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Results for “Structural validation”

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PubMed2006

Factor structure of the brief symptom inventory--18 in adult survivors of childhood cancer: results from the childhood cancer survivor study.

The factor structure of the Brief Symptom Inventory--18 (BSI-18; L. R. Derogatis, 2000) was investigated in a sample of adult survivors of childhood cancer enrolled in the Childhood Cancer Survivor Study (CCSS; N = 8,945). An exploratory factor analysis with a randomly chosen subsample supported a 3-factor structure closely corresponding to the 3 BSI-18 subscales: Depression, Anxiety, and Somatization. Confirmatory factor analysis with structural equation modeling validated this 3-dimensional structure in a separate subsample, though an alternative 4-factor model also fit the data. Analysis of the 3-factor model showed consistent fit in male and female participants. Compared with available community-based norms, survivors reported fewer symptoms of psychological distress. Together, results support the hypothesized 3-dimensional structure of the BSI-18 and indicate the measure may be useful in assessing psychological distress in this growing population of cancer survivors.

Adolescent↗

PubMed2003

As easy to memorize as they are to classify: the 5-4 categories and the category advantage.

Recently, it has been suggested that some categories commonly used in category learning research are eliciting primarily item-level memorization strategies. A new measure of generalization, the category advantage, was introduced and used to test performance on the popular "5-4" categories. To estimate a category advantage, performance on a standard category learning task is compared with performance in an identification task, where participants learn a unique response to each stimulus. Once corrected for differences in chance expectancy, the advantage shown for the category learning task represents the degree to which participants capitalize on the natural similarity structure of the categories. In Experiment 1, the category advantage measure was validated on structured and unstructured categories. In Experiments 2 and 3, the 5-4 categories failed to produce a category advantage when tested with either of two stimulus types, suggesting that these categories elicit predominantly memorization.

Cognition↗

PubMed2005

Structural neural correlates of prosaccade and antisaccade eye movements in healthy humans.

We previously reported that prosaccade amplitude gain and antisaccade error rate are correlated with cerebellar and posterior frontal grey matter volume, respectively. This study sought to replicate and extend these findings in a sample of 32 right-handed, healthy volunteers (14 males, 18 females). Participants underwent structural magnetic resonance imaging (MRI) at 1.5 T and an off-line eye movement assessment using infrared oculography at 500 Hz. Separate blocks of prosaccades and antisaccades were carried out (60 trials each). Optimised volumetric voxel-based morphometry (VBM) implemented in SPM99 was used to investigate the relationship of saccadic performance measures to regional grey matter volume, covarying for age. A significant negative correlation was obtained between prosaccade spatial error and grey matter volume in the right inferior cerebellar lobe (lobule VIIIB, extending into the vermis, centred at x = 11; y = -64; z = -61), indicating that more grey matter volume in this area was associated with better spatial accuracy. On the antisaccade task, the error rate was significantly negatively correlated with grey matter volume in the right middle frontal gyrus (Brodmann area 6) in an area anterior to the frontal eye field (centred at x = 27; y = 18; z = 50), indicating that more grey matter volume in this area was associated with fewer antisaccade errors. These findings extend our previous observations by identifying the relationship between brain structure and saccadic performance on a spatially highly localised scale and support the validity of structural neuroimaging methods in delineating the neural mechanisms underlying human oculomotor control.

Aged↗

PubMed2004

Quantification of bone lesions in rheumatoid arthritis by MRI multispectral tissue class transition analysis.

Recent advances in the development of disease-modifying antirheumatic drugs (DMARDs) bring hope for a treatment that will provide inhibition of the structural damage associated with the disease. DMARD development presents great challenges for the validation of structural surrogate markers to evaluate the performance of these new therapies in clinical trials, where they will likely be compared with active controls. These challenges are being addressed in part by the medical imaging community by developing quantitative measures of RA disease progression for evaluation of new treatments during clinical trials. Recently, a novel multispectral (MS) MRI analysis method was presented to quantify temporal changes in bone lesions observed in the hands of RA patients. This technique employs image registration and MS analysis to identify MS tissue class transitions between serial MRI exams. This review will examine the use of MS class transition analysis as a means to quantify changes in bone lesions in the hands and wrists of patients with RA.

Algorithms↗

PubMed1998

The factor structure of the SF-36 Health Survey in 10 countries: results from the IQOLA Project. International Quality of Life Assessment.

Studies of the factor structure of the SF-36 Health Survey are an important step in its construct validation. Its structure is also the psychometric basis for scoring physical and mental health summary scales, which are proving useful in simplifying and interpreting statistical analyses. To test the generalizability of the SF-36 factor structure, product-moment correlations among the eight SF-36 Health Survey scales were estimated for representative samples of general populations in each of 10 countries. Matrices were independently factor analyzed using identical methods to test for hypothesized physical and mental health components, and results were compared with those published for the United States. Following simple orthogonal rotation of two principal components, they were easily interpreted as dimensions of physical and mental health in all countries. These components accounted for 76% to 85% of the reliable variance in scale scores across nine European countries, in comparison with 82% in the United States. Similar patterns of correlations between the eight scales and the components were observed across all countries and across age and gender subgroups within each country. Correlations with the physical component were highest (0.64 to 0.86) for the Physical Functioning, Role Physical, and Bodily Pain scales, whereas the Mental Health, Role Emotional, and Social Functioning scales correlated highest (0.62 to 0.91) with the mental component. Secondary correlations for both clusters of scales were much lower. Scales measuring General Health and Vitality correlated moderately with both physical and mental health components. These results support the construct validity of the SF-36 translations and the scoring of physical and mental health components in all countries studied.

Cross-Cultural Comparison↗

PubMed2026

Multitargeted comparative evaluation suggests 2-Aoeobenoxmide shows favourable in silico binding compared to Tucatinib against ERα, HER2, AKT1, EGFR, and PIK3CA in breast cancer.

Breast cancer is a leading cause of cancer-related morbidity and mortality globally, with the WHO reporting approximately 2.3 million new cases and 685,000 deaths annually. Drug resistance in breast cancer complicates treatment, with mutations in critical proteins contributing to therapy failure. Key oncogenic proteins involved in breast cancer progression-namely ERα (a ligand-activated nuclear receptor; PDB: 1A52) and the kinase domains of HER2 (PDB ID: 3PP0), AKT1 (PDB ID: 4EJN), EGFR (PDB ID: 4I23) and PIK3CA (PDB ID: 7R9V)-are pivotal in tumour progression and resistance mechanisms. Targeting these proteins using multitargeted therapeutic strategies may overcome resistance by disrupting key signalling pathways involved in cell proliferation, survival, and metastasis. Such combinatorial approaches promise to improve treatment efficacy and patient outcomes in cases of resistant breast cancer. In this study, we performed multitarget docking on prepared and validated protein structures against the ZINC natural compound library using HTVS, SP, and XP, with pose validation using MM-GBSA. We identified 2-Aoeobenoxmide (2-[1-(2-amino-2-oxo-ethoxy)-6-oxo-benzo[c]chromen-3-yl]oxyacetamide, ZINC134008) with docking and MM-GBSA scores ranging from -8.162 to -10.327 kcal/mol and from -47.18 to -57.62 kcal/mol, respectively, and compared the results with the FDA-approved drug Tucatinib, which exhibited lower binding affinity scores. We further evaluated pharmacokinetic properties using QikProp and electronic properties using DFT (Jaguar) and compared the descriptors of 2-Aoeobenoxmide with those of Tucatinib and with accepted reference ranges. We also performed the WaterMap for 5 nanoseconds (ns), computed various energies, interactions and hydration sites, and the comparison suggests that 2-Aoeobenoxmide shows more favourable hydration-site displacement and binding interactions than Tucatinib. Additionally, a 100 ns MD Simulation has resulted in far less deviation, fluctuations, and intermolecular interactions than Tucatinib, suggesting stable protein-ligand interactions, while the binding free energy and total complex energy computed across 0-1000 frames of the MD trajectories indicate that 2-Aoeobenoxmide is a promising in silico candidate. Importantly, because the entire study is computational, the findings should be interpreted as in silico hypotheses, and experimental validation through in vitro and in vivo assays is warranted before any clinical translation is considered.

Humans↗

PubMed2002

The dual-diagnosis concept used by Swedish social workers: limited validity upon examination using a structured diagnostic approach.

A co-existence of chemical dependence and other psychiatric syndromes is commonly referred to as "dual-diagnosis." This categorization is commonly made by social workers in several European countries assigned the primary responsibility for the care of drug and alcohol dependence. Here, we examined the validity of this categorization through systematic, structured patient evaluation following a minimum of 3 weeks of abstinence from drugs and alcohol. Less than one-third of patients originally labelled as suffering from "dual-diagnosis" by the social services did in fact obtain any Axis I DSM IIIR diagnosis, and less than half of the patients had any psychiatric diagnosis other than dependence. Syndromes commonly discussed in the context of self-medication, i.e., unipolar depression and anxiety syndromes, were not over-represented compared to a population sample, while chronic psychoses and bipolar syndromes were highly significantly more common. We conclude that the dual-diagnosis concept, unless substantiated through stringent diagnostic procedures by psychiatrically trained personnel, may be of questionable utility in caring for patients presenting with psychiatric symptoms and substance dependence. A systematic individual evaluation in an alcohol- and drug-free state of sufficient duration is necessary to obtain a basis for an adequate individual treatment plan.

Adult↗

PubMed1998

The association of psychiatric diagnosis with weather conditions in a large urban homeless sample.

Assessment of psychiatric disorders encounters unique complexities in homeless populations. Although the use of structured diagnostic instruments has significantly improved research methodology in this area, questions remain about the validity of using cross-sectional diagnostic methods derived from studies of more general populations. In particular, the validity of structured diagnostic instruments in the assessment of schizophrenia, depression, drug use disorder, and antisocial personality disorder (ASPD) in homeless populations has been questioned. The purpose of this study was to examine the association of psychiatric diagnoses with the weather. It was hypothesized that self-report of psychiatric illness may be affected by prevailing weather conditions. Nine hundred homeless subjects randomly sampled from St. Louis shelters, day centers, and unsheltered locations were interviewed over a 1-year period. Official average daily temperature and amount of precipitation on the day of each subject's interview were compared with lifetime and current psychiatric diagnoses ascertained by the Diagnostic Interview Schedule. Similar analyses were performed in general population data from the Epidemiologic Catchment Area study. The study found that among homeless men, inclement weather on the day of interview was associated with lifetime and current diagnoses of major depression, lifetime drug use disorder, lifetime diagnosis of ASPD, and current alcohol use disorder. These findings, however, were not present in homeless women and not reflected in the general population. The results, although limited, suggest that weather may confound cross-sectional, standardized methods of psychiatric diagnosis in homeless men. Weather-related factors among homeless men are associated with ascertainment of both lifetime and current diagnosis of major depression, as well as lifetime drug use disorder and ASPD and current alcohol use disorder. Possible interpretations of these findings are discussed, with implications for intervention strategies for psychiatric disorders in the larger context of homelessness and social problems.

Adult↗

PubMed2003

Phylogenetic classification of protozoa based on the structure of the linker domain in the bifunctional enzyme, dihydrofolate reductase-thymidylate synthase.

We have determined the crystal structure of dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Cryptosporidium hominis, revealing a unique linker domain containing an 11-residue alpha-helix that has extensive interactions with the opposite DHFR-TS monomer of the homodimeric enzyme. Analysis of the structure of DHFR-TS from C. hominis and of previously solved structures of DHFR-TS from Plasmodium falciparum and Leishmania major reveals that the linker domain primarily controls the relative orientation of the DHFR and TS domains. Using the tertiary structure of the linker domains, we have been able to place a number of protozoa in two distinct and dissimilar structural families corresponding to two evolutionary families and provide the first structural evidence validating the use of DHFR-TS as a tool of phylogenetic classification. Furthermore, the structure of C. hominis DHFR-TS calls into question surface electrostatic channeling as the universal means of dihydrofolate transport between TS and DHFR in the bifunctional enzyme.

Amino Acid Sequence↗

PubMed1998

Medical outcomes study short form 36: testing and cross-validating a second-order factorial structure for health system employees.

OBJECTIVE: To test the factorial validity of the SF-36. DATA SOURCE: Sample data collected in 1995 and 1996 using telephone interviews with health system employees as part of a study of health status. METHODS OF ANALYSIS: Confirmatory factor analysis and structural equation modeling techniques were used to evaluate the data. PRINCIPAL FINDINGS: The results of this study suggest that (1) Mental Health and Physical Health are not independent; (b) Mental Health cross-loads onto Physical Health; (c) general health loads onto Mental Health instead of Physical Health; (d) many of the error terms are correlated; (e) the physical function subscale is not reliable across the samples or the "age" or "education" subgroups; and (f) the mental health subscale path from Mental Health is not reliable across some subgroups. This hierarchical factor pattern was replicated across both samples. CONCLUSIONS: This study supports the second-order factorial structure of the SF-36. Adding the covariance path between the variables Physical Health and Mental Health improved model fit. Two paths from the second-order latent variables to the first-order latent variables differ from the original hypothesized structure of the SF-36. Health perception was influenced by Mental Health rather than Physical Health, and mental health was influenced by both Mental Health and Physical Health. This cross-loading suggests that the perception of Physical Health greatly affects mental health. Scale instabilities in the SF-36 across subgroups suggest that a comparison of mean scores or summary scores is inappropriate. Data interpretation can be improved if multigroups structural equation modeling is used.

Activities of Daily Living↗

PubMedDate not supplied

Psychometric properties of the Impact of Event Scale amongst women at increased risk for hereditary breast cancer.

The Impact of Event Scale (IES; Horowitz MJ, Wilner N, Alvarez W. 1979. Psychosom Med 41: 209-218) has been widely used in the psycho-oncology literature as a measure of cancer-related anxiety. More recently, the IES has been applied to the assessment of breast cancer-related anxiety amongst women who are at increased risk of developing hereditary breast cancer. Despite its widespread use, no studies to date have described the validity of the IES amongst these women. The present study is a replication of reliability analyses and exploration of the factor structure and validity of the IES amongst a sample of 480 female hereditary breast cancer clinic patients. Results suggest good internal consistency (Cronbach's alpha=0.84-0.91), and satisfactory test-retest reliability (IES-Total r=0.80). The IES was found to have good face validity and be an acceptable instrument to women at increased risk of breast cancer. The two-factor (intrusion and avoidance) structure originally reported (Horowitz et al. 1979; Zilberg NJ, Weiss DS, Horowitz MJ. 1982. J Consult Clin Psychol 50: 407-414) was replicated by factor analysis in the present study. Analysis of correlation coefficients between the IES, breast cancer-related events and attitudes and other standardized measures of distress and general somatic concern, provide some preliminary support for the concurrent and discriminative validity of the IES amongst women at increased risk of developing hereditary breast cancer.

Anxiety↗

PubMed2003

A novel MHCp binding prediction model.

Many statistical and molecular mechanics models have been developed and tested for major histocompatibility complex peptide (MHCp) binding predictions during the last decade. The statistical model prediction using pooled peptide sequence data and three-dimensional modeling prediction by molecular mechanics calculations have been assessed for efficiency and human leukocyte antigen diversity coverage. We describe a novel predictive model using information gleaned from 29 human MHCp crystal structures. The validation for the new model is performed using four different sets of data: (1) MHCp crystal structures, (2) peptides with known IC(50) binding values, (3) peptides tested positive by tetramer staining, (4) peptides with known binding information at the MHCBN database. The model produces high prediction efficiencies (average 60 %) with good sensitivity (approximately 50%-73%) and specificity (52%-58%) values. The average positive predictive value of the model is 89%, while the average negative predictive value is only 18%. The efficiency is very high in predicting binders and very low in predicting nonbinders. This model is superior to many existing methods because of its potential application to any given MHC allele whose sequence is clearly defined.

Amino Acid Sequence↗

PubMed2004

Membrane localization and flexibility of a lipidated ras peptide studied by molecular dynamics simulations.

Lipid-modified membrane-binding proteins are essential in signal transduction events of the cell, a typical example being the GTPase ras. Recently, membrane binding of a doubly lipid-modified heptapeptide from the C-terminus of the human N-ras protein was studied by spectroscopic techniques. It was found that membrane binding is mainly due to lipid chain insertion, but it is also favored by interactions between apolar side chains and the hydrophobic region of the membrane. Here, 10 explicit solvent molecular dynamics simulations for a total time of about 150 ns are used to investigate the atomic details of the peptide-membrane association. The 16:0 peptide lipid chains are more mobile than the 14:0 phospholipid chains, which is in agreement with (2)H NMR experiments. Peptide-lipid and peptide-solvent interactions, backbone and side-chain distributions, as well as the effects of lipidated peptide insertion onto the structure, and dynamics of a 1,2-dimyristoylglycero-3-phosphocholine bilayer are described. The simulation results validate the structural model proposed by the analysis of spectroscopic data and highlight the main aspects of the insertion mechanism. The peptide in the membrane is rather rigid over the simulation time scale of about 10 ns, but different partially extended conformations devoid of backbone hydrogen bonds are observed in different trajectories.

Computer Simulation↗

PubMed2003

Discrimination of native protein structures using atom-atom contact scoring.

We introduce a method for discriminating correctly folded proteins from well designed decoy structures using atom-atom and atom-solvent contact surfaces. The measure used to quantify contact surfaces integrates the solvent accessible surface and interatomic contacts into one quantity, allowing solvent to be treated as an atom contact. A scoring function was derived from statistical contact preferences within known protein structures and validated by using established protein decoy sets, including the "Rosetta" decoys and data from the CASP4 structure predictions. The scoring function effectively distinguished native structures from all corresponding decoys in >90% of the cases, using isolated protein subunits as target structures. If contacts between subunits within quaternary structures are included, the accuracy increases to 97%. Interactions beyond atom-atom contact range were not required to distinguish native structures from the decoys using this method. The contact scoring performed as well or better than existing statistical and physicochemical potentials and may be applied as an independent means of evaluating putative structural models.

Cations↗

PubMed2002

How to avoid spurious cluster validation? A methodological investigation on simulated and fMRI data.

This paper presents an evaluation of a common approach that has been considered as a promising option for exploratory fMRI data analyses. The approach includes two stages: creating from the data a sequence of partitions with increasing number of subsets (clustering) and selecting the one partition in this sequence that exhibits the clearest indications of an existing structure (cluster validation). In order to achieve that the selected partition is actually the best characterization of the data structure, previous studies were directed to find the most appropriate validity function(s). In our analysis protocol, we first optimize the sequence of partitions according to the given objective function. Our study showed that an insufficient optimization of the partition, for one or more numbers of clusters, can easily yield a spurious validation result which, in turn, may lead the analyst to a misleading interpretation of the fMRI experiment. However, a sufficient optimization, for each included number of clusters, provided the basis for a reliable, adequate characterization of the data Furthermore, it enabled an adequate evaluation of the validity functions. These findings were obtained independently for three clustering algorithms (representing the hard and fuzzy clustering variant) and three up-to-date cluster validity functions. The findings were derived from analyses of Gaussian clusters, simulated data sets that mimic typical fMRI response signals, andreal fMRI data. Based on our results we propose a number of options of how to configure improved clustering tools.

Algorithms↗

PubMed1994

Valid and invalid implementations of GOR secondary structure predictions.

GOR algorithms have long been a standard methodology for predicting protein secondary structure from primary sequence. We have developed two short validation sequences for the GOR I and GOR II algorithms. Use of these sequences with seven commercial and non-commercial implementations of these algorithms demonstrated that several were incorrect implementations, including two of the three commercial modules implementing the GOR I algorithm. This may be due to an easy misinterpretation of the GOR I algorithm and related data tables. We present the validation sequences and discuss implications of this widely propagated error on secondary and tertiary structure prediction, using several proteins of known structure in three different structural classes as examples. A valid GOR I implementation predicts secondary structure increases the accuracy of predictions by from 1-13 percentage points over an invalid implementation based on the easy misinterpretation. A valid implementation of the GOR I and GOR II algorithms is available from the authors.

Algorithms↗

PubMed2000

Study of conformational rearrangement and refinement of structural homology models by the use of heteronuclear dipolar couplings.

For an increasing fraction of proteins whose structures are being studied, sequence homology to known structures permits building of low resolution structural models. It is demonstrated that dipolar couplings, measured in a liquid crystalline medium, not only can validate such structural models, but also refine them. Here, experimental 1H-15N, 1Halpha-13Calpha, and 13C'-13Calpha dipolar couplings are shown to decrease the backbone rmsd between various homology models of calmodulin (CaM) and its crystal structure. Starting from a model of the Ca2+-saturated C-terminal domain of CaM, built from the structure of Ca2+-free recoverin on the basis of remote sequence homology, dipolar couplings are used to decrease the rmsd between the model and the crystal structure from 5.0 to 1.25 A. A better starting model, built from the crystal structure of Ca2+-saturated parvalbumin, decreases in rmsd from 1.25 to 0.93 A. Similarly, starting from the structure of the Ca2+-ligated CaM N-terminal domain, experimental dipolar couplings measured for the Ca2+-free form decrease the backbone rmsd relative to the refined solution structure of apo-CaM from 4.2 to 1.0 A.

Amino Acid Sequence↗

PubMed1999

Validation of nuclear magnetic resonance structures of proteins and nucleic acids: hydrogen geometry and nomenclature.

A statistical analysis is reported of 1,200 of the 1,404 nuclear magnetic resonance (NMR)-derived protein and nucleic acid structures deposited in the Protein Data Bank (PDB) before 1999. Excluded from this analysis were the entries not yet fully validated by the PDB and the more than 100 entries that contained < 95% of the expected hydrogens. The aim was to assess the geometry of the hydrogens in the remaining structures and to provide a check on their nomenclature. Deviations in bond lengths, bond angles, improper dihedral angles, and planarity with respect to estimated values were checked. More than 100 entries showed anomalous protonation states for some of their amino acids. Approximately 250,000 (1.7%) atom names differed from the consensus PDB nomenclature. Most of the inconsistencies are due to swapped prochiral labeling. Large deviations from the expected geometry exist for a considerable number of entries, many of which are average structures. The most common causes for these deviations seem to be poor minimization of average structures and an improper balance between force-field constraints for experimental and holonomic data. Some specific geometric outliers are related to the refinement programs used. A number of recommendations for biomolecular databases, modeling programs, and authors submitting biomolecular structures are given.

Data Interpretation, Statistical↗