Search

In clinical trials, a surrogate outcome ( S) can be measured before the outcome of interest ( T) and may provide early information regarding the treatment ( Z) effect on T. Many methods of surrogacy validation rely on models for the conditional distribution of T given Z and S. However, S is a post-randomization variable, and unobserved, simultaneous predictors of S and T may exist, resulting in a non-causal interpretation. Frangakis and Rubin developed the concept of principal surrogacy, stratifying on the joint distribution of the surrogate marker under treatment and control to assess the association between the causal effects of treatment on the marker and the causal effects of treatment on the clinical outcome. Working within the principal surrogacy framework, we address the scenario of an ordinal categorical variable as a surrogate for a censored failure time true endpoint. A Gaussian copula model is used to model the joint distribution of the potential outcomes of T, given the potential outcomes of S. Because the proposed model cannot be fully identified from the data, we use a Bayesian estimation approach with prior distributions consistent with reasonable assumptions in the surrogacy assessment setting. The method is applied to data from a colorectal cancer clinical trial, previously analyzed by Burzykowski et al. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to develop a real-time quantitative PCR test to recognize and quantify the DNA levels of the increasingly important barley pathogen Ramularia collo-cygni. Methods and Results: The method described uses specifically designed primers and a molecular beacon probe based on an internal transcribed spacer (ITS) sequence. Pathogen extracted from barley leaves could be quantified to the picogram level in both leaves showing symptoms of infection and symptomless barley leaves. Conclusions: A relationship between R. collo-cygni DNA levels and disease symptoms was established in spring barley under natural infection conditions. Significance and Impact of the Study: To our knowledge, this is the first report of a test of this type and makes an important contribution to studies into the life cycle of this pathogen. [ABSTRACT FROM AUTHOR]

Purpose : To investigate the existence of enhanced sensitivity of dermal tissue to low radiation doses in the range of 0.1 Gy to 4 Gy/fraction. Materials and methods : Top-up technique of giving higher radiation doses to skin alone from 150 kVp X-rays followed by fractionated experimental doses to total body from 137Cs were given to C3H mice. Full-depth incisions were made and the tensile strength of skin from 14 day wounds were measured as a response of dermal tissue to radiation. Results : There was no evidence of enhanced radiosensitivity to doses as low as 0.1 Gy. The data were better fitted by a nonparametric method that predicted the shape of survival curve better than an induced-repair model. Conclusions : Dermal tissue like spinal cord has a low sensitive fraction of cells, unlike jejunum, kidney or lung that showed sensitivity at these doses. Tissue kinetics play an important role in the use of low dose fractions to avoid injury to normal tissues. [ABSTRACT FROM AUTHOR]

Motivation: RNA sequencing (RNA-Seq) is a powerful new technology for mapping and quantifying transcriptomes using ultra high-throughput next generation sequencing technologies. Using deep sequencing, gene expression levels of all transcripts including novel ones can be quantified digitally. Although extremely promising, the massive amounts of data generated by RNA-Seq, substantial biases, and uncertainty in short read alignment pose challenges for data analysis. In particular, large base-specific variation and between-base dependence make simple approaches, such as those that use averaging to normalize RNA-Seq data and quantify gene expressions, ineffective. Results: In this study, we propose a Poisson mixed-effects (or in short, POME) model to characterize base-level read coverage within each transcript. The underlying expression level is included as a key parameter in this model. Because the proposed model is capable of incorporating base-specific variation as well as between-base dependence that affect read coverage profile throughout the transcript, it can lead to improved quantification of the true underlying expression level. Availability and Implementation: POME can be freely downloaded at http://www.stat.purdue.edu/~yuzhu/pome.html., Statistics

Background: Regulatory agencies and others have expressed concern about the uncritical use of dose expansion cohorts (DECs) in phase I oncology trials. Nonetheless, by several metrics--prevalence, size and number--their popularity is increasing. Although early efficacy estimation in defined populations is a common primary endpoint of DECs, the types of designs best equipped to identify efficacy signals have not been established. Methods: We conducted a simulation study of six phase I design templates with multiple DECs: three dose-assignment/ adjustment mechanisms multiplied by two analytic approaches for estimating efficacy after the trial is complete. We also investigated the effect of sample size and interim futility analysis on trial performance. Identifying populations in which the treatment is efficacious (true positives) and weeding out inefficacious treatment/populations (true negatives) are competing goals in these trials. Thus, we estimated true and false positive rates for each design. Results: Adaptively updating the MTD during the DEC improved true positive rates by 8--43% compared with fixing the dose during the DEC phase while maintaining false positive rates. Inclusion of an interim futility analysis decreased the number of patients treated under inefficacious DECs without hurting performance. Conclusion: A substantial gain in efficiency is obtainable using a design template that statistically models toxicity and efficacy against dose level during expansion. Design choices for dose expansion should be motivated by and based upon expected performance. Similar to the common practice in single-arm phase II trials, cohort sample sizes should be justified with respect to their primary aim and include interim analyses to allow for early stopping. [ABSTRACT FROM AUTHOR]