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PubMed2002

Psychometric characteristics of dyspnea descriptor ratings in emergency department patients with exacerbated chronic obstructive pulmonary disease.

The purpose of this study was to evaluate the reliability, content validity, and factor structure of dyspnea sensory quality descriptor ratings in emergency department (ED) patients with exacerbated chronic obstructive pulmonary disease (COPD). During an ED visit 104 patients with COPD rated the intensity of 16 dyspnea sensory quality descriptors (numerical ratings of 0-10) in relation to how they felt when they decided to come to the ED (Decision) and 1 week before the visit. Content validity of 15 descriptors was supported. Factor analysis of Decision ratings resulted in seven descriptors and three factors (alpha=.88; 74% common variance): Smothering/Suffocating/Hunger for air (alpha=.87); Effort/Work (alpha=.87); and Tight/Constricted (alpha=.74). Results indicate that the intensity of sensory quality descriptors can be measured reliably in COPD patients during an exacerbation of COPD. The initial descriptor list of descriptors could be cut by more than half while retaining satisfactory psychometric properties.

Dyspnea↗
PubMed1999

Validation of a new restraint docking method for solution structure determinations of protein-ligand complexes.

A new method is proposed for docking ligands into proteins in cases where an NMR-determined solution structure of a related complex is available. The method uses a set of experimentally determined values for protein-ligand, ligand-ligand, and protein-protein restraints for residues in or near to the binding site, combined with a set of protein-protein restraints involving all the other residues which is taken from the list of restraints previously used to generate the reference structure of a related complex. This approach differs from ordinary docking methods where the calculation uses fixed atomic coordinates from the reference structure rather than the restraints used to determine the reference structure. The binding site residues influenced by replacing the reference ligand by the new ligand were determined by monitoring differences in 1H chemical shifts. The method has been validated by showing the excellent agreement between structures of L. casei dihydrofolate reductase trimetrexate calculated by conventional methods using a full experimentally determined set of restraints and those using this new restraint docking method based on an L. casei dihydrofolate reductase methotrexate reference structure.

Binding Sites↗
PubMed1998

Structure of the capsid of Pf3 filamentous phage determined from X-ray fibre diffraction data at 3.1 A resolution.

We have recorded X-ray diffraction patterns at 3.1 A resolution from magnetically aligned fibres of the Pf3 strain of filamentous bacteriophage (Inovirus). The patterns are similar to patterns from the higher-temperature form of the Pf1 strain, indicating that the Pf3 and Pf1 virions have the same helix symmetry and similar protein subunit shape. This is of particular interest, given that the primary structures of the two protein subunits are quite different; and the nucleotide/protein subunit ratio in the Pf3 virion is more than twice that in Pf1, indicating important differences in DNA packaging. We have built a molecular model of the Pf3 protein capsid based on the model of Pf1, and refined it against the diffraction data using simulated annealing. The refinement confirms that the two structures are similar, which may reflect a fundamental motif of alpha-helix packing. However, there are some differences between the structures: the Pf3 subunit appears to be completely alpha-helical, beginning at the N terminus, whereas the first few residues of the Pf1 subunit are not helical; and the structure of the C-terminal region of the Pf3 subunit at the inner surface of the tubular capsid indicates that DNA/protein interactions in this virion may involve both aromatic side-chains and positively charged side-chains, whereas those in the Pf1 virion involve predominantly only the latter. In the course of this work, we have developed new approaches to refinement and validation of helical structures with respect to continuous transform fibre diffraction data.

Amino Acid Sequence↗
PubMed1995

Development and validation of scales to measure organisational features of acute hospital wards.

In order to make comparisons between wards and explain variations in outcomes of nursing care, there is a growing need in nursing research for reliable and valid measures of the organisational features of acute hospital wards. This research developed The Ward Organisational Features Scales (WOFS); each set of six scales comprising 14 subscales which measure discrete dimensions of acute hospital wards. A study of a nationally representative sample of 825 nurses working in 119 acute wards in 17 hospitals, drawn from seven Regional Health Authorities in England provides evidence for the structure, reliability and validity of this comprehensive set of measures related to: the physical environment of the ward, professional nursing practice, ward leadership, professional working relationships, nurses' influence and job satisfaction. Implications for further research are discussed.

Factor Analysis, Statistical↗
PubMed2006

Psychometric evaluation of the Chinese version of the Fagerstrom Tolerance Questionnaire as a measure of cigarette dependence.

AIM: The aim of this study is to estimate the psychometric properties of the Chinese version of the Fagerstrom Tolerance Questionnaire as a measure of nicotine dependence. BACKGROUND: The Chinese Fagerstrom Tolerance Questionnaire has been used in smoking cessation programmes in Taiwan. However, the psychometric properties of the Chinese version have not been tested. METHODS: A cross-sectional, descriptive study was conducted from June 2004 to July 2005 with 247 adult smokers. The criterion validity of the Chinese Fagerstrom Tolerance Questionnaire was determined using two biomarkers (exhaled CO and saliva cotinine levels). Because the responses to the items are dichotomous or nominal, the validity and factorial structures were examined using tetrachoric techniques. Construct reliability was evaluated to accommodate the lack of tau-equivalence assumed in computing Cronbach's alpha. FINDINGS: The item 'smoke more in the morning' was not statistically significantly correlated with either biomarker because many participants expressed the desire to smoke after meals instead of in the morning. The items 'nicotine yield' and 'inhalation' performed poorly in terms of criterion validity and construct validity. This evidence supports modification of the Chinese version of the Fagerstrom Tolerance Questionnaire to the six-item Fagerstrom Test for Nicotine Dependence. In addition, the item 'difficulty refraining from smoking in forbidden places' had relatively poor psychometric performance. The reason may be culturally specific, having to do with the relative lack of forbidden places and restrictions on tobacco use in Taiwan. The predictive ability of the Chinese version of the Fagerstrom Tolerance Questionnaire for biomarkers is higher than the English version. The reliability coefficient (0.65) was higher than Cronbach's alpha, but did not meet the satisfactory standard of 0.70. CONCLUSION: The Chinese version of the Fagerstrom Tolerance Questionnaire is a fairly reliable and valid scale, but needs to be revised to accommodate cross-cultural differences.

Adolescent↗
PubMed2006

A novel workflow for the inverse QSPR problem using multiobjective optimization.

A workflow for the inverse quantitative structure-property relationship (QSPR) problem is reported in this paper for the de novo design of novel chemical entities (NCE) in silico through the application of existing QSPR models to calculate multiple objectives, including prediction confidence measures, to be optimized during the de novo design process. Two physical property datasets are applied as case studies of the inverse QSPR workflow (IQW): mean molecular polarizability and aqueous solubility. The case studies demonstrate the optimization of molecular structures to within a property range of interest; the optimized structures are then validated against QSPR models that are generated from sets of alternative descriptors to those used in the IQW. The paper concludes with a discussion of the results from the case studies.

Least-Squares Analysis↗
PubMed1999

Evaluation and improvement of multiple sequence methods for protein secondary structure prediction.

A new dataset of 396 protein domains is developed and used to evaluate the performance of the protein secondary structure prediction algorithms DSC, PHD, NNSSP, and PREDATOR. The maximum theoretical Q3 accuracy for combination of these methods is shown to be 78%. A simple consensus prediction on the 396 domains, with automatically generated multiple sequence alignments gives an average Q3 prediction accuracy of 72.9%. This is a 1% improvement over PHD, which was the best single method evaluated. Segment Overlap Accuracy (SOV) is 75.4% for the consensus method on the 396-protein set. The secondary structure definition method DSSP defines 8 states, but these are reduced by most authors to 3 for prediction. Application of the different published 8- to 3-state reduction methods shows variation of over 3% on apparent prediction accuracy. This suggests that care should be taken to compare methods by the same reduction method. Two new sequence datasets (CB513 and CB251) are derived which are suitable for cross-validation of secondary structure prediction methods without artifacts due to internal homology. A fully automatic World Wide Web service that predicts protein secondary structure by a combination of methods is available via http://barton.ebi.ac.uk/.

Algorithms↗
PubMed1998

Pharmacophoric search and 3D-QSAR comparative molecular field analysis studies on agonists of melatonin sheep receptors.

Conformational analysis was used to characterize the agonist pharmacophore for melatonin sheep brain receptor recognition and activation. The molecular geometry shared by all conformations of the selected active ligands was determined. Assuming that all the compounds interact at the same binding site at the receptor level, 2-iodomelatonin pharmacophoric conformation served as a template for the superimposition of 64 structurally heterogeneous agonists constituting the training set used to perform a three-dimensional quantitative structure-activity relationship study via the comparative molecular field analysis method. A statistically significant model was obtained for the totality of the compounds (n = 64, q2 = 0.62, N = 6, r2 = 0.96, s = 0.28, F = 249) with steric, electrostatic, and lipophilic relative contributions of 28%, 35%, and 37%, respectively. The predictive power of the proposed model was discerned by successfully testing the 78 agonist ligands constituting the test set. The model so obtained and validated brings important structural insights to aid the design of novel melatoninergic agonist ligands prior to their synthesis.

Animals↗
PubMed2004

Fine-scale geographical structure, intra-individual polymorphism and recombination in nuclear ribosomal internal transcribed spacers in Armeria (Plumbaginaceae).

BACKGROUND AND AIMS: Isolation and drift are the main causes for geographic structure of molecular variation. In contrast, the one found in a previous survey in Armeria (Plumbaginaceae) for nuclear ribosomal ITS multicopy regions was species-independent and has been hypothesized to be due to extensive gene-flow and biased concerted evolution. Since this was inferred from a genus-level phylogenetic analysis, the aim of this study was to check for the occurrence of such structure and the validity of the proposed model at a local scale, in a southern Spanish massif (Sierra Nevada), as well as to examine the evolutionary implications at the organism level. METHODS: In addition to 117 sequences of direct PCR products from genomic DNA, 50 sequences of PCR products from cloned DNA were obtained to analyse cases of intragenomic polymorphisms for the ITS regions. KEY RESULTS: Sequence data confirm the occurrence of a species-independent structure at a local scale and reveal insights through the analysis of contact areas between different ITS copies (ribotypes). A comparison between cloned and direct sequences (a) confirms that, within these contact areas, ITS copies co-occur both in different individuals and within single genomes; and (b) reveals recombination between different copies. CONCLUSIONS: This study supports the utility of direct sequences for detecting intra-individual polymorphism and for partially inferring the ITS copies involved, given previous knowledge of the variability. The main evolutionary implication at the organism level is that gene-flow and concerted evolution shape the geographic structure of ITS variation.

Base Sequence↗
PubMed1997

A self report measure of affective lability.

OBJECTIVES: The development and validation of the Center for Neurologic Study-Lability Scale (CNS-LS), the first self report measure of affective lability in patients with amyotrophic lateral sclerosis (ALS). METHODS: Potential questionnaire items were identified through interviews with patients and families and expert review. Potential items, as well as measures of affect intensity, affective lability in psychopathology, and depression were administered to 99 patients with ALS for item selection and the examination of factor structure and construct validity. Test-retest reliability was examined using an additional sample of 31 patients with ALS, and criterion related validity was examined by comparing CNS-LS scores with physicians' diagnoses of affective lability in a sample of 77 patients with ALS. RESULTS: A seven item questionnaire emerged, composed of two subscales measuring labile laughter (four items) and labile tearfulness (three items). The CNS-LS showed a pattern of associations with affect intensity, affective lability in psychopathology, and depression consistent with a scale measuring affective lability. The CNS-LS also showed good test-retest reliability and internal consistency, and successfully predicted physicians' diagnoses of affective lability. An auxiliary subscale measuring labile frustration, anger, and impatience also emerged. CONCLUSIONS: The CNS-LS is a short, easily administered, and psychometrically sound measure of affective lability for use with patients with ALS. It has potential applications as both a clinical screening device and a research tool. The need for future research into the relation of depression as well as labile frustration, anger, and impatience to the syndrome of affective lability in neurological disorders is discussed.

Affect↗
PubMedDate not supplied

Confirmatory factor analysis of a Spanish version of the sex fantasy questionnaire: assessing gender differences.

The objective of this study was to validate the factor structure of Wilson's Sex Fantasy Questionnaire (SFQ; Wilson, 1978; Wilson & Lang, 1981) using a Spanish version. In order to do this, we conducted confirmatory factor analysis on two nonclinical samples containing 195 men and 315 women. Both groups were tested for the structure proposed by Wilson and also for some alternative models. Confirmatory factor analysis showed that four factors were reasonably distinct, especially for the men. We proposed shortened version of the instrument that would have sufficient psychometric guarantees for assessing sexual fantasies in both genders. This abridged version improved the fit of the four-factor oblique factor equally for both the samples of men and women. In the light of the results of the validation hypothesis established with some criterion variables (dyadic sexual desire, unconventional sex, homophobia), we discuss discrepancies between both versions.

Adolescent↗
PubMed1999

Assessing behavioral health outcomes in outpatient programs: reliability and validity of the BASIS-32.

The Behavior and Symptom Identification Scale (BASIS-32) was developed to assess mental health outcomes among patients with severe illness treated on inpatient programs. However, its applicability and utility to those treated in outpatient programs has not been determined. The objective of this study was to assess reliability, validity, and sensitivity to change of the BASIS-32 among mental health consumers treated in outpatient programs. A total of 407 outpatients completed the BASIS-32 and the Short Form Health Status Profile (SF-36) at the beginning of a treatment episode and again 30 to 90 days later. Outpatients reported less difficulty at intake than did inpatients, and the BASIS-32 detected statistically significant changes 30 to 90 days after beginning outpatient treatment. Factor structure and construct validity were partially confirmed on this sample of outpatient consumers. Analyses of data from a wide range of facilities and samples would add to validation efforts and to further refinement of the BASIS-32.

Adolescent↗
PubMed1991

SESAM: a relational database for structure and sequence of macromolecules.

A system is described that provides ways of integrating data on protein structure, sequence, and survey results, with molecular graphics and molecular mechanics software. Its major component is the relational database SESAM, presently implemented under the commercial package SYBASE. By design, the database allows full integration--within the same data organization--of raw data on protein structure, sequence, ligands, and heterogroups, obtained from the Brookhaven Protein Databank, with pure sequence information available from other databanks such as SWISS-PROT. It contains in addition higher level descriptions of structural and topological properties, as well as survey results, obtained by executing specialized computer programs. Aside from the very useful attribute of closely combining structural and nonstructural information, other important features distinguish it from analogous systems developed elsewhere. It includes a molecular dictionary with complete description of geometric properties and energy parameters used in modeling and conformational energy calculations. Using this dictionary, structural data are validated by checking for localized inconsistencies in atomic coordinates, atomic symbols, chirality definitions, and flagging errors and incomplete entries. Because of both the dictionary and the validation procedures, SESAM can be readily interfaced with conventional molecular graphics and mechanics software packages, or with other specialized application programs. With the aid of appropriate interfaces, data access is sufficiently fast for SESAM to be interrogated interactively. Prototypes of user interfaces, as well as an interface with the molecular graphics package BRUGEL, are described and the power of the system is illustrated in applications such as homology-based protein modeling, computer-aided protein design, protein structure predictions, analysis of local structure motifs, and of relationships between protein sequence and structure.

Amino Acid Sequence↗
PubMed2004

Direct AFM observation of saposin C-induced membrane domains in lipid bilayers: from simple to complex lipid mixtures.

Saposin C (Sap C) is a small glycoprotein required by glucosylceramidase (GCase) for hydrolysis of glucosylceramide to ceramide and glucose in lysosomes. The molecular mechanism underlying Sap C stimulation of the enzyme activation is not fully understood. Here, atomic force microscopy (AFM) has been used to study Sap C-membrane interactions under physiological conditions. First, to establish how Sap C-membrane interactions affect membrane structure, lipid bilayers containing zwitterionic and anionic phospholipids were used. It was observed that Sap C induced two types of membrane restructuring effects, i.e., the formation of patch-like domains and membrane destabilization. Bilayers underwent extensive structural reorganization. To validate the biological importance of the membrane restructuring effects, interaction of Sap C with lipid bilayers composed of cholesterol, sphingomyelin, and zwitterionic and anionic phospholipids were studied. Although similar membrane restructuring effects were observed, Sap C-membrane interactions, in this case, were remarkably modulated and their effects were restricted to a limited area. As a result, nanometer-sized domains were formed. The establishment of a model membrane system will allow us to further study the dynamics, structure and mechanism of the Sap C-associated membrane domains and to examine the important role that these domains may play in enzyme activation.

Complex Mixtures↗
PubMedDate not supplied

Quality of life of head and neck cancer patient: validation of the European organization for research and treatment of cancer QLQ-C30 and European organization for research and treatment of cancer QLQ-H&N 35 in Indian patients.

AIMS: To present the first cross-culture validation of the European organization for research and treatment of cancer (EORTC) quality of life questionnaires, the EORTC-QLQ-C30, and the QLQ-H&N 35 in India. SETTINGS AND DESIGN: These questionnaires were translated into two vernacular languages and pilot test was done on 15 patients. Two hundred head and neck cancer patients completed the QLQ-C30 and the QLQ-H&N 35 at two time points during their treatment. Psychometric evaluation of the structure, reliability, and validity of the questionnaire was undertaken. RESULTS: The data supports the reliability of the scales. Validity was tested by item-scale, scale--scale correlation and by performing known group comparisons. The results demonstrated that the items correlated with their respective scale and no significant correlation was found between scales. The questionnaire was responsive to change over a period of time. SUMMARY: This data suggests that the EORTC QLO-C30 and the QLQ-H&N 35 are reliable and valid questionnaires when applied to a sample of head and neck cancer patients in India.

Combined Modality Therapy↗
PubMed2005

Application of validated QSAR models of D1 dopaminergic antagonists for database mining.

Rigorously validated quantitative structure-activity relationship (QSAR) models have been developed for 48 antagonists of the dopamine D1 receptor and applied to mining chemical datasets to discover novel potential antagonists. Several QSAR methods have been employed, including comparative molecular field analysis (CoMFA), simulated annealing-partial least squares (SA-PLS), k-nearest neighbor (kNN), and support vector machines (SVM). With the exception of CoMFA, these approaches employed 2D topological descriptors generated with the MolConnZ software package (EduSoft, LLC. MolconnZ, version 4.05; http://www.eslc.vabiotech.com/ [4.05], 2003). The original dataset was split into training and test sets to allow for external validation of each training set model. The resulting models were characterized by cross-validated R2 (q2) for the training set and predictive R2 values for the test set of (q2/R2) 0.51/0.47 for CoMFA, 0.7/0.76 for kNN, R2 for the training and test sets of 0.74/0.71 for SVM, and training set fitness and test set R2 values of 0.68/0.63 for SA-PLS. Validated QSAR models with R2 > 0.7, (i.e., kNN and SVM) were used to mine three publicly available chemical databases: the National Cancer Institute (NCI) database of ca. 250,000 compounds, the Maybridge Database of ca. 56,000 compounds, and the ChemDiv Database of ca. 450,000 compounds. These searches resulted in only 54 consensus hits (i.e., predicted active by all models); five of them were previously characterized as dopamine D1 ligands, but were not present in the original dataset. A small fraction of the purported D1 ligands did not contain a catechol ring found in all known dopamine full agonist ligands, suggesting that they may be novel structural antagonist leads. This study illustrates that the combined application of predictive QSAR modeling and database mining may provide an important avenue for rational computer-aided drug discovery.

Databases, Factual↗
PubMed2003

Solution structure of a de novo protein from a designed combinatorial library.

Combinatorial libraries of de novo amino acid sequences can provide a rich source of diversity for the discovery of novel proteins. Randomly generated sequences, however, rarely fold into well ordered protein-like structures. To enhance the quality of a library, diversity must be focused into those regions of sequence space most likely to yield well folded structures. We have constructed focused libraries of de novo sequences by designing the binary pattern of polar and nonpolar amino acids to favor structures that contain abundant secondary structure, while simultaneously burying hydrophobic side chains in the protein interior and exposing hydrophilic side chains to solvent. Because binary patterning specifies only the polar/nonpolar periodicity, but not the identities of the side chains, detailed structural features, including packing interactions, cannot be designed a priori. Can binary patterned libraries nonetheless encode well folded proteins? An unambiguous answer to this question requires determination of a 3D structure. We used NMR spectroscopy to determine the structure of S-824, a novel protein from a recently constructed library of 102-residue sequences. This library is "naïve" in that it has not been subjected to high-throughput screens or directed evolution. The experimentally determined structure of S-824 is a four-helix bundle, as specified by the design. As dictated by the binary-code strategy, nonpolar side chains are buried in the protein interior, and polar side chains are exposed to solvent. The polypeptide backbone and buried side chains are well ordered, demonstrating that S-824 is not a molten globule and forms a unique structure. These results show that amino acid sequences that have neither been selected by evolution, nor designed by computer, nor isolated by high-throughput screening, can form native-like structures. These findings validate the binary-code strategy as an effective method for producing vast collections of well folded de novo proteins.

Amino Acid Sequence↗
PubMed2000

Five-factor model of schizophrenic psychopathology: how valid is it?

Aim of the study was to examine the consistency of the five-factor model of schizophrenic symptoms, assess its validity and evaluate its dimensional factor structure using confirmatory factor (CFA) analysis. A sample of 258 randomly assigned DSM-III R patients with schizophrenic disorders were studied by means of the structured clinical interview for the Greek validated Positive and Negative Syndrome Scale (PANSS) and were rated on its 30 items. Patients' scores were subjected to principal component analysis (PCA) with varimax rotation. Internal consistency for each of the components was determined by the use of Cronbach's alpha. External validity of the model derived was investigated by searching for possible relationships between the components and sociodemographic characteristics with the aid of canonical correlation analysis. Confirmatory factor analysis (CFA) was also performed. Using the scree plot criterion PCA revealed a five-factor model. These factors were interpreted as representing--in a decreasing order of relative importance--the following dimensions of schizophrenic psychopathology: negative, excitement, depression, positive and cognitive impairment. The model was comparable with six previous factor analytic studies. Internal consistency was quite satisfactory whereas external validity was found to be not so powerful. CFA did not show that the proposed model yields an adequate factor structure.

Adult↗