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PubMed2006

Annotated regions of significance of SELDI-TOF-MS spectra for detecting protein biomarkers.

Peak detection is a key step in the analysis of SELDI-TOF-MS spectra, but the current default method has low specificity and poor peak annotation. To improve data quality, scientists still have to validate the identified peaks visually, a tedious and time-consuming process, especially for large data sets. Hence, there is a genuine need for methods that minimize manual validation. We have previously reported a multi-spectral signal detection method, called RS for 'region of significance', with improved specificity. Here we extend it to include a peak quantification algorithm based on annotated regions of significance (ARS). For each spectral region flagged as significant by RS, we first identify a dominant spectrum for determining the number of peaks and the m/z region of these peaks. From each m/z region of peaks, a peak template is extracted from all spectra via the principal component analysis. Finally, with the template, we estimate the amplitude and location of the peak in each spectrum with the least-squares method and refine the estimation of the amplitude via the mixture model. We have evaluated the ARS algorithm on patient samples from a clinical study. Comparison with the standard method shows that ARS (i) inherits the superior specificity of RS, and (ii) gives more accurate peak annotations than the standard method. In conclusion, we find that ARS alleviates the main problems in the preprocessing of SELDI-TOF spectra. The R-package ProSpect that implements ARS is freely available for academic use at http://www.meb.ki.se/ yudpaw.

Adenocarcinoma↗

PubMed2002

PipTools: a computational toolkit to annotate and analyze pairwise comparisons of genomic sequences.

Sequence conservation between species is useful both for locating coding regions of genes and for identifying functional noncoding segments. Hence interspecies alignment of genomic sequences is an important computational technique. However, its utility is limited without extensive annotation. We describe a suite of software tools, PipTools, and related programs that facilitate the annotation of genes and putative regulatory elements in pairwise alignments. The alignment server PipMaker uses the output of these tools to display detailed information needed to interpret alignments. These programs are provided in a portable format for use on common desktop computers and both the toolkit and the PipMaker server can be found at our Web site (http://bio.cse.psu.edu/). We illustrate the utility of the toolkit using annotation of a pairwise comparison of the mouse MHC class II and class III regions with orthologous human sequences and subsequently identify conserved, noncoding sequences that are DNase I hypersensitive sites in chromatin of mouse cells.

Animals↗

PubMed2004

Annotating proteins from endoplasmic reticulum and Golgi apparatus in eukaryotic proteomes.

The sub-cellular localization of a native protein constitutes one coarse-grained aspect of its function. Transport between compartments is often regulated through short sequence motifs. Here, we analyzed experimentally characterized endoplasmic reticulum (ER)/ Golgi retrieval motifs and investigated the accuracy of homology-transfer. Only the C-terminal ER retrieval motifs KDEL, HDEL and AIAKE were sufficiently specific. However, even unspecific motifs may help, provided we know the probability for localization given the motif. We provided such estimates. We also rigorously estimated the accuracy and coverage for inferring ER and Golgi localization through homology-transfer by sequence similarity. In entire proteomes, we could thereby annotate 3304 ER (3182 membrane) and 1853 Golgi (759 membrane) proteins. We identified another putative 5157 globular and 3941 membrane ER or Golgi proteins. Each experimental annotation yielded, on average, one to three high-accuracy and five to six low-accuracy homology-transfers in the six proteomes. These numbers will increase with each new experimental annotation.

Amino Acid Motifs↗

PubMed2006

Toward automated biochemotype annotation for large compound libraries.

Combinatorial chemistry allows scientists to probe large synthetically accessible chemical space. However, identifying the sub-space which is selectively associated with an interested biological target, is crucial to drug discovery and life sciences. This paper describes a process to automatically annotate biochemotypes of compounds in a library and thus to identify bioactivity related chemotypes (biochemotypes) from a large library of compounds. The process consists of two steps: (1) predicting all possible bioactivities for each compound in a library, and (2) deriving possible biochemotypes based on predictions. The Prediction of Activity Spectra for Substances program (PASS) was used in the first step. In second step, structural similarity and scaffold-hopping technologies are employed. These technologies are used to derive biochemotypes from bioactivity predictions and the corresponding annotated biochemotypes from MDL Drug Data Report (MDDR) database. About a one million (982,889) commercially available compound library (CACL) has been tested using this process. This paper demonstrates the feasibility of automatically annotating biochemotypes for large libraries of compounds. Nevertheless, some issues need to be considered in order to improve the process. First, the prediction accuracy of PASS program has no significant correlation with the number of compounds in a training set. Larger training sets do not necessarily increase the maximal error of prediction (MEP), nor do they increase the hit structural diversity. Smaller training sets do not necessarily decrease MEP, nor do they decrease the hit structural diversity. Second, the success of systematic bioactivity prediction relies on modeling, training data, and the definition of bioactivities (biochemotype ontology). Unfortunately, the biochemotype ontology was not well developed in the PASS program. Consequently, "ill-defined" bioactivities can reduce the quality of predictions. This paper suggests the ways in which the systematic bioactivities prediction program should be improved.

Chemistry, Pharmaceutical↗

PubMed2005

CLAGen: a tool for clustering and annotating gene sequences using a suffix tree algorithm.

Most multiple gene sequence alignment methods rely on conventions regarding the score of a multiple alignment in pairwise fashion. Therefore, as the number of sequences increases, the runtime of sequencing expands exponentially. In order to solve the problem, this paper presents a multiple sequence alignment method using a linear-time suffix tree algorithm to cluster similar sequences at one time without pairwise alignment. After searching for common subsequences, cross-matching common subsequences were generated, and sometimes inexact matching was found. So, a procedure aimed at masking the inexact cross-matching pairs was suggested here. In addition, BLAST was combined with a clustering tool in order to annotate the clusters generated by suffix tree clustering. The proposed method for clustering and annotating genes consists of the following steps: (1) construction of a suffix tree; (2) searching and overlapping common subsequences; (3) grouping subsequence pairs; (4) masking cross-matching pairs; (5) clustering gene sequences; (6) annotating gene clusters by the BLAST search. The performance of the proposed system, CLAGen, was successfully evaluated with 42 gene sequences in a TCA cycle (a citrate cycle) of bacteria. The system generated 11 clusters and found the longest subsequences of each cluster, which are biologically significant.

Algorithms↗

PubMed2006

Aetiology-specific patterns in end-stage heart failure patients identified by functional annotation and classification of microarray data.

BACKGROUND: The objective of the present study was to use gene expression profiling, functional annotations and classification to identify aetiology-specific biological processes and potential molecular markers for different aetiologies of end-stage heart failure. METHODS AND RESULTS: Individual left ventricular myocardial samples from eleven coronary artery disease and nine dilated cardiomyopathy transplant patients were co-hybridized with pooled RNA from four non-failing hearts on custom-made arrays of 7000 human genes. Significance analysis identified differential expression of 153 and 147 genes, respectively, in coronary artery disease or dilated cardiomyopathy versus non-failing hearts. Analysis of Gene Ontology biological process annotations indicated aetiology-specific patterns, primarily related to genes involved in catabolism and in regulation of protein kinase activity. Gene expression classifiers were obtained and used for class prediction of random samples of coronary artery diseased and dilated cardiomyopathic hearts. Best classifiers frequently included matrix metalloproteinase 3, fibulin 1, ATP-binding cassette, sub-family B member 1 and iroquois homeobox protein 5. CONCLUSION: Combining functional annotation from microarray data and classification analysis constitutes a potent strategy to identify disease-specific biological processes and gene expression markers in e.g. end-stage coronary artery disease and dilated cardiomyopathy.

Adult↗

PubMed2005

Using the transcriptome to annotate the genome revisited: application of massively parallel signature sequencing (MPSS).

Transcriptome analysis can provide useful data for refining genome sequence annotation. Application of massively parallel signature sequencing (MPSS) revealed reproducible transcription, in multiple MPSS cycles, from 73% of computationally predicted genes in the Theileria parva schizont lifecycle stage. Signatures spanning consecutive exons confirmed 142 predicted introns. MPSS identified 83 putative genes, >100 codons overlooked by annotation software, and 139 potentially incorrect gene models (with either truncated ORFs or overlooked exons) by interfacing signature locations with stop codon maps. Twenty representative models were confirmed as likely to be incorrect using reverse transcription PCR amplification from independent schizont cDNA preparations. More than 50% of the 60 putative single copy genes in T. parva that were absent from the genome of the closely related T. annulata had MPSS signatures. This study illustrates the utility of MPSS for improving annotation of small, gene-rich microbial eukaryotic genomes.

Animals↗

PubMed2006

Gene functional annotation by statistical analysis of biomedical articles.

BACKGROUND: Functional annotation of genes is an important task in biology since it facilitates the characterization of genes relationships and the understanding of biochemical pathways. The various gene functions can be described by standardized and structured vocabularies, called bio-ontologies. The assignment of bio-ontology terms to genes is carried out by means of applying certain methods to datasets extracted from biomedical articles. These methods originate from data mining and machine learning and include maximum entropy or support vector machines (SVM). PURPOSE: The aim of this paper is to propose an alternative to the existing methods for functionally annotating genes. The methodology involves building of classification models, validation and graphical representations of the results and reduction of the dimensions of the dataset. METHODS: Classification models are constructed by Linear discriminant analysis (LDA). The validation of the models is based on statistical analysis and interpretation of the results involving techniques like hold-out samples, test datasets and metrics like confusion matrix, accuracy, recall, precision and F-measure. Graphical representations, such as boxplots, Andrew's curves and scatterplots of the variables resulting from the classification models are also used for validating and interpreting the results. RESULTS: The proposed methodology was applied to a dataset extracted from biomedical articles for 12 Gene Ontology terms. The validation of the LDA models and the comparison with the SVM show that LDA (mean F-measure 75.4%) outperforms the SVM (mean F-measure 68.7%) for the specific data. CONCLUSION: The application of certain statistical methods can be beneficial for functional gene annotation from biomedical articles. Apart from the good performance the results can be interpreted and give insight of the bio-text data structure.

Abstracting and Indexing↗

PubMed2006

The MitoDrome database annotates and compares the OXPHOS nuclear genes of Drosophila melanogaster, Drosophila pseudoobscura and Anopheles gambiae.

The oxidative phosphorylation (OXPHOS) is the primary energy-producing process of all aerobic organisms and the only cellular function under the dual control of both the mitochondrial and the nuclear genomes. Functional characterization and evolutionary study of the OXPHOS system is of great importance for the understanding of many as yet unclear aspects of nucleus-mitochondrion genomic co-evolution and co-regulation gene networks. The MitoDrome database is a web-based database which provides genomic annotations about nuclear genes of Drosophila melanogaster encoding for mitochondrial proteins. Recently, MitoDrome has included a new section annotating genomic information about OXPHOS genes in Drosophila pseudoobscura and Anopheles gambiae and their comparative analysis with their Drosophila melanogaster and human counterparts. The introduction of this new comparative annotation section into MitoDrome is expected to be a useful resource for both functional and structural genomics related to the OXPHOS system.

Animals↗

PubMedDate not supplied

The Massachusetts General Hospital annotated bibliography. For residents training in consultation-liaison psychiatry.

The annotated bibliography for the resident's division of the Avery D. Weisman Psychiatry Consultation Service at the Massachusetts General Hospital (MGH) equips the residents with a practical knowledge in consultation-liaison (C-L) psychiatry for their forays onto the floors of the general hospital. As an annotated bibliography, it is not intended to be a comprehensive source for C-L training. However, the basic fund of knowledge prepares MGH's psychiatric residents in a practical way for the variety of questions posed to the C-L service. The authors present this annotated bibliography as a guide for future efforts to establish a core content of knowledge for residents training in C-L psychiatry.

Hospitals, General↗

PubMed2003

How incorrect annotations evolve--the case of short ORFs.

The draft of the human genome sequence is still incomplete. The outstanding tasks include filling in some gaps, finalizing the assembly of short sequences, improving sequence accuracy and correctly identifying coding regions. However, a closely related problem that receives little attention is the substantial number of incorrect annotations that have penetrated some of the widely used databases. This article illustrates this problem using the example of ubiquitin genes, and draws some conclusions that apply to false annotations in other short open reading frames (ORFs). Although the focus is on the human genome, other genomes are equally prone to similar propagation of false annotations.

Databases, Nucleic Acid↗

PubMed2002

Protein interaction verification and functional annotation by integrated analysis of genome-scale data.

Assays capable of determining the properties of thousands of genes in parallel present challenges with regard to accurate data processing and functional annotation. Collections of microarray expression data are applied here to assess the quality of different high-throughput protein interaction data sets. Significant differences are found. Confidence in 973 out of 5342 putative two-hybrid interactions from S. cerevisiae is increased. Besides verification, integration of expression and interaction data is employed to provide functional annotation for over 300 previously uncharacterized genes. The robustness of these approaches is demonstrated by experiments that test the in silico predictions made. This study shows how integration improves the utility of different types of functional genomic data and how well this contributes to functional annotation.

Animals↗

PubMed2002

Large-scale mutational analysis for the annotation of the mouse genome.

After sequencing the human and mouse genomes, the annotation of these sequences with biological functions is an important challenge in genomic research. A major tool to analyse gene function on the organismal level is the analysis of mutant phenotypes. Because of its genetic and physiological similarity to man, the mouse has become the model organism of choice for the study of genetic diseases. In addition, there is at the moment no other vertebrate for which versatile techniques to manipulate the genome are as well developed. Several mouse mutagenesis projects have provided the proof-of-principle that a systematic and comprehensive mutagenesis of every gene in the mammalian genome will be feasible. An exhaustive functional annotation of the mammalian genome can only be achieved in a combination of phenotype- and gene-driven approaches in large- and small-scale academic and private projects. Major challenges will be to develop standardised phenotyping protocols for the clinical and pathological characterisation of mouse mutants, the improvement of mutation detection methods and the dissemination of resources and data. Beyond gene annotation, it will be necessary to understand how gene functions are integrated into the complex network of regulatory interactions in the cell.

Animals↗

PubMed2003

Diagnostic value of onset-recordings and marker annotations in dual chamber pacemaker stored electrograms.

AIMS: Stored electrograms (EGM) have recently been introduced into pacemaker therapy. New generation devices offer the possibility to store the onset of the EGM (several seconds preceding storage trigger) and marker annotations. The aim of the study was to evaluate whether the diagnostic capabilities of EGMs are improved by these new features. METHODS: We studied 65 patients (age 68+/-12 years, 41 male) implanted with a DDDR-system (PulsarMax II 1280; Guidant). During a 1-month period 319 EGMs have been recorded. EGM triggers were: Ventricular Tachycardia (VT), Non-Sustained VT (NSVT), Atrial Tachycardia Response (ATR), Pacemaker Mediated Tachycardia (PMT) and Sudden Bradycardia Response (SBR). First, each EGM was analysed with onset and markers blinded. EGMs were classified with respect to their trigger as confirmed, not-confirmed or false-positive. Analysis was then repeated with markers visible but without onset, and thereafter vice versa. Finally, EGMs were analysed with both features. It was noted whether the presence of marker annotations and/or onset-recording changed the initial classification of the stored EGMs. RESULTS: 169 EGMs were triggered by SBR, which can only be confirmed with onset recording. False positive EGMs (atrial undersensing) occurred in 12%. The remaining 150 EGMs were triggered by ATR (80%), NSVT (11%), VT (6%) and by PMT (3%). Without onset/markers 37 of these 150 EGMs (25%) could not be confirmed. With markers and onset 33/37 (89%) of these EGMs could now be classified as confirmed or false positive. These EGMs became diagnostic with onset alone in 24%, with markers alone in 24%, and with the combination of both in 41%. In 4 EGMs no definite diagnosis could be established. CONCLUSION: Stored electrograms provide direct insights into device function, thereby providing a validation of diagnostic data. The expanded recording of onset and markers results in markedly improved diagnostic capabilities - compared with conventional EGMs. These new features were necessary to interpret correctly 61% of all stored electrograms, without which a diagnosis would not have been possible. Both onset-recording and marker annotation are necessary for optimal analysis.

Aged↗

PubMed2002

Controlling methicillin-resistant Staphylococcus aureus: a feedback approach using annotated statistical process control charts.

OBJECTIVES: To investigate the benefit of a hospitalwide feedback program regarding methicillin-resistant Staphylococcus aureus (MRSA), using annotated statistical process control charts. DESIGN: Retrospective and prospective analysis of MRSA rates using statistical process control charts. PARTICIPANTS: Twenty-four medical, medical specialty, surgical, intensive care, and cardiothoracic care wards and units at four Glasgow Royal Infirmary hospitals. METHODS: Annotated control charts were applied to prospective and historical monthly data on MRSA cases from each ward and unit during a 46-month period from January 1997 through September 2000. Results were fed back from December 1999 and then on a regular monthly basis to medical staff, ward managers, senior managers, and hotel services. RESULTS: Monthly reductions in the MRSA acquisition rate started 2 months after the introduction of the feedback program and have continued to the present time. The overall MRSA rate currently is approximately 50% lower than when the program began and has become more consistent and less variable within departments throughout Glasgow Royal Infirmary. The control charts have helped to detect rate changes and manage resources more effectively. Medical and nursing staff and managers also report that they find this the most positive form of MRSA feedback they have received. CONCLUSIONS: Feedback programs that provide current information to front-line staff and incorporate annotated control charts can be effective in reducing the rate of MRSA.

Humans↗

PubMed2006

Evidence standards in experimental and inferential INSDC Third Party Annotation data.

The Third Party Annotation (TPA) project collects and presents high-quality annotation of nucleotide sequence. Annotation is submitted by researchers who have not themselves generated novel nucleotide sequence. In its first few years, the resource has proven to be popular with submitters from a range of biological research areas. Central to the project is the requirement for high-quality data, resulting from experimental and inferred analysis discussed in peer-reviewed publications. The data are divided into two tiers: those with experimental evidence and those with inferential evidence. Standards for TPA are detailed and illustrated with the aid of case studies.

Animals↗

PubMed2003

The Drosophila melanogaster genome sequencing and annotation projects: a status report.

The sequence and genome annotations of Drosophila melanogaster were initially published in late 1999 and early 2000. Since then, the Berkeley Drosophila Genome Project (BDGP) and FlyBase have improved the quality of the sequence and reviewed the annotations by hand, respectively, to produce an account of the fruit fly genome that is of the highest quality. This review discusses the main features of this process, both from the point of view of the biology revealed in the end result and in the development of software that has been central to this genome sequencing and annotation project.

Animals↗

PubMed2003

Viewing and annotating sequence data with Artemis.

Artemis is a widely used software tool for annotating and viewing sequence data. No database is required to use Artemis. Instead, individual sequence data files can be analysed with little or no formatting, making it particularly suited to the study of small genomes and chromosomes, and straightforward for a novice user to get started. Since its release in 1999, Artemis has been used to annotate a diverse collection of prokaryotic and eukaryotic genomes, ranging from Streptomyces coelicolor to, more recently, a large proportion of the Plasmodium falciparum genome. Artemis allows annotated genomes to be easily browsed and makes it simple to add useful biological information to raw sequence data. This paper gives an overview of some of the features of Artemis and includes how it facilitates manual gene prediction and can provide an overview of entire chromosomes or small compact genomes--useful for uncovering unusual features such as pathogenicity islands.

Animals↗