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PubMed2005

Lack of correlation between regional pollen counts and percutaneous reactivity to tree pollen extracts in patients with seasonal allergic rhinitis.

BACKGROUND: Although seasonal patterns of tree pollination have been reported, it is unknown if aerobiologic data correlate with patterns of in vivo sensitization. OBJECTIVE: To evaluate the relationship between regional tree pollen exposure and patterns of in vivo percutaneous reactivity to specific tree pollen extracts in a local patient population with seasonal allergic rhinitis. METHODS: Patients with spring seasonal allergic rhinitis and percutaneous sensitivity to 1 or more regional tree pollens were studied. Tree pollen counts were collected at the same urban site from 1997 to 2002 and at a suburban site in 2002. Patients underwent skin prick testing with commercial extracts of 15 indigenous tree species. Serum specific IgE measurements were assayed in a subset of sensitized patients. RESULTS: Of 127 patients who reported symptoms consistent with seasonal allergic rhinitis during the spring pollen season, 93 qualified based on demonstration of at least 1 positive skin prick test result. Mean 5-year pollen counts (1997-2001) and 2002 urban counts were highly correlated (Spearman r = 0.95, P < .001), indicating that year-to-year pollen counts were consistent. No significant correlation was found between mean seasonal pollen counts (urban site, 1997-2001) and frequencies of skin prick test reactivity to specific tree pollen allergens (Spearman r = -0.03, P = .93). No significant relationship was found between 5-year mean tree pollen counts and positive serum specific IgE tests for specific tree pollens (Spearman r = -0.42, P = .30). Eight of 15 species elicited percutaneous reactions in more than 50% of patients (ie, satisfying definition of a major in vivo allergen). However, 6 of the 8 major tree allergens each represented 5% or less of 5-year mean total tree pollen counts. CONCLUSION: No correlation was found between overall frequencies of in vivo sensitization to tree pollen allergens in a local population and regional pollen exposure data.

Adolescent↗

PubMed1996

Protein interaction with immobilized metal ion affinity ligands under high ionic strength conditions.

An investigation into the adsorption behavior under batch equilibrium binding conditions of hen egg white lysozyme (HEWL) with the immobilized metal ion affinity chromatographic adsorbent, Cu(2+)-IDA Sepharose CL-4B, in the presence of high concentrations of NaCl or KCl has been undertaken. When the concentration of NaCl or KCl in the adsorption buffer was < or = 0.2 M, the adsorption data correlated with predictions based on the Langmuir model. However, when the salt concentration was > or = 0.5 M, the adsorption data appeared to follow the Freundlich-Langmuir model under these higher ionic strength conditions. Under elevated ionic strength conditions, the protein-ligand interactions were shown to involve positive cooperativity by Scatchard plot analysis of the experimental data. The number, n, of interacting protein molecules increased with the salt concentration, while the apparent dissociation constant Kd under these high ionic strength conditions was less dependent on the type of salt present in the adsorption buffer. These studies reveal that the binding of Cu(2+)-IDA Sepharose CL-4B to HEWL acceptor molecules under conditions of high ionic strength is characteristic of general heterogeneous interactions, whereby the immobilized metal ion affinity chromatography (IMAC) ligands bind to a protein acceptor undergoing isodesmic indefinite self-association and multisite attachment. As a consequence, these results on the adsorption behavior of HEWL have important general implications for the preparative use of immobilized metal ion affinity adsorbents in packed and expanded bed systems, particularly with regard to the resolution and productivity of the separation for the target protein. In addition, the results from these studies are relevant to investigations involving analytical affinity chromatographic or biosensor assessment of the interaction of proteins with immobilized IMAC ligands when high ionic strength equilibration feedstocks or conditions are employed.

Adsorption↗

PubMed1992

The influence of metal backing in unicompartmental tibial component fixation. An in vivo roentgen stereophotogrammetric analysis of micromotion.

The fixation of the tibial component in 36 patients with conventionally cemented unicompartmental knee arthroplasties for femorotibial gonarthrosis was studied using roentgen stereophotogrammetric analysis (RSA). Twenty-four tibial components were all-polyethylene while 12 were metal-backed. The follow-up was for 6 years. Significant migration was detected for all cases but two and ranged from 0.3 mm to 5.4 mm. The greater part of the migration occurred during the first 1-2 years, after which two-thirds of the prostheses remained stable. Seven all-polyethylene components were subjected to a stress examination after 1-2 years and displacement, induced by external forces, was found in all seven. A strong correlation was found between the extension of the radiolucent line and the migration. Otherwise, neither demographic, clinical, nor radiographic data correlated with the RSA results. In this study metal backing did not have any influence on prosthetic fixation as measured by RSA.

Aged↗

PubMed1997

Serotonin function in human subjects: intercorrelations among central 5-HT indices and aggressiveness.

Three central indices of serotonin (5-HT) system activity in human subjects were examined to: (a) estimate intercorrelations among 5-HT indices and (b) compare correlations of these indices with a measure of assaultiveness (Buss-Durkee 'Assault') in personality-disordered individuals. Cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentration and prolactin responses to m-chlorophenylpiperazine (m-CPP) m-CPP (PRL[m-CPP]) and fenfluramine (PRL[FEN]), served as indices of pre-, post- and 'net'-synaptic central 5-HT activity, respectively. PRL[D,L-FEN] responses were inversely related to CSF 5-HIAA concentration and positively correlated with PRL[m-CPP] responses. Both PRL[D,L-FEN] and PRL[m-CPP] response data correlated equally, and inversely, with BD Buss-Durkee Assault when the same subjects were examined. Basal CSF 5-HIAA concentration did not correlate with Buss-Durkee 'Assault'. PRL responses to challenge probes which involve activation of 5-HT post-synaptic receptors may correlate better than a basal measure of pre-synaptic 5-HT function with a tendency to assaultive behavior in non-criminally aggressive personality-disordered individuals.

Adult↗

PubMed2002

Strong-association-rule mining for large-scale gene-expression data analysis: a case study on human SAGE data.

BACKGROUND: The association-rules discovery (ARD) technique has yet to be applied to gene-expression data analysis. Even in the absence of previous biological knowledge, it should identify sets of genes whose expression is correlated. The first association-rule miners appeared six years ago and proved efficient at dealing with sparse and weakly correlated data. A huge international research effort has led to new algorithms for tackling difficult contexts and these are particularly suited to analysis of large gene-expression matrices. To validate the ARD technique we have applied it to freely available human serial analysis of gene expression (SAGE) data. RESULTS: The approach described here enables us to designate sets of strong association rules. We normalized the SAGE data before applying our association rule miner. Depending on the discretization algorithm used, different properties of the data were highlighted. Both common and specific interpretations could be made from the extracted rules. In each and every case the extracted collections of rules indicated that a very strong co-regulation of mRNA encoding ribosomal proteins occurs in the dataset. Several rules associating proteins involved in signal transduction were obtained and analyzed, some pointing to yet-unexplored directions. Furthermore, by examining a subset of these rules, we were able both to reassign a wrongly labeled tag, and to propose a function for an expressed sequence tag encoding a protein of unknown function. CONCLUSIONS: We show that ARD is a promising technique that turns out to be complementary to existing gene-expression clustering techniques.

Algorithms↗

PubMed1995

[Neurofunctional MRI imaging of higher cognitive performance of the human brain].

Functional magnetic resonance imaging (fMRI) offers a powerful experimental tool for mapping activated cortical regions in man. Thereby, the paramagnetic deoxyhemoglobin in the red blood cells acts as an endogenous susceptibility contrast agent, which allows the noninvasive detection of stimulus-induced transient changes in regional cerebral blood flow and volume. Fifteen normal subjects were examined on a conventional 1.5-T MR system to visualize cortical activation during the performance of high-level cognitive tasks. A computer-controlled videoprojector was employed to present psychometrically optimized activation paradigms. Reaction times and error rates of the volunteers were acquired online during stimulus presentation. The time course of cortical activation was measured in a series of strongly T2*-weighted gradient-echo images from three or four adjacent slices. For anatomical correlation, picture elements showing a stimulus-related significant signal increase were color-coded and superimposed on T1-weighted spin-echo images. Analysis of the fMRI data revealed a subtle (range 2-5%), but statistically significant (P < 0.05) increase in signal intensity during the periods of induced cortical activation. Judgment of semantic relatedness of word pairs, for example, activated selectively cortical areas in left frontal and left temporal brain regions. The strength of cortex activation in the semantic task decreased significantly in the course of stimulus presentation and was paralleled by a decrease in the corresponding reaction times. With its move into the area of cognitive neuroscience, fMRI calls both for the careful design of activation schemes and for the acquisition of behavioral data. For example, brain regions involved in language processing could only be identified clearly when psychometrically matched activation paradigms were employed. The reaction time data correlated well with selective learning and thus helped to facilitate interpretation of the fMRI data sets.

Arousal↗

PubMed2007

Properties of analysis methods that account for clustering in volume-outcome studies when the primary predictor is cluster size.

In recent years health services researchers have conducted 'volume-outcome' studies to evaluate whether providers (hospitals or surgeons) who treat many patients for a specialized condition have better outcomes than those that treat few patients. These studies and the inherent clustering of events by provider present an unusual statistical problem. The volume-outcome setting is unique in that 'volume' reflects both the primary factor under study and also the cluster size. Consequently, the assumptions inherent in the use of available methods that correct for clustering might be violated in this setting. To address this issue, we investigate via simulation the properties of three estimation procedures for the analysis of cluster correlated data, specifically in the context of volume-outcome studies. We examine and compare the validity and efficiency of widely-available statistical techniques that have been used in the context of volume-outcome studies: generalized estimating equations (GEE) using both the independence and exchangeable correlation structures; random effects models; and the weighted GEE approach proposed by Williamson et al. (Biometrics 2003; 59:36-42) to account for informative clustering. Using data generated either from an underlying true random effects model or a cluster correlated model we show that both the random effects and the GEE with an exchangeable correlation structure have generally good properties, with relatively low bias for estimating the volume parameter and its variance. By contrast, the cluster weighted GEE method is inefficient.

Aged↗

PubMed1998

Development and internal validation of an in vitro-in vivo correlation for a hydrophilic metoprolol tartrate extended release tablet formulation.

PURPOSE: To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a hydrophilic matrix extended release metoprolol tablet. METHODS: In vitro dissolution of the metoprolol tablets was examined using the following methods: Apparatus II, pH 1.2 & 6.8 at 50 rpm and Apparatus I, pH 6.8, at 100 and 150 rpm. Seven healthy subjects received three metoprolol formulations (100 mg): slow, moderate, fast releasing and an oral solution (50 mg). Serial blood samples were collected over 48 hours and analyzed by a validated HPLC assay using fluorescence detection. The f2 metric (similarity factor) was used to analyze the dissolution data. Correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted metoprolol concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for Cmax and AUC to determine the validity of the correlation. RESULTS: Apparatus I operated at 150 rpm, and pH of 6.8 was found to be the most discriminating dissolution method. There was a significant linear relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for Cmax and AUC for all formulations of less than 10% was found for all IVIVC models. CONCLUSIONS: The relatively low prediction errors for Cmax and AUC observed strongly suggest that the metoprolol IVIVC models are valid. The average percent prediction error of less than 10% indicates that the correlation is predictive and allows the associated dissolution data to be used as a surrogate for bioavailability studies.

Adrenergic beta-Antagonists↗

PubMed2000

Penalized weighted least-squares image reconstruction for dual energy X-ray transmission tomography.

We present a dual-energy (DE) transmission computed tomography (CT) reconstruction method. It is statistically motivated and features nonnegativity constraints in the density domain. A penalized weighted least squares (PWLS) objective function has been chosen to handle the non-Poisson noise added by amorphous silicon (aSi:H) detectors. A Gauss-Seidel algorithm has been used to minimize the objective function. The behavior of the method in terms of bias/standard deviation tradeoff has been compared to that of a DE method that is based on filtered back projection (FBP). The advantages of the DE PWLS method are largest for high noise and/or low flux cases. Qualitative results suggest this as well. Also, the reconstructed images of an object with opaque regions are presented. Possible applications of the method are: attenuation correction for positron emission tomography (PET) images, various quantitative computed tomography (QCT) methods such as bone mineral densitometry (BMD), and the removal of metal streak artifacts.

Algorithms↗

PubMed2006

Dual binding mode of a novel series of DHODH inhibitors.

Human dihydroorotate dehydrogenase (DHODH) represents an important target for the treatment of hyperproliferative and inflammatory diseases. In the cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine biosynthesis. DHODH inhibition results in beneficial immunosuppressant and antiproliferative effects in diseases such as rheumatoid arthritis. Here, we present high-resolution X-ray structures of human DHODH in complex with a novel class of low molecular weight compounds that inhibit the enzyme in the nanomolar range. Some compounds showed an interesting dual binding mode within the same cocrystal strongly depending on the nature of chemical substitution. Measured in vitro activity data correlated with the prevailing mode of binding and explained the observed structure-activity relationship. Additionally, the X-ray data confirmed the competitive nature of the inhibitors toward the putative ubiquinone binding site and will guide structure-based design and synthesis of molecules with higher activity.

Amides↗

PubMed1982

Content analysis of verbal behaviour in psychotherapy research: a comparison between two methods.

Verbal behaviour of a mixed patient population during psychotherapeutic interviews was analysed for affective content by means of two content analytic techniques, the Gottschalk-Gleser method and the 'anxiety topics dictionary' developed at the University of Ulm. Both methods share basic theoretical assumptions regarding affect definition and strive for pragmatic relevance in their meaning categories. They differ with respect to the analysis program they employ, the main difference being the coding unit and the extent to which they take into account contextual information. Correlational data presented shows a significant positive relationship between scores for shame and separation anxiety from both methods. A somewhat weaker correlation was found for guilt anxiety. These results suggest a formal similarity between these constructs as operationalized by both methods and call for further research on the comparability of meaning categories in studies of verbal behaviour.

Adult↗

PubMed1997

Total creatine in muscle: imaging and quantification with proton MR spectroscopy.

PURPOSE: To provide a noninvasive method of imaging and quantifying total creatine (phosphorylated plus unphosphorylated) in human muscle with proton magnetic resonance (MR) spectroscopy. MATERIALS AND METHODS: Water-suppressed, long echo time, stimulated-echo hydrogen-1 chemical shift imaging and short echo time unsuppressed chemical shift imaging were performed on the lower legs of 10 healthy volunteers at rest. Spatial resolution was 4.5-8.0 cm3. Water signals in unsuppressed data sets were quantified and used as chemical shift and concentration references. Images of the integrated N-CH3 resonance assigned to total creatine were extracted from the water-suppressed chemical shift image data. Correlations between the total creatine, lipid, and water signals from the same voxels were tested. The concentration of total creatine in skeletal muscle was calculated from the ratio of the relaxation-corrected N-CH3 and water signals from the same voxels. RESULTS: Total creatine was localized to muscle bundles. Lipid signals contributed less than 6% to the variance of total creatine signal on images and in measurements and did not correlate with total creatine in the same voxels (P > .1). Total creatine and unsuppressed water signals were positively correlated (P < .0001). MR spectroscopy yielded a total creatine value of 36.2 mmol/kg wet weight +/- 5.0, consistent with prior biopsy data. CONCLUSION: H-1 MR spectroscopy can be used to image and noninvasively quantify total creatine in human muscle. Its use could improve the understanding of the role of altered creatine metabolism in muscle disease and aid quantification of the response to creatine therapies.

Adult↗

PubMed2003

Analysis of multiple 2x2 tables with site-specific periodontal data.

Periodontal data typically consist of observations made at multiple sites within each patient. Observations within a patient tend to be positively correlated; hence, standard statistical techniques that assume independence are invalid. Regression techniques for correlated data have been proposed; communicating results from these models, however, is difficult, due to their inherent complexity. Simpler statistical approaches have also been proposed, but many of these methods can be applied only when covariates are specific to the subject, and do not vary from site to site within a subject. In this paper, we present two methods for the analysis of multiple 2x2 tables containing site-specific periodontal data. The methods presented are modifications of the well-known Mantel-Haenszel methods. We illustrate these methods using a subset of data from a clinical trial examining the effects of scaling and root planing on levels of interleukin-1 beta.

Chi-Square Distribution↗

PubMed2006

Anticancer drug clustering in lung cancer based on gene expression profiles and sensitivity database.

BACKGROUND: The effect of current therapies in improving the survival of lung cancer patients remains far from satisfactory. It is consequently desirable to find more appropriate therapeutic opportunities based on informed insights. A molecular pharmacological analysis was undertaken to design an improved chemotherapeutic strategy for advanced lung cancer. METHODS: We related the cytotoxic activity of each of commonly used anti-cancer agents (docetaxel, paclitaxel, gemcitabine, vinorelbine, 5-FU, SN38, cisplatin (CDDP), and carboplatin (CBDCA)) to corresponding expression pattern in each of the cell lines using a modified NCI program. RESULTS: We performed gene expression analysis in lung cancer cell lines using cDNA filter and high-density oligonucleotide arrays. We also examined the sensitivity of these cell lines to these drugs via MTT assay. To obtain our reproducible gene-drug sensitivity correlation data, we separately analyzed two sets of lung cancer cell lines, namely 10 and 19. In our gene-drug correlation analyses, gemcitabine consistently belonged to an isolated cluster in a reproducible fashion. On the other hand, docetaxel, paclitaxel, 5-FU, SN-38, CBDCA and CDDP were gathered together into one large cluster. CONCLUSION: These results suggest that chemotherapy regimens including gemcitabine should be evaluated in second-line chemotherapy in cases where the first-line chemotherapy did not include this drug. Gene expression-drug sensitivity correlations, as provided by the NCI program, may yield improved therapeutic options for treatment of specific tumor types.

Antimetabolites, Antineoplastic↗

PubMed2006

Meta-analysis of diagnostic and screening test accuracy evaluations: methodologic primer.

OBJECTIVE: Interest in evidence-based diagnosis is growing rapidly as diagnostic and screening techniques proliferate. In this article we provide an overview of systematic reviews of diagnostic performance and discuss in detail statistical methods for the most common variant of the problem: meta-analysis of studies in which a pair of estimates of sensitivity and specificity is reported. The need to account for possible variations in threshold for test positivity across studies led to the formulation of the Summary ROC (SROC) curve method. We discuss graphical and model-based ways to estimate, summarize, and compare SROC curves, and we present an example from a meta-analysis of data on techniques for staging cervical cancer. We also present a brief survey of the methodologic literature for addressing heterogeneity, correlated data, multiple thresholds per study, and systematic reviews of ROC studies. We conclude with a discussion of the significant methodologic challenges that continue to face investigators in this area of diagnostic medicine research. CONCLUSION: Systematic reviews of diagnostic performance are a rigorous approach to examining and synthesizing evidence in the evaluation of diagnostic and screening tests. The information from such reviews is needed by clinicians, health policy makers, researchers in diagnostic medicine, developers of diagnostic techniques, and the general public. However, despite progress in study quality and reporting and in methodologic development, major challenges confront investigators undertaking these reviews.

Diagnostic Techniques and Procedures↗

PubMed2004

Permanent prostate brachytherapy: the significance of postimplant dosimetry.

Recent developments in imaging science and treatment-planning software allow for accurate postimplant dosimetric assessment in all patients after prostate brachytherapy. This article reviews the available data correlating cancer control and morbidity with dosimetric quantifiers obtained from postimplant dosimetric assessment after prostate brachytherapy. Continued collection of dosimetric data in patients treated with prostate brachytherapy will allow for further refinements in the technique, leading to continued high rates of cure with increasingly lower rates of morbidity.

Journal Article↗

PubMed1996

Measure and statistical test for cross-correlation between paired neuronal spike trains with small sample size.

Recent development of multi-unit recording techniques such as optical recording and multi-electrode arrays makes it possible to record neuronal activities from tens or hundreds of neurons simultaneously. To analyze functional connections between these neurons, cross-correlation analysis has been most commonly applied to the hundreds to thousands of pairs of these neurons. However, conventional cross-correlation data needs statistical tests for significance especially when the sample size of recorded spike trains is small. Here, a multiple hypergeometric model based on a transformation of the cross-correlogram data to a 2 x J table has been suggested. The exact p value for significance can be obtained by the generalized Fisher's method with small sample size and a cross-correlation coefficient for the strength of cross-correlation can be obtained based on the R-square analogue for nominal data. For large sample size, chi 2 test can be applied based on the same transformation. Examples of real spike train data set and simulation show that the methods are applicable to the data of multi-unit activity with only tens of spikes. These methods are especially useful when thousands of cross-correlograms need to be screened quickly and automatically.

Action Potentials↗

PubMed1986

Quantitation of glycogen synthase and phosphorylase protein in mouse liver: correlation between enzymatic protein and enzyme activity.

Phosphorylase and glycogen synthase protein were measured in normal and genetically diabetic (C57BL/KsJ db/db) mice liver extracts using rocket immunoelectrophoresis, and these data correlated with measurements of total phosphorylase and total glycogen synthase activities, respectively. Phosphorylase protein in 5-week-old normal mice was about 5 micrograms/mg protein and reached 8 micrograms/mg protein by 9 weeks. In comparison, the diabetic mice had elevated levels of phosphorylase protein (11-13 micrograms/mg protein) which correlated with an increased total phosphorylase activity compared to normals. The correlation coefficient for the phosphorylase activity vs protein plot was highly significant (r = 0.73, P less than 0.001). The molar concentration of phosphorylase subunit in normal mouse liver was calculated to be 11 microM and up to 23 microM in the diabetic mice. The liver concentration of glycogen synthase was relatively constant in normal mice at 400 ng/mg protein (corresponding to approximately 1.4 microM) but varied from 230 to 441 ng/mg protein (0.9 to 1.8 microM) in diabetic mice. There was little correlation between glycogen synthase activity and enzymatic protein (r = 0.15). These results indicate (1) that phosphorylase is present at concentrations approximately 10 times that of glycogen synthase, and (2) that glycogen synthase activity is relatively more dependent upon factors other than the amount of enzymatic protein.

Animals↗