will likely have underestimated abundances. For those systems with Doppler parameters b > 5 km s^(–1), we have measured low-metallicity DLA gas with [X/H] < –2.4 for at least one of C, O, Si, or Fe. Assuming non-saturated components, we estimate that several DLA systems have [X/H] < –2.8, including five DLA systems with both low equivalent widths and low metallicity in transitions of both C II and O I. All of the measured DLA metallicities, however, exceed or are consistent with a metallicity of at least 1/1000 of solar, regardless of the effects of saturation in our spectra. Our results indicate that the metal-poor tail of galaxies at z ~ 3 drops exponentially at [X/H] ≾ –3. If the distribution of metallicity is Gaussian, the probability of identifying interstellar medium gas with lower abundance is extremely small, and our results suggest that DLA systems with [X/H] < –4.0 are extremely rare, and could comprise only 8 × 10^(–7) of DLA systems. The relative abundances of species within these low-metallicity DLA systems are compared with stellar nucleosynthesis models, and are consistent with stars having masses of 30 M_⊙ < M * < 100 M_⊙. The observed ratio of [C/O] for values of [O/H] < –2.5 exceeds values seen in moderate metallicity DLA systems, and also exceeds theoretical nucleosynthesis predictions for higher mass Population III stars. We also have observed a correlation between the column density N(C IV) with [Si/H] metallicity, suggestive of a trend between mass of the DLA system and its metallicity

The Direct Assignment Option as a Modular Design Component: An Example for the Setting of Two Predefined Subgroups

Background. A phase II design with an option for direct assignment (stop randomization and assign all patients to experimental treatment based on interim analysis, IA) for a predefined subgroup was previously proposed. Here, we illustrate the modularity of the direct assignment option by applying it to the setting of two predefined subgroups and testing for separate subgroup main effects. Methods. We power the 2-subgroup direct assignment option design with 1 IA (DAD-1) to test for separate subgroup main effects, with assessment of power to detect an interaction in a post-hoc test. Simulations assessed the statistical properties of this design compared to the 2-subgroup balanced randomized design with 1 IA, BRD-1. Different response rates for treatment/control in subgroup 1 (0.4/0.2) and in subgroup 2 (0.1/0.2, 0.4/0.2) were considered. Results. The 2-subgroup DAD-1 preserves power and type I error rate compared to the 2-subgroup BRD-1, while exhibiting reasonable power in a post-hoc test for interaction. Conclusion. The direct assignment option is a flexible design component that can be incorporated into broader design frameworks, while maintaining desirable statistical properties, clinical appeal, and logistical simplicity

Bayesian Variable Selection with Joint Modeling of Categorical and Survival Outcomes: An Application to Individualizing Chemotherapy Treatment in Advanced Colorectal Cancer

Colorectal cancer is the second leading cause of cancer related deaths in the United States, with more than 130,000 new cases of colorectal cancer diagnosed each year. Clinical studies have shown that genetic alterations lead to different responses to the same treatment, despite the morphologic similarities of tumors. A molecular test prior to treatment could help in determining an optimal treatment for a patient with regard to both toxicity and efficacy. This article introduces a statistical method appropriate for predicting and comparing multiple endpoints given different treatment options and molecular profiles of an individual. A latent variable-based multivariate regression model with structured variance covariance matrix is considered here. The latent variables account for the correlated nature of multiple endpoints and accommodate the fact that some clinical endpoints are categorical variables and others are censored variables. The mixture normal hierarchical structure admits a natural variable selection rule. Inference was conducted using the posterior distribution sampling Markov chain Monte Carlo method. We analyzed the finite-sample properties of the proposed method using simulation studies. The application to the advanced colorectal cancer study revealed associations between multiple endpoints and particular biomarkers, demonstrating the potential of individualizing treatment based on genetic profiles.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66395/1/j.1541-0420.2008.01181.x.pd

Synteny conservation between two distantly-related Rosaceae genomes: Prunus (the stone fruits) and Fragaria (the strawberry)

<p>Abstract</p> <p>Background</p> <p>The Rosaceae encompass a large number of economically-important diploid and polyploid fruit and ornamental species in many different genera. The basic chromosome numbers of these genera are <it>x </it>= 7, 8 and 9 and all have compact and relatively similar genome sizes. Comparative mapping between distantly-related genera has been performed to a limited extent in the Rosaceae including a comparison between <it>Malus </it>(subfamily Maloideae) and <it>Prunus </it>(subfamily Prunoideae); however no data has been published to date comparing <it>Malus </it>or <it>Prunus </it>to a member of the subfamily Rosoideae. In this paper we compare the genome of <it>Fragaria</it>, a member of the Rosoideae, to <it>Prunus</it>, a member of the Prunoideae.</p> <p>Results</p> <p>The diploid genomes of <it>Prunus </it>(<it>2n </it>= <it>2x </it>= 16) and <it>Fragaria </it>(<it>2n </it>= <it>2x </it>= 14) were compared through the mapping of 71 anchor markers – 40 restriction fragment length polymorphisms (RFLPs), 29 indels or single nucleotide polymorphisms (SNPs) derived from expressed sequence tags (ESTs) and two simple-sequence repeats (SSRs) – on the reference maps of both genera. These markers provided good coverage of the <it>Prunus </it>(78%) and <it>Fragaria </it>(78%) genomes, with maximum gaps and average densities of 22 cM and 7.3 cM/marker in <it>Prunus </it>and 32 cM and 8.0 cM/marker in <it>Fragaria</it>.</p> <p>Conclusion</p> <p>Our results indicate a clear pattern of synteny, with most markers of each chromosome of one of these species mapping to one or two chromosomes of the other. A large number of rearrangements (36), most of which produced by inversions (27) and the rest (9) by translocations or fission/fusion events could also be inferred. We have provided the first framework for the comparison of the position of genes or DNA sequences of these two economically valuable and yet distantly-related genera of the Rosaceae.</p

A High-Density Linkage Map of the Ancestral Diploid Strawberry, Fragaria iinumae, Constructed with Single Nucleotide Polymorphism Markers from the IStraw90 Array and Genotyping by Sequencing

Fragaria iinumae Makino is recognized as an ancestor of the octoploid strawberry species, which includes the cultivated strawberry, Fragaria ×ananassa Duchesne ex Rozier. Here we report the construction of the first high-density linkage map for F. iinumae. The F. iinumae linkage map (Fii map) is based on two high-throughput techniques of single nucleotide polymorphism (SNP) genotyping: the IStraw90 Array (hereafter “Array”), and genotyping by sequencing (GBS). The F2 generation mapping population was derived by selfing F. iinumae hybrid F1D, the product of a cross between two divergent F. iinumae accessions collected from Hokkaido, Japan. The Fii map consists of seven linkage groups (LGs) and has an overall length of 451.7 cM as defined by 496 loci populated by 4173 markers: 3280 from the Array and 893 from GBS. Comparisons with two versions of the Fragaria vesca ssp. vesca L. ‘Hawaii 4’ pseudo-chromosome (PC) assemblies reveal substantial conservation of synteny and colinearity, yet identified differences that point to possible genomic divergences between F. iinumae and F. vesca, and/or to F. vesca genomic assembly errors. The Fii map provides a basis for anchoring a F. iinumae genome assembly as a prerequisite for constructing a second diploid reference genome for Fragaria