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PubMed2005

[The application of a systematic-dynamic model to study the computer simulation of severe acute respiratory syndrome transmission and the impact of control measures].

OBJECTIVE: (1) Building a macroscopical systematic-dynamic model of severe acute respiratory syndrome (SARS) transmission and disease control process. (2) To determine key variables on the control of SARS epidemic through computer simulation methodology, especially to analyze the effect of "screening for fever" practice during the epidemics. (3) To provide evidence for related decision-making. METHODS: Parameters in the model were collected from local hospitals and municapal CDC through interview, questionnaire survey, literature review and case analysis. A systematic-dynamic model was built under similar studies. 'What-if' analysis was used during the simulation process. RESULTS: (1) The mean duration between disease onset and hospital admission, rate of contacts of each infectious individual as well as the rate of contacts in hospital of each infectious individual appeared to be the key variables in the process of SARS transmission. (2) Physician's alertness/sense and practice of self-protection on SARS, measures on quarantine and isolation to the patients, ventilation and disinfection process in the wards appeared to be the key variables for the control of epidemics. (3) "Screening for fever" practice on each patient at the entrance of the hospital did not seem to act as an important factor to the control of the epidemics. CONCLUSION: The health system in Beijing can control SARS epidemic rapidly based on current applied disease control measures and plan.

China↗
PubMed1996

The computer-assisted microscope analysis of Feulgen-stained nuclei linked to a supervised learning algorithm as an aid to prognosis assessment in invasive transitional bladder cell carcinomas.

The aim of the present work is to ascertain whether additional information to grading and staging can be obtained for the prognosis of invasive bladder tumours (T2, T3, T4) by means of two computer-assisted methodologies. The first methodology relates to the digital image analysis of Feulgen-stained nuclei and the second to a supervised learning algorithm named Decision Tree. The digital image analysis of Feulgen-stained nuclei generated 11 variables for nuclear DNA content and 15 for quantitatively describing chromatin pattern. These 26 variables were submitted to a Decision Tree technique which produces multi-attribute logical classification rules by selecting informative variables and determining discriminatory values for each of them. A series of 41 patients for which the majority of the T2 bladder tumours (68%) were associated with a 'good' prognosis (remission) while the majority of the T3-T4 ones (77%) were associated with a 'bad' one (clinical progression or death) were submitted to the proposed approach. The results show that the decision tree was able to characterise the tumours associated with a 'bad' prognosis in the T2 sub-group (32%) and the tumours associated with a 'good' prognosis in the T3-T4 one (23%), by using only few image-generated variables (added to the clinical stage).

Adult↗
PubMedDate not supplied

Indications for posthepatectomy hepatic vein reconstruction from functional and morphological studies: clamping test and hepatic vein branch distribution determined by three-dimensional computed tomography.

BACKGROUND/AIMS: Indications for hepatic vein reconstruction for preserving remnant liver function after hepatectomy were assessed using the clamping test and the findings of preoperative 3D-CT (3-dimensional computed tomography). METHODOLOGY: Fifteen patients who underwent hepatectomy for malignant tumors in segment VII or VIII, or both, were examined with preoperative 3D-CT and an intraoperative clamping test. RESULTS: On the basis of changes in right hepatic venous pressure during clamping, we classified all patients into 3 types: the persistent elevation type (P-type, 8 patients), the no elevation type (N-type, 3 patients) and the transitory elevation type (T-type, 4 patients). Hepatic venous hemoglobin oxygen saturation (ShvO2) decreased significantly in the P type but hardly changed in the T and N types during the clamping test. Both the inferior right hepatic vein (IRV6) and the tributary of the middle hepatic vein draining segment V (MV5) were detected by preoperative 3D-CT in the T and N types. CONCLUSIONS: Assessments of hepatic vein branch distribution using preoperative 3D-CT served to predict the results of the hepatic vein clamping test. The results of preoperative 3D-CT were useful as indications for hepatic vein reconstruction.

Adult↗
PubMed1994

Decision trees based on automatic learning and their use in cardiology.

Computerized information systems, especially decision support systems, have become an increasingly important role in medical applications, particularly in those where important decision must be made effectively and reliably. But the possibility of using computers in medical decision making is limited by many difficulties, including the complexity of conventional computer languages, methodologies and tools. Thus a conceptual simple decision making model with the possibility of automating learning should be used. In this paper we introduce a cardiological knowledge-based system based on the decision tree approach supporting the mitral valve prolapse determination. Prolapse is defined as the displacement of a bodily part from its normal position. The term mitral valve prolaps (PMV), therefore, implies that the mitral leaflets are displaced relative to some structure, generally taken to the mitral annulus. The implications of the PMV are the following: disturbed normal laminar blood flow, turbulence of the blood flow, injury of the chordae tendinae, the possibility of thrombus's composition, bacterial endocarditis, and finally hemodynamic changes defined as mitral insufficiency and mitral regurgitation. Uncertainty persists about how it should be diagnosed and about its clinical importance. It is our deep belief that the echocardiography enables properly trained experts armed with proper criteria to evaluate PMV almost 100%. But unfortunately, there are some problems concerned with the use of echocardiography. In that manner we have decided to start a research project aimed at finding new criteria and enabling the general practitioner to evaluate PMV using conventional methods and to select potential patients from the general population.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2004

Targacept active conformation search: a new method for predicting the conformation of a ligand bound to its protein target.

Targacept active conformation search (TACS) is a novel variation of well-established three-dimensional quantitative structure--activity relationship methodologies that seeks to determine probable conformation(s) of ligands bound to their protein targets. A combination of affinity or activity data and energetically accessible conformational ensembles, each conformer described by three-dimensional (3-D) sensitive descriptors, forms the basis of the TACS data model. Recursive pruning is used to reduce the size of both the conformational ensemble and the descriptor space until the TACS data model contains just enough information to determine probable conformation(s) of ligands bound to their protein targets. The TACS algorithm is comprised of five components: (1) conformational ensemble generation, (2) 3-D sensitive descriptor calculation, (3) ensemble descriptor preprocessing, (4) model generation, and (5) prediction of bound conformation(s). Significantly, this method precludes the need for subjective or objective molecular alignment. We report the application of this technique to five benchmark protein-ligand couples where the conformation of a bound ligand has been previously established using X-ray crystallography: 9-cis-retinoic (1) and 9-trans-retinoic acid (2), both agonists for the retinoic acid receptor gamma, compounds KH1060 (3) and MC1288 (4), which bind to the vitamin D3 receptor, and R04 (5), an inhibitor bound to human rhinovirus 14 thermolysin. The binding conformations predicted by TACS were compared to the crystallographic structures extracted from their respective binding sites using root-mean-squared deviation (rmsd) criteria. Three of the conformations found using TACS were within crystallographic error. 9-cis-Retinoic acid, 9-trans-retinoic acid, and MC1288, when superimposed on their crystallographic structures, gave rmsd values of 0.22, 0.17, and 0.34 A, respectively. The rmsd values for KH1060 (1.54 A) and R04 (1.01 A) were larger but still reasonable.

Binding Sites↗
PubMed1996

The linear organization of cell columns in human and nonhuman anthropoid Tpt cortex.

Neurons in the cerebral cortex are organized horizontally into laminae and vertically into columns and modules. Little is known about the structural variation of neuronal organization in the vertical (pia to white matter) dimension. We describe here a new computer-assisted methodology that quantifies the linear arrangement of cells and shows how cortical columns in a homologous region differ by species and age. Perikarya in eulaminate temporal cortex, Tpt, were segmented from the background on the basis of their optical densities and sizes in human, rhesus (Macaca mulatta), and chimpanzee (Pantroglodytes) brains. Within each lamina, the two-dimensional arrays of neurons were divided into repetitive, objectively defined vertical clusters. Following this, ratios and indices quantified the displacement of perikaryal centroids from the central axis and from the center point in each cell cluster. The extremely linear and vertical arrangement of cells in the prelaminated fetal cortical plate served as the template to which the other arrays were compared. In all species, the linear arrangements of perikarya in lamina III, and to a lesser extent, in lamina V, closely resemble that of the early fetal template, whereas perikaryal arrangements in layers II and IV diverge from the template formation. Corroborating subjective visualization, each lamina had its own 'fingerprint'. As expected, cell density is less in the species with larger brains, with most of the differences in density coming from increased spacing between cellular columns rather than among the cells within columns. Not all aspects of perik-aryal organization alter when bigger brains are compared with smaller ones. Although chimpanzee brains are about four times bigger than those of rhesus monkeys and human brains are about three times larger than chimpanzee brains, absolute measures of cellular linearity in chimpanzees and rhesus monkeys resemble each other more closely than the same measures do in humans and chimpanzees. After accounting for differences in interval widths, the parameters of linearity sorted on the basis of brain weight in pyramidal cell layers III and V, but not in the stellate cell layers II and IV. Human perikarya have the widest horizontal dispersion and this displacement is most pronounced in layer II, least in layer III.

Adult↗
PubMed2004

Surveillance of medical device-related hazards and adverse events in hospitalized patients.

CONTEXT: Although adverse drug events have been extensively evaluated by computer-based surveillance, medical device errors have no comparable surveillance techniques. OBJECTIVES: To determine whether computer-based surveillance can reliably identify medical device-related hazards (no known harm to patient) and adverse medical device events (AMDEs; patient experienced harm) and to compare alternative methods of detection of device-related problems. DESIGN, SETTING, AND PARTICIPANTS: This descriptive study was conducted from January through September 2000 at a 520-bed tertiary teaching institution in the United States with experience in using computer tools to detect and prevent adverse drug events. All 20 441 regular and short-stay patients (excluding obstetric and newborn patients) were included. MAIN OUTCOME MEASURES: Medical device events as detected by computer-based flags, telemetry problem checklists, International Classification of Diseases, Ninth Revision (ICD-9) discharge code (which could include AMDEs present at admission), clinical engineering work logs, and patient survey results were compared with each other and with routine voluntary incident reports to determine frequencies, proportions, positive predictive values, and incidence rates by each technique. RESULTS: Of the 7059 flags triggered, 552 (7.8%) indicate a device-related hazard or AMDE. The estimated 9-month incidence rates (number per 1000 admissions [95% confidence intervals]) for AMDEs were 1.6 (0.9-2.5) for incident reports, 27.7 (24.9-30.7) for computer flags, and 64.6 (60.4-69.1) for ICD-9 discharge codes. Few of these events were detected by more than 1 surveillance method, giving an overall incidence of AMDE detected by at least 1 of these methods of 83.7 per 1000 (95% confidence interval, 78.8-88.6) admissions. The positive predictive value of computer flags for detecting device-related hazards and AMDEs ranged from 0% to 38%. CONCLUSIONS: More intensive surveillance methods yielded higher rates of medical device problems than found with traditional voluntary reporting, with little overlap between methods. Several detection methods had low efficiency in detecting AMDEs. The high rate of AMDEs suggests that AMDEs are an important patient safety issue, but additional research is necessary to identify optimal AMDE detection strategies.

Adult↗
PubMed1998

A comparison of one-sided methods to identify significant individual outcomes in a multiple outcome setting: stepwise tests or global tests with closed testing.

We compare two approaches to the identification of individual significant outcomes when a comparison of two groups involves multiple outcome variables. The approaches are all designed to control the familywise error rate (FWE) with any subset of the null hypothesis being true (in the strong sense). The first approach is initially to use a global test of the overall hypothesis that the groups are equivalent for all variables, followed by an application of the closed testing algorithm of Marcus, Peritz and Gabriel. The global tests considered here are ordinary least squares (OLS), generalized least squares (GLS), an approximation to a likelihood ratio test (ALR), and a new test based on an approximation to the most powerful similar test for simple alternatives. The second approach is that of stepwise testing, which tests the univariate hypotheses in a specific order with appropriate adjustment to the univariate p-values for multiplicity. The stepwise tests considered include both step-down and step-up tests of a general type, and likewise permutation tests that incorporate the dependence structure of the data. We illustrate the tests with two examples of birth outcomes: a comparison of cocaine-exposed new-borns to control new-borns on neurobehavioural and physical growth variables, and, in a separate study, a comparison of babies born to diabetic mothers and babies born to non-diabetic mothers on minor malformations. After describing the methods and analysing the birth outcome data, we use simulations on Gaussian data to provide guidelines for the use of these procedures in terms of power and computation.

Adult↗
PubMed1996

An efficient laboratory protocol for the sequencing of large numbers of lacI mutants recovered from Big Blue transgenic animals.

Mutational spectra provide a powerful approach to investigate both the mutagenic potential and the mechanism of action of suspected mutagens and carcinogens. Recently, transgenic techniques have made it possible to generate mutational spectra in animals. Such a spectrum may consist of 50 to 200 mutants depending on the nature of the mutations, and many spectra can be generated depending on the design of the experiment. This report describes a practical approach for the processing and sequencing of large numbers of lacI mutants recovered from Big Blue animals.

Animals↗
PubMed2006

Bioprocess monitoring and computer control: key roots of the current PAT initiative.

This review article has been written for the journal, Biotechnology and Bioengineering, to commemorate the 70th birthday of Daniel I.C. Wang, who served as doctoral thesis advisor to each of the co-authors, but a decade apart. Key roots of the current PAT initiative in bioprocess monitoring and control are described, focusing on the impact of Danny Wang's research as a professor at MIT. The history of computer control and monitoring in biochemical processing has been used to identify the areas that have already benefited and those that are most likely to benefit in the future from PAT applications. Past applications have included the use of indirect estimation methods for cell density, expansion of on-line/at-line and on-line/in situ measurement techniques, and development of models and expert systems for control and optimization. Future applications are likely to encompass additional novel measurement technologies, measurements for multi-scale and disposable bioreactors, real time batch release, and more efficient data utilization to achieve process validation and continuous improvement goals. Dan Wang's substantial contributions in this arena have been one key factor in steering the PAT initiative towards realistic and attainable industrial applications.

Bioreactors↗
PubMed2007

Comparison of 2D fingerprint methods for multiple-template similarity searching on compound activity classes of increasing structural diversity.

We studied the similarity search performance of differently designed molecular fingerprints using multiple reference structures and different search strategies. For this purpose, nine compound activity classes were assembled that exclusively consisted of molecules with different core structures and that represented different levels of intra-class structural diversity. Thus, there was a strict one-to-one correspondence between test compounds and core structures. Analysis of unique core structures was found to be a better measure of class diversity than distributions of simplified scaffolds. On increasingly diverse classes, a trainable fingerprint using a unique search strategy performed better than others tested herein. Overall, clear preferences were detected for nearest-neighbor search strategies over fingerprint-averaging techniques. Nearest-neighbor searching that relied on selecting database compounds most similar to one of the reference structures often improved compound recovery over other averaging methods, but at the cost of decreasing the ability to detect hits that were structurally distinct from reference molecules.

Algorithms↗
PubMed2004

Hybrid integral-equation/simulation models: from complexation thermodynamics to direct free energies.

Statistical-mechanical integral equation theory, an approximate methodology for computing distribution functions and thermodynamic properties of the liquid state, can be advantageously combined with molecular simulations to overcome inherent limitations of both approaches. This Concept discusses a number of conceptual applications that illustrate the capabilities of hybrid models: A study of complex formation in solution by explicit simulation of only the solute molecules, the correction of artefacts induced by truncated potentials, and an approach to the direct computation of free energies from a simulation of a single state.

Journal Article↗
PubMed2003

Logistic regression of family data from retrospective study designs.

We wish to study the effects of genetic and environmental factors on disease risk, using data from families ascertained because they contain multiple cases of the disease. To do so, we must account for the way participants were ascertained, and for within-family correlations in both disease occurrences and covariates. We model the joint probability distribution of the covariates of ascertained family members, given family disease occurrence and pedigree structure. We describe two such covariate models: the random effects model and the marginal model. Both models assume a logistic form for the distribution of one person's covariates that involves a vector beta of regression parameters. The components of beta in the two models have different interpretations, and they differ in magnitude when the covariates are correlated within families. We describe ascertainment assumptions needed to estimate consistently the parameters beta(RE) in the random effects model and the parameters beta(M) in the marginal model. Under the ascertainment assumptions for the random effects model, we show that conditional logistic regression (CLR) of matched family data gives a consistent estimate beta(RE) for beta(RE) and a consistent estimate for the covariance matrix of beta(RE). Under the ascertainment assumptions for the marginal model, we show that unconditional logistic regression (ULR) gives a consistent estimate for beta(M), and we give a consistent estimator for its covariance matrix. The random effects/CLR approach is simple to use and to interpret, but it can use data only from families containing both affected and unaffected members. The marginal/ULR approach uses data from all individuals, but its variance estimates require special computations. A C program to compute these variance estimates is available at http://www.stanford.edu/dept/HRP/epidemiology. We illustrate these pros and cons by application to data on the effects of parity on ovarian cancer risk in mother/daughter pairs, and use simulations to study the performance of the estimates.

Algorithms↗
PubMed2005

Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations.

TP53 alteration is the most frequent genetic alteration found in human cancers. To date, more than 15,000 tumors with TP53 mutations have been published, leading to the description of more than 1,500 different TP53 mutants (http://p53.curie.fr). The frequency of these mutants is highly heterogeneous, with 11 hotspot mutants found more than 100 times, whereas 306 mutants have been reported only once. So far, little is known concerning the biological significance of these rare mutants, as the majority of biological studies have focused on classic hotspot mutants. In order to gain a deeper knowledge about the significance of all of these mutants, we have cross-checked each mutant of the TP53 mutation database for its activity, derived from a library of 2,314 TP53 mutants representing all possible amino acid substitutions caused by a point mutation. The transactivation activity of all of these mutant was analyzed with respect to eight transcription promoters [Kato S, et al., Proc Natl Acad Sci USA (2003)100:8424-8429]. Although the most frequent TP53 mutants sustain a clear loss of transactivation activity, more than 50% of the rare TP53 mutants display significant activity. Analysis in specific types of cancer or in normal skin patches demonstrates a similar distribution of TP53 loss of activity, with the exception of melanoma, in which the majority of TP53 mutants display significant activity. Our data indicate that TP53 mutants represent a highly heterogeneous population with a large diversity in terms of loss of transactivation activity that could account for the heterogeneous tumor phenotypes and the difficulty of clinical studies.

Arthritis, Rheumatoid↗
PubMed1991

Fetotoxic alterations in the normal ontogenies of rat microsomal and lysosomal enzymes.

The activity patterns during development for acid phosphatase (Ac-P), alkaline phosphatase (A1-P), beta-glucuronidase (beta G), and UDP-glucuronyltransferase (UDPGT) have been determined in various tissues of the rat for corn oil and distilled water controls as well as in animals prenatally exposed to four fetotoxic chemicals. Postnatal assays were performed on both sexes separately. In control animals, tissue-specific differences between male and female activity levels were found for UDPGT. In the liver of mature offspring, enzyme activity was greater in males than in females. Although no sex difference was observed in the intestine, the kidneys of females exhibited higher values than those of males. An original computer-assisted methodology is presented, designed (a) to permit a mathematical description for the complex curves exhibited by these ontogeny profiles, and (b) to assess the statistical significance of chemical-induced alterations in these complex developmental patterns, specifically, to target sensitive periods and subtle changes near the fetotoxic threshold. Oral administration (days 6-18 of gestation) of 3,3',4,4'-tetrachlorobiphenyl (4CB) to pregnant females resulted in an induction of liver UDPGT activity in offspring postnatally, and some alterations in the perinatal pattern of beta G in the same tissue. This treatment also produced differences in the intestinal patterns of Ac-P and male UDPGT. No significant changes were observed in offspring exposed to diethylstilbestrol (DES). Treatment with zeranol (ZN) caused reductions in activity over the entire postnatal period for beta G in liver, brain, intestine, and kidney, for A1-P in brain, and for Ac-P in the intestine. Cadmium-treated dams gave birth to offspring that exhibited slightly altered ontogenies only in intestine for UDPGT and AcP. The alterations in these developmental profiles indicate periods of increased sensitivity, and may be useful in directing more specific studies into the fetotoxic mechanisms of these compounds.

Acid Phosphatase↗
PubMed2005

Parallelization of MRCI based on hole-particle symmetry.

The parallel implementation of multireference configuration interaction program based on the hole-particle symmetry is described. The platform to implement the parallelization is an Intel-Architectural cluster consisting of 12 nodes, each of which is equipped with two 2.4-G XEON processors, 3-GB memory, and 36-GB disk, and are connected by a Gigabit Ethernet Switch. The dependence of speedup on molecular symmetries and task granularities is discussed. Test calculations show that the scaling with the number of nodes is about 1.9 (for C1 and Cs), 1.65 (for C2v), and 1.55 (for D2h) when the number of nodes is doubled. The largest calculation performed on this cluster involves 5.6 x 10(8) CSFs.

Algorithms↗