A Survival-Adjusted Quantal-Response Test for Analysis of Tumor Incidence Rates in Animal Carcinogenicity Studies

In rodent cancer bioassays, groups of animals are exposed to different doses of a chemical of interest and followed for tumor occurrence. The resulting tumor rates are commonly analyzed using a survival-adjusted Cochran-Armitage (CA) trend test. The CA trend test has reasonable power when the tumor-response curve is linear in dose, but it may be underpowered for a nonlinear response. An alternative survival-adjusted test procedure based on isotonic regression methodology has previously been proposed. Although this alternative procedure performs well when the tumor response is nonlinear in dose, it has less power than the CA trend test when the response is linear in dose. Here, we introduce a new survival-adjusted test procedure that makes use of both the CA trend test and the isotonic regression-based trend test. Using a broad range of experimental conditions typical of National Toxicology Program (NTP) bioassays, we conducted extensive computer simulations to compare the false-positive error rate and power of the proposed procedure with the survival-adjusted CA trend test. The new procedure competes well with the survival-adjusted CA trend test when observed tumor rates are linear in dose and performs substantially better when observed tumor rates are nonlinear in dose. Further, the proposed trend test almost always has a smaller false-positive rate than does the survival-adjusted CA trend test. We also developed an order-restricted inference-based procedure for performing multiple pairwise comparisons between each of the dose groups and the control group. The trend test and the multiple pairwise comparisons test are demonstrated using an example from a study conducted by the NTP

Circular piecewise regression with applications to cell-cycle data

Applications of circular regression models appear in many different fields such as evolutionary psychology, motor behavior, biology, and, in particular, in the analysis of gene expressions in oscillatory systems. Specifically, for the gene expression problem, a researcher may be interested in modeling the relationship among the phases of cell-cycle genes in two species with differing periods. This challenging problem reduces to the problem of constructing a piecewise circular regression model and, with this objective in mind, we propose a flexible circular regression model which allows different parameter values depending on sectors along the circle. We give a detailed interpretation of the parameters in the model and provide maximum likelihood estimators. We also provide a model selection procedure based on the concept of generalized degrees of freedom. The model is then applied to the analysis of two different cell-cycle data sets and through these examples we highlight the power of our new methodology

Second-Trimester Placental and Thyroid Hormones Are Associated With Cognitive Development From Ages 1 to 3 Years

Adequate maternal thyroid hormone (TH) is necessary for fetal brain development. The role of placental human chorionic gonadotropin (hCG) in ensuring the production of TH is less well understood. The objective of the study was to evaluate 1) associations of placental hCG and its subunits, and maternal TH in the second trimester, and 2) the single and joint effects of TH and placental hormones on cognitive development and communication at ages 1 and 3 years. Fifty individuals (5%) were selected from the CANDLE (Conditions Affecting Neurocognitive Development and Early Learning) pregnancy cohort in Memphis, Tennessee, with recruitment from 2006 to 2011, to equally represent male and female fetuses. Participants were 68% Black and 32% White. Hormones measured were maternal thyroid (thyrotropin [TSH] and free thyroxine [FT4]) and placental hormones (hCG, its hyperglycosylated form [hCG-h], and free alpha- [hCG alpha] and beta-subunits [hCG beta]) in maternal serum (17-28 weeks). The primary outcome measurement was the Bayley Scales of Infant and Toddler Development. All forms of hCG were negatively associated with FT4 and not associated with TSH. hCG alpha was associated with cognitive development at age 1 year and jointly interacted with TSH to predict cognitive development at age 3 years. This pilot study added insight into the thyrotropic actions of hCG in the second trimester, and into the significance of this mechanism for brain development. More research is warranted to elucidate differences between hCG alpha, hCG beta, and hCG-h in relation to TH regulation and child brain function.Peer reviewe

Paradigm of tunable clustering using binarization of consensus partition matrices (Bi-CoPaM) for gene discovery

Copyright @ 2013 Abu-Jamous et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Clustering analysis has a growing role in the study of co-expressed genes for gene discovery. Conventional binary and fuzzy clustering do not embrace the biological reality that some genes may be irrelevant for a problem and not be assigned to a cluster, while other genes may participate in several biological functions and should simultaneously belong to multiple clusters. Also, these algorithms cannot generate tight clusters that focus on their cores or wide clusters that overlap and contain all possibly relevant genes. In this paper, a new clustering paradigm is proposed. In this paradigm, all three eventualities of a gene being exclusively assigned to a single cluster, being assigned to multiple clusters, and being not assigned to any cluster are possible. These possibilities are realised through the primary novelty of the introduction of tunable binarization techniques. Results from multiple clustering experiments are aggregated to generate one fuzzy consensus partition matrix (CoPaM), which is then binarized to obtain the final binary partitions. This is referred to as Binarization of Consensus Partition Matrices (Bi-CoPaM). The method has been tested with a set of synthetic datasets and a set of five real yeast cell-cycle datasets. The results demonstrate its validity in generating relevant tight, wide, and complementary clusters that can meet requirements of different gene discovery studies.National Institute for Health Researc

Technology advancement of the CCD201-20 EMCCD for the WFIRST coronagraph instrument: sensor characterization and radiation damage

The Wide Field InfraRed Survey Telescope-Astrophysics Focused Telescope Asset (WFIRST-AFTA) mission is a 2.4-m class space telescope that will be used across a swath of astrophysical research domains. JPL will provide a high-contrast imaging coronagraph instrument—one of two major astronomical instruments. In order to achieve the low noise performance required to detect planets under extremely low flux conditions, the electron multiplying charge-coupled device (EMCCD) has been baselined for both of the coronagraph’s sensors—the imaging camera and integral field spectrograph. JPL has established an EMCCD test laboratory in order to advance EMCCD maturity to technology readiness level-6. This plan incorporates full sensor characterization, including read noise, dark current, and clock-induced charge. In addition, by considering the unique challenges of the WFIRST space environment, degradation to the sensor’s charge transfer efficiency will be assessed, as a result of damage from high-energy particles such as protons, electrons, and cosmic rays. Science-grade CCD201-20 EMCCDs have been irradiated to a proton fluence that reflects the projected WFIRST orbit. Performance degradation due to radiation displacement damage is reported, which is the first such study for a CCD201-20 that replicates the WFIRST conditions. In addition, techniques intended to identify and mitigate radiation-induced electron trapping, such as trap pumping, custom clocking, and thermal cycling, are discussed

The Role of Particulate Matter-Associated Zinc in Cardiac Injury in Rats

Background: Exposure to particulate matter (PM) has been associated with increased cardiovascular morbidity; however, causative components are unknown. Zinc is a major element detected at high levels in urban air.Objective We investigated the role of PM-associated zinc in cardiac injury. Methods: We repeatedly exposed 12- to 14-week-old male Wistar Kyoto rats intratracheally (1×/week for 8 or16 weeks) to a) saline (control); b) PM having no soluble zinc (Mount St. Helens ash, MSH); or c) whole-combustion PM suspension containing 14.5 μg/mg of water-soluble zinc at high dose (PM-HD) and d ) low dose (PM-LD), e) the aqueous fraction of this suspension (14.5 μg/mg of soluble zinc) (PM-L), or f ) zinc sulfate (rats exposed for 8 weeks received double the concentration of all PM components of rats exposed for 16 weeks). Results: Pulmonary inflammation was apparent in all exposure groups when compared with saline (8 weeks greater than 16 weeks). PM with or without zinc, or with zinc alone caused small increases in focal subepicardial inflammation, degeneration, and fibrosis. Lesions were not detected in controls at 8 weeks but were noted at 16 weeks. We analyzed mitochondrial DNA damage using quantitative polymerase chain reaction and found that all groups except MSH caused varying degrees of damage relative to control. Total cardiac aconitase activity was inhibited in rats receiving soluble zinc. Expression array analysis of heart tissue revealed modest changes in mRNA for genes involved in signaling, ion channels function, oxidative stress, mitochondrial fatty acid metabolism, and cell cycle regulation in zinc but not in MSH-exposed rats. Conclusion: These results suggest that water-soluble PM-associated zinc may be one of the causal components involved in PM cardiac effects

Bioinformatics on the Cloud Computing Platform Azure

We discuss the applicability of the Microsoft cloud computing platform, Azure, for bioinformatics. We focus on the usability of the resource rather than its performance. We provide an example of how R can be used on Azure to analyse a large amount of microarray expression data deposited at the public database ArrayExpress. We provide a walk through to demonstrate explicitly how Azure can be used to perform these analyses in Appendix S1 and we offer a comparison with a local computation. We note that the use of the Platform as a Service (PaaS) offering of Azure can represent a steep learning curve for bioinformatics developers who will usually have a Linux and scripting language background. On the other hand, the presence of an additional set of libraries makes it easier to deploy software in a parallel (scalable) fashion and explicitly manage such a production run with only a few hundred lines of code, most of which can be incorporated from a template. We propose that this environment is best suited for running stable bioinformatics software by users not involved with its development. © 2014 Shanahan et al

Difference-based clustering of short time-course microarray data with replicates

<p>Abstract</p> <p>Background</p> <p>There are some limitations associated with conventional clustering methods for short time-course gene expression data. The current algorithms require prior domain knowledge and do not incorporate information from replicates. Moreover, the results are not always easy to interpret biologically.</p> <p>Results</p> <p>We propose a novel algorithm for identifying a subset of genes sharing a significant temporal expression pattern when replicates are used. Our algorithm requires no prior knowledge, instead relying on an observed statistic which is based on the first and second order differences between adjacent time-points. Here, a pattern is predefined as the sequence of symbols indicating direction and the rate of change between time-points, and each gene is assigned to a cluster whose members share a similar pattern. We evaluated the performance of our algorithm to those of K-means, Self-Organizing Map and the Short Time-series Expression Miner methods.</p> <p>Conclusions</p> <p>Assessments using simulated and real data show that our method outperformed aforementioned algorithms. Our approach is an appropriate solution for clustering short time-course microarray data with replicates.</p

Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer

PURPOSE: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM). PATIENTS AND METHODS: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading. RESULTS: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced (P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing. CONCLUSION: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety