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PubMed1995

The Objective Structured Clinical Examination. The new gold standard for evaluating postgraduate clinical performance.

OBJECTIVE: The authors determine the reliability, validity, and usefulness of the Objective Structured Clinical Examination (OSCE) in the evaluation of surgical residents. SUMMARY BACKGROUND DATA: Interest is increasing in using the OSCE as a measurement of clinical competence and as a certification tool. However, concerns exist about the reliability, feasibility, and cost of the OSCE. Experience with the OSCE in postgraduate training programs is limited. METHODS: A comprehensive 38-station OSCE was administered to 56 surgical residents. Residents were grouped into three levels of training; interns, junior residents, and senior residents. The reliability of the examination was assessed by coefficient alpha; its validity, by the construct of experience. Differences between training levels and in performance on the various OSCE problems were determined by a three-way analysis of variance with two repeated measures and the Student-Newman-Keuls post hoc test. Pearson correlations were used to determine the relationship between OSCE and American Board of Surgery In-Training Examination (ABSITE) scores. RESULTS: The reliability of the OSCE was very high (0.91). Performance varied significantly according to level of training (postgraduate year; p < 0.0001). Senior residents performed best, and interns performed worst. The OSCE problems differed significantly in difficulty (p , 0.0001). Overall scores were poor. Important and specific performance deficits were identified at all levels of training. The ABSITE clinical scores, unlike the basic science scores, correlated modestly with the OSCE scores when level of training was held constant. CONCLUSION: The OSCE is a highly reliable and valid clinical examination that provides unique information about the performance of individual residents and the quality of postgraduate training programs.

Clinical Competence↗
PubMed1998

Differentiating infection from vaccination in foot-and-mouth disease using a panel of recombinant, non-structural proteins in ELISA.

A profiling ELISA was developed to detect antibody to the non-structural (NS) proteins Lb, 2C, 3A, 3D, and the polyprotein 3ABC, of foot-and-mouth disease virus (FMDV). The assay was used to examine panels of sera from naive cattle, and from experimentally infected or vaccinated animals. All sera from cattle experimentally infected with any of the seven serotypes of FMDV were positive for antibody to 2C, 3A, 3D and 3ABC, and the majority were positive for Lb. The three categories of sera could be differentiated on the basis of the presence or absence of antibody to the structural and/or NS proteins of FMDV. The assay is simple, rapid and reproducible and can be used to identify previous infection in animals which are seropositive for antibody to the structural proteins of the virus. Validating the assay with field sera demonstrated that antibody to 3ABC, and usually one or more of the other non-structural proteins, was detected only in animals reported to have shown clinical signs of FMD. Vaccinated cattle which had received less than five vaccinations, were frequently positive for antibody to 3D but were negative for antibody to 3ABC. Occasional animals which had received more than ten vaccinations had NS protein antibody profiles which were similar to those seen following infection.

Animals↗
PubMedDate not supplied

Evaluation of qsars for ecotoxicity: a method for assigning quality and confidence.

Validation of a quantitative structure-activity relationship (QSAR) is now considered as an integral part of its development. Assessment of the quality of a QSAR and the confidence that may be placed in predictions from it are vital to any validation procedure. A number of terms associated with the quality of a QSAR, confidence in that QSAR, or both may be quantified. These terms include the: (1) goodness of fit of the model (r2); (2) predictivity of the model (Q2); (3) stability of the model described as the difference between fit and predictivity (Dfp); (4) number of compounds used in the training set (Nc); (5) number of descriptors used in the model (Nd); (6) range of toxicity values (Tr); (7) number of mechanisms of toxic action covered by the training set (Nm), as well as two factors associated with the biological data-confidence associated with, (8) reproducibility of the data (Rconf) and (9) confidence in the source of the data (Sconf). While all these factors may influence the quality of, and/or confidence in a particular QSAR, each varies within different limits. To enable a quantitative assessment of quality and confidence in a QSAR, the terms deemed to be important were weighed and combined to create a Confidence Index (CI): ((r2)4 x 6) x ((Q2)4 x 6) x (ln(Nc/10)) x (Tr) x (Sconf)0.5 (ln(N2d + 2)) x (ln(N2m + 2)) x ((r2)4 x 6) - ((Q2)4 x 6) + 1) x (Rconf)

Algorithms↗
PubMed2006

Quantifying the directional parameter of structural anisotropy in porous media.

A new method has been developed to define the directional parameter and characterize the structural anisotropy of a highly porous structure with extensive pore interconnectivity and surface area, such as scaffolds in tissue engineering. This new method called intercept segment deviation (ISD) was validated through the comparison of structural anisotropy from ISD measurements with mechanical anisotropy from finite-element stress analysis. This was carried out on a generated two-dimensional (2D) image of a two-phase material and a real three-dimensional (3D) image of a tissue scaffold. The performance of other methods for quantification of the directional parameter was also assessed. The results indicate that the structural anisotropy obtained from this new method conforms to the actual mechanical anisotropy and provides a better prediction of the material orientation than the other methods for the 2D and 3D images studied.

Anisotropy↗
PubMed1996

Two-phase helical CT for pancreatic tumors: pancreatic versus hepatic phase enhancement of tumor, pancreas, and vascular structures.

PURPOSE: To quantitatively evaluate and validate a two-phase helical computed tomographic (CT) protocol for evaluation of pancreatic tumors. MATERIALS AND METHODS: Twenty-seven patients with pathologically proved pancreatic adenocarcinomas prospectively underwent two-phase CT examination with helical acquisition during the pancreatic phase (40-70 seconds after infusion of intravenous contrast material at 3 mL/sec) and the hepatic phase (70-100 seconds after infusion). Mean CT attenuation values of tumor, bordering pancreas, and all major peripancreatic vessels were obtained for both time intervals. RESULTS: Mean tumor-pancreas contrast was significantly greater during the pancreatic phase (67 HU +/- 19) than the hepatic phase (39 HU +/- 16) (P < .001) This was the result of both greater enhancement of normal pancreas and lower tumor enhancement during the pancreatic phase. Opacification of all vascular structures, including the portal vein, was also greater during the pancreatic phase (P < .001). CONCLUSION: Two-phase helical CT with pancreatic phase acquisition provides statistically significantly better pancreatic, arterial, and portal venous enhancement than that of hepatic phase imaging, with improved tumor-pancreas contrast.

Adenocarcinoma↗
PubMed2005

The need for microsimulation to evaluate osteoporosis interventions.

Simulations play an increasingly important role in the evaluation of osteoporosis interventions. Existing evaluations have been based on "reduced-form" cohort simulations that do not reflect the complexity and heterogeneity of osteoporosis and its outcomes. Such simplified models offer parsimony and ease of use, but they also are limited in their ability to explain and extrapolate outcomes in a way that is most useful for both clinical and health policy decision makers. Alternatively, evaluations could be based on "structural" microsimulations, which explicitly model the underlying biology of osteoporosis at the individual level. The structural approach presents technical challenges, including the need to obtain more-detailed data and the requirement that underlying biological models be validated. However, evaluations based on structural microsimulation may ultimately provide substantially more useful information, resulting in improved decision making.

Computer Simulation↗
PubMed1984

An analysis of incorrectly folded protein models. Implications for structure predictions.

Proteins with homologous amino acid sequences have similar folds and it has been assumed that an unknown three-dimensional structure can be obtained from a known homologous structure by substituting new side-chains into the polypeptide chain backbone, followed by relatively small adjustment of the model. To examine this approach of structure prediction and, more generally, to isolate the characteristics of native proteins, we constructed two incorrectly folded protein models. Sea-worm hemerythrin and the variable domain of mouse immunoglobulin K-chain, two proteins with no sequence homology, were chosen for study; the former is composed of a bundle of four alpha-helices and the latter consists of two 4-stranded beta-sheets. Using an automatic computer procedure, hemerythrin side-chains were substituted into the immunoglobulin domain and vice versa. The structures were energy-minimized with the program CHARMM and the resulting structures compared with the correctly folded forms. It was found that the incorrect side-chains can be incorporated readily into both types of structures (alpha-helices, beta-sheets) with only small structural adjustments. After constrained energy-minimization, which led to an average atomic co-ordinate shift of no more than 0.7 to 0.9 A, the incorrectly folded models arrived at potential energy values comparable to those of the correct structures. Detailed analysis of the energy results shows that the incorrect structures have less stabilizing electrostatic, van der Waals' and hydrogen-bonding interactions. The difference is particularly pronounced when the electrostatic and van der Waals' energy terms are calculated by modified equations that include an approximate representation of solvent effects. The incorrectly folded structures also have a significantly larger solvent-accessible surface and a greater fraction of non-polar side-chain atoms exposed to solvent. Examination of their interior shows that the packing of side-chains at the secondary structure interfaces, although corresponding to sterically allowed conformations, deviates from the characteristics found in normal proteins. The analysis of incorrectly folded structures has made it clear that the absence of bad non-bonded contacts, though necessary, is not sufficient to demonstrate the validity of model-built structures and that modeling of homologous structures has to be accompanied by a thorough quantitative evaluation of the results. Further, certain features that characterize native proteins are made evident by their absence in misfolded models.

Amino Acid Sequence↗
PubMed1996

ABGEN: a knowledge-based automated approach for antibody structure modeling.

Immunoglobulin (Ig) amino acid sequences are highly conserved and often have sequence homology ranging from 70 to 95%. Antigen binding fragments (Fab), variable region fragments (Fv), and single chain Fv (scFv) of more than 50 myeloma proteins and monoclonal antibodies (mAb) have been crystallized and display a high degree of structural similarity. Based on this observation, several homology modeling approaches have been developed for the prediction of Fab and Fv structures prior to their experimental determination. We have extracted features from existing Ig sequences, 44 known Fab and Fv structures to create an automated AntiBody structure GENeration (ABGEN) algorithm for obtaining structural models of antibody fragments. ABGEN utilizes a homology based scaffolding technique, and includes the use of invariant and strictly conserved residues, structural motifs of known Fab, canonical features of hypervariable loops, torsional constraints for residue replacements and key inter-residue interactions. The validity of the ABGEN algorithm has been tested using a five-fold cross validation with the existing Fab structures. Molecular mechanics and dynamics methods have been implemented with ABGEN models to accurately predict two Fab structures of anti-sweetener antibodies prior to crystallographic determinations.

Algorithms↗
PubMed2005

Measuring peripheral resistance and conduit arterial structure in humans using Doppler ultrasound.

The purpose of this study was to establish valid indexes of conduit and resistance vessel structure in humans by using edge detection and wall tracking of high-resolution B-mode arterial ultrasound images, combined with synchronized Doppler waveform envelope analysis, to calculate conduit artery blood flow and diameter continuously across the cardiac cycle. Nine subjects aged 36.7 (9.2) yr underwent, on separate days, assessment of brachial artery blood flow and diameter response to 5-, 10-, and 15-min periods of forearm ischemia in the presence and absence of combined sublingual glyceryl trinitrate (GTN) administration. Two further sessions examined responses to ischemic exercise, one in combination with GTN. The peak brachial artery diameter was observed in response to the combination of ischemic exercise and GTN; a significant difference existed between resting brachial artery diameter and peak brachial artery diameter, indicating that resting diameter may be a poor measure of conduit vessel structure in vivo. Peak brachial artery flow was also observed in response to a combination of forearm ischemia exercise and GTN administration, the response being greater than that induced by periods of ischemia, GTN, or ischemic exercise alone. These data indicate that noninvasive indexes of conduit and resistance vessel structure can be simultaneously determined in vivo in response to a single, brief, stimulus and that caution should be applied in using resting arterial diameter as a surrogate measure of conduit artery structure in vivo.

Adult↗
PubMed2005

Validated ligand mapping of ACE active site.

Crystal structures of angiotensin-converting enzyme (ACE) complexed with three inhibitors (lisinopril, captopril, enalapril) provided experimental data for testing the validity of a prior active site model predicting the bound conformation of the inhibitors. The ACE active site model - predicted over 18 years ago using a series of potent ACE inhibitors of diverse chemical structure - was recreated using published data and commercial software. Comparison between the predicted structures of the three inhibitors bound to the active site of ACE and those determined experimentally yielded root mean square deviation (RMSD) values of 0.43-0.81 A, among the distances defining the active site map. The bound conformations of the chemically relevant atoms were accurately deduced from the geometry of ligands, applying the assumption that the geometry of the active site groups responsible for binding and catalysis of amide hydrolysis was constrained. The mapping of bound inhibitors at the ACE active site was validated for known experimental compounds, so that the constrained conformational search methodology may be applied with confidence when no experimentally determined structure of the enzyme yet exists, but potent, diverse inhibitors are available.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2007

Statistical validation of the root-mean-square-distance, a measure of protein structural proximity.

Despite its well-documented limitations, the root-mean-square-distance (rmsd) between pairs of equivalent atoms is routinely used to monitor the degree of similarity between two optimally superposed protein three-dimensional structures. A robust method for assessing the statistical significance of the difference between two rmsd values is presented here. It is based on the comparison of two protein structures through the correlation coefficient between equivalent inter-atomic distances and the subsequent application of the Fisher transformation that allows one to estimate the probability of identity between two correlation coefficient values. The relationship between the rmsd and Fisher correlation coefficient allows then to estimate the statistical significance of the difference between two rmsd values. Such a procedure is exemplified with the analysis of the possible classifications of the immunoglobulin-like domains of filamin and is compared to related estimations of structural similarity. The possibility to estimate the probability of the difference between two rmsd values can be used to optimize the protein structural classifications and comparisons, independent of the procedure used to derive the rmsds.

Algorithms↗
PubMed1996

Curved beam model of the proximal femur for estimating stress using dual-energy X-ray absorptiometry derived structural geometry.

The investigation of individual differences in hip strength requires a method to measure structural geometry in vivo and a valid analytical approach to calculate mechanical stress. We developed a method for deriving structural geometry of the femur from the proximal shaft through the femoral neck, using data from dual energy X-ray absorptiometry. The geometric properties are employed in a two-dimensional curved beam model of the proximal femur to estimate stresses on the lateral and medial bone surfaces. Stresses calculated by this method are compared with those from the conventional flexure formula and with results produced from a cadaver femur with use of three-dimensional finite element analysis of computed tomography data. Loading conditions simulating a one-legged stance and a fall on the greater trochanter are employed. Stresses calculated by curved beam theory are in much better agreement with three-dimensional finite element analysis than are those for which the conventional straight beam formula was used. In simulation of a fall on the greater trochanter, all three methods show peaks of stress at the femoral neck but only the curved beam and finite element analysis methods show an additional peak at the medial intertrochanteric margin. Both neck and trochanter regions correspond to common failure sites for hip fractures in the elderly. The curved beam treatment of hip structure derived from dual-energy X-ray absorptiometry provides an approach for the in vivo engineering analysis of hip structure that is not practical by other methods.

Absorptiometry, Photon↗
PubMed2005

Addiction severity assessment tool: development of a self-report measure for clients in substance abuse treatment.

This article describes the development and reliability and validity testing of the Addiction Severity Assessment Tool (ASAT), a brief, 27-item multidimensional self-report measure of problem severity in daily functioning, relational functioning, dysphoric states, dependence severity, recovery skill/self-efficacy, and existential factors for adult substance abuse clients. Items generated for an Alpha version were conceptually and empirically evaluated. A Beta version underwent further empirical evaluation and item selection. Cross validation of the final version examined internal consistency, test-retest reliability, factor structure, and convergent/discriminant and known groups validity. Sensitivity to change was evaluated in a 3-month outcome study. Clients were recruited from inpatient, outpatient and residential substance abuse treatment centers, and a sample of 238 nonpatients were also recruited from community groups. The Beta version was tested with 201 clients, and cross validation involved 242 clients. Well-known standardized, self-report and interview-based comparison measures were used to test convergent/discriminant validity of the ASAT. Reliability coefficients for the six ASAT domains were acceptable. Reasonable convergent/discriminant and known groups, construct validity were demonstrated, along with sensitivity to change of the domain scale scores. The ASAT appears to comprise a useful new tool for assessing clinical outcomes of adult clients in substance abuse treatment.

Adult↗
PubMed2006

Osmotic coefficients of atomistic NaCl (aq) force fields.

Solvated ions are becoming increasingly important for (bio)molecular simulations. But there are not much suitable data to validate the intermediate-range solution structure that ion-water force fields produce. We compare six selected combinations of four biomolecular Na-Cl force fields and four popular water models by means of effective ion-ion potentials. First we derive an effective potential at high dilution from simulations of two ions in explicit water. At higher ionic concentration multibody effects will become important. We propose to capture those by employing a concentration dependent dielectric permittivity. With the so obtained effective potentials we then perform implicit solvent simulations. We demonstrate that our effective potentials accurately reproduce ion-ion coordination numbers and the local structure. They allow us furthermore to calculate osmotic coefficients that can be directly compared with experimental data. We show that the osmotic coefficient is a sensitive and accurate measure for the effective ion-ion interactions and the intermediate-range structure of the solution. It is therefore a suitable and useful quantity for validating and parametrizing atomistic ion-water force fields.

Journal Article↗
PubMed1997

Assigning folds to the proteins encoded by the genome of Mycoplasma genitalium.

A crucial step in exploiting the information inherent in genome sequences is to assign to each protein sequence its three-dimensional fold and biological function. Here we describe fold assignment for the proteins encoded by the small genome of Mycoplasma genitalium. The assignment was carried out by our computer server (http://www.doe-mbi.ucla.edu/people/frsvr/ frsvr. html), which assigns folds to amino acid sequences by comparing sequence-derived predictions with known structures. Of the total of 468 protein ORFs, 103 (22%) can be assigned a known protein fold with high confidence, as cross-validated with tests on known structures. Of these sequences, 75 (16%) show enough sequence similarity to proteins of known structure that they can also be detected by traditional sequence-sequence comparison methods. That is, the difference of 28 sequences (6%) are assignable by the sequence-structure method of the server but not by current sequence-sequence methods. Of the remaining 78% of sequences in the genome, 18% belong to membrane proteins and the remaining 60% cannot be assigned either because these sequences correspond to no presently known fold or because of insensitivity of the method. At the current rate of determination of new folds by x-ray and NMR methods, extrapolation suggests that folds will be assigned to most soluble proteins in the next decade.

Algorithms↗
PubMedDate not supplied

Validation of the 16-item Negative Symptom Assessment.

The dimensional structure of the 16-item Negative Symptom Assessment (NSA-16) was validated in a sample of 223 unmedicated schizophrenic inpatients and cross-validated on an independent sample of 276 patients with schizophrenia. Using a confirmatory factor analytic procedure, a five factor model was found to best characterize the structure of this rating instrument. These factors include: Communication, Emotion/Affect, Social Involvement, Motivation, and Retardation. The latent structure of the NSA-16 is similar to the larger instrument from which it was derived. The findings provide support for a multidimensional model of negative symptoms in schizophrenia and offer a useful measure for their assessment.

Adult↗
PubMedDate not supplied

The Paris-Sud yeast structural genomics pilot-project: from structure to function.

We present here the outlines and results from our yeast structural genomics (YSG) pilot-project. A lab-scale platform for the systematic production and structure determination is presented. In order to validate this approach, 250 non-membrane proteins of unknown structure were targeted. Strategies and final statistics are evaluated. We finally discuss the opportunity of structural genomics programs to contribute to functional biochemical annotation.

Genomics↗
PubMed1997

The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin.

Coumarin antibiotics, such as clorobiocin, novobiocin, and coumermycin A1, inhibit the supercoiling activity of gyrase by binding to the gyrase B (GyrB) subunit. Previous crystallographic studies of a 24-kDa N-terminal domain of GyrB from E. coli complexed with novobiocin and a cyclothialidine analogue have shown that both ligands act by binding at the ATP-binding site. Clorobiocin is a natural antibiotic isolated from several Streptomyces strains and differs from novobiocin in that the methyl group at the 8 position in the coumarin ring of novobiocin is replaced by a chlorine atom, and the carbamoyl at the 3' position of the noviose sugar is substituted by a 5-methyl-2-pyrrolylcarbonyl group. To understand the difference in affinity, in order that this information might be exploited in rational drug design, the crystal structure of the 24-kDa GyrB fragment in complex with clorobiocin was determined to high resolution. This structure was determined independently in two laboratories, which allowed the validation of equivalent interpretations. The clorobiocin complex structure is compared with the crystal structures of gyrase complexes with novobiocin and 5'-adenylyl-beta, gamma-imidodiphosphate, and with information on the bound conformation of novobiocin in the p24-novobiocin complex obtained by heteronuclear isotope-filtered NMR experiments in solution. Moreover, to understand the differences in energetics of binding of clorobiocin and novobiocin to the protein, the results from isothermal titration calorimetry are also presented.

Binding Sites↗