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PubMed2006

How should gaps be treated in parsimony? A comparison of approaches using simulation.

Simulation with indels was used to produce alignments where true site homologies in DNA sequences were known; the gaps from these datasets were removed and the sequences were then aligned to produce hypothesized alignments. Both alignments were then analyzed under three widely used methods of treating gaps during tree reconstruction under the maximum parsimony principle. With the true alignments, for many cases (82%), there was no difference in topological accuracy for the different methods of gap coding. However, in cases where a difference was present, coding gaps as a fifth state character or as separate presence/absence characters outperformed treating gaps as unknown/missing data nearly 90% of the time. For the hypothesized alignments, on average, all gap treatment approaches performed equally well. Data sets with higher sequence divergence and more pectinate tree shapes with variable branch lengths are more affected by gap coding than datasets associated with shallower non-pectinate tree shapes.

Computer Simulation↗
PubMed2026

Beyond species trees: pervasive gene flow limits phylogenomic resolution in the diversification of Juniperus from the Qinghai-Tibet Plateau.

Understanding how lineages diversify despite persistent ancestral polymorphism and recurrent gene flow remains a central challenge in evolutionary biology. Juniperus distributed across the Qinghai-Tibet Plateau provide an ideal system for addressing this question because repeated geological uplift and climatic oscillations have likely promoted cycles of lineage divergence, range shifts, and secondary contact. Here, we combined approximately 1.08 million genome-wide SNPs from 164 individuals representing thirteen Juniperus lineages with phylogenomic datasets comprising 3,381 nuclear single-copy genes and nearly complete plastomes. We detected extensive phylogenomic discordance and cytonuclear incongruence across genomic datasets. Topology weighting, coalescent simulations, quartet-based tests, and analyses of gene flow and reticulation collectively support the interpretation that these patterns were shaped by the combined effects of prolonged incomplete lineage sorting and gene flow during lineage diversification. Ecological niche analyses further provide a spatial and climatic context in which environmentally similar lineages may have had greater opportunities for secondary contact during historical range shifts. Collectively, our results reveal that the evolutionary history of Qinghai-Tibet Plateau Juniperus is characterized by reticulate diversification rather than strictly bifurcating evolution, and demonstrate how genome-wide discordance can provide biological insights into the evolutionary processes underlying lineage diversification.

Gene Flow↗
PubMed2005

Simulation of consumer exposure to deoxynivalenol according to wheat crop management and grain segregation: case studies and methodological considerations.

We combined agronomic data and a model simulating exposure based on consumption data to assess the impact of crop management and grain segregation procedures on consumer exposure to deoxynivalenol. We used three scenarios of soil tillage at a regional scale and three scenarios of grain segregation for a supply area. The soil tillage scenarios were applied to a range of mean crop contamination levels, with various coefficients representing the degree of tillage. The grain segregation scenarios were applied to two real datasets of DON content distributions. We found that the increase in consumer exposure in response to increases in "risky" crop management practices such as direct-drilling depends largely on mean contamination and on the value of the tillage coefficient. The results for grain segregation procedures showed that exposure was most strongly affected by contamination distributions as the segregation procedure minimising risk differed for the two datasets.

Agriculture↗
PubMed2003

Modelling risk factors for injuries from dog bites in Greece: a case-only design and analysis.

We conducted a study using a newly developed dataset based on Emergency Departments records of a network of hospitals from Greece on injuries from dog bites. Our goal is three-fold: (a) to investigate if surrogate factors of leisure time are associated with increased risk of injury from bites; (b) to address recently reported contradictory results on putative association of lunar periods and injuries from dog bites; and (c) to offer a general methodology for addressing similar case-only designs with combined factors of which some can exhibit cyclical patterns. To address these goals, we used a case-only design of our dataset, and conducted an analysis where we controlled simultaneously for weekday/weekend effects, season of year (winter, spring/fall, summer), and lunar periods, because any one of these factors can contribute to the degree of exposure to injuries from dog bites. We found that increased risk of injury from bites was associated with weekends versus weekdays (RR=1.19, 95% CI: 1.10-1.29), summer versus winter (RR=1.24, 95% CI: 1.11-1.39), and fall or spring versus winter (RR=1.31, 95% CI: 1.19-1.45). The results support the hypothesis that longer leisure time at these levels of factors does increase the risk of having a bite injury. Moreover, after controlling for these factors, risk of bite injury was not associated with moon periods, thereby also helping settle a longstanding argument.

Animals↗
PubMed2003

Estimating transport fatality risk from past accident data.

This paper examines the statistical properties of estimates of fatal accident rates, mean fatalities per accident, and fatality rates when these estimates are based on past accident data. The statistical properties are illustrated by two long-term transport fatal accident datasets from Great Britain, the principal one for railways and the other for roads, chosen to provide a statistical contrast. In both modes, the accident rates have fallen substantially over the long term. Two statistical estimates of current accident and fatality rates are presented for each dataset, one based only on recent data and the other based on estimates of long-term trends. The trend-based estimate is preferred for train accidents because this makes maximum use of the limited and variable data; the recent data are preferred for road accidents because this avoids unnecessary dependence on modelling the trends. For train accidents, the estimated fatality rate based on past accidents is compared with an estimate produced by the railway industry using a risk model. The statistical estimate is less than half the industry's estimate, and the paper concludes that the statistical estimate is to be preferred.

Accidents↗
PubMed1997

Laparoscopy during pregnancy: a study of five fetal outcome parameters with use of the Swedish Health Registry.

OBJECTIVE: Our purpose was to compare five fetal outcome variables between laparoscopy and laparotomy performed during pregnancy with use of the Swedish Health Registries from 1973 to 1993. STUDY DESIGN: A dataset was produced by linking computerized records from three Swedish Health Registries. The dataset includes records for women who were delivered between 1973 and 1993 and had an operation within 1 year before giving birth. The data were divided according to surgical procedure(s) and grouped according to diagnostic code(s). The following end points were studied in singleton births: birth weight, gestational duration, intrauterine growth restriction, congenital malformations, stillbirths, and neonatal deaths. In the analysis confounding by maternal age and parity, year of birth of the infant, maternal smoking, period of involuntary infertility, and maternal cohabitation was taken into consideration. A chi 2 analysis was used to compare proportions. Variables were stratified with use of the Mantel-Haenszel procedure. Risk ratios were calculated for observed/expected ratios when outcomes for the total population were compared or as odds ratios when laparoscopy and laparotomy cohorts were compared. Expected values were calculated from the total population of women with singleton pregnancies. RESULTS: The study covered 2,015,000 deliveries in Sweden from 1973 to 1993. Data for this study were restricted to singleton pregnancies who had nonobstetric operations between the fourth and twentieth weeks of pregnancy. Too few laparoscopic procedures were performed after 20 weeks to allow comparison. A total of 2181 laparoscopies and 1522 laparotomies met criteria for analysis. There were no significant differences between the two groups in any demographic variable. Pregnancies with operations were compared with the total population for birth weight, gestational duration, growth restriction, infant survival, and fetal malformations. On the basis of relative risks, there was an increased risk for infants in both laparoscopy and laparotomy groups to weigh < 2500 gm, to be delivered before 37 weeks, and to have an increased incidence of growth restriction compared with the total population. There was no difference between laparoscopy and laparotomy in cumulative infant survival up to 1 year (odds ratio 0.85, 95% confidence interval 0.48 to 1.51). There was no difference in the rate of fetal malformations between laparoscopy (risk ratio 1.09, 95% confidence interval 0.90 to 1.11), laparotomy (risk ratio 1.08, 95% confidence interval 0.85 to 1.11), and the total population. CONCLUSION: There is no difference in five fetal outcome variables for patients undergoing laparoscopy versus laparotomy in singleton pregnancies between 4 and 20 weeks of gestation.

Adolescent↗
PubMed1998

Visualization and quantification of myocardial mass at risk using three-dimensional contrast echocardiography.

OBJECTIVE: Three-dimensional echocardiographic assessment of myocardial ischemia using contrast echocardiography has been hampered by limitations of available contrast agents and analytic software. In the study presented, a three-dimensional perfusion imaging method was evaluated in the porcine model of myocardial ischemia using a novel contrast agent. METHODS: Three-dimensional echocardiography was performed in eight open-chested pigs before, during and after left anterior descending (six animals) or circumflex (two animals) coronary artery occlusion. The intramyocardial contrast effect was obtained by left atrial injection of Myomap, a deposit contrast agent. RESULTS: Myocardial opacification was visible in all studies and retained in all three-dimensional datasets. Three-dimensional intensity analysis demonstrated a significant difference, exceeding 20 intensity units in every animal (in 127-level scale), between perfused and non-perfused myocardium. Reperfusion followed by contrast reinjection resulted in homogenous myocardial enhancement. Myocardial mass at risk was clearly delineated in all studies and measured with a mean error of -0.1 +/- 2.0 g against real mass (p = non-significant). Spatial extent of ischemia could be displayed in volume-rendered reconstruction of separate perfusion territories. CONCLUSIONS: Quantitative analysis of myocardial contrast enhancement from three-dimensional datasets is feasible and allows accurate measurement of myocardial mass at risk.

Animals↗
PubMed2004

Crystallographic analysis of AcrB.

A His-tagged derivative of the multidrug efflux pump AcrB could be crystallized in three different space groups (R3, R32 and P321). Experimental MAD-phasing maps from R32 AcrB(His) crystals were obtained to a resolution of 3.5 A. Datasets of native and substrate soaked AcrB(His) crystals were collected at the Swiss Light Source X06SA beamline up to a resolution of 2.7 A and refinement of these data provided good quality electron density maps, which allowed us to complement the published AcrB structure (PDB code 1iwg). Introduction of amino acids 860-865 and 868 lacking in the 1iwg structure and deletion of a highly disordered region (amino acids 669-678) improved R(free) and average B factors in the 2.7 A model. We could not identify significant densities indicating specific antibiotic binding sites in the AcrB R32 space group datasets under the soaking conditions tested.

Carrier Proteins↗
PubMed2003

Ligament fibre recruitment and forces for the anterior drawer test at the human ankle joint.

Although the anterior drawer test at the ankle joint is commonly used in routine clinical practice, very little is known about the sharing of load between the individual passive structures and the joint response at different flexion angles.A mathematical model of the ankle joint was devised to calculate ligament fibre recruitment and load/displacement curves at different flexion angles. Ligaments were modelled as three-dimensional arrays of fibres, and their orientations at different flexion angles were taken from a previously validated four-bar-linkage model in the sagittal plane. A non-linear stress/strain relationship was assumed for ligament fibres and relevant mechanical parameters were taken from two reports in the literature. Talus and calcaneus were assumed to move as a single rigid body. Antero/distal motion of the talus relative to the tibia was analysed. The ankle joint was found to be stiffer at the two extremes of the flexion range, and the highest laxity was found around the neutral position, confirming previous experimental works. With a first dataset, a 20N anterior force produced 4.3, 5.5, and 4.4mm displacement respectively at 20 degrees plantarflexion, at neutral, and at 20 degrees dorsiflexion. At 10 degrees plantarflexion, for a 6mm displacement, 65% of the external force was supported by the anterior talofibular, 11% by the deep anterior tibiotalar and 5.5% by the tibionavicular ligament. Corresponding results from a second dataset were 1.4, 2.4 and 1.8mm at 40N force, and 80%, 0% and 2% for a 3mm displacement. A component of the contact force supported the remainder.

Ankle Joint↗
PubMed2003

High-speed peak matching algorithm for retention time alignment of gas chromatographic data for chemometric analysis.

A rapid retention time alignment algorithm was developed as a preprocessing utility to be used prior to chemometric analysis of large datasets of diesel fuel profiles obtained using gas chromatography (GC). Retention time variation from chromatogram-to-chromatogram has been a significant impediment against the use of chemometric techniques in the analysis of chromatographic data due to the inability of current chemometric techniques to correctly model information that shifts from variable to variable within a dataset. The alignment algorithm developed is shown to increase the efficacy of pattern recognition methods applied to diesel fuel chromatograms by retaining chemical selectivity while reducing chromatogram-to-chromatogram retention time variations and to do so on a time scale that makes analysis of large sets of chromatographic data practical. Two sets of diesel fuel gas chromatograms were studied using the novel alignment algorithm followed by principal component analysis (PCA). In the first study, retention times for corresponding chromatographic peaks in 60 chromatograms varied by as much as 300 ms between chromatograms before alignment. In the second study of 42 chromatograms, the retention time shifting exhibited was on the order of 10 s between corresponding chromatographic peaks, and required a coarse retention time correction prior to alignment with the algorithm. In both cases, an increase in retention time precision afforded by the algorithm was clearly visible in plots of overlaid chromatograms before and then after applying the retention time alignment algorithm. Using the alignment algorithm, the standard deviation for corresponding peak retention times following alignment was 17 ms throughout a given chromatogram, corresponding to a relative standard deviation of 0.003% at an average retention time of 8 min. This level of retention time precision is a 5-fold improvement over the retention time precision initially provided by a state-of-the-art GC instrument equipped with electronic pressure control and was critical to the performance of the chemometric analysis. This increase in retention time precision does not come at the expense of chemical selectivity, since the PCA results suggest that essentially all of the chemical selectivity is preserved. Cluster resolution between dissimilar groups of diesel fuel chromatograms in a two-dimensional scores space generated with PCA is shown to substantially increase after alignment. The alignment method is robust against missing or extra peaks relative to a target chromatogram used in the alignment, and operates at high speed, requiring roughly 1 s of computation time per GC chromatogram.

Algorithms↗
PubMed2003

Human population-based identification of CD4(+) T-cell peptide epitope determinants.

A human cell-based method to identify functional CD4(+) T-cell epitopes in any protein has been developed. Proteins are tested as synthetic 15-mer peptides offset by three amino acids. Percent responses within a large donor population are tabulated for each peptide in the set. Peptide epitope regions are designated by difference in response frequency from the overall background response rate for the compiled dataset. Epitope peptide responses are reproducible, with a median coefficient of variance of 21% when tested on multiple random-donor sets. The overall average response rate within the dataset increases with increasing putative human population antigenic exposure to a given protein. The background rate was high for HPV16 E6, and was low for human-derived cytokine proteins. The assay identified recall epitope regions within the donor population for the protein staphylokinase. For an industrial protease with minimal presumed population exposure, immunodominant epitope peptides were identified that were found to bind promiscuously to many HLA class II molecules in vitro. The peptide epitope regions identified in presumably unexposed donors represent a subset of the total recall epitopes. Finally, as a negative control, the assay found no peptide epitope regions in human beta2-microglobulin. This method identifies functional CD4(+) T-cell epitopes in any protein without pre-selection for HLA class II, suggests whether a donor population is pre-exposed to a protein of interest, and does not require sensitized donors for in vitro testing.

Blood Donors↗
PubMed2002

Intrinsic disorder in cell-signaling and cancer-associated proteins.

The number of intrinsically disordered proteins known to be involved in cell-signaling and regulation is growing rapidly. To test for a generalized involvement of intrinsic disorder in signaling and cancer, we applied a neural network predictor of natural disordered regions (PONDR VL-XT) to four protein datasets: human cancer-associated proteins (HCAP), signaling proteins (AfCS), eukaryotic proteins from SWISS-PROT (EU_SW) and non-homologous protein segments with well-defined (ordered) 3D structure (O_PDB_S25). PONDR VL-XT predicts >or=30 consecutive disordered residues for 79(+/-5)%, 66(+/-6)%, 47(+/-4)% and 13(+/-4)% of the proteins from HCAP, AfCS, EU_SW, and O_PDB_S25, respectively, indicating significantly more intrinsic disorder in cancer-associated and signaling proteins as compared to the two control sets. The disorder analysis was extended to 11 additional functionally diverse categories of human proteins from SWISS-PROT. The proteins involved in metabolism, biosynthesis, and degradation together with kinases, inhibitors, transport, G-protein coupled receptors, and membrane proteins are predicted to have at least twofold less disorder than regulatory, cancer-associated and cytoskeletal proteins. In contrast to 44.5% of the proteins from representative non-membrane categories, just 17.3% of the cancer-associated proteins had sequence alignments with structures in the Protein Data Bank covering at least 75% of their lengths. This relative lack of structural information correlated with the greater amount of predicted disorder in the HCAP dataset. A comparison of disorder predictions with the experimental structural data for a subset of the HCAP proteins indicated good agreement between prediction and observation. Our data suggest that intrinsically unstructured proteins play key roles in cell-signaling, regulation and cancer, where coupled folding and binding is a common mechanism.

Amino Acid Sequence↗
PubMed2003

Incorporation of DNA chip technology to the simulation and validation of flux analysis in yeast diauxic growth.

We incorporated gene expression information from cDNA microarray into flux analysis to simulate yeast diauxic growth. Expression ratios of both growth phases were applied to assign the split ratio at glyoxylate shunt during simulation, in which the equation was mathematically unsolvable due to the singularity and artificial split ratios, which were traditionally introduced without biological evidence. In addition, the directionality of microarray dataset was used as a further constraint during simulation. Metabolic fluxes obtained by this modified approach are in general consistent with microarray analysis. However, discrepancies occurred when the quantity of fluxes was compared, probably due to the substantial reduction of substrates at phase II in which the increase in the enzymatic levels was not proportional to the increase of substrate flow, as would be predicted from microarray dataset. The modified flux analysis might have brought a new approach to investigate other cellular pathways.

Algorithms↗
PubMed1997

The quality of histopathology data in a computerised cancer registration system: implications for future audit of care.

Electronic linkage between pathology data sources and other information systems has not realised its full potential benefits due to the poor quality of histopathology coding. This study showed that 38% of a sample of 158 pathology reports were coded accurately. Of the incorrectly coded reports, 25% had the potential to distort published cancer incidence figures. The incidence figures of the most common cancers are less likely to be affected by coding errors. Areas in which all errors, both topographical and morphological, could have significant impact include examining resource allocation at directorate level and adjusting outcome indicators for casemix. This study concludes that electronic linkage between histopathology systems and cancer registries is not sufficient to improve the quality of registration data. As cancer registries become more dependent on computerised information provided through hospital information systems, registries need to be aware of poor quality data and put in place appropriate quality assurance measures specifically tailored to support electronic cancer registration. Purchasers and providers need to be aware that incomparable datasets could be produced if other bodies use computerised pathology datasets without first validating the data.

England↗
PubMed2003

Structure-activity relationship study of human liver microsomes-catalyzed hydrolysis rate of ester prodrugs of MENT by comparative molecular field analysis (CoMFA).

A series of MENT esters (3-71) was designed, prepared and tested to study the structure-activity relationship (SAR) of the hydrolysis rate with human liver microsomes of these prodrugs. Compounds were obtained covering a wide range of metabolic stability. The results are useful for the proper selection of prodrugs for different pharmaceutical formulations to deliver the potent and prostate-sparing androgen MENT. The MENT esters can especially be administered for male hormone replacement therapy and male contraception. Comparative molecular field analysis (CoMFA) was applied to a dataset of 28 esters, for which ED50 values could be obtained. The CoMFA model where the electrostatic and H-bond molecular fields were combined turned out to be most predictive. Despite the limited size of the dataset, CoMFA can help to rationalize the SAR of the ester hydrolysis rate of ester prodrugs of MENT.

Esters↗
PubMed2003

Quantitative structure-property relationships for physiologically based pharmacokinetic modeling of volatile organic chemicals in rats.

The objective of present study was to develop quantitative structure-property relationships (QSPRs) for the chemical-specific input parameters of rat physiologically based pharmacokinetic (PBPK) models (i.e., blood:air partition coefficient (P(b)), liver:air partition coefficient (P(l)), muscle:air partition coefficient (P(m)), fat:air partition coefficient (P(f)), and hepatic clearance (CL(h))), for simulating the inhalation pharmacokinetics of volatile organic chemicals (VOCs). The literature data on P(b), P(l), P(f), and P(m) for 46 low-molecular-weight VOCs as well as CL(h) for 25 such VOCs primarily metabolized by CYP2E1 (alkanes, haloalkanes, haloethylenes, and aromatic hydrocarbons) were analysed to develop QSPRs. The QSPRs developed in this study were essentially multilinear additive models, which imply that each fragment in the molecular structure has an additive and constant contribution to partition coefficients and hepatic clearance. Most of the values in the calibration set could be reproduced adequately with the QSPR approach, which involved the calculation of the sum of the frequency of occurrence of fragments (CH(3), CH(2), CH, C, C=C, H, Cl, Br, F, benzene ring, and H in benzene ring structure) times the fragment-specific contributions determined in this study. The QSPRs for P(b), P(l), P(m), P(f), and CL(h) were then included within a PBPK model, which only required the specification of the frequency of occurrence of fragments in a molecule along with exposure concentration and duration as input for conducting pharmacokinetic simulations. This QSPR-PBPK model framework facilitated the prediction of the inhalation pharmacokinetics of four VOCs present in the calibration dataset (toluene, dichloromethane, trichloroethylene, and 1,1,1-trichloroethane) and four VOCs that were not part of the calibration set (1,2,4-trimethyl benzene, ethyl benzene, 1,3-dichloropropene, and 2,2-dichloro-1,1,1-trifluoroethane) but that could be described using the molecular fragments investigated in the present study. The QSPRs developed in this study should be potentially useful for providing a first-cut evaluation of the inhalation pharmacokinetics of VOCs prior to experimentation, as long as the number and nature of the fragments do not exceed the ones in the calibration dataset used in this study.

Animals↗
PubMed2001

Long-term variability in the deposition of marine ions at west coast sites in the UK Acid Waters Monitoring Network: impacts on surface water chemistry and significance for trend determination.

Eight lake sites in central and south-west Scotland, north-west England and north Wales, forming part of the UK Acid Waters Monitoring Network (UKAWMN), have been studied with regard to the influence of marine ions on surface water chemistry. Since monitoring began in 1988 these sites have exhibited large and long-term variation in Cl concentration, which are consistent between regions and can be linked to inter-annual variations in wet deposition. Through regression analysis against Cl, the response of other solutes to these fluctuations has been assessed. Sites show a highly consistent pattern of Na, and Mg retention during periods of high Cl, in accordance with the 'sea-salt' mechanism of marine cation adsorption onto soil exchange sites following large marine inputs. An associated displacement of cations with non-marine sources is also observed, with one or more of non-marine Ca, labile Al and hydrogen ions exhibiting a positive relationship with Cl at all sites. The relative extent to which these are released appears not to follow a simple relationship to site acidity, and may be linked to site/region-specific geology and soil characteristics. In addition, an inverse relationship between non-marine SO4 and Cl is observed at five of the sites, and the possibility is considered that a sea-salt related process, with soil retention and subsequent release, may also operate for SO4. A mechanism that might explain this process is suggested. The impact of marine inputs on non-marine solutes, including important indicators of acidification such as pH, labile Al and non-marine SO4, has clear implications for the detection of long-term trends in acidity status and is, therefore, of particular relevance to the UKAWMN. Due to their unpredictability, and the long timescale over which they operate, fluctuations caused by marine inputs may be difficult to separate from acid deposition related long-term trends. Evidence from a longer Cl time series from mid-Wales shows that fluctuations in concentration could be linked to the North Atlantic Oscillation and might therefore be expected to exhibit a similar, decal periodicity. Currently, the UKAWMN dataset only appears long enough to represent one climatic cycle. Consequently, and since few surface water chemistry datasets in the UK extend over more than a decade, it is important that: (a) trend analyses of current data from marine-impacted areas take account of possible marine input cycles; and (b) long-term monitoring is maintained into the future so that the impact of these cycles can be better quantified, and distinguished from anthopogenically-induced long-term changes.

Acid Rain↗
PubMed2001

Multivariate outlier detection and remediation in geochemical databases.

In this study, outliers are classified into three types: (1) range outliers; (2) spatial outliers; and (3) relationship outliers, defined as observations that fall outside of the values expected from correlation within the dataset. The multivariate methods of principal component analysis (PCA), multiple regression analysis (MRA) and an autoassociation neural network (AutoNN) method are applied to a dataset comprising 203 samples of rare earth element (REE) concentrations in soils of Jamaica which shows the expected good correlations between the elements. PCA is shown to be effective in detection of high value range outliers, while AutoNN and MRA are effective in detection of relationship outliers. A backpropagation neural network was used to predict the 'expected values' of the outliers. Four obvious relationship outliers with unexpected low Sm concentrations were selected as an example for remediation. The predicted Sm values were confirmed on remeasurement. Neural network methods, with the advantages of being model-free and effective in solving non-linear relationship problems, appear to provide an automated and effective way for the quality control of environmental databases.

Databases, Factual↗