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PubMed1998

Mapping diplosporous apomixis in tetraploid Tripsacum: one gene or several genes?

Polyploids in Tripsacum, a wild relative of maize, reproduce through the diplosporous type of apomixis, an asexual mode of reproduction through seeds. Diplosporous apomixis involves both the failure of meiosis and the parthenogenetic development of the unreduced gametes, resulting in progenies that are exact genetic copies of the mother plant. Apomixis is believed to be controlled by one single dominant allele, responsible for the whole developmental process. Construction of a linkage map for the chromosome controlling diplosporous apomixis in Tripsacum was carried out in both tetraploid-apomictic and diploid-sexual Tripsacum species using maize restriction fragment length polymorphism (RFLP) probes. A high level of collinearity was observed between the Tripsacum chromosome carrying the control of apomixis and a duplicated segment in the maize genome. In the apomictic tetraploid, there was a strong restriction to recombination, as compared to the corresponding genomic segment in sexual plants and maize. This suggests that apomixis, although inherited as a single Mendelian allele, might really be controlled by a cluster of linked loci. The analysis also revealed the tetrasomic nature of the inheritance of the chromosomal segment controlling apomixis, which contradicts the usually accepted hypothesis of an allopolyploid origin of apomictic species. The implications of these data for the transfer of apomixis into cultivated crops are discussed, and a new approach to studying the genetics of apomixis, based on comparative mapping, is proposed.

Chromosome Mapping↗

PubMed2006

Effects of residual smoothing on the posterior of the fixed effects in disease-mapping models.

Disease-mapping models for areal data often have fixed effects to measure the effect of spatially varying covariates and random effects with a conditionally autoregressive (CAR) prior to account for spatial clustering. In such spatial regressions, the objective may be to estimate the fixed effects while accounting for the spatial correlation. But adding the CAR random effects can cause large changes in the posterior mean and variance of fixed effects compared to the nonspatial regression model. This article explores the impact of adding spatial random effects on fixed effect estimates and posterior variance. Diagnostics are proposed to measure posterior variance inflation from collinearity between the fixed effect covariates and the CAR random effects and to measure each region's influence on the change in the fixed effect's estimates by adding the CAR random effects. A new model that alleviates the collinearity between the fixed effect covariates and the CAR random effects is developed and extensions of these methods to point-referenced data models are discussed.

Bayes Theorem↗

PubMed2000

A note on statistical analysis of shape through triangulation of landmarks.

In an earlier paper, the author jointly with S. Suryawanshi proposed statistical analysis of shape through triangulation of landmarks on objects. It was observed that the angles of the triangles are invariant to scaling, location, and rotation of objects. No distinction was made between an object and its reflection. The present paper provides the methodology of shape discrimination when reflection is also taken into account and makes suggestions for modifications to be made when some of the landmarks are collinear.

Journal Article↗

PubMed1994

Conformation of the central, three-helix junction of the 5 S ribosomal RNA of Sulfolobus acidocaldarius.

The current investigation has focused on the structure of the central, three-helix junction of the 5 S ribosomal RNA from Sulfolobus acidocaldarius, a thermoacidophilic archaebacterium. The 5 S molecule from S. acidocaldarius represents a paradigm for the study of the 5 S junction (and branched RNA structures in general) due to its unusually high degree of predicted secondary structure and stability. In order to study the junction in isolation, a set of three RNA heteroduplex molecules was assembled in which pairs of helices bounding the junction were extended by 70 base-pairs per helix. Since the extended helices comprise more than 95% of the heteroduplex structure, the relative solution conformations of the heteroduplex molecules, in effect, "report" the interhelix (branch) angles bounded by the extended pairs of helices. Examination of these heteroduplex molecules, using a combination of gel electrophoresis and transient electric birefringence measurements, has revealed a tertiary structure for the central branch in which helices I and V are essentially collinear, and in which helix II is relatively free to reorient with respect to the I-V axis.

Base Sequence↗

PubMedDate not supplied

"Battered data"--some clinical effects of the abuse of multiple regression methods: the NSD.

The NSD equation, D = 1850 x T0.11 x N0.24, is a celebrated transmogrification of Cohen's two well-known collations of data on response to clinical irradiations (3 degrees erythema and 0.90 ablation of skin cancer) in which the relation of D and T is fixed by the data selected by Cohen and the additional constraint that N correspond to a schedule of five treatments per week is imposed subsequently by Ellis. The present paper shows that the equation, if correct, would have little clinical significance because the proportion, P, in which the dose, D, elicits the 3 degree erythema is unspecified: D = D(P) = D(?). Since the two Cohen collations each summarize the measurements on a different set of observational units, it is questionable whether the equation can be correct. This paper further shows that the appropriate (Least Squares) estimates of the three-parameter equation derived for the Cohen data under the Ellis constraint (five treatments per week) is in fact: D(1.0) = 1710 x T0.54 x N-0.26. The paper shows that the NSD equation is also incorrect because the ad hoc method by which Ellis estimates the exponents is inconsistent with the constraints imposed by Cohen and Ellis upon the parameters of the multivariate frequency distribution of the data set. The paper shows that the method by which the correct LS estimates of the exponents were obtained from the Cohen-Ellis data is consistent with these constraints and, therefore, this equation is a correct graduation of any other set of treatment regimens which is also consistent with the Cohen and Ellis constraints. The paper further shows that for such data sets there are, in fact, only two independent continuous variables, either D and T or D and N, since the Ellis constraint requires that N and T be collinear. Thus, the best linear graduation has the typical form: D congruent to 1900T0.32. This is "best" in the usual sense: both prediction and confidence intervals are provided for the estimates of the conditional "tolerance dose" D; these are not inflated by the presence of a collinear variable. This equation is biased, however, by the absence of the collinear variable. The TDF and the CRE concepts are derived from the NSD and, therefore, the deficiencies of the latter concept which we discuss may be expected to encumber these progeny as well. The two characteristic features of the Cohen (Ellis)-type data which impede the construction of useful estimates of the putative separate effects of N and T upon the response of tissues to irradiation are that (1) these data do not include specifications of either a tissue defect or its incidence, and (2) the variables N and T are collinear. Appendices I and II describe methods by which the effects of these features may be eliminated (I) or reduced (II).

Carcinoma, Squamous Cell↗

PubMed2005

Population pharmacokinetic studies in pediatrics: issues in design and analysis.

The current review addresses the following 3 frequently encountered challenges in the design and analysis of population pharmacokinetic studies in pediatrics: (1) body size adjustments during the development of pharmacostatistical models, (2) design and validation of limited sampling strategies, and (3) the integration of historical priors in data analysis and trial simulation. Size adjustments with empiric approaches based on body weight or body surface area have frequently proven as a pragmatic tool to overcome large size differences in a pediatric study population. Allometric size adjustments, however, provide a more mechanistic, physiologically based approach that, if used a priori, allows delineation of the effect of size from that of other covariates that show a high degree of collinearity. The frequent lack of dense data sets in pediatric clinical pharmacology because of ethical and logistic constraints in study design can be overcome with the application of D-optimality-based limited sampling schemes in combination with Bayesian and nonlinear mixed-effects modeling approaches. Empirically based dose selection and clinical trial designs for pediatric clinical pharmacology studies can be improved by applying clinical trial simulation techniques, especially if they integrate adult and pediatric in vitro and/or in vivo data as historic priors. Although integration of these concepts and techniques in population pharmacokinetic analyses is not only limited to pediatric research, their application allows researchers to overcome some major hurdles frequently encountered in pharmacokinetic studies in pediatrics and, thus, provides the basis for additional clinical pharmacology research in this previously insufficiently studied fraction of the general population.

Humans↗

PubMed2006

A comparative study between PCR and PLS in simultaneous spectrophotometric determination of diphenylamine, aniline, and phenol: Effect of wavelength selection.

Partial least squares (PLS) and principal component regression (PCR) have received considerable attention in the chemometrics for multicomponent analysis where superiority of one over another is a challenging problem yet. Considering the effect of wavelength selection, a comparison was made between PCR and PLS methods by application those to simultaneous spectrophotometric determination of diphenylamine (DPA), a compound from the third European Union list of priority pollutants, and its environmentally related products aniline and phenol. The UV absorbance spectra of the methanolic solutions of the analytes were measured in the concentration ranges of 1.0-10.0 microg mL(-1) and then subjected to PCR and PLS. The models refinement procedure and validation was performed by cross-validation. A modified changeable size moving windows strategy, where optimized the intervals between the sensors in a selected windows, was also proposed to select the more informative spectral regions for each of the analytes. It was found that wavelength selection improved the quality of predictions for both regression methods whereas more reliable results were obtained by removing of the highly collinear neighboring wavelengths. The resultant data explained that PLS produced more or less better results when whole spectral data were used but in the case of selected wavelength regions both methods produced similar results and no comments could be given about the superiority of one against another. The major difference was obtaining the higher number of factors for PCR, which is not a significant problem.

Aniline Compounds↗

PubMed2006

Systematic line selection for online coating thickness measurements of galvanised sheet steel using LIBS.

LIBS can be used as an online method of characterizing galvanized coatings on sheet steel moving through a production line. The traversing sheet steel is irradiated with a series of single laser bursts, each at a different position on the sheet steel. An ablation depth in the same range as the coating thickness (about 10 microm) is achieved by using a Nd:YAG laser at 1064 nm in collinear double-pulse mode. The coating thickness is determined from the ratio of the intensities of an iron line and a zinc line measured at a burst energy high enough to penetrate the coating with a single burst. Experiments at different burst energies were carried out to optimize the thickness resolution, and a method of systematically selecting iron and zinc lines was deduced, which is based on multivariate data analysis (MVDA) of the intensity ratios calculated for a set of 6 zinc lines and 21 iron lines. A temperature correction was applied, because the parameters of the plasma change with burst energy, and the influence of this on the thickness resolution is discussed. The ambient atmosphere present (air, Ar, N2) as well as self-absorption of spectral lines both have an influence on the thickness resolution. At optimum conditions, a thickness measurement accuracy of better than 150 nm was obtained for a set of electrolytic galvanized sheet steels with coating thicknesses in the range 4.1-11.2 microm.

Journal Article↗

PubMed1993

Continuous geriatric care in orthopedic wards: a valuable alternative to orthogeriatric units.

The aim of this study was to assess whether assigning a geriatrician to provide daily medical care to geriatric patients in the orthopedic ward can improve the prognosis and reduce the length of stay. Time series analysis was performed in two parts: 1) prospective analysis of two years' workload, and 2) retrospective analysis of data collected over the 4 years prior to the intervention. Intervention and control populations were pooled, and the effects of geriatric care and patient-related factors on outcome measures were assessed by logistic regression analysis. All subjects were patients aged > or = 70 years who attended the orthopedic ward in a university hospital in years 1989-90 (studied group: 287 cases) and in years 1985-88 (control group: 474 cases). In the study period, mortality was 8.4% compared to 18% in 1985-86 (p < 0.0006) and 14% in 1987-88 (p < 0.01). The operation rate in the study period was 89.9% vs 83.8% in 1985-86 (p < 0.02) and 81.8% in 1987-88 (p < 0.005). Length of stay was 26.2 +/- 14.4 days vs 32.9 +/- 30.9 days in 1985-86 (p < 0.05) and 26.9 +/- 16.5 days in 1987-88 (NS). Length of stay was more strikingly shortened in the subset of patients with femoral fracture undergoing surgical management (28.5 +/- 12.7 vs 37.6 +/- 32.6 days in 1985-86, p < 0.003, and 30.8 +/- 15 days in 1987-88, p < 0.02). Given the positive relationship between geriatric care and operation rate (o.r. = 1.5, CI = 1.1-1.9), the protective effect of surgical treatment on mortality (o.r. = 0.6, CI = 0.4-0.8) to some extent may mask the collinear effect of geriatric care. We conclude that assigning a geriatrician to assist with the medical care of elderly orthopedic patients in orthopedic wards is associated with increased operation rate, decreased mortality and shortened length of stay.

Aged↗

PubMed1994

Nucleotide sequence analysis of a 38.5-kilobase-pair region of the genome of human herpesvirus 6 encoding human cytomegalovirus immediate-early gene homologs and transactivating functions.

Human herpesvirus 6 (HHV-6) is prevalent in the human population, with primary infection occurring early in life. Its predominant CD4+ T-lymphocyte tropism, its ability to activate human immunodeficiency virus type 1 (HIV-1) gene expression in vitro, and its upregulation of CD4 expression has led to speculation that HHV-6 may act as a positive cofactor in the progression of HIV infection to AIDS in individuals infected with both viruses. Previous sequencing studies of restricted regions of the 161.5-kbp genome of HHV-6 have demonstrated unequivocally that it is a member of the betaherpesvirus subgroup and have indicated that the HHV-6 genome is generally collinear with the unique long (UL) component of human cytomegalovirus (HCMV). In the work described in this report we have extended these sequencing studies by determining the primary structure of 38.5-kbp of the HHV-6 genome (genomic position 21.0 to 59.5 kbp). Within the sequenced region lie 31 open reading frames, 20 of which are homologous to positional counterparts in HCMV. Of particular significance is the identification of homologs of the HCMV UL36-38 and US22-type genes, which have been shown to encode transactivating proteins. We show that DNA sequences encoding these HHV-6 homologs were able to transactivate HIV-1 long terminal repeat-directed chloramphenicol acetyltransferase expression in cotransfection assays, thus demonstrating functional as well as structural conservation of these betaherpesvirus-specific gene products. Our data therefore confirm the close relationship between HHV-6 and HCMV and identify putative immediate-early regulatory genes of HHV-6 likely to play key roles in lytic replication and possibly also in the interactions between HHV-6 and HIV in dually infected cells.

Animals↗

PubMed1996

A new approach to mechanical testing and modeling of biological tissues, with application to blood vessels.

The collection and processing of data from mechanical tests of biological tissues usually follow classical principles appropriate for studying engineering materials. However, difficulties specific to biological tissues have generally kept such methods from producing quantitative results for statistically-oriented studies. This paper demonstrates a different approach linking testing and data reduction with modern statistical tools. Experimental design theory is used to minimize the detrimental effects of collinearity on the stability of the parameters in constitutive equations. The numerical effects of time-dependent biasing factors such as viscoelasticity are reduced by randomizing the order of collection of data points. Some of the parameters of the model are allowed to vary from specimen to specimen while the others are computed once from a database of designed experiments on several specimens. Finally, a new self-modeling algorithm based on principal component analysis is used to generate uncorrelated parameters for a model that is linear in its specimen-dependent parameters. The method, associated with a recently published complementary energy formulation for vascular mechanics, is illustrated with biaxial canine saphenous vein data. Results show that three specimen-dependent linear parameters are enough to characterize the experimental data and that they can be repeatedly estimated from different data sets. Independently collected biaxial inflation data can also be predicted reasonably well with this model.

Algorithms↗

PubMed1999

Quantitative structure-activity relationships and comparative molecular field analysis of TIBO derivatised HIV-1 reverse transcriptase inhibitors.

Quantitative structure-activity relationships (QSAR) and Comparative Molecular Field Analysis (CoMFA) have been applied in order to explain the structural requirements of HIV-1 reverse transcriptase (HIV-1 RT) inhibitory activity of TIBO derivatives on the MT-4 cells. The best QSAR model is satisfactory in both statistical significance and predictive ability. The derived structural descriptors indicate the importance of electronic contributions toward the HIV-1 RT inhibition of this class of compounds. However, it could not reveal any hydrophobic influence because of high collinearity between C2 and log P variables. In order to cope with steric interaction in the correlation, 3D-QSAR was performed using CoMFA. The obtained CoMFA model shows high predictive ability, rcv2 = 0.771, and clearly demonstrates its potential in the steric feature of the molecules through contour maps, explaining a majority (81.8%) of the variance in the data. Consequently, these results can be useful in identifying the structural requirements of TIBO derivatives and helpful for better understanding the HIV-1 RT inhibition. Eventually, they provide a beneficial basis to design new and more potent inhibitors of HIV-1 RT.

Benzodiazepines↗

PubMed1984

An empiric study of ecological inference.

Aggregate-level (macro) data are sometimes used when examining health care issues. Although they may be more accessible than individual (micro) observations, their interpretation is subject to ecological bias which in most cases is not measurable. This paper examines the implications of using aggregate-level data by conducting two separate analyses (micro and macro). Using as a database hospital episodes of care for the North Carolina Medicare aged population, regression models are developed from an examination of geographic grouping effects to explore the impact of extended care services, skilled nursing facility, and home health agency care on acute care hospital days. Specific problems encountered are: variable definition, collinearity , variance reduction, dilution of effect, spurious correlation, and observation influence. Stronger collinear (correlation among independent variables) relations occur at the macro-level than at the micro-level and spurious macro-correlations result from model specification and definition of interaction effects.

Aged↗

PubMed2000

Spatial associations among density of cattle, abundance of wild canids, and seroprevalence to Neospora caninum in a population of beef calves.

OBJECTIVE: To determine the epidemiologic plausibility of a sylvatic transmission cycle for Neospora caninum between wild canids and beef cattle. DESIGN: Spatial analysis study. ANIMALS: 1,009 weaned beef steers from 94 beef herds in Texas. PROCEDURE: Calves were grouped on the basis of seroprevalence for N caninum and ecologic region in Texas. The Morans I test was used to evaluate spatial interdependence for adjusted seroprevalence by ecologic region. Cattle density (Number of cattle/259 km2 [Number of cattle/100 mile2] of each ecologic region) and abundance indices for gray foxes and coyotes (Number of animals/161 spotlight-transect [census] km [Number of animals/100 census miles] of each ecologic region) were used as covariates in spatial regression models, with adjusted seroprevalence as the outcome variable. A geographic information system (GIS) that used similar covariate information for each county was used to validate spatial regression models. Results-Spatial interdependence was not detected for ecologic regions. Three spatial regression models were tested. Each model contained a variable for cattle density for the ecologic regions. Results for the 3 models revealed that seroprevalence was associated with cattle density and abundances of gray foxes, coyotes, or both. Abundances of gray foxes and coyotes were collinear. Results of a GIS-generated model validated these spatial models. CONCLUSIONS AND CLINICAL RELEVANCE: In Texas, beef cattle are at increased risk of exposure to N caninum as a result of the abundance of wild canids and the density of beef cattle. It is plausible that a sylvatic transmission cycle for neosporosis exists.

Animals↗

PubMed1999

The effect of collinearity on parameter estimates in nonlinear mixed effect models.

PURPOSE: To demonstrate how correlations among predictor variables in a population pharmacokinetic model affect the ability to discern which covariates should enter into the structural pharmacokinetic model. METHODS: Monte Carlo simulation was used to generate multiple-dose concentration-time data similar to that seen in a Phase III clinical trial. The drugs' pharmacokinetics were dependent on two covariates. Five data sets were simulated with increasing correlation between the two covariates. All data sets were analyzed using NONMEM both with and without inclusion of the covariates in the structural pharmacokinetic model. Summary measures for ill-conditioning and sensitivity analysis were used to examine how increasing correlation among covariates affects the accuracy and precision of the parameter estimates. RESULTS: When covariates were included in the structural pharmacokinetic model and the correlation between covariates increased, the standard error of the parameter estimates increased and the value of parameter estimates themselves became increasingly biased. When the correlation between predictor variables was 0.75, the standard errors of the parameter estimates were too large to declare statistical significance. CONCLUSIONS: Correlations among predictor variables greater than 0.5 when entered into the model simultaneously should be a warning to researchers because the (1) the accuracy of the parameter estimates themselves may be biased and (2) the precision of the estimates may be inflated due to ill-conditioning.

Clinical Trials, Phase III as Topic↗

PubMed2004

An integrated approach for comparative mapping in rice and barley with special reference to the Rph16 resistance locus.

The accumulated sequence information of the almost completed rice genome and the transcriptome of other cereals provide an excellent starting point for comparative genome analysis. We performed targeted synteny-based marker saturation for the Rph16 leaf rust resistance locus in barley by extensively exploiting these newly available resources. Out of a collection of over 320,000 public barley ESTs 309 non-redundant candidate syntenic clones have been identified for this region in a two-step in silico selection procedure. For mapping, 54 barley cDNA-clones were selected due to the even distribution of their homologs on a putatively collinear 3-Mb rice BAC contig. Out of these, 97% (30) of the polymorphic markers could be genetically assigned in collinearity to the target region in barley and a set of 11 markers was integrated into an rph16 high-resolution map. Although, the collinear target region of rice does not contain an obvious candidate gene for rph16 the results demonstrate the potential of the presented procedure to efficiently utilize EST resources for synteny-based marker saturation. The systematic genome-wide exploitation of the increasing sequence data resources will strongly improve our current view of genome conservation and likely facilitate a synteny-based isolation of genes conserved across cereal species.

Chromosome Mapping↗

PubMed2005

Assessment of EEG synchronization based on state-space analysis.

Cortical computation involves the formation of cooperative neuronal assemblies characterized by synchronous oscillatory activity. A traditional method for the identification of synchronous neuronal assemblies has been the coherence analysis of EEG signals. Here, we suggest a new method called S estimator, whereby cortical synchrony is defined from the embedding dimension in a state-space. We first validated the method on clusters of chaotic coupled oscillators and compared its performance to that of other methods for assessing synchronization. Then nine adult subjects were studied with high-density EEG recordings, while they viewed in the two hemifields (hence with separate hemispheres) identical sinusoidal gratings either arranged collinearly and moving together, or orthogonally oriented and moving at 90 degrees . The estimated synchronization increased with the collinear gratings over a cluster of occipital electrodes spanning both hemispheres, whereas over temporo-parietal regions of both hemispheres, it decreased with the same stimulus and it increased with the orthogonal gratings. Separate calculations for different EEG frequencies showed that the occipital clusters involved synchronization in the beta band and the temporal clusters in the alpha band. The gamma band appeared to be insensitive to stimulus diversity. Different stimulus configurations, therefore, appear to cause a complex rearrangement of synchronous neuronal assemblies distributed over the cortex, in particular over the visual cortex.

Adult↗

PubMed2005

Regression analysis of longitudinal binary data with time-dependent environmental covariates: bias and efficiency.

Generalized estimating equations (Liang and Zeger, 1986) is a widely used, moment-based procedure to estimate marginal regression parameters. However, a subtle and often overlooked point is that valid inference requires the mean for the response at time t to be expressed properly as a function of the complete past, present, and future values of any time-varying covariate. For example, with environmental exposures it may be necessary to express the response as a function of multiple lagged values of the covariate series. Despite the fact that multiple lagged covariates may be predictive of outcomes, researchers often focus interest on parameters in a 'cross-sectional' model, where the response is expressed as a function of a single lag in the covariate series. Cross-sectional models yield parameters with simple interpretations and avoid issues of collinearity associated with multiple lagged values of a covariate. Pepe and Anderson (1994), showed that parameter estimates for time-varying covariates may be biased unless the mean, given all past, present, and future covariate values, is equal to the cross-sectional mean or unless independence estimating equations are used. Although working independence avoids potential bias, many authors have shown that a poor choice for the response correlation model can lead to highly inefficient parameter estimates. The purpose of this paper is to study the bias-efficiency trade-off associated with working correlation choices for application with binary response data. We investigate data characteristics or design features (e.g. cluster size, overall response association, functional form of the response association, covariate distribution, and others) that influence the small and large sample characteristics of parameter estimates obtained from several different weighting schemes or equivalently 'working' covariance models. We find that the impact of covariance model choice depends highly on the specific structure of the data features, and that key aspects should be examined before choosing a weighting scheme.

Air Pollutants↗