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Results for “Propensity Score”

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PubMed2003

Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: results from a large observational inception study.

OBJECTIVE: To determine the effect of early treatment with disease-modifying antirheumatic drugs (DMARDs) in reducing radiographic progression over a 5-year period in patients with new-onset inflammatory polyarthritis. METHODS: Three hundred thirty-five consecutive patients with paired radiographs obtained 1 year and 5 years after enrollment in a population-based arthritis register were studied. Logistic regression was used to model differences in baseline factors associated with the start of DMARDs. The time from symptom onset to first use of DMARDs was stratified to represent 4 groups: no DMARD use, <6 months, 6-12 months, and >12 months. Radiographs of the hands and feet were scored using the Larsen method. Progression in the Larsen score was evaluated as a 5-year score adjusted for the first film score. Negative binomial regression was used to compare Larsen score progression for each of the 3 treatment groups with that for patients not receiving DMARDs. Results were then adjusted for severity, based on propensity modeling. RESULTS: Patients who received treatment had more radiographic progression than did patients who were untreated. Coefficients (95% confidence intervals), expressed as a multiple of the Larsen score in DMARD-treated patients compared with untreated patients, were as follows: 1.6 (1.1-2.3) for <6 months, 2.4 (1.5-3.6) for 6-12 months, and 2.0 (1.4-2.8) for >12 months. As expected, patients receiving treatment had more severe disease at baseline. Using the propensity score as a method of adjusting for disease severity, the influence of treatment on outcome became attenuated as follows: 1.1 (0.8-1.7) for <6 months, 1.6 (1.0-2.6) for 6-12 months, and 1.5 (1.0-2.2) for >12 months. This effect was also seen in the crude Larsen score at year 5. CONCLUSION: In this observational study, DMARD treatment was a marker not only of worse disease at presentation but also of the radiographic state and radiographic progression at 5 years. After adjustments were made for baseline disease severity, earlier therapy was shown to have a beneficial effect on outcome.

Adult↗

PubMed2002

Composites of local structure propensities: evidence for local encoding of long-range structure.

To estimate how extensively the ensemble of denatured-state conformations is constrained by local side-chain-backbone interactions, propensities of each of the 20 amino acids to occur in mono- and dipeptides mapped to discrete regions of the Ramachandran map are computed from proteins of known structure. In addition, propensities are computed for the trans, gauche-, and gauche+ rotamers, with or without consideration of the values of phi and psi. These propensities are used in scoring functions for fragment threading, which estimates the energetic favorability of fragments of protein sequence to adopt the native conformation as opposed to hundreds of thousands of incorrect conformations. As finer subdivisions of the Ramachandran plot, neighboring residue phi/psi angles, and rotamers are incorporated, scoring functions become better at ranking the native conformation as the most favorable. With the best composite propensity function, the native structure can be distinguished from 300,000 incorrect structures for 71% of the 2130 arbitrary protein segments of length 40, 48% of 2247 segments of length 30, and 20% of 2368 segments of length 20. A majority of fragments of length 30-40 are estimated to be folded into the native conformation a substantial fraction of the time. These data suggest that the variations observed in amino acid frequencies in different phi/psi/chi1 environments in folded proteins reflect energetically important local side-chain-backbone interactions, interactions that may severely restrict the ensemble of conformations populated in the denatured state to a relatively small subset with nativelike structure.

Amino Acids↗

PubMed2006

A supersecondary structure library and search algorithm for modeling loops in protein structures.

We present a fragment-search based method for predicting loop conformations in protein models. A hierarchical and multidimensional database has been set up that currently classifies 105,950 loop fragments and loop flanking secondary structures. Besides the length of the loops and types of bracing secondary structures the database is organized along four internal coordinates, a distance and three types of angles characterizing the geometry of stem regions. Candidate fragments are selected from this library by matching the length, the types of bracing secondary structures of the query and satisfying the geometrical restraints of the stems and subsequently inserted in the query protein framework where their fit is assessed by the root mean square deviation (r.m.s.d.) of stem regions and by the number of rigid body clashes with the environment. In the final step remaining candidate loops are ranked by a Z-score that combines information on sequence similarity and fit of predicted and observed phi/psi main chain dihedral angle propensities. Confidence Z-score cut-offs were determined for each loop length that identify those predicted fragments that outperform a competitive ab initio method. A web server implements the method, regularly updates the fragment library and performs prediction. Predicted segments are returned, or optionally, these can be completed with side chain reconstruction and subsequently annealed in the environment of the query protein by conjugate gradient minimization. The prediction method was tested on artificially prepared search datasets where all trivial sequence similarities on the SCOP superfamily level were removed. Under these conditions it is possible to predict loops of length 4, 8 and 12 with coverage of 98, 78 and 28% with at least of 0.22, 1.38 and 2.47 A of r.m.s.d. accuracy, respectively. In a head-to-head comparison on loops extracted from freshly deposited new protein folds the current method outperformed in a approximately 5:1 ratio an earlier developed database search method.

Algorithms↗

PubMedDate not supplied

Cytotoxicity and cell death pathways invoked by two new rhodium-ferrocene complexes in benign and malignant prostatic cell lines.

BACKGROUND: Apoptotic propensity is currently viewed as an important parameter in drug-induced toxicity. But other cell death pathways exist e.g. micronucleation, intermitotic cell death, abnormal nuclear morphology and necrosis. This investigation explores the onset of apoptosis and abnormal morphology in response to 3 drugs i.e. Cisplatin, a novel Ferrocene (fctfa) and a novel Rhodium-Ferrocene [Rh(fctfa)(cod)] complex. MATERIALS AND METHODS: A pair of prostate cell lines from normal human prostate epithelium (1542N) and malignant human prostate epithelium (1542T) were exposed to increasing concentrations of the drugs for 24 hours, double-stained with FITC-Annexin V and with Propidium Iodide and analysed by dual parameter flow cytometry to quantitate viable cells in quadrant I, early apoptotic cells in quadrant IV and late apoptotic/necrotic cells in quadrant III. Apoptosis was also scored by microscopy after Acridine Orange staining, by Western blots for caspase 3 induction and for caspase 8 induction using a colorimetric assay. RESULTS: The toxicity of Cisplatin and the Ferrocene and Rhodium-Ferrocene complexes was found to be 0.9-1.3 microM; 4.1-4.5 microM and 10.1-13.2 microM, respectively. Apoptotic propensity scored after 24 hours was found to be dose-dependent and in the range of 7-19% for Cisplatin and 1-4.1% for the Ferrocene and Rhodium-Ferrocene complexes. Cisplatin produces a distinct apoptotic response followed by a necrotic response, whereas the Ferrocene and the Rhodium-Ferrocene complexes produce a massive necrotic reaction in the region of 3-19% and very little if any apoptosis. Absence of apoptosis was corroborated by lack of caspase 3 activation, absence of typical apoptotic morphology and by lack of caspase 8 activation. CONCLUSION: The 3 drugs Cisplatin, the novel Ferrocene and the novel Rhodium-Ferrocene complexes show similar toxicities in the 1-10 micro-molar range in prostate cell lines. However the drugs differ significantly in the activation of death pathways. While Cisplatin predominantly induces apoptosis documented by morphology, Annexin V staining and caspase 8 activation, the Ferrocene and Rhodium-Ferrocene complexes induce late necrosis and abnormal nuclear morphology. Unlike Cisplatin-treated cells which enter apoptosis and necrosis sequentially, the 2 Ferrocene drugs invoke direct entry of cells into late necrosis without first entering the early apoptotic compartment.

Antineoplastic Agents↗

PubMed1993

A study of attitudes to gender and nursing stereotypes in newly recruited student nurses.

This article presents the findings of a study which investigated the attitudes of 100 newly recruited student nurses towards gender and nursing stereotypes. The students were in their second day of the Common Foundation Programme at North Staffordshire College of Nursing and Midwifery. The data were collected using a researcher developed instrument which utilised a Likert scale for measurement of attitudes in relationship to statements pertaining to gender and nursing stereotypes. The findings reveal overall high mean scores and an implied propensity towards beliefs in gender and nursing stereotypes. Analysis related to demographic variables of gender, age and sex gives a number of significant results. The highest proportion of significant results were related to gender differences in the sample. The data provide a basis for evaluation of teaching and learning related to students in the sample course of studies. The findings also have more general implications for curricular issues and the development of teaching strategies.

Adolescent↗

PubMed2005

Relationship between preterm birth and circadian typology in adolescence.

A possible relationship between preterm birth and circadian typology was investigated in two pilot survey studies involving 13-year-old teen-agers. Two different questionnaires were used: the Junior Morningness-Eveningness Questionnaire (MEQ) (administered to 55 preterm and 210 fullterm subjects) and the Junior Composite Scale (CS) (administered to 40 preterm and 318 fullterm subjects). In both surveys, preterm groups presented significantly higher total scores, indicating a higher propensity to morningness. Indeed in the preterm samples no evening types were found. The results are discussed in relation to recent models of circadian regulation of the sleep-wake cycle.

Adolescent↗

PubMed2005

Simple adjustments for randomized trials with nonrandomly missing or censored outcomes arising from informative covariates.

In randomized trials with missing or censored outcomes, standard maximum likelihood estimates of the effect of intervention on outcome are based on the assumption that the missing-data mechanism is ignorable. This assumption is violated if there is an unobserved baseline covariate that is informative, namely a baseline covariate associated with both outcome and the probability that the outcome is missing or censored. Incorporating informative covariates in the analysis has the desirable result of ameliorating the violation of this assumption. Although this idea of including informative covariates is recognized in the statistics literature, it is not appreciated in the literature on randomized trials. Moreover, to our knowledge, there has been no discussion on how to incorporate informative covariates into a general likelihood-based analysis with partially missing outcomes to estimate the quantities of interest. Our contribution is a simple likelihood-based approach for using informative covariates to estimate the effect of intervention on a partially missing outcome in a randomized trial. The first step is to create a propensity-to-be-missing score for each randomization group and divide the scores into a small number of strata based on quantiles. The second step is to compute stratum-specific estimates of outcome derived from a likelihood-analysis conditional on the informative covariates, so that the missing-data mechanism is ignorable. The third step is to average the stratum-specific estimates and compute the estimated effect of intervention on outcome. We discuss the computations for univariate, survival, and longitudinal outcomes, and present an application involving a randomized study of dual versus triple combinations of HIV-1 reverse transcriptase inhibitors.

Acquired Immunodeficiency Syndrome↗

PubMed2006

A normalised scale for structural genomics target ranking: the OB-Score.

Target selection and ranking is fundamental to structural genomics. We present a Z-score scale, the "OB-Score", to rank potential targets by their predicted propensity to produce diffraction-quality crystals. The OB-Score is derived from a matrix of predicted isoelectric point and hydrophobicity values for nonredundant PDB entries solved to or=1 member with a high OB-Score, presenting favourable candidates for structural studies.

Databases, Protein↗

PubMed2005

High accuracy prediction of beta-turns and their types using propensities and multiple alignments.

We have developed a method that predicts both the presence and the type of beta-turns, using a straightforward approach based on propensities and multiple alignments. The propensities were calculated classically, but the way to use them for prediction was completely new: starting from a tetrapeptide sequence on which one wants to evaluate the presence of a beta-turn, the propensity for a given residue is modified by taking into account all the residues present in the multiple alignment at this position. The evaluation of a score is then done by weighting these propensities by the use of Position-specific score matrices generated by PSI-BLAST. The introduction of secondary structure information predicted by PSIPRED or SSPRO2 as well as taking into account the flanking residues around the tetrapeptide improved the accuracy greatly. This latter evaluated on a database of 426 reference proteins (previously used on other studies) by a sevenfold crossvalidation gave very good results with a Matthews Correlation Coefficient (MCC) of 0.42 and an overall prediction accuracy of 74.8%; this places our method among the best ones. A jackknife test was also done, which gave results within the same range. This shows that it is possible to reach neural networks accuracy with considerably less computional cost and complexity. Furthermore, propensities remain excellent descriptors of amino acid tendencies to belong to beta-turns, which can be useful for peptide or protein engineering and design. For beta-turn type prediction, we reached the best accuracy ever published in terms of MCC (except for the irregular type IV) in the range of 0.25-0.30 for types I, II, and I' and 0.13-0.15 for types VIII, II', and IV. To our knowledge, our method is the only one available on the Web that predicts types I' and II'. The accuracy evaluated on two larger databases of 547 and 823 proteins was not improved significantly. All of this was implemented into a Web server called COUDES (French acronym for: Chercher Ou Une Deviation Existe Surement), which is available at the following URL: http://bioserv.rpbs.jussieu.fr/Coudes/index.html within the new bioinformatics platform RPBS.

Amino Acid Sequence↗

PubMed2003

Prediction of protein structure by emphasizing local side-chain/backbone interactions in ensembles of turn fragments.

The prediction strategy used in the CASP5 experiment was premised on the assumption that local side-chain/backbone interactions are the principal determinants of protein structure at low resolution. Our implementation of this assumption made extensive use of a scoring function based on the propensities of the 20 amino acids for 137 different sub-regions of the Ramachandran plot, allowing estimation of the quality of fit between a sequence segment and a known conformation. New folds were predicted in three steps: prediction of secondary structure, threading to isolate fragments of protein structures corresponding to one turn plus flanking helices/strands, and recombination of overlapping fragments. The most important step in this fragment ensemble approach, the isolation of turn fragments, employed 2 to 6 sequence homologues when available, with clustering of the best scoring fragments to recover the most common turn arrangement. Recombinants formed between 3 to 8 turn fragments, with cross-overs confined to helix/strand segments, were selected for compactness plus low energy as estimated by empirical amino acid pair potentials, and the most common overall topology identified by visual inspection. Because significant amounts of steric overlap were permitted during the recombination step, the final model was manually adjusted to reduce overlap and to enhance protein-like structural features. Even though only one or two models were submitted per target, for several targets the correct chain topology was predicted for fragment lengths up to 100 amino acids.

Binding Sites↗

PubMed2006

Protein binding site prediction using an empirical scoring function.

Most biological processes are mediated by interactions between proteins and their interacting partners including proteins, nucleic acids and small molecules. This work establishes a method called PINUP for binding site prediction of monomeric proteins. With only two weight parameters to optimize, PINUP produces not only 42.2% coverage of actual interfaces (percentage of correctly predicted interface residues in actual interface residues) but also 44.5% accuracy in predicted interfaces (percentage of correctly predicted interface residues in the predicted interface residues) in a cross validation using a 57-protein dataset. By comparison, the expected accuracy via random prediction (percentage of actual interface residues in surface residues) is only 15%. The binding sites of the 57-protein set are found to be easier to predict than that of an independent test set of 68 proteins. The average coverage and accuracy for this independent test set are 30.5 and 29.4%, respectively. The significant gain of PINUP over expected random prediction is attributed to (i) effective residue-energy score and accessible-surface-area-dependent interface-propensity, (ii) isolation of functional constraints contained in the conservation score from the structural constraints through the combination of residue-energy score (for structural constraints) and conservation score and (iii) a consensus region built on top-ranked initial patches.

Algorithms↗

PubMedDate not supplied

Bone mass cannot be predicted by estimations of frailty in elderly ambulatory women.

BACKGROUND/METHODS: High biological age, or frailty, a possible risk factor for fragility fracture, and its relation to known risk factors for fracture (low bone mineral density (BMD), low muscle strength, poor gait performance and poor balance, previous falls, previous fractures and future risk of falls) were investigated in 993 randomly selected 75-year-old women. Frailty, which has no accepted definition, was here defined as a subjective immediate impression of an individual's general health appearance and was transferred into an arbitrary scale. 993 individuals were scored by at least one of four observers. RESULTS: The frailty score and BMD were not correlated. A high frailty score was significantly correlated to poor gait (r = 0.53-0.59, p < 0.0001), poor balance (r = -0.49, p < 0.0001), low muscle strength (r = -0.25 to -0.41, p < 0.0001), low activity level (r = -0.43, p < 0.0001) and a high risk of falling (r = 0.24, p < 0.0001). The group of women who had experienced at least one fall the previous year had a higher frailty score (p < 0.0001) compared to those who had not. Women who had sustained a hip or femoral fracture after the age of 70 had a higher frailty score than women with no earlier fracture at all. CONCLUSIONS: Bone mass cannot be predicted by our subjective frailty score in elderly, ambulant women. Since a high frailty score correlates with factors that affect or are likely to affect fall propensity, this could indicate that a high frailty score is a risk factor for fracture, independent of bone mass. Frailty may be regarded as a complex risk factor, including several assessments that can be objectively measured. Whether estimation of frailty is a method to improve the assessment of the patient at risk for a fragility fracture is yet to be proven and can only be shown in a prospective study of fracture occurrence.

Aged↗

PubMed2003

Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences.

Early in infection, human immunodeficiency virus type 1 (HIV-1) generally uses the CCR5 chemokine receptor (along with CD4) for cellular entry. In many HIV-1-infected individuals, viral genotypic changes arise that allow the virus to use CXCR4 (either in addition to CCR5 or alone) as an entry coreceptor. This switch has been associated with an acceleration of both CD3(+) T-cell decline and progression to AIDS. While it is well known that the V3 loop of gp120 largely determines coreceptor usage and that positively charged residues in V3 play an important role, the process of genetic change in V3 leading to altered coreceptor usage is not well understood. Further, the methods for biological phenotyping of virus for research or clinical purposes are laborious, depend on sample availability, and present biosafety concerns, so reliable methods for sequence-based "virtual phenotyping" are desirable. We introduce a simple bioinformatic method of scoring V3 amino acid sequences that reliably predicts CXCR4 usage (sensitivity, 84%; specificity, 96%). This score (as determined on the basis of position-specific scoring matrices [PSSM]) can be interpreted as revealing a propensity to use CXCR4 as follows: known R5 viruses had low scores, R5X4 viruses had intermediate scores, and X4 viruses had high scores. Application of the PSSM scoring method to reconstructed virus phylogenies of 11 longitudinally sampled individuals revealed that the development of X4 viruses was generally gradual and involved the accumulation of multiple amino acid changes in V3. We found that X4 viruses were lost in two ways: by the dying off of an established X4 lineage or by mutation back to low-scoring V3 loops.

Computational Biology↗

PubMed2006

Prediction of small-molecule binding to cytochrome P450 3A4: flexible docking combined with multidimensional QSAR.

The inhibition of cytochrome P450 3A4 (CYP3A4) by small molecules is a major mechanism associated with undesired drug-drug interactions, which are responsible for a substantial number of late-stage failures in the pharmaceutical drug-development process. For a quantitative prediction of associated pharmacokinetic parameters, a computational model was developed that allows prediction of the inhibitory potential of 48 structurally diverse molecules. Based on the experimental structure of CYP3A4, possible binding modes were first sampled by using automated docking (Yeti software) taking protein flexibility into account. The results are consistent with both X-ray crystallographic data and data from metabolic studies. Next, an ensemble of energetically favorable orientations was composed into a 4D dataset for use as input for a multidimensional QSAR technique (Raptor software). A dual-shell binding-site model that allows an explicit induced fit was then generated by using hydrophobicity scoring and hydrogen-bond propensity. The simulation reached a cross-validated r2 value of 0.825 and a predictive r2 value of 0.659. On average, the predicted binding affinity of the training ligands deviates by a factor of 2.7 from the experiment; those of the test set deviate by a factor of 3.8 in Ki.

Cytochrome P-450 CYP3A↗

PubMed2003

Eating disorders and aggressiveness among adolescents.

OBJECTIVE: To explore the links between propensity to aggression and eating disorders in a sample of school-aged adolescents in a northeastern area of Italy. METHOD: In a mixed male-female sample of 1000 adolescents (10% of the district's population aged 15-19 years) we administered the Eating Attitudes Test, the Bulimic Investigatory Test of Edinburgh and the Body Attitudes Test, as measures of abnormal eating attitudes and behaviours, and the Aggression Questionnaire, as a measure of the propensity to aggression. RESULTS: Females scored significantly higher than males at all eating disorders inventories (P < 0.0001). Males scored higher than females at the Aggression Questionnaire. In both genders, there was a positive correlation between scores at any of the eating disorders inventories and those at the Aggression Questionnaire (P < 0.0001). CONCLUSION: Overtly expressed aggression might have a negative impact on the course of eating disorders and on the compliance with treatment, also enhancing the risk of suicide.

Adolescent↗

PubMed2006

Intramolecular surface contacts contain information about protein-protein interface regions.

MOTIVATION: Some amino acids clearly show preferences over others in protein-protein interfaces. These preferences, or so-called interface propensities can be used for a priori interface prediction. We investigated whether the prediction accuracy could be improved by considering not single but pairs of residues in an interface. Here we present the first systematic analysis of intramolecular surface contacts in interface prediction. RESULTS: We show that preferences do exist for contacts within and around an interface region within one molecule: specific pairs of amino acids are more often occurring than others. Using intramolecular contact propensities in a blind test, higher average scores were assigned to interface residues than to non-interface residues. This effect persisted as small but significant when the contact propensities were corrected to eliminate the influence of single amino acid interface propensity. This indicates that intramolecular contact propensities may replace interface propensities in protein-protein interface prediction. AVAILABILITY: The source code is available on request from the authors.

Algorithms↗

PubMed1993

Brain amino acid levels are related to seizure propensity in the gerbil (Meriones unguiculatus).

1. Gerbils were scored for seizure severity and duration and ambulatory and rearing behaviours on presentation with an "open field". 2. Eight seizure-prone (SP) and eight non-seizure-prone (NSP) gerbils were killed and their brains treated to inactivate enzymes before division into corticate and decorticate regions for amino acid analysis. 3. SP animals showed more ambulatory activity on later presentations (trials 3-5) with the open field compared to NSP animals. 4. Statistics showed seizure propensity related to high levels of glutamine and arginine and to low levels of glutamate, aspartate, citrulline, cysteine and glycine. 5. These results suggest aspects of glucose and/or amino acid metabolism may be responsible for behavioural differences in SP compared to NSP gerbils.

Amino Acids↗

PubMed1986

Principal dimensions of the Framingham Type A scale: differential relationships to cardiovascular reactivity and anxiety.

The present investigation sought to identify the principal dimensions of the Framingham Type A scale (FTAS) and then to examine their physiological and psychological correlates. A factor analysis of the FTAS items, which was cross-validated, revealed two factors. Items concerning achievement and competitive-striving loaded primarily on the first factor. Scores on a subscale composed of these items (labeled Competitive Drive) were related to systolic blood pressure reactivity during an interpersonal task but were unrelated to anxiety. FTAS items concerning impatient, time urgent, and domineering propensities loaded primarily on the second factor. Scores on a subscale composed of these items (labeled Speed and Impatience) were not related to cardiovascular reactivity during the task but were related to anxiety. Results are discussed in terms of the psychological heterogeneity of the Type A behavior pattern and possible differences between dimensions of the overall Type A pattern and their association with different manifestations of coronary heart disease.

Achievement↗