Detection of bladder cancer using proteomic profiling of urine sediments

We used protein expression profiles to develop a classification rule for the detection and prognostic assessment of bladder cancer in voided urine samples. Using the Ciphergen PBS II ProteinChip Reader, we analyzed the protein profiles of 18 pairs of samples of bladder tumor and adjacent urothelium tissue, a training set of 85 voided urine samples (32 controls and 53 bladder cancer), and a blinded testing set of 68 voided urine samples (33 controls and 35 bladder cancer). Using t-tests, we identified 473 peaks showing significant differential expression across different categories of paired bladder tumor and adjacent urothelial samples compared to normal urothelium. Then the intensities of those 473 peaks were examined in a training set of voided urine samples. Using this approach, we identified 41 protein peaks that were differentially expressed in both sets of samples. The expression pattern of the 41 protein peaks was used to classify the voided urine samples as malignant or benign. This approach yielded a sensitivity and specificity of 59% and 90%, respectively, on the training set and 80% and 100%, respectively, on the testing set. The proteomic classification rule performed with similar accuracy in low- and high-grade bladder carcinomas. In addition, we used hierarchical clustering with all 473 protein peaks on 65 benign voided urine samples, 88 samples from patients with clinically evident bladder cancer, and 127 samples from patients with a history of bladder cancer to classify the samples into Cluster A or B. The tumors in Cluster B were characterized by clinically aggressive behavior with significantly shorter metastasis-free and disease-specific survival.     

Evidence for Convergent Evolution in Gape Morphology of the Bat Hawk (Macheiramphus alcinus) with Swifts,Swallows, and Goatsuckers

Gape morphology has been linked to feeding and breeding ecology in raptors, according to the ingestion rate hypothesis. Mammal feeding raptors have larger gapes, allowing them to ingest prey more rapidly than bird feeders, which have evolved smaller average body sizes and gapes to capture more agile prey. One highly derived raptor, however, the Bat Hawk (Macheiramphus alcinus), specializes on colonial bats and swiftlets concentrated daily in a limited temporal window by capturing and swallowing them whole in flight. We hypothesized that the gape of the Bat Hawk evolved to feed rapidly on agile vertebrates limited temporally. We predicted that the gape of the Bat Hawk would be significantly larger than the gape of other raptors, more closely resembling the gapes of swifts (Apodidae), swallows (Hirundinidae), and goatsuckers (Caprimulgiformes). We measured gape area of the lower mandible in museum specimens representing 138 bird species in six orders. We also compared gape area by prey type in over 100 raptor species in three orders. We predicted that insectivorous raptors would exhibit gapes similar to mammal feeders but would differ from bird feeders because insects are not agile prey. The Bat Hawk had the largest gape of any raptor and more closely resembled the gape of insectivorous birds, which also swallow prey whole in flight. The evolution of an enlarged gape may have permitted the Bat Hawk to exploit a previously unrealized ecological niche. Gapes of bird feeding raptors were smaller than in mammal and insect feeders, supporting the ingestion rate hypothesis.     

Traumatic Wound Microbiome Workshop

On May 9-10, 2011, the Walter Reed Army Institute of Research, as the Army Center of Excellence for Infectious Disease, assembled over a dozen leaders in areas related to research into the communities of microorganisms which colonize and infect traumatic wounds. The objectives of the workshop were to obtain guidance for government researchers, to spur research community involvement in the field of traumatic wound research informed by a microbiome perspective, and to spark collaborative efforts serving the Wounded Warriors and similarly wounded civilians. During the discussions, it was made clear that the complexity of these infections will only be met by developing a new art of clinical practice that engages the numerous microbes and their ecology. It requires the support of dedicated laboratories and technologists who advance research methods such as community sequencing, as well as the kinds of data analysis expertise and facilities. These strategies already appear to be bearing fruit in the clinical management of chronic wounds. There are now funding announcements and programs supporting this area of research open to extramural collaborators.     

Learning from our GWAS mistakes: from experimental design to scientific method

Many public and private genome-wide association studies that we have analyzed include flaws in design, with avoidable confounding appearing as a norm rather than the exception. Rather than recognizing flawed research design and addressing that, a category of quality-control statistical methods has arisen to treat only the symptoms. Reflecting more deeply, we examine elements of current genomic research in light of the traditional scientific method and find that hypotheses are often detached from data collection, experimental design, and causal theories. Association studies independent of causal theories, along with multiple testing errors, too often drive health care and public policy decisions. In an era of large-scale biological research, we ask questions about the role of statistical analyses in advancing coherent theories of diseases and their mechanisms. We advocate for reinterpretation of the scientific method in the context of large-scale data analysis opportunities and for renewed appreciation of falsifiable hypotheses, so that we can learn more from our best mistakes.     

A Bayesian model for classifying all differentially expressed proteins simultaneously in 2D PAGE gels

ABSTRACT: BACKGROUND: Two-dimensional polyacrylamide gel electrophoresis (2D PAGE) is commonly used to identify differentially expressed proteins under two or more experimental or observational conditions. Wu et al (2009) developed a univariate probabilistic model which was used to identify differential expression between Case and Control groups, by applying a Likelihood Ratio Test (LRT) to each protein on a 2D PAGE. In contrast to commonly used statistical approaches, this model takes into account the two possible causes of missing values in 2D PAGE: either (1) the non-expression of a protein; or (2) a level of expression that falls below the limit of detection. RESULTS: We develop a global Bayesian model which extends the previously described model. Unlike the univariate approach, the model reported here is able treat all differentially expressed proteins simultaneously. Whereas each protein is modelled by the univariate likelihood function previously described, several global distributions are used to model the underlying relationship between the parameters associated with individual proteins. These global distributions are able to combine information from each protein to give more accurate estimates of the true parameters. In our implementation of the procedure, all parameters are recovered by Markov chain Monte Carlo (MCMC) integration. The 95% highest posterior density (HPD) intervals for the marginal posterior distributions are used to determine whether differences in protein expression are due to differences in mean expression intensities, and/or differences in the probabilities of expression. CONCLUSIONS: Simulation analyses showed that the global model is able to accurately recover the underlying global distributions, and identify more differentially expressed proteins than the simple application of a LRT. Additionally, simulations also indicate that the probability of incorrectly identifying a protein as differentially expressed (i.e., the False Discovery Rate) is very low. The source code is available at https://github.com/stevenhwu/BIDE-2D.     

Current status and future directions of post-marketing vaccine safety monitoring with focus on USA and Europe

Vaccine safety research is a key component of public health programs. Regulatory agencies need to be able to make informed decisions. Public health authorities need to respond to vaccine concerns before they turn into large scale scares reducing vaccine uptake and derailing immunization programs. Several post-licensure vaccine safety monitoring systems have been established in the USA and Europe, and methods such as rapid cycle analysis have been developed for real-time detection and analysis of safety issues. Accurate and reliable vaccine product testing and monitoring requires high quality data of populations of 100 million and above depending on the frequency of the event, vaccine coverage, and the time pressure during which data need to be generated. This requires post-licensure safety studies utilizing large linked population based databases of exposure and outcomes. Harmonized methods for development and linkage of these databases across countries need to be further developed, validated and implemented. Concerted action between the US and Europe could move vaccine safety monitoring to today's level of requirements globally and should be pursued.     

Post-licensure evaluation of vaccine safety: current status and future directions. Symposium organised by the International Alliance for Biological Standardization (IABS) in Barcelona, Spain, 27-28 April 2011

Adverse events following immunization, while rare, unfortunately do occur. And when they do, the public's faith in vaccines waves. It's a known fact, for example, that vaccine safety concerns are among the most important factors contributing to parents refusing vaccination for their children. How best, then, to tackle these concerns and increase public confidence in the vaccine safety system? In an effort to contribute to identifying the right mechanisms, the International Alliance for Biological Standardization organized an international symposium on "Post-Licensure Evaluation of Vaccine Safety" in Barcelona in early Spring. Delegates from 24 countries took a close look at the current status of this challenging problem and identified several practical measures which could help address the situation. They suggested an integrated vaccine safety program to be in place in all countries and standardized so that information and data can be exchanged on a routine basis. Another proposal was to put in place simple measures such as the use of bar codes on vaccine vials.     

Prior eccentric exercise reduces v[combining dot above]o2peak and ventilatory threshold but does not alter movement economy during cycling exercise

Exercise-induced muscle damage (EIMD) has been shown to reduce force production and result in delayed-onset soreness and pain in the damaged muscle(s). Cycling in the presence of EIMD reduces peak power output and time-trial performance. However, its effect on peak aerobic capacity has not been widely studied. The purpose of this study was to examine the impact of EIMD targeted specifically to the quadriceps muscle group on peak oxygen consumption (V[Combining Dot Above]O2peak) during cycling. Ten participants (4 men, 6 women) completed a V[Combining Dot Above]O2peak test on a cycle ergometer before and 48 hours after performing 24 eccentric contractions with their right and left quadriceps with a weight equal to 120% of 1-repetition maximal concentric strength (1RM). The EIMD was assessed using 1RM, and muscle soreness was assessed using a 100-mm visual analog scale. The presence of EIMD was confirmed by a 9% reduction in 1RM (p = 0.0001) and increased ratings of soreness from 2.4 ± 2.1 to 24.6 ± 10.8 mm (p = 0.001). The V[Combining Dot Above]O2peak was reduced from 46.2 ± 9.7 to 41.8 ± 10.7 ml·kg·min (10%; p = 0.01) with participants terminating exercise at lower heart rates 191 ± 9 vs. 186 ± 10 b·min (p = 0.02) and power output 248 ± 79 vs. 238 ± 81 W (p = 0.02) after EIMD. Additionally, ventilatory threshold decreased from 34.2 ± 7.8 to 30.5 ± 8.5 ml·kg·min (11%; p = 0.031). Despite the reduction in V[Combining Dot Above]O2peak, cycling economy (p = 0.17) did not differ pre-EIMD and post-EIMD. These findings indicate that EIMD reduced peak aerobic exercise capacity to an extent that could result in meaningful reductions in exercise performance. The reduction is likely attributable to a combination of reduced strength, earlier accumulation of lactic acid, and heightened muscle pain during exercise.