Biomedical subjects

P D Karp

Publications and source records attributed to P D Karp.

At least 19 recordsLinked to original sources

PubMed2026

Assessment of the impact of manual curation in BioCyc.

INTRODUCTION: BioCyc is an extensive collection of databases of genomic and pathway information for microorganisms and model eukaryotes. These organismal databases integrate diverse biological data by combining computationally inferred information, data imported from other databases, and, for selected organisms, literature-based manual curation. This study investigates the magnitude and significance of annotation changes performed during the curation of 10 prokaryotic genomes to better understand the rate of erroneous annotations and the value of BioCyc curation. METHODS: We identified curation changes by finding cases where the annotation of the protein at the start of the curation process differed from its annotation at the end of the process. RESULTS: We found that across a sample of curated databases (n = 10), the annotation of 6,753, or 25.6% of the proteins in the pooled protein dataset (n = 26,126) were modified. Assessment of considerable sampling fractions of these proteins found that a median of 62% (mean of 52.9%) represented functionally informative name changes, rather than stylistic annotation changes. These results were then extrapolated to total proteins with name changes with uncertainty quantified via finite population correction, indicating that most Tier 2 Biocyc PGDBs received hundreds of functionally informative name changes during manual curation. On average 363, or13% (±5.4% SD) of the proteins encoded in each genome received functionally informative annotation changes, ranging from 5.3% (Streptococcus pneumoniae D39V) to 22.7% (Staphylococcus aureus NCTC 8325). DISCUSSION: These findings demonstrate a substantial improvement in the accuracy of manually curated BioCyc databases compared with automated annotation pipelines. This result is particularly impactful as the rate of downstream propagation of erroneous annotations across biological databases can significantly compromise scientific discovery.

annotation errors↗

PubMed1999

Eco Cyc: encyclopedia of Escherichia coli genes and metabolism.

The EcoCyc database describes the genome and gene products of Escherichia coli, its metabolic and signal-transduction pathways, and its tRNAs. The database describes 4391 genes of E.coli, 695 enzymes encoded by a subset of these genes, 904 metabolic reactions that occur in E.coli, and the organization of these reactions into 129 metabolic pathways. The EcoCyc graphical user interface allows scientists to query and explore the EcoCyc database using visualization tools such as genomic-map browsers and automatic layouts of metabolic pathways. EcoCyc has many references to the primary literature, and is a (qualitative) computational model of E. coli metabolism. EcoCyc is available at URL http://ecocyc. PangeaSystems.com/ecocyc/

Classification↗

PubMed1998

EcoCyc: Encyclopedia of Escherichia coli genes and metabolism.

The encyclopedia of Escherichia coli genes and metabolism (EcoCyc) is a database that combines information about the genome and the intermediary metabolism of E.coli. The database describes 3030 genes of E.coli , 695 enzymes encoded by a subset of these genes, 595 metabolic reactions that occur in E.coli, and the organization of these reactions into 123 metabolic pathways. The EcoCyc graphical user interface allows scientists to query and explore the EcoCyc database using visualization tools such as genomic-map browsers and automatic layouts of metabolic pathways. EcoCyc can be thought of as an electronic review article because of its copious references to the primary literature, and as a (qualitative) computational model of E.coli metabolism. EcoCyc is available at URL http://ecocyc.PangeaSystems.com/ecocyc/

Computer Graphics↗

PubMed1998

Metabolic databases.

Explore the source record for details and available documents.

Biochemical Phenomena↗

PubMed1997

The complete genome sequence of the gastric pathogen Helicobacter pylori.

Helicobacter pylori, strain 26695, has a circular genome of 1,667,867 base pairs and 1,590 predicted coding sequences. Sequence analysis indicates that H. pylori has well-developed systems for motility, for scavenging iron, and for DNA restriction and modification. Many putative adhesins, lipoproteins and other outer membrane proteins were identified, underscoring the potential complexity of host-pathogen interaction. Based on the large number of sequence-related genes encoding outer membrane proteins and the presence of homopolymeric tracts and dinucleotide repeats in coding sequences, H. pylori, like several other mucosal pathogens, probably uses recombination and slipped-strand mispairing within repeats as mechanisms for antigenic variation and adaptive evolution. Consistent with its restricted niche, H. pylori has a few regulatory networks, and a limited metabolic repertoire and biosynthetic capacity. Its survival in acid conditions depends, in part, on its ability to establish a positive inside-membrane potential in low pH.

Antigenic Variation↗

PubMed1997

EcoCyc: Enyclopedia of Escherichia coli Genes and Metabolism.

The Encyclopedia of Genes and Metabolism (EcoCyc) is a database that combines information about the genome and the intermediary metabolism of Escherichia coli. It describes 2970 genes of E.coli, 547 enzymes encoded by these genes, 702 metabolic reactions that occur in E.coli and the organization of these reactions into 107 metabolic pathways. The EcoCyc graphical user interface allows scientists to query and explore the EcoCyc database using visualization tools such as genomic-map browsers and automatic layouts of metabolic pathways. EcoCyc spans the space from sequence to function to allow scientists to investigate an unusually broad range of questions. EcoCyc can be thought of as both an electronic review article because of its copious references to the primary literature, and as an in silicio model of E.coli metabolism that can be probed and analyzed through computational means.

Amino Acid Sequence↗

PubMed1997

Estimation of equilibrium constants using automated group contribution methods.

MOTIVATION: Group contribution methods are frequently used for estimating physical properties of compounds from their molecular structures. An algorithm for estimating Gibbs energies of formation through group contribution methods has been automated in an object-oriented framework. The algorithm decomposes compound structures according to a basis set of groups. It permits the use of wildcards and is able to distinguish between ring groups and chain groups that use similar search structures. Past methods relied on manual decomposition of compounds into constituent groups. RESULTS: The software is written in Common LISP and requires < 2 min to estimate Gibbs energies of formation for a database of 780 species of varying size and complexity. The software allows rapid expansion to incorporate different basis sets and to estimate a variety of other physical properties.

Algorithms↗

PubMed1997

Prediction of enzyme classification from protein sequence without the use of sequence similarity.

We describe a novel approach for predicting the function of a protein from its amino-acid sequence. Given features that can be computed from the amino-acid sequence in a straightforward fashion (such as pI, molecular weight, and amino-acid composition), the technique allows us to answer questions such as: Is the protein an enzyme? If so, in which Enzyme Commission (EC) class does it belong? Our approach uses machine learning (ML) techniques to induce classifiers that predict the EC class of an enzyme from features extracted from its primary sequence. We report on a variety of experiments in which we explored the use of three different ML techniques in conjunction with training datasets derived from PDB and from Swiss-Prot. We also explored the use of several different feature sets. Our method is able to predict the first EC number of an enzyme with 74% accuracy (thereby assigning the enzyme to one of six broad categories of enzyme function), and to predict the second EC number of an enzyme with 68% accuracy (thereby assigning the enzyme to one of 57 subcategories of enzyme function). This technique could be a valuable complement to sequence-similarity searches and to pathway-analysis methods.

Algorithms↗

PubMed1996

Adapting EcoCyc for use on the World Wide Web.

The World Wide Web (WWW) offers the potential to deliver specialized information to an audience of unprecedented size. Along with this exciting new opportunity comes a challenge for software developers: instead of rewriting our software applications to operate over the WWW, how can we maximize software reuse by retrofitting existing applications? We have developed a Web server tool, written in Common Lisp, that allows existing graphical user interface applications written using the Common Lisp Interface Manager (CLIM) to hook easily into the WWW. This tool-CWEST (CLIM-WEb Server Tool, pronounced "quest")-was developed to operate with EcoCyc, an electronic encyclopedia of the genes and metabolism of the bacterium E. coli. EcoCyc consists of a database of objects relevant to E. coli biochemistry and a user interface, implemented in CLIM, that runs on the X-window system and generates graphical displays appropriate to biological objects. Each query to the EcoCyc WWW server is treated as a command to the EcoCyc program, which dynamically generates an appropriate CLIM drawing. CWEST translates that drawing, which can be a mixture of text and graphics, into the HyperText Markup Language (HTML) and/or the Graphics Interchange Format (GIF), which are returned to the client. Sensitive regions embedded in the CLIM drawing are converted to hyperlinks with Universal Resource Locators (URLs) that generate further EcoCyc queries. This tight coupling of CLIM output with Web output makes CLIM a powerful high-level programming tool for Web applications. The flexibility of Common Lisp and CLIM made implementation of the server tool surprisingly easy, requiring few changes to the existing EcoCyc program. The results can be seen at URL http: @www.ai.sri.com/ecocyc/browser.html. We have made CWEST available to the CLIM community at large, with the hope that it will spur other software developers to make their CLIM applications available over the WWW.

Computer Communication Networks↗

PubMed1996

EcoCyc: an encyclopedia of Escherichia coli genes and metabolism.

The encyclopedia of Escherichia coli genes and metabolism (EcoCyc) is a database that combines information about the genome and the intermediary metabolism of E.coli. It describes 2034 genes, 306 enzymes encoded by these genes, 580 metabolic reactions that occur in E.coli and the organization of these reactions into 100 metabolic pathways. The EcoCyc graphical user interface allows query and exploration of the EcoCyc database using visualization tools such as genomic map browsers and automatic layouts of metabolic pathways. EcoCyc spans the space from sequence to function to allow investigation of an unusually broad range of questions. EcoCyc can be thought of as both an electronic review article, because of its copious references to the primary literature, and as an in silico model of E.coli that can be probed and analyzed through computational means.

Computer Communication Networks↗

PubMed1996

Database links are a foundation for interoperability.

Several techniques are being introduced into the bioinformatics community to permit interoperation between molecular biology databases (DBs). The common factor to these approaches is the creation of links between entities in different DBs. Links can connect pieces of information about a single protein that are partitioned across multiple DBs, and can also encode relationships between different biological entities, such as relationships between an enzyme, its gene and its catalytic activity. This article provides an overview of the DB-interoperation problem, and offers several solutions. It discusses how links are used in molecular biology DBs, and describes the potential stumbling blocks when DB links are created and used.

Biotechnology↗

PubMed1996

Integrated access to metabolic and genomic data.

The EcoCyc system consists of a knowledge base (KB) that describes the genes and intermediary metabolism of Escherichia coli, and a graphical user interface (GUI) for accessing that knowledge. This paper addresses two problems: How can we create a GUI that provides integrated access to metabolic and genomic data? We describe the design and implementation of visual presentations that closely mimic those found in the biology literature, and that offer hypertext navigation among related entities, and multiple views of the same entity. We employ a frame knowledge representation system (FRS) called HyperTHEO to manage the EcoCyc knowledge base. Among the advantages of FRSs are an expressive data model for capturing the complexities of biological information, and schema-evolution capabilities that facilitate the constant schema changes that biological databases tend to undergo. HyperTHEO also includes rule-based inference facilities that are the foundation of expert systems, a constraint language for maintaining data integrity, and a declarative query language. A graphic KB editor and browser allow the EcoCyc developers to interactively inspect and modify this evolving KB.

Artificial Intelligence↗

PubMed1996

HinCyc: a knowledge base of the complete genome and metabolic pathways of H. influenzae.

We present a methodology for predicting the metabolic pathways of an organism from its genomic sequence by reference to a knowledge base of known metabolic pathways. We applied these techniques to the genome of H. influenzae by reference to the EcoCyc knowledge base to predict which of 81 metabolic pathways of E. coli are found in H. influenzae. The resulting prediction is a complex hypothesis that is presented in computer form as HinCyc: an electronic encyclopedia of the genes and metabolic pathways of H. influenzae. HinCyc connects the predicted genes, enzymes, enzyme-catalyzed reactions, and biochemical pathways in a WWW-accessible knowledge base to allow scientists to explore this complex hypothesis.

Computer Communication Networks↗

PubMed1996

A protocol for maintaining multidatabase referential integrity.

The bioinformatics community is becoming increasingly reliant on the creation of links among biological databases (DBs) as a foundation for DB interoperability. For example, a link might be created from a protein in one DB (such as PIR), to a gene in another DB (such as GDB), by storing the unique identifier (id) of the gene object within an attribute of the protein object. User interfaces can then support navigation from the protein to the gene, and multiDB queries can join the protein with the gene. The unique id of the gene is serving as a foreign key. However, a variety of factors, such as changes in the underlying biology, can cause object ids to become invalid, thus producing invalid links among DBs. Invalid links are a violation of multidatabase referential integrity. We propose a network protocol whereby a database administrator can provide information about changes to the identifiers of objects in their database via Internet, to allow other databases to maintain referential integrity. We request comments from the bioinformatics community for the purpose of building a consensus on the proposed protocol.

Computational Biology↗

PubMed1995

A strategy for database interoperation.

To realize the full potential of biological databases (DBs) requires more than the interactive, hypertext flavor of database interoperation that is now so popular in the bioinformatics community. Interoperation based on declarative queries to multiple network-accessible databases will support analyses and investigations that are orders of magnitude faster and more powerful than what can be accomplished through interactive navigation. I present a vision of the capabilities that a query-based interoperation infrastructure should provide, and identify assumptions underlying, and requirements of, this vision. I then propose an architecture for query-based interoperation that includes a number of novel components of an information infrastructure for molecular biology. These components include a knowledge base that describes relationships among the conceptualizations used in different biological databases, a module that can determine the DBs that are relevant to a particular query, a module that can translate a query and its results from one conceptualization to another, a collection of DB drivers that provide uniform physical access to different database management systems, a suite of translators that can interconvert among different database schema languages, and a database that describes the network location and access methods for biological databases. A number of the components are translators that bridge the heterogeneities that exist between biological DBs at several different levels, including the conceptual level, the data model, the query language, and data formats.

Artificial Intelligence↗

PubMed1994

Representations of metabolic knowledge: pathways.

The automatic generation of drawings of metabolic pathways is a challenging problem that depends intimately on exactly what information has been recorded for each pathway, and on how that information is encoded. The chief contributions of the paper are a minimized representation for biochemical pathways called the predecessor list, and inference procedures for converting the predecessor list into a pathway-graph representation that can serve as input to a pathway-drawing algorithm. The predecessor list has several advantages over the pathway graph, including its compactness and its lack of redundancy. The conversion between the two representations can be formulated as both a constraint-satisfaction problem and a logical inference problem, whose goal is to assign directions to reactions, and to determine which are the main chemical compounds in the reaction. We describe a set of production rules that solves this inference problem. We also present heuristics for inferring whether the exterior compounds that are substrates of reactions at the periphery of a pathway are side or main compounds. These techniques were evaluated on 18 metabolic pathways from the EcoCyc knowledge base.

Animals↗

PubMed1993

Representations of metabolic knowledge.

Construction of electronic repositories of metabolic information is an increasingly active area of research. Encoding detailed knowledge of a complex biological domain requires finely honed representations. We survey representations used for several metabolic databases, including Eco-Cyc, and reach the following conclusions. Representation of the metabolism must distinguish enzyme classes from individual enzymes, because there is not a one-to-one mapping from enzymes to the reactions they catalyze. Individual enzymes must be represented explicitly as proteins, e.g., by encoding their subunit structure. The species variation of metabolism must be represented. So must the substrate specificity of enzymes, which may be treated in several ways.

Databases, Factual↗

PubMed1992

A knowledge base of the chemical compounds of intermediary metabolism.

This paper describes a publicly available knowledge base of the chemical compounds involved in intermediary metabolism. We consider the motivations for constructing a knowledge base of metabolic compounds, the methodology by which it was constructed, and the information that it currently contains. Currently the knowledge base describes 981 compounds, listing for each: synonyms for its name, a systematic name, CAS registry number, chemical formula, molecular weight, chemical structure and two-dimensional display coordinates for the structure. The Compound Knowledge Base (CompoundKB) illustrates several methodological principles that should guide the development of biological knowledge bases. I argue that biological datasets should be made available in multiple representations to increase their accessibility to end users, and I present multiple representations of the CompoundKB (knowledge base, relational data base and ASN. 1 representations). I also analyze the general characteristics of these representations to provide an understanding of their relative advantages and disadvantages. Another principle is that the error rate of biological data bases should be estimated and documented-this analysis is performed for the CompoundKB.

Artificial Intelligence↗