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PubMedDate not supplied

Statistical methods of computing reference values for side-to-side differences in nerve conduction studies.

This study uses theoretic derivations, statistical simulations, and empirical estimations to compare two ways of deriving reference values for side-to-side differences in nerve conduction parameters of healthy subjects. The two methods involve using the side-to-side differences (STSD) and the absolute values of the STSD (AVSTSD). The theoretic derivations showed that the population reference value of the AVSTSD is greater than the STSD reference values by 0.18%. Simulation studies showed that the AVSTSD yields greater sampling errors than the STSD method when establishing the reference values for nerve conduction parameters. However, the sampling variability is substantially reduced by using study samples of greater than 50, and the differences between the two methods in sampling errors are trivial as sample size approaches 100. Using H reflex (HR) and extensor digitorum brevis reflex (EDBR) clinical data, the two methods were compared. In contrast to the small theoretic differences in reference values, the AVSTSD method overestimated the reference value by 0.5 ms for the EDBR and 0.1 ms for the H reflex, when using data from a population sample, increasing the type II error (reducing sensitivity) for the EDBR. The STSD method is recommended for establishment of normal values and for clinical comparisons.

Electromyography↗
PubMed2005

Sample size computations for PK/PD population models.

We describe an accurate, yet simple and fast sample size computation method for hypothesis testing in population PK/PD studies. We use a first order approximation to the nonlinear mixed effects model and chi-square distributed Wald statistic to compute the minimum sample size to achieve given degree of power in rejecting a null hypothesis in population PK/PD studies. The method is an extension of Rochon's sample size computation method for repeated measurement experiments. We compute sample sizes for PK and PK/PD models with different conditions, and use Monte Carlo simulation to show that the computed sample size retrieves the required power. We also show the effect of different sampling strategies, such as minimal, i.e., as many observations per individual as parameters in the model, and intensive on sample size. The proposed sample size computation method can produce estimates of minimum sample size to achieve the desired power in hypothesis testing in a greatly reduced time than currently available simulation-based methods. The method is rapid and efficient for sample size computation in population PK/PD study using nonlinear mixed effect models. The method is general and can accommodate any type of hierarchical models. Simulation results suggest that intensive sampling allows the reduction of the number of patients enrolled in a clinical study.

Algorithms↗
PubMedDate not supplied

[Methods of computer modeling and conformational mobility of DNA duplexes].

The review is focused on issues of transferability of the context-sensitive conformational characteristics of DNA estimated from crystallographic structural data on the DNA in aqueous solution. The state of the art in molecular dynamics of charged biopolymers in aqueous solution is covered. Elaboration of expedient force fields and algorithms of calculating long-range electrostatic interactions and solving combined equations of atomic motion have made it possible to generate stable nanosecond trajectories of thermal atomic motion of the biopolymer in aqueous solution in the presence of counterions and salt ions over reasonable time. Tools for analyzing the atomic statistical trajectories of DNA duplexes in aqueous solution to infer context-sensitive conformational dynamic characteristics are discussed together with advances in simulating the mechanisms of global axial bend in DNA duplexes. These techniques allow one to consecutively analyze relationships between the contextual composition of the duplex and the basic modes of essential motions, their amplitude and extent of fluctuation. Development of satisfactory methods for estimating the free energy of biopolymer conformations in solution permits qualitative assessment of the conformational thermodynamic stability of biopolymers and their complexes.

Computer Simulation↗
PubMed1995

Update on computer-aided drug design.

Recent advances in computational methods for drug design include developments in quantitative structure-activity relationship approaches as well as novel structure-based strategies. Many new protein structures of pharmaceutical interest have been solved, a number of which contain a bound inhibitor. Continued progress has been reported in algorithms for de novo design, ligand docking, and scoring of protein-ligand binding energy. Meanwhile, several drugs that were designed by intensive use of computational methods are advancing through clinical trials.

Biotechnology↗
PubMed2003

A structural-informatics approach for mining beta-sheets: locating sheets in intermediate-resolution density maps.

Here, we report a new computational method, called sheetminer, for mining beta-sheets in the density maps at intermediate resolutions of 6 to 10A. The method employs a multi-step ad hoc morphological analysis of density maps to identify the unique characteristics of beta-sheets. It was tested on density maps from 12 protein crystal structures that were artificially blurred to intermediate resolutions. There are a total of 35 independent beta-sheets with a wide distribution of morphology. The method successfully located 34 of them and missed only one. The method was also applied to an experimental 9A electron cryomicroscopic structure and an 8A X-ray density map. In both cases, the sheet-searching results were found to agree very well with known high-resolution crystal structures. Collectively, these results demonstrate clearly the robustness of sheetminer in locating the regions belonging to beta-sheets in the intermediate-resolution density maps. Furthermore, sheetminer is completely complementary to all other existing computational methods, including helixhunter and threading algorithms. Their combined usage has the potential to significantly enhance the computational modeling capacity for a much more complete interpretation of structural data at intermediate resolutions, from which extraction of functional information would be more effective. This is particularly important in the field of structural genomics, in which the fast screening approach may not always yield crystals that diffract to atomic resolution. An exciting future application of sheetminer is as a valuable tool for revealing the structures of amyloid fibrils that are rich in beta-motifs.

Algorithms↗
PubMedDate not supplied

[Possibilities of radiologic methods (ultrasonography, computed tomography) in the preoperative evaluation of intramural invasion of gastric cancer].

By analyzing the findings in 72 patients with gastric cancer, the authors show the potentialities of noninvasive techniques of radiation diagnosis (transabdominal ultrasonography (USG) and X-ray computed tomography (CT) in the preoperative evaluation of the T-stage of gastric cancer. Ultrasound and computed tomographic semiotics of intramural invasion of gastric carcinoma is made. Ultrasonography was found to have the highest specificity in detecting early-stage gastric cancers prior to computed tomography. In the authors' opinion, a complex use of the data obtained by these techniques reveals the degree of invasion of gastric carcinoma and its extent with high precision. Transabdominal USG and CT should rank with the initial methods used for diagnosing gastric cancer. Transabdominal USG should be most expediently used as an initial technique of the above studies, by taking into account its wide accessibility, easiness-to-use, and lack of radiation load.

Adenocarcinoma↗
PubMed2003

Computational discovery of internal micro-exons.

Very short exons, also known as micro-exons, occur in large numbers in some eukaryotic genomes. Existing annotation tools have a limited ability to recognize these short sequences, which range in length up to 25 bp. Here, we describe a computational method for the identification of micro-exons using near-perfect alignments between cDNA and genomic DNA sequences. Using this method, we detected 319 micro-exons in 4 complete genomes, of which 224 were previously unknown, human (170), the nematode Caenorhabditis elegans (4), the fruit fly Drosophila melanogaster (14), and the mustard plant Arabidopsis thaliana (36). Comparison of our computational method with popular cDNA alignment programs shows that the new algorithm is both efficient and accurate. The algorithm also aids in the discovery of micro-exon-skipping events and cross-species micro-exon conservation.

Alternative Splicing↗
PubMed2002

Applications of computational toxicology methods at the Agency for Toxic Substances and Disease Registry.

In its efforts to provide consultations to state and local health departments, other federal agencies, health professionals, and the public on the health effects of environmental pollutants, the Agency for Toxic Substances and Disease Registry relies on the latest advances in computational toxicology. The computational toxicology laboratory at the agency is continually engaged in developing and applying models for decision-support tools such as physiologically based pharmacokinetic (PBPK) models, benchmark dose (BMD) models, and quantitative structure-activity relationship (QSAR) models. PBPK models are suitable for connecting exposure scenarios to biological indicators such as tissue dose or end point response. The models are used by the agency to identify the significance of exposure routes in producing tissue levels of possible contaminants for people living near hazardous waste sites. Additionally, PBPK models provide a credible scientific methodology for route-to-route extrapolations of health guidance values, which are usually determined from a very specific set of experiments. Also, scientists at the computational toxicology laboratory are using PBPK models for advancing toxicology research in such areas as joint toxicity assessment and child-based toxicity assessments. With BMD modeling, all the information embedded in an experimentally determined dose-response relationship is used to estimate, with minimum extrapolations, human health guidance values for environmental substances. Scientists in the laboratory also rely on QSAR models in the many cases where consultations from the agency are reported for chemicals that lack adequate experimental documentation.

Benchmarking↗
PubMed1999

A method for computational combinatorial peptide design of inhibitors of Ras protein.

A computational combinatorial approach is proposed for the design of a peptide inhibitor of Ras protein. The procedure involves three steps. First, a 'Multiple Copy Simultaneous Search' identifies the location of specific functional groups on the Ras surface. This search method allowed us to identify an important binding surface consisting of two beta strands (residues 5-8 and 52-56), in addition to the well known Ras effector loop and switch II region. The two beta strands had not previously been reported to be involved in Ras-Raf interaction. Second, after constructing the peptide inhibitor chain based on the location of N-methylacetamide (NMA) minima, functional groups are selected and connected to the main chain Calpha atom. This step generates a number of possible peptides with different sequences on the Ras surface. Third, potential inhibitors are designed based on a sequence alignment of the peptides generated in the second step. This computational approach reproduces the conserved pattern of hydrophobic, hydrophilic and charged amino acids identified from the Ras effectors. The advantages and limitations of this approach are discussed.

Acetamides↗
PubMed1995

Unlocking clinical data from narrative reports: a study of natural language processing.

OBJECTIVE: To evaluate the automated detection of clinical conditions described in narrative reports. DESIGN: Automated methods and human experts detected the presence or absence of six clinical conditions in 200 admission chest radiograph reports. STUDY SUBJECTS: A computerized, general-purpose natural language processor; 6 internists; 6 radiologists; 6 lay persons; and 3 other computer methods. MAIN OUTCOME MEASURES: Intersubject disagreement was quantified by "distance" (the average number of clinical conditions per report on which two subjects disagreed) and by sensitivity and specificity with respect to the physicians. RESULTS: Using a majority vote, physicians detected 101 conditions in the 200 reports (0.51 per report); the most common condition was acute bacterial pneumonia (prevalence, 0.14), and the least common was chronic obstructive pulmonary disease (prevalence, 0.03). Pairs of physicians disagreed on the presence of at least 1 condition for an average of 20% of reports. The average intersubject distance among physicians was 0.24 (95% Cl, 0.19 to 0.29) out of a maximum possible distance of 6. No physician had a significantly greater distance than the average. The average distance of the natural language processor from the physicians was 0.26 (Cl, 0.21 to 0.32; not significantly greater than the average among physicians). Lay persons and alternative computer methods had significantly greater distance from the physicians (all > 0.5). The natural language processor had a sensitivity of 81% (Cl, 73% to 87%) and a specificity of 98% (Cl, 97% to 99%); physicians had an average sensitivity of 85% and an average specificity of 98%. CONCLUSIONS: Physicians disagreed on the interpretation of narrative reports, but this was not caused by outlier physicians or a consistent difference in the way internists and radiologists read reports. The natural language processor was not distinguishable from the physicians and was superior to all other comparison subjects. Although the domain of this study was restricted (six clinical conditions in chest radiographs), natural language processing seems to have the potential to extract clinical information from narrative reports in a manner that will support automated decision-support and clinical research.

Humans↗
PubMed1999

Integrating computation and visualization for biomolecular analysis: an example using python and AVS.

One of the challenges in biocomputing is to enable the efficient use of a wide variety of fast-evolving computational methods to simulate, analyze, and understand the complex properties and interactions of molecular systems. Our laboratory investigates several areas including molecular visualization, protein-ligand docking, protein-protein docking, molecular surfaces, and the derivation of phenomenological potentials. In this paper we present an approach based on the Python programming language to achieve a high level of integration between these different computational methods and our primary visualization system AVS. This approach removes many limitations of AVS while increasing dramatically the inter-operability of our computational tools. Several examples are shown to illustrate how this approach enables a high level of integration and inter-operability between different tools, while retaining modularity and avoiding the creation of a large monolithic package that is difficult to extend and maintain.

Capsid↗
PubMed1990

Vertebral cortical bone mass measurement by a new quantitative computer tomography method: correlations with vertebral trabecular bone measurements.

Previous studies comparing axial and appendicular skeleton have shown that trabecular bone loss is greater than cortical bone loss. However, whether the same difference exists between the trabecular and the cortical compartments of the vertebral body remains to be determined. In this study, we used quantitative computer tomography (QCT) to simultaneously measure the cortical rim of the vertebral body as well as trabecular bone. In 99 Caucasian women (mean age 53.8 +/- 13.0 years, range 26-79 years) we found a significant correlation between cortical mineral content (BMCC) and both single (SE) and dual energy (DE) trabecular mineral content (BMCT) (r = 0.62, P less than 0.0001 for both regressions). The cross-sectional rates of bone loss per year were 1.32%, 1.16%, and 0.59% for SE-BMCT, DE-BMCT, and BMCC, respectively. BMCC decreased at a rate that was 45-51% that of SE-BMCT and DE-BMCT, respectively. Our results indicate that (1) QCT may provide a useful means to selectively measure cortical density in vertebral bodies; (2) the decrease of cortical density over time in the spine appears to have been underestimated previously by extrapolation from appendicular bone measurements; (3) because measurements of the entire vertebral body (exclusive of the posterior elements) may provide information that is more representative of spine changes with age, a measurement that includes both areas might be more useful than one measuring only the trabecular region.

Adult↗
PubMed1987

A computer-based method of measuring facial asymmetry. Results from an assessment of the repair of cleft lip deformities.

The appearance of the nose, mouth and nostrils was analysed in two series of unilateral, complete cleft lip patients. A programme was written for use on a BBC microcomputer to measure the symmetry of facial features traced from photographs. Symmetry was measured using one of two methods: determining the area of non-overlap when one side was reflected on the other (area method) or calculating the distance from regularly spaced points on the outline of one side to the nearest point on the reflection of the opposite side (curve method). The rankings of the photographs based on these results were compared with the subjective rankings given by a lay panel. The results based on the curve method agreed well with the subjective rankings (P for Spearman Rank Correlation Coefficients = less than 0.02). The technique provides a cheap, simple and quick method of comparing symmetry in groups of patients.

Adolescent↗