Parametric Query Optimization (PQO) is an important problem in database systems, yet existing approaches suffer from high training costs, sensitivity to estimation errors, and vulnerability to severe performance regressions. This paper introduces PAR 2 QO (PARametric Penalty-Aware Robust Query Optimization), a system that integrates robust query optimization into PQO. PAR 2 QO strategically obtains plans from a well-balanced set of probe locations informed by the workload, and caches them as plan-penalty profiles. At runtime, PAR 2 QO selects the plan with the lowest expected penalty, explicitly accounting for selectivity uncertainties. Extensive experiments show that PAR 2 QO delivers significant speedups over existing methods while ensuring robustness against performance degradation. Additionally, we introduce CARVER , a workload generator aimed at covering possible cardinalities of subqueries. Not only does CARVER provide a more comprehensive way to evaluate PQO methods, but when used for training learned methods, it can also enhance their generalizability and stability.

Abstract Histogram Equalization (HE) is one of the most popular techniques for this purpose. Most histogram equalization techniques, including Contrast Limited Adaptive Histogram Equalization (CLAHE) and Local Contrast Modification CLAHE (LCM CLAHE), use a fixed block size technique for feature enhancement. Due to this, all these state of art techniques are used to give poor denoising performance after feature enhancement. In this paper, a deep learning based new approach, namely Dynamic Block Size Technique (DBST), is used to improve image denoising. In this approach, we use the Categorical Subjective Image Quality (CSIQ) image set, an image database generally used for preprocessing of images. The results obtained from experiments show better performance for different important parameters (used by state of art techniques). The work is novel in the preprocessing of images because in this work, we classify the image depending upon the image features for selecting appropriate block sizes dynamically during preprocessing. Proposed work outperforms in terms of PSNR, MSE, NRMSE, SSIM and SYNTROPY. The average respective values are 18.92, 863.86, 0.25, 0.81 and 19.35 and are better in comparison of CLAHE and LCM CLAHE.

BACKGROUND: Determining which target to pursue is a challenging and error-prone first step in developing a therapeutic treatment for a disease, where missteps are potentially very costly given the long-time frames and high expenses of drug development. With current informatics technology and machine learning algorithms, it is now possible to computationally discover therapeutic hypotheses by predicting clinically promising drug targets based on the evidence associating drug targets with disease indications. We have collected this evidence from Open Targets and additional databases that covers 17 sources of evidence for target-indication association and represented the data as a tensor of 21,437 × 2211 × 17. RESULTS: As a proof-of-concept, we identified examples of successes and failures of target-indication pairs in clinical trials across 875 targets and 574 disease indications to build a gold-standard data set of 6140 known clinical outcomes. We designed and executed three benchmarking strategies to examine the performance of multiple machine learning models: Logistic Regression, LASSO, Random Forest, Tensor Factorization and Gradient Boosting Machine. With 10-fold cross-validation, tensor factorization achieved AUROC = 0.82 ± 0.02 and AUPRC = 0.71 ± 0.03. Across multiple validation schemes, this was comparable or better than other methods. CONCLUSION: In this work, we benchmarked a machine learning technique called tensor factorization for the problem of predicting clinical outcomes of therapeutic hypotheses. Results have shown that this method can achieve equal or better prediction performance compared with a variety of baseline models. We demonstrate one application of the method to predict outcomes of trials on novel indications of approved drug targets. This work can be expanded to targets and indications that have never been clinically tested and proposing novel target-indication hypotheses. Our proposed biologically-motivated cross-validation schemes provide insight into the robustness of the prediction performance. This has significant implications for all future methods that try to address this seminal problem in drug discovery.

Target selection is the first and pivotal step in drug discovery. An incorrect choice may not manifest itself for many years after hundreds of millions of research dollars have been spent. We collected a set of 332 targets that succeeded or failed in phase III clinical trials, and explored whether Omic features describing the target genes could predict clinical success. We obtained features from the recently published comprehensive resource: Harmonizome. Nineteen features appeared to be significantly correlated with phase III clinical trial outcomes, but only 4 passed validation schemes that used bootstrapping or modified permutation tests to assess feature robustness and generalizability while accounting for target class selection bias. We also used classifiers to perform multivariate feature selection and found that classifiers with a single feature performed as well in cross-validation as classifiers with more features (AUROC = 0.57 and AUPR = 0.81). The two predominantly selected features were mean mRNA expression across tissues and standard deviation of expression across tissues, where successful targets tended to have lower mean expression and higher expression variance than failed targets. This finding supports the conventional wisdom that it is favorable for a target to be present in the tissue(s) affected by a disease and absent from other tissues. Overall, our results suggest that it is feasible to construct a model integrating interpretable target features to inform target selection. We anticipate deeper insights and better models in the future, as researchers can reuse the data we have provided to improve methods for handling sample biases and learn more informative features. Code, documentation, and data for this study have been deposited on GitHub at https://github.com/arouillard/omic-features-successful-targets.

The drug discovery enterprise provides strong drivers for data integration. While attention in this arena has tended to focus on integration of primary data from omics and other large platform technologies contributing to drug discovery and development, the scientific literature remains a major source of information valuable to pharmaceutical enterprises, and therefore tools for mining such data and integrating it with other sources are of vital interest and economic impact. This review provides a brief overview of approaches to literature mining as they relate to drug discovery, and offers an illustrative case study of a 'lightweight' approach we have implemented within an industrial context.

MOTIVATION: Given the complex nature of biological systems, pathways often need to function in a coordinated fashion in order to produce appropriate physiological responses to both internal and external stimuli. Therefore, understanding the interaction and crosstalk between pathways is important for understanding the function of both cells and more complex systems. RESULTS: We have developed a computational approach to detect crosstalk among pathways based on protein interactions between the pathway components. We built a global mammalian pathway crosstalk network that includes 580 pathways (covering 4753 genes) with 1815 edges between pathways. This crosstalk network follows a power-law distribution: P(k) approximately k(-)(gamma), gamma = 1.45, where P(k) is the number of pathways with k neighbors, thus pathway interactions may exhibit the same scale-free phenomenon that has been documented for protein interaction networks. We further used this network to understand colorectal cancer progression to metastasis based on transcriptomic data. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Microarray experiments measure changes in the expression of thousands of genes. The resulting lists of genes with changes in expression are then searched for biologically related sets using several divergent methods such as the Fisher Exact Test (as used in multiple GO enrichment tools), Parametric Analysis of Gene Expression (PAGE), Gene Set Enrichment Analysis (GSEA), and the connectivity map. RESULTS: We describe an analytical method (Geneva: Gene Vector Analysis) to relate genes to biological properties and to other similar experiments in a uniform way. This new method works on both gene sets and on gene lists/vectors as input queries, and can effectively query databases consisting of sets of biologically related sets, or of results from other microarray experiments. We also present an improvement to the null model estimate by using the empirical background distribution drawn from previous experiments. We validated Geneva by rediscovering a number of previous findings, and by finding significant relationships within microarrays in the GEO repository. CONCLUSION: Provided a reasonable corpus of previous experiments is available, this method is more accurate than the class label permutation model, especially for data sets with limited number of replicates. Geneva is, moreover, computationally faster because the background distributions can be precomputed. We also provide a standard evaluation data set based on 5 pairs of related experiments that should share similar functional relationships and 28 pairs of unrelated experiments from GEO. Discovering relationships amongst GEO data sets has implications for drug repositioning, and understanding relationships between diseases and drugs.

MOTIVATION: A number of omic technologies such as transcriptional profiling, proteomics, literature searches, genetic association, etc. help in the identification of sets of important genes. A subset of these genes may act in a coordinated manner, possibly because they are part of the same biological pathway. Interpreting such gene lists and relating them to pathways is a challenging task. Databases of biological relationships between thousands of mammalian genes can help in deciphering omics data. The relationships between genes can be assembled into a biological network with each protein as a node and each relationship as an edge between two proteins (or nodes). This network may then be searched for subnetworks consisting largely of interesting genes from the omics experiment. The subset of genes in the subnetwork along with the web of relationships between them helps to decipher the underlying pathways. Finding such subnetworks that maximally include all proteins from the query set but few others is the focus for this paper. RESULTS: We present a heuristic algorithm and a scoring function that work well both on simulated data and on data from known pathways. The scoring function is an extension of a previous study for a single biological experiment. We use a simple set of heuristics that provide a more efficient solution than the simulated annealing method. We find that our method works on reasonably complex curated networks containing approximately 9000 biological entities (genes and metabolites), and approximately 30,000 biological relationships. We also show that our method can pick up a pathway signal from a query list including a moderate number of genes unrelated to the pathway. In addition, we quantify the sensitivity and specificity of the technique.

Article Free Access Share on Detecting non-adjoining correlations with signals in DNA Authors: Pankaj Agarwal SmithKline Beecham Pharmaceuticals R&D, UW2230, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA SmithKline Beecham Pharmaceuticals R&D, UW2230, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PAView Profile , Vineet Bafna SmithKline Beecham Pharmaceuticals R&D, UW2230, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA SmithKline Beecham Pharmaceuticals R&D, UW2230, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PAView Profile Authors Info & Claims RECOMB '98: Proceedings of the second annual international conference on Computational molecular biologyMarch 1998 Pages 2–8https://doi.org/10.1145/279069.279076Published:01 March 1998Publication History 17citation142DownloadsMetricsTotal Citations17Total Downloads142Last 12 Months5Last 6 weeks3 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my AlertsNew Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteeReaderPDF

MOTIVATION: Searching a protein sequence database for homologs is a powerful tool for discovering the structure and function of a sequence. Two new methods for searching sequence databases have recently been described: Probabilistic Smith-Waterman (PSW), which is based on Hidden Markov models for a single sequence using a standard scoring matrix, and a new version of BLAST (WU-BLAST2), which uses Sum statistics for gapped alignments. RESULTS: This paper compares and contrasts the effectiveness of these methods with three older methods (Smith-Waterman: SSEARCH, FASTA and BLASTP). The analysis indicates that the new methods are useful, and often offer improved accuracy. These tools are compared using a curated (by Bill Pearson) version of the annotated portion of PIR 39. Three different statistical criteria are utilized: equivalence number, minimum errors and the receiver operating characteristic. For complete-length protein query sequences from large families, PSW's accuracy is superior to that of the other methods, but its accuracy is poor when used with partial-length query sequences. False negatives are twice as common as false positives irrespective of the search methods if a family-specific threshold score that minimizes the total number of errors (i.e. the most favorable threshold score possible) is used. Thus, sensitivity, not selectivity, is the major problem. Among the analyzed methods using default parameters, the best accuracy was obtained from SSEARCH and PSW for complete-length proteins, and the two BLAST programs, plus SSEARCH, for partial-length proteins.

In developmental biology, modeling and simulation play an important role in understanding cellular behavior. This article includes a review of the general models of development that are based on cellular interaction. Inspired by these models, we suggest a simple language, the Cell Programming Language (CPL), to write computer programs to describe this developmental behavior. These programs are an estimate of the minimal information needed to model realistically such developmental systems. Using these programs, it is possible to simulate and visualize cell behavior. We have employed CPL to model the following: aggregation in cellular slime mold in response to a chemotactic agent, cellular segregation and engulfment due to differential adhesion, and precartilage formation in vertebrate limbs. We believe CPL is a useful tool for developing, understanding, and checking biological models.

In developmental biology, modeling and simulation play an important role in understanding cellular interactions. We suggest a simple language, the Cell Programming Language (CPL), to write computer programs to describe this behavior. Using these programs, it is possible to simulate and visualize intercellular behavior. We employ CPL to model aggregation in Dictyostelium in response to a chemotactic agent. CPL programs are utilized to model a variety of aggregation behavior including streaming, spiral formation and the effect of amoeba density on aggregation patterns. We believe CPL is a useful tool for developing, understanding and checking biological models that utilize cellular interactions.

This paper describes the architecture and working of a recently implemented knowledge-based GIS (KBGIS-II) that was designed to satisfy several general criteria for GIS. The system has four major functions, query-answering, learning, editing and training. The main query finds constrained locations for spatial objects that are describable in a predicate-calculus based spatial object language. The main search procedures include a family of constraint-satisfaction procedures that use a spatial object knowledge base to search efficiently for complex spatial objects in large, multi-layered spatial data bases. These data bases are represented in quadtree form. The search strategy is designed to reduce the computational cost of search in the average case. The learning capabilities of the system include the addition of new locations of complex spatial objects to the knowledge base as queries are answered, and the ability to learn inductively definitions of new spatial objects from examples. The new definitions are added to the knowledge base by the system. The system is currently performing all its designated tasks successfully, although currently implemented on inadequate hardware.