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Windows to the ward: graphically oriented report forms. Presentation of complex, interrelated laboratory data for electrophoresis/immunofixation, cerebrospinal fluid, and urinary protein profiles.

BACKGROUND: Automated laboratory analyzers that mass produce data have been linked to information systems for more than two decades, but little progress has been made in developing more comprehensible report forms. Results are still reported in computer-generated printouts containing hundreds of numbers crowded into columns on each printed page. METHODS: We developed three software applications focusing on the graphic presentation of laboratory results. RESULTS: The first application summarizes data for a patient with a monoclonal gammopathy. The report provides a cumulative graphic presentation of immunofixation/electrophoresis data without any additional interpretation, focuses on a color-coded electrophoresis scan, and records up to 5 years on a single page. The second application deals with cerebrospinal fluid analysis. The report calculates relevant data and graphs the complex relationship between albumin and immunoglobulin results from paired serum and cerebrospinal fluid samples. Manually added interpretive text assures an output comprehensible to clinicians in all specialties. The third application produces a report summarizing quantitatively measured urinary marker protein profiles. The report form is generated by a flexible, completely user-definable knowledge-based system. It calculates numerous ratios and formulae, supports reflex testing, supplies an automated interpretation, and generates a specific graphic signature pattern of the results (MDI LabLink proteinuria differentiation). CONCLUSIONS: Increased clinical demand for graphically oriented report forms 5 years after their introduction has provided evidence that these reports transfer complex laboratory data and results to the clinician more effectively. The highest (more than threefold) increase in demand has been for reports for urinary marker protein profiles that feature a largely self-explanatory graphic signature pattern.

Autoanalysis↗

Whole-proteome prediction of protein function via graph-theoretic analysis of interaction maps.

MOTIVATION: Determining protein function is one of the most important problems in the post-genomic era. For the typical proteome, there are no functional annotations for one-third or more of its proteins. Recent high-throughput experiments have determined proteome-scale protein physical interaction maps for several organisms. These physical interactions are complemented by an abundance of data about other types of functional relationships between proteins, including genetic interactions, knowledge about co-expression and shared evolutionary history. Taken together, these pairwise linkages can be used to build whole-proteome protein interaction maps. RESULTS: We develop a network-flow based algorithm, FunctionalFlow, that exploits the underlying structure of protein interaction maps in order to predict protein function. In cross-validation testing on the yeast proteome, we show that FunctionalFlow has improved performance over previous methods in predicting the function of proteins with few (or no) annotated protein neighbors. By comparing several methods that use protein interaction maps to predict protein function, we demonstrate that FunctionalFlow performs well because it takes advantage of both network topology and some measure of locality. Finally, we show that performance can be improved substantially as we consider multiple data sources and use them to create weighted interaction networks. AVAILABILITY: http://compbio.cs.princeton.edu/function

Algorithms↗

Biochemical networks with uncertain parameters.

The modelling of biochemical networks becomes delicate if kinetic parameters are varying, uncertain or unknown. Facing this situation, we quantify uncertain knowledge or beliefs about parameters by probability distributions. We show how parameter distributions can be used to infer probabilistic statements about dynamic network properties, such as steady-state fluxes and concentrations, signal characteristics or control coefficients. The parameter distributions can also serve as priors in Bayesian statistical analysis. We propose a graphical scheme, the 'dependence graph', to bring out known dependencies between parameters, for instance, due to the equilibrium constants. If a parameter distribution is narrow, the resulting distribution of the variables can be computed by expanding them around a set of mean parameter values. We compute the distributions of concentrations, fluxes and probabilities for qualitative variables such as flux directions. The probabilistic framework allows the study of metabolic correlations, and it provides simple measures of variability and stochastic sensitivity. It also shows clearly how the variability of biological systems is related to the metabolic response coefficients.

Animals↗

A knowledge-based model construction approach to medical decision making.

We present a framework for representing the probabilistic effects of actions and contingent treatment plans. Our language has a well-defined declarative semantics and we have developed an implemented algorithm (named BNG) that generates Bayesian networks (BN) to compute the posterior probabilities of queries. In this paper we address the problem of projecting a contingent treatment plan by automatically constructing a structure of interrelated BNs, which we call a BN-graph, and applying the available propagation procedures on it. To address the optimal plan generation, we base our approach on the observation that normally the target plan space has a well-defined structure. We provide a language to describe plan spaces which resembles a programming language with loops and conditionals. We briefly present the procedures for finding the optimal plan(s) from such specified plan spaces.

Acute Disease↗

A hypergraph-based method for unification of existing protein structure- and sequence-families.

Classification of proteins is a major challenge in bioinformatics. Here an approach is presented, that unifies different existing classifications of protein structures and sequences. Protein structural domains are represented as nodes in a hypergraph. Shared memberships in sequence families result in hyperedges in the graph. The presented method partitions the hypergraph into clusters of structural domains. Each computed cluster is based on a set of shared sequence family memberships. Thus, the clusters put existing protein sequence families into the context of structural family hierarchies. Conversely, structural domains are related to their sequence family memberships, which can be used to gain further knowledge about the respective structural families.

Databases, Protein↗

Hierarchical functional organization of formal biological systems: a dynamical approach. III. The concept of non-locality leads to a field theory describing the dynamics at each level of organization of the (D-FBS) sub-system.

In paper I, the construction of the graph of interactions, called (O-FBS), was deduced from the 'self-association hypothesis'. In paper II, a criterion of evolution during development for the (O-FBS), which represents the topology of the biological system, was deduced from an optimum principle leading to specific dynamics. Experimental verification of the proposed extremum hypothesis is possible because precise knowledge of the dynamics is not necessary; only knowledge of the monotonic variation of the number of sinks is required for given initial conditions. Essentially, the properties of the (O-FBS) are based on the concept of non-symmetry of functional interactions, as shown by the 'orgatropy' function (paper II). In this paper, a field theory is proposed to describe the (D-FBS), i.e. the physiological processes expressed by functional interactions: (i) physiological processes are conceived as the transport of a field variable submitted to the action of a field operator; (ii) because of hierarchy, this field theory is based on the concept of non-locality, and includes a non-local and non-symmetric interaction operator; (iii) the geometry of the structure contributes to the dynamics via the densities of structural units; and (iv) because a physiological process evolves on a particular timescale, it is possible to classify the levels of organization according to distinct timescales, and, therefore, to obtain a 'decoupling' of dynamics at each level. Thus, a property of structurality for a biological system is proposed, which is based on the finiteness of the velocity of the interaction, thus, with distinct values of timescales for the construction of the hierarchy of the system. Three axioms are introduced to define the fields associated with the topology of the system: (i) the existence of the fields; (ii) the decoupling of the dynamics; and (iii) the ability of activation-inhibition. This formulation leads to a self-coherent definition of auto-organization: an FBS is self-organized if it goes from one stable state for the (D-FBS) to another under the influence of certain modifications of its topology, i.e. a modification of the (O-FBS). It is shown that properties deduced with this formalism give the relationship between topology and geometry in an FBS, and particularly, the geometrical re-distribution of units.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

[Activation of student cognitive activities in the process of teaching medical microbiology].

The main trends of methodical work conducted at the chair of microbiology of Orenburng Medical Institute are presented. For the purpose of activation of cognition activity of students during medical microbiology teaching the following methods were applied: presentation of the teaching material, creation of visual teaching methods in a single methodical plan in accordance with the logic structure graphs of the subject as a whole, its individual sections and themes; introduction of problem teaching method, solution of practical tasks of the II and III learning level; introduction of scientific achievements of the chair into the teaching process. Result of evaluation of the efficacy of the teaching-methodical work of the chair carried out demonstrated that knowledge of the principal microbiology problems in the students and interns persisted for long periods of time.

Cognition↗

An approach to completely automatic comparison of two-dimensional electrophoresis gels.

The problem addressed is that of determining the similarities and differences appearing in a sequence of two-dimensional polyacrylamide gels where we have no a priori knowledge of the intensity and spatial distribution of the protein spots. It is assumed that the gels are not in precise registration. An attempt is being made to develop a completely automatic program for use in genetic studies, which will compare a sequence of three gels run on samples from father, mother, and child. The program constructs a graph by using as nodes those spot cues that exceed a given intensity threshold. The graphs are then compared to determine an initial subset of spots that are common to all three gels. From this subset of common spots the program then determines whether the remaining graph differences are real or result from quantitative variation causing spots to fall below threshold.

Adult↗

[Pressure distribution on the sole of the human foot while standing and walking, barefoot and with shoes].

For more than a century, scientists and practicians of orthopedic shoe production have been increasing their knowledge on the normal statics and dynamics of the lower extremities as well as on innate or often acquired posture anomalies and foot deformities. Even amongst young adults, barely half of one percent has so-called "inconspicuous" feet without restrictive signs of foot deformities. Consequently, the resulting primary illnesses and secondary injuries must be treated. Quantitative pressure distribution graphs in isobaric representation at the heel barefoot when standing and walking were determined by means of an improved, locally fixed device by Elftman and Helm. For the first time, a newly developed mobile measuring process allows measuring pressures at the heel inside the shoe while standing as well as while walking, running or jumping. The rolloff motion of the heel allowed the determination of a "maximum pressure line." Orthopedic recommendations for the production of true-to-form and true-to-function shoes for walking and sports shoes are included.

Biomechanical Phenomena↗

A comparative study of cells in inflammation, EAE and MS using biomedical literature data mining.

Biomedical literature and database annotations, available in electronic forms, contain a vast amount of knowledge resulting from global research. Users, attempting to utilize the current state-of-the-art research results are frequently overwhelmed by the volume of such information, making it difficult and time-consuming to locate the relevant knowledge. Literature mining, data mining, and domain specific knowledge integration techniques can be effectively used to provide a user-centric view of the information in a real-world biological problem setting. Bioinformatics tools that are based on real-world problems can provide varying levels of information content, bridging the gap between biomedical and bioinformatics research. We have developed a user-centric bioinformatics research tool, called BioMap, that can provide a customized, adaptive view of the information and knowledge space. BioMap was validated by using inflammatory diseases as a problem domain to identify and elucidate the associations among cells and cellular components involved in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). The BioMap system was able to demonstrate the associations between cells directly excavated from biomedical literature for inflammation, EAE and MS. These association graphs followed the scale-free network behavior (average gamma = 2.1) that are commonly found in biological networks.

Animals↗

Likelihood analysis of phylogenetic networks using directed graphical models.

A method for computing the likelihood of a set of sequences assuming a phylogenetic network as an evolutionary hypothesis is presented. The approach applies directed graphical models to sequence evolution on networks and is a natural generalization of earlier work by Felsenstein on evolutionary trees, including it as a special case. The likelihood computation involves several steps. First, the phylogenetic network is rooted to form a directed acyclic graph (DAG). Then, applying standard models for nucleotide/amino acid substitution, the DAG is converted into a Bayesian network from which the joint probability distribution involving all nodes of the network can be directly read. The joint probability is explicitly dependent on branch lengths and on recombination parameters (prior probability of a parent sequence). The likelihood of the data assuming no knowledge of hidden nodes is obtained by marginalization, i.e., by summing over all combinations of unknown states. As the number of terms increases exponentially with the number of hidden nodes, a Markov chain Monte Carlo procedure (Gibbs sampling) is used to accurately approximate the likelihood by summing over the most important states only. Investigating a human T-cell lymphotropic virus (HTLV) data set and optimizing both branch lengths and recombination parameters, we find that the likelihood of a corresponding phylogenetic network outperforms a set of competing evolutionary trees. In general, except for the case of a tree, the likelihood of a network will be dependent on the choice of the root, even if a reversible model of substitution is applied. Thus, the method also provides a way in which to root a phylogenetic network by choosing a node that produces a most likely network.

Computer Graphics↗

[Mortality analysis: when is single evaluation of the basic cause of death allowable, when should multi-causality be assessed?].

Data quality is often a critical point in mortality studies. The purpose of the present report is to present criteria for assessing the value of death-certificate-based mortality studies. For this purpose all 57,454 Swiss death certificates of the year 1979 were analysed. Reliability of the diagnosis listed on the death certificate was investigated by comparing for each case of a linked sample of 12,478 deaths the cause of death with medical information available from the hospital record. Retrieval rates (percentage of cases for which the given diagnosis appears in both registries) were calculated for the primary diagnoses named in each data set. These can be considered as measures of reliability of diagnoses. The graphs given indicate a high reliability for cancers and accidents. Reliability was lower for other causes of death such as cardiovascular diseases, diabetes mellitus, rheumatic diseases. Restriction to the primary cause of death can be accepted for most cancers, accidents and violent deaths. For other causes of death, decisions must be made individually and multicausal analysis may be indicated. In addition, knowledge of the reliability of the diagnoses of interest is necessary for the interpretation of results derived from death certificate-based mortality studies.

Cause of Death↗

Internal temperature calibration for 1H NMR spectroscopy studies of blood plasma and other biofluids.

A method for temperature calibration of human blood plasma and cerebrospinal fluid (CSF) samples inside a high resolution NMR spectrometer is presented. This calibration is based on the temperature dependence of the chemical shift difference between the water signal and that from the H-1 proton of endogenous alpha-glucose or, in some circumstances, beta-glucose. This dependence can be fitted using a second-order polynomial equation and functions for both human blood plasma and human CSF are given. Similar graphs could easily be generated for other fluids. The blood plasma calibration appears to be accurate to +/- 0.9 K in test samples. The use of the blood plasma calibration graph has also been evaluated using the 1H NMR spectra of CSF and shown to overestimate the CSF internal temperature by ca 1.3 K. This approach should have a general applicability to blood plasma and CSF samples from normal and pathological situations or from other species, because there are unlikely to be large changes in ionic strength or pH even in disease states. Knowledge of the exact internal temperature of plasma samples is likely to be of particular importance in the investigation of lipid and lipoprotein interactions because of the significant temperature dependence of lipid and lipoprotein NMR linewidths in such samples.

Body Fluids↗

CoryneRegNet: an ontology-based data warehouse of corynebacterial transcription factors and regulatory networks.

BACKGROUND: The application of DNA microarray technology in post-genomic analysis of bacterial genome sequences has allowed the generation of huge amounts of data related to regulatory networks. This data along with literature-derived knowledge on regulation of gene expression has opened the way for genome-wide reconstruction of transcriptional regulatory networks. These large-scale reconstructions can be converted into in silico models of bacterial cells that allow a systematic analysis of network behavior in response to changing environmental conditions. DESCRIPTION: CoryneRegNet was designed to facilitate the genome-wide reconstruction of transcriptional regulatory networks of corynebacteria relevant in biotechnology and human medicine. During the import and integration process of data derived from experimental studies or literature knowledge CoryneRegNet generates links to genome annotations, to identified transcription factors and to the corresponding cis-regulatory elements. CoryneRegNet is based on a multi-layered, hierarchical and modular concept of transcriptional regulation and was implemented by using the relational database management system MySQL and an ontology-based data structure. Reconstructed regulatory networks can be visualized by using the yFiles JAVA graph library. As an application example of CoryneRegNet, we have reconstructed the global transcriptional regulation of a cellular module involved in SOS and stress response of corynebacteria. CONCLUSION: CoryneRegNet is an ontology-based data warehouse that allows a pertinent data management of regulatory interactions along with the genome-scale reconstruction of transcriptional regulatory networks. These models can further be combined with metabolic networks to build integrated models of cellular function including both metabolism and its transcriptional regulation.

Computer Graphics↗

Genomic insights into natural selection in recent human history.

For over a century, scientists have debated the extent to which genetic and phenotypic variation among present-day humans is the result of natural selection - in which heritable traits influence survival or reproduction - versus neutral processes such as genetic drift or population history. The initial sequencing of the human genome and subsequent population resequencing studies enabled genome-scale searches for signatures of selection in present-day genomes. This first generation of genome-wide selection scans identified many targets but left open questions about the timing and nature of selection, making it challenging to identify environmental and biological drivers. Recent methodological advances based on reconstructing ancestral recombination graphs have increased the potential power and resolution of selection scans based on present-day genomes, while the availability of new data on ancient DNA has facilitated the direct reconstruction of genetic change through time. However, there is little consensus on how to use these data to detect and interpret signatures of selection, while avoiding confounders. Here, we review the current state of knowledge about the impact of selection on human genomic diversity and highlight conceptual advances in our understanding of human evolution over the past 10,000 years.

Journal Article↗

Co-clustering of biological networks and gene expression data.

MOTIVATION: Large scale gene expression data are often analysed by clustering genes based on gene expression data alone, though a priori knowledge in the form of biological networks is available. The use of this additional information promises to improve exploratory analysis considerably. RESULTS: We propose constructing a distance function which combines information from expression data and biological networks. Based on this function, we compute a joint clustering of genes and vertices of the network. This general approach is elaborated for metabolic networks. We define a graph distance function on such networks and combine it with a correlation-based distance function for gene expression measurements. A hierarchical clustering and an associated statistical measure is computed to arrive at a reasonable number of clusters. Our method is validated using expression data of the yeast diauxic shift. The resulting clusters are easily interpretable in terms of the biochemical network and the gene expression data and suggest that our method is able to automatically identify processes that are relevant under the measured conditions.

Algorithms↗

GeneInfoViz: constructing and visualizing gene relation networks.

Large amounts of knowledge about genes have been stored in public databases. One of the most challenging problems in Bioinformatics is, given all the information about the genes in the databases, determining the relationships between the genes. For example, how can we determine if genes are related and how closely they are related based on existing knowledge about their biological roles. We developed GeneInfoViz, a web tool for batch retrieval of gene information and construction and visualization of gene relation networks. We created a database containing compiled Gene Ontology information for the genes of several model organisms. Users can batch search for a group of genes and get the Gene Ontology terms that are associated with the genes. Directed acyclic graphs are generated to show the hierarchical structure of the Gene Ontology tree. GeneInfoViz calculates an adjacency matrix to determine whether the genes are related and, if so, how closely they are related based on biological processes, molecular functions, or cellular components they are associated with and then displays a dynamic graph layout of the network among the selected genes.

Databases, Genetic↗

Knowledge on collection and analysis of health information of state certified nurses from rural health centres, Masvingo Province.

OBJECTIVE: To assess the knowledge on collection and analysis of health information of State Certified Nurses (SCNs) from Rural Health Centres (RHCs), Masvingo Province. DESIGN: Three methods were employed during the assessment: a questionnaire, observation, and practical exercises (calculations). SETTINGS: 19 RHCs in Chiredzi and Bikita Districts, Masvingo Province. SUBJECTS: 19 SCNs in charge of Rural Health Centres. MAIN OUTCOME MEASURES: Ability to analyze and utilize health information, availability of graphs, master cards summaries (health diaries) and minutes. Presence or absence of catchment maps, charts on population breakdown and immunization coverage charts. Ability to calculate some rates and percentages. RESULTS: Of 19 SCNs in charge who said they do school health programmes, only six had any evidence that they do so; of nine SCNs in charge who reported that they have graphs on weekly reported diseases, only four had graphs displayed. Of 18 SCNs in charge who said they had immunization coverage targets only 11 had charts displayed; of 18 SCNs in charge who reported that they discuss health problems in their areas, only one had minutes documenting the discussion. Only six of 19 SCNs at rural centres could calculate coverage rates and only one of 19 SCNs at health centres could calculate dropout rates. CONCLUSION: Comparing the questionnaire responses with the findings from observations, it can be seen that more is reported than is actually done. From the practical exercises it was evident that the ability to do basic calculations was often lacking.

Data Collection↗