ALBERT

Description: Background: Recently, the Bayesian method becomes more popular for analyzing high dimensional gene expression data as it allows us to borrow information across different genes and provides powerful estimators for evaluating gene expression levels. It is crucial to develop a simple but efficient gene selection algorithm for detecting differentially expressed (DE) genes based on the Bayesian estimators. Results: In this paper, by extending the two-criterion idea of Chen et al. (Chen M-H, Ibrahim JG, Chi Y-Y. A new class of mixture models for differential gene expression in DNA microarray data. J Stat Plan Inference. 2008;138:387–404), we propose two new gene selection algorithms for general Bayesian models and name these new methods as the confident difference criterion methods. One is based on the standardized differences between two mean expression values among genes; the other adds the differences between two variances to it. The proposed confident difference criterion methods first evaluate the posterior probability of a gene having different gene expressions between competitive samples and then declare a gene to be DE if the posterior probability is large. The theoretical connection between the proposed first method based on the means and the Bayes factor approach proposed by Yu et al. (Yu F, Chen M-H, Kuo L. Detecting differentially expressed genes using alibrated Bayes factors. Statistica Sinica. 2008;18:783–802) is established under the normal-normal-model with equal variances between two samples. The empirical performance of the proposed methods is examined and compared to those of several existing methods via several simulations. The results from these simulation studies show that the proposed confident difference criterion methods outperform the existing methods when comparing gene expressions across different conditions for both microarray studies and sequence-based high-throughput studies. A real dataset is used to further demonstrate the proposed methodology. In the real data application, the confident difference criterion methods successfully identified more clinically important DE genes than the other methods. Conclusion: The confident difference criterion method proposed in this paper provides a new efficient approach for both microarray studies and sequence-based high-throughput studies to identify differentially expressed genes.

Description: Background: Plant organ segmentation from 3D point clouds is a relevant task for plant phenotyping and plant growth observation. Automated solutions are required to increase the efficiency of recent high-throughput plant phenotyping pipelines. However, plant geometrical properties vary with time, among observation scales and different plant types. The main objective of the present research is to develop a fully automated, fast and reliable data driven approach for plant organ segmentation. Results: The automated segmentation of plant organs using unsupervised, clustering methods is crucial in cases where the goal is to get fast insights into the data or no labeled data is available or costly to achieve. For this we propose and compare data driven approaches that are easy-to-realize and make the use of standard algorithms possible. Since normalized histograms, acquired from 3D point clouds, can be seen as samples from a probability simplex, we propose to map the data from the simplex space into Euclidean space using Aitchisons log ratio transformation, or into the positive quadrant of the unit sphere using square root transformation. This, in turn, paves the way to a wide range of commonly used analysis techniques that are based on measuring the similarities between data points using Euclidean distance. We investigate the performance of the resulting approaches in the practical context of grouping 3D point clouds and demonstrate empirically that they lead to clustering results with high accuracy for monocotyledonous and dicotyledonous plant species with diverse shoot architecture. Conclusion: An automated segmentation of 3D point clouds is demonstrated in the present work. Within seconds first insights into plant data can be deviated – even from non-labelled data. This approach is applicable to different plant species with high accuracy. The analysis cascade can be implemented in future high-throughput phenotyping scenarios and will support the evaluation of the performance of different plant genotypes exposed to stress or in different environmental scenarios.

Description: Background: Host genetic variability has been implicated in chemotherapy-induced peripheral neuropathy (CIPN). A dose-limiting toxicity for chemotherapy agents, CIPN is also a debilitating condition that may progress to chronic neuropathic pain. We utilized a bioinformatics approach, which captures the complexity of intracellular and intercellular interactions, to identify genes for CIPN. Methods: Using genes pooled from the literature as a starting point, we used Ingenuity Pathway Analysis (IPA) to generate gene networks for CIPN. Results: We performed IPA core analysis for genes associated with platinum-, taxane- and platinum-taxane–induced neuropathy. We found that IL6, TNF, CXCL8, IL1B and ERK1/2 were the top genes in terms of the number of connections in platinum-induced neuropathy and TP53, MYC, PARP1, P38 MAPK and TNF for combined taxane-platinum–induced neuropathy. Conclusion: Neurotoxicity is common in cancer patients treated with platinum compounds and anti-microtubule agents and CIPN is one of the debilitating sequela. The bioinformatic approach helped identify genes associated with CIPN in cancer patients.

Description: Background: Tumorigenesis is an evolutionary process by which tumor cells acquire mutations through successive diversification and differentiation. There is much interest in reconstructing this process of evolution due to its relevance to identifying drivers of mutation and predicting future prognosis and drug response. Efforts are challenged by high tumor heterogeneity, though, both within and among patients. In prior work, we showed that this heterogeneity could be turned into an advantage by computationally reconstructing models of cell populations mixed to different degrees in distinct tumors. Such mixed membership model approaches, however, are still limited in their ability to dissect more than a few well-conserved cell populations across a tumor data set. Results: We present a method to improve on current mixed membership model approaches by better accounting for conserved progression pathways between subsets of cancers, which imply a structure to the data that has not previously been exploited. We extend our prior methods, which use an interpretation of the mixture problem as that of reconstructing simple geometric objects called simplices, to instead search for structured unions of simplices called simplicial complexes that one would expect to emerge from mixture processes describing branches along an evolutionary tree. We further improve on the prior work with a novel objective function to better identify mixtures corresponding to parsimonious evolutionary tree models. We demonstrate that this approach improves on our ability to accurately resolve mixtures on simulated data sets and demonstrate its practical applicability on a large RNASeq tumor data set. Conclusions: Better exploiting the expected geometric structure for mixed membership models produced from common evolutionary trees allows us to quickly and accurately reconstruct models of cell populations sampled from those trees. In the process, we hope to develop a better understanding of tumor evolution as well as other biological problems that involve interpreting genomic data gathered from heterogeneous populations of cells.

Description: Background: Understanding the architecture and function of RNA molecules requires methods for comparing and analyzing their tertiary and quaternary structures. While structural superposition of short RNAs is achievable in a reasonable time, large structures represent much bigger challenge. Therefore, we have developed a fast and accurate algorithm for RNA pairwise structure superposition called SETTER and implemented it in the SETTER web server. However, though biological relationships can be inferred by a pairwise structure alignment, key features preserved by evolution can be identified only from a multiple structure alignment. Thus, we extended the SETTER algorithm to the alignment of multiple RNA structures and developed the MultiSETTER algorithm. Results: In this paper, we present the updated version of the SETTER web server that implements a user friendly interface to the MultiSETTER algorithm. The server accepts RNA structures either as the list of PDB IDs or as user-defined PDB files. After the superposition is computed, structures are visualized in 3D and several reports and statistics are generated. Conclusion: To the best of our knowledge, the MultiSETTER web server is the first publicly available tool for a multiple RNA structure alignment. The MultiSETTER server offers the visual inspection of an alignment in 3D space which may reveal structural and functional relationships not captured by other multiple alignment methods based either on a sequence or on secondary structure motifs.

Description: Background: Today’s modern research of B and T cell antigen receptors (the immunoglobulins (IG) or antibodies and T cell receptors (TR)) forms the basis for detailed analyses of the human adaptive immune system. For instance, insights in the state of the adaptive immune system provide information that is essentially important in monitoring transplantation processes and the regulation of immune suppressiva. In this context, algorithms and tools are necessary for analyzing the IG and TR diversity on nucleotide as well as on amino acid sequence level, identifying highly proliferated clonotypes, determining the diversity of the cell repertoire found in a sample, comparing different states of the human immune system, and visualizing all relevant information. Results: We here present IMEX, a software framework for the detailed characterization and visualization of the state of human IG and TR repertoires. IMEX offers a broad range of algorithms for statistical analysis of IG and TR data, CDR and V-(D)-J analysis, diversity analysis by calculating the distribution of IG and TR, calculating primer efficiency, and comparing multiple data sets. We use a mathematical model that is able to describe the number of unique clonotypes in a sample taking into account the true number of unique sequences and read errors; we heuristically optimize the parameters of this model. IMEX uses IMGT/HighV-QUEST analysis outputs and includes methods for splitting and merging to enable the submission to this portal and to combine the outputs results, respectively. All calculation results can be visualized and exported. Conclusion: IMEX is an user-friendly and flexible framework for performing clonality experiments based on CDR and V-(D)-J rearranged regions, diversity analysis, primer efficiency, and various different visualization experiments. Using IMEX, various immunological reactions and alterations can be investigated in detail. IMEX is freely available for Windows and Unix platforms at http://bioinformatics.fh-hagenberg.at/immunexplorer/.

Description: Background: Bacterial vaginosis (BV) is a disease associated with the vagina microbiome. It is highly prevalent and is characterized by symptoms including odor, discharge and irritation. No single microbe has been found to cause BV. In this paper we use random forests and logistic regression classifiers to model the relationship between the microbial community and BV. We use subsets of the microbial community features in order to determine which features are important to the classification models. Results: We find that models generated using logistic regression and random forests perform nearly identically and identify largely similar important features. Only a few features are necessary to obtain high BV classification accuracy. Additionally, there appears to be substantial redundancy between the microbial community features. Conclusions: These results are in contrast to a previous study in which the important features identified by the classifiers were dissimilar. This difference appears to be the result of using different feature importance measures. It is not clear whether machine learning classifiers are capturing patterns different from simple correlations.

Description: Background: With the introduction and implementation of a variety of government programs and policies to encourage adoption of electronic medical records (EMRs), EMRs are being increasingly adopted in North America. We sought to evaluate the completeness of a variety of EMR fields to determine if family physicians were comprehensively using their EMRs and the suitability of use of the data for secondary purposes in Ontario, Canada. Methods: We examined EMR data from a convenience sample of family physicians distributed throughout Ontario within the Electronic Medical Record Administrative data Linked Database (EMRALD) as extracted in the summer of 2012. We identified all physicians with at least one year of EMR use. Measures were developed and rates of physician documentation of clinical encounters, electronic prescriptions, laboratory tests, blood pressure and weight, referrals, consultation letters, and all fields in the cumulative patient profile were calculated as a function of physician and patient time since starting on the EMR. Results: Of the 167 physicians with at least one year of EMR use, we identified 186,237 patients. Overall, the fields with the highest level of completeness were for visit documentations and prescriptions (〉70 %). Improvements were observed with increasing trends of completeness overtime for almost all EMR fields according to increasing physician time on EMR. Assessment of the influence of patient time on EMR demonstrated an increasing likelihood of the population of EMR fields overtime, with the largest improvements occurring between the first and second years. Conclusions: All of the data fields examined appear to be reasonably complete within the first year of adoption with the biggest increase occurring the first to second year. Using all of the basic functions of the EMR appears to be occurring in the current environment of EMR adoption in Ontario. Thus the data appears to be suitable for secondary use.

Description: Background: Recognising the limitations of a paper-based approach to documenting vital sign observations and responding to national clinical guidelines, we have explored the use of an electronic solution that could improve the quality and safety of patient care. We have developed a system for recording vital sign observations at the bedside, automatically calculating an Early Warning Score, and saving data such that it is accessible to all relevant clinicians within a hospital trust. We have studied current clinical practice of using paper observation charts, and attempted to streamline the process. We describe our user-focussed design process, and present the key design decisions prior to describing the system in greater detail. Results: The system has been deployed in three pilot clinical areas over a period of 9 months. During this time, vital sign observations were recorded electronically using our system. Analysis of the number of observations recorded (21,316 observations) and the number of active users (111 users) confirmed that the system is being used for routine clinical observations. Feedback from clinical end-users was collected to assess user acceptance of the system. This resulted in a System Usability Scale score of 77.8, indicating high user acceptability. Conclusions: Our system has been successfully piloted, and is in the process of full implementation throughout adult inpatient clinical areas in the Oxford University Hospitals. Whilst our results demonstrate qualitative acceptance of the system, its quantitative effect on clinical care is yet to be evaluated.

Description: Background: Biological data mining is a powerful tool that can provide a wealth of information about patterns of genetic and genomic biomarkers of health and disease. A potential disadvantage of data mining is volume and complexity of the results that can often be overwhelming. It is our working hypothesis that visualization methods can greatly enhance our ability to make sense of data mining results. More specifically, we propose that 3-D printing has an important role to play as a visualization technology in biological data mining. We provide here a brief review of 3-D printing along with a case study to illustrate how it might be used in a research setting. Results: We present as a case study a genetic interaction network associated with grey matter density, an endophenotype for late onset Alzheimer’s disease, as a physical model constructed with a 3-D printer. The synergy or interaction effects of multiple genetic variants were represented through a color gradient of the physical connections between nodes. The digital gene-gene interaction network was then 3-D printed to generate a physical network model. Conclusions: The physical 3-D gene-gene interaction network provided an easily manipulated, intuitive and creative way to visualize the synergistic relationships between the genetic variants and grey matter density in patients with late onset Alzheimer’s disease. We discuss the advantages and disadvantages of this novel method of biological data mining visualization.