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Recruited leukocytes and local synthesis account for increased matrix metalloproteinase-9 activity in cerebrospinal fluid of dogs with central nervous system neoplasm.

Matrix metalloproteinases (MMP) 2 and 9 are enzymes known to degrade several protein components of the extracellular matrix. In humans, increased concentrations of these enzymes have been demonstrated in the cerebrospinal fluid (CSF) of subjects affected by many neurological conditions including brain tumours; nevertheless comparative data in dogs are completely lacking. Aim of this study was to investigate these molecules in CSF of dogs diagnosed with CNS neurological diseases. Higher activity of MMP 2 and 9 was revealed in dogs with space occupying lesions of likely neoplastic origin in comparison to dogs with idiopathic epilepsy. Statistical modelling reveals that increased MMP 9 activity is mainly due to leukocytes recruitment and local synthesis.

Animals↗

Atrial septal defect: a diagnostic approach.

A simple objective screening method for diagnosis of the atrial septal defect (ASD) is needed. Acoustic signals were collected from 61 children with ASD and 60 with a physiological murmur. The second heart sound (S2) and the spectrum of systolic murmur were analysed. A statistical model was designed using stepwise logistic regression analysis. Significant variables distinguishing pathological form normal findings were the interval between the first heart sound and the beginning of systolic murmur or the respiratory variation of S2, and the frequency of the murmur at its maximum intensity. The area under the ROC curve was 0.922; indicating very good fit of the model and the confidence interval was 0.872-0.971. The sensitivity of the model was 91% and the specificity 73%. The analysis of acoustic findings from the heart is a valuable tool in diagnosing ASD. The next step will be automating this process.

Adolescent↗

Study of vesicle leakage induced by melittin.

The leakage induced by melittin, a membrane-perturbing amphipathic peptide, from large unilamellar 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) vesicles was studied using calcein as fluorescent marker. The extent of leakage has been found to be regulated by the melittin/lipid molar ratio. Melittin leads to the complete release of trapped calcein from some vesicles. This all-or-none mechanism leads to the co-existence of two different vesicle populations: the 'empty' and the intact one. Intervesicular migration of melittin was not observed. The results reveal a specific targeting of the lysed vesicles by melittin. The presence of negatively charged lipids (unprotonated palmitic acid or 1-palmitoyl-2-oleoylphosphatidylglycerol) in the neutral POPC matrix inhibits the lytic power of melittin; this inhibition increases with increasing surface charge density. It is proposed that the anchorage of the peptide on the charged surface prevents the formation of defects allowing leakage. A statistical model based on a random distribution of the peptide molecules on the vesicles is proposed to describe the release induced by melittin. It is proposed that about 250 melittin molecules per vesicle are required to affect the bilayer permeability and to empty a vesicle of its content. This large number suggests that leakage is more likely due to collective membrane perturbation by the peptide rather than to the formation of a well-defined pore.

Electrochemistry↗

Impact of the mass media on calls to the CDC National AIDS Hotline.

This paper considers new computer methodologies for assessing the impact of different types of public health information. The example used public service announcements (PSAs) and mass media news to predict the volume of attempts to call the CDC National AIDS Hotline from December 1992 through to the end of 1993. The analysis relied solely on data from electronic databases. Newspaper stories and television news transcripts were obtained from the NEXIS electronic database and were scored by machine for AIDS coverage. The PSA database was generated by computer monitoring of advertising distributed by the Centers for Disease Control and Prevention (CDC) and by others. The volume of call attempts was collected automatically by the public branch exchange (PBX) of the Hotline telephone system. The call attempts, the PSAs and the news story data were related to each other using both a standard time series method and the statistical model of ideodynamics. The analysis indicated that the only significant explanatory variable for the call attempts was PSAs produced by the CDC. One possible explanation was that these commercials all included the Hotline telephone number while the other information sources did not.

Acquired Immunodeficiency Syndrome↗

Determination of hprt mutant frequencies in T-lymphocytes from a healthy pediatric population: statistical comparison between newborn, children and adult mutant frequencies, cloning efficiency and age.

Somatic cell mutant frequencies at the hprt locus of the X-chromosome were measured with the T-lymphocyte cloning assay in a healthy pediatric population. Assays were performed on 49 subjects (29 males and 20 females) ranging in age from 0.08 to 15.2 years. A statistical analysis of the thioguanine-resistant (TGr) mutant frequency (MF), unselected cloning efficiency (CE) and age was performed using data obtained in this study and those previously obtained in our laboratory on 66 newborn umbilical cord blood samples and 230 adult blood samples. For statistical comparisons pediatric subjects were divided into 4 groups. Group I included cord blood samples (age 0 years); Group II were subjects between 0 and 5 years; Group III were between 6 and 11 years and Group IV were between 12 and 17 years. The ln MF of Groups I and II were significantly lower than Groups III and IV (p < 0.05). The mean ln MF for each of Groups I-IV was significantly lower than the adult value. The cloning efficiency for Group I was significantly lower than that for Groups II-IV and adults. The relationships among the ln MF, unselected CE and age were expressed by the equations: ln (MF) = 0.945 -2.453 CE (p < 0.001) and ln (MF) = 0.114 + 0.063 age (p 0.004). The slope coefficients for unselected CE and age were significantly different from adults (p < 0.05). Regression analysis of combined data from Groups I-IV and adults were performed using both age and unselected CE as well as terms to reflect differences in their relationships with ln MF in adults and children. The results showed that the intercept and the age coefficients differ significantly for children and adults after adjustment for CE and yielded the following equations: ln (MF) = 0.548 -1.676 CE + 0.075 age, (Groups I-IV) and ln (MF) = 2.263 -1.676 CE + 0.014 age (adults). An alternative statistical model using ln (age ), ln (MF) = 0.381 -1.767 CE + 0.673 ln (age + 1), (p < 0.001), describes the rapid increase in MF with age that levels off in late adolescence. These findings demonstrate the changing influence of age on mutant frequency in the pediatric population as compared to the adult populations. These studies also illustrate that the increase in background somatic mutant frequencies at the hprt locus in T-lymphocytes is not linear from birth to adolescence and is significantly different from that seen in the adult population.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

Estimating sporozoite rates by examining pooled samples of mosquitoes.

Pooling sampled mosquitoes for sporozoite detection by immunoassays is an efficient and economic approach in situations of very low vector infectivity. In the present study a strategy was proposed to estimate sporozoite rates using this approach. For this purpose there should be only one infected mosquito in any positive pool, so that the number of positive pools examined is an approximation of the number of infected mosquitoes in sample collections. The rationale underlying the strategy is to specify the maximal pool sizes for the given sporozoite rates so that it is reasonable to assert there is no more than one infected mosquito in any positive pool. A statistical model was developed to calculate the maximal pool sizes for various guessed sporozoite rates. The results showed that maximal pool size declined non-linearly with increases in the given sporozoite rates. With a guessed sporozoite rate < 1% as many as 35 mosquitoes could be pooled for sporozoite determination.

Animals↗

Economic aspects of patterns of mental health care: cost variation by setting.

The paper examines the evidence regarding the extent to which differences exist in health and mental health status of psychiatric patients treated in the specialty mental health, general medical, and informal care sectors. Differences in types of patients treated in the three sectors are important to identify since there are dramatic differences in the average costs of treatment. We use data from the Baltimore Epidemiological Catchment Area Survey to estimate a statistical model of treatment setting choice. Our results suggest that there is little support for attributing major differences in treatment costs across sectors to differences in the health and mental health status of patients.

Costs and Cost Analysis↗

Computer-aided surveillance of surgical infections and identification of risk factors.

A continuous record of postoperative surgical infections was carried out by electronic data processing (EDP) of 4340 orthopaedic and general operations. The overall infection rate was 6.3%, ranging from 2.3% (clean wounds) to 27.1% (dirty wounds). The corresponding deep infection rates were 1.6%, 0.4% and 4.6%. Employing a multiple logistic regression analysis, 10 risk factors were evaluated. Factors found to be significant were: wound contamination, department, duration of operation, date of operation and age, and in addition for the department of general surgery: surgeon, planning of operation, length of preoperative stay and anatomic groups. A statistical model for identification of risk patients is described. Postoperative stay was on average 20.5 days longer in infected patients. We find that EDP-recording may result in an annual cost reduction of at least 175,000 pounds for our hospital.

Denmark↗

Estimation of the coefficient of variation from laboratory analysis of split specimens for quality control in clinical trials.

An explicit statistical model is proposed for the coefficient of variation for laboratory analyses of constituents of blood, serum, saliva, or other specimens. A method for computing the maximum likelihood estimate of the key parameter is described, and compared with two simpler noniterative estimates. Validity of the model is explored by analysis of data from the central laboratory of a large cooperative clinical trial. Simulation studies are employed to compare the accuracy of the three estimators of the coefficient of variation. For most laboratory measurements for which the model is valid, one of the two noniterative estimates is nearly as accurate and unbiased as the maximum likelihood estimate.

Clinical Trials as Topic↗

Statistical optimization applied to the spectrophotometric study of a tolmetin-copper(II) complex.

Tolmetin sodium has been investigated and determined from dosage forms as its Cu(II) complex and method optimized by statistical optimization. The assay was developed using two mathematical statistical models: factorial design and response-surface mapping. The decision to apply experimental design techniques to the development of the method was made after a series of screening experiments revealed that the complex formation and extraction are maximized as a function of supporting electrolyte concentration, concentration of Cu(II) acetate and pH of the reaction mixture. One set of two-level three variable factorial experiments was carried out in order to evaluate the main effect, as well as the interaction among factors. The final step was to optimize the values of variables using response surface design. The best set of conditions was selected for further investigation.

Copper↗

Testosterone levels as a marker of prognosis to goserelin treatment in metastatic breast cancer.

Testosterone levels were measured in blood and urine of 35 premenopausal metastatic breast cancer patients before starting therapy with the gonadotrophin-releasing hormone (GnRH) analogue, goserelin. The aim of the study was to verify the reliability of testosterone measurement as a marker of prognosis. The time interval between starting therapy and progressive disease (time to progression) was chosen to assess prognosis. Univariate and multivariate analysis showed that only urinary testosterone levels were significantly associated with time to progression (Wald test 6.66, P = 0.01 for univariate and Wald test 7.93, P = 0.0049 for multivariate analysis), whereas no association was found for testosterone in blood. A statistical model is proposed to evaluate probability of progressive disease in relation to testosterone values in urine at different times. According to the model, the probability of progression decreases with increasing urinary testosterone values.

Adult↗

A nomogram for predicting lifetime hip fracture risk from radius bone mineral density and age.

A statistical model for predicting a woman's lifetime risk of hip fracture using her bone mineral density at menopause has been proposed by Black et al. (1992b). We made an additional assumption concerning the correlation of bone mineral density between any two ages among postmenopausal women and applied the modified model to baseline ages between 50 and 85 years and any bone mineral density level likely to be observed in the population. The results are displayed in a form more convenient for application of this model in the clinical setting.

Aged↗

On sampling bones for microcracks.

This paper addresses the problem of designing experiments to measure microcrack density in cortical bone. Microcracks are relatively scarce in bone cross-sections, and their size requires microscope settings having small fields of view. Thus, substantial time is required to count cracks in each cross-section. Consequently, most studies evaluate a relatively small cross-sectional area from each specimen, the chance of finding a crack in any given field is small, and there is a significant chance of not finding even one crack in the specimens representing a particular subject. Therefore, a statistical model for microcrack counting was created to develop guidelines for sampling bones for microcracks. Three questions were addressed. 1) What are the relationships of sample size to variability in microcrack density results and the probability of crackless specimens? 2) How can sample size be chosen a priori so as to reduce the probability of crackless specimens and the associated variability in the data to an acceptable level? 3) What are the confidence intervals for the mean density of microcracks measured using microscopic counting? Using a Poisson model for the distribution of microcracks within microscope fields the total area (mm(2)) that should be examined for each specimen is given by A(s)=-ln(F)/Cr.Dn, where Cr.Dn is the expected microcrack density for an individual sample and F is the desired probability (expressed as a fraction) that the individual sample will contain no microcracks. This equation is validated against 8 results from three different experiments.

Animals↗

Statistical analysis of oligonucleotide microarray data.

Microchip arrays have become one of the most rapidly growing techniques for monitoring gene expression at the genomic level and thereby gaining valuable insight about various important biological mechanisms. Examples of such mechanisms are: identifying disease-causing genes, genes involved in the regulation of some aspect of the cell cycle, etc. In this article, we discuss the problem of estimating gene expression based on a proper statistical model. More precisely, we show how the model introduced by Li and Wong can be used in its full bivariate generality to provide a new measure of gene expression from high-density oligonucleotide arrays. We also present a second gene expression index based on a new way of reducing the model into a simpler univariate model. In both cases, the gene expression indices are shown to be unbiased and to have lower variance than the established ones. Moreover, we present a bootstrap method aiming at providing non-parametric confidence intervals for the expression index.

Gene Expression↗

Physiological dysregulation and changes in health in an older population.

We investigate whether a multi-system measure of physiological dysregulation based on 16 biological measures is associated with deterioration in physical and mental health over a 3-year period. The data come from a national survey of persons 54 and older in Taiwan that collected standard clinical markers related to cardiovascular and metabolic function and "non-clinical" measures pertaining to the immune, neuroendocrine and sympathetic nervous systems. The dysregulation score counts the number of biomarkers for which values are in the lowest or highest decile. Statistical models examine whether dysregulation predicts four health outcomes (survival, physical functioning, cognitive functioning and depressive symptoms), in the presence of extensive controls for baseline health. The estimates reveal significant associations between dysregulation and health for each outcome, although there is variability across outcomes. The associations are often attenuated in the presence of health controls, underscoring the importance of longitudinal analysis. This study extends previous research on the health consequences of physiological dysregulation by considering a broader range of outcomes and biomarkers in a non-Western population-based sample. Our analysis suggests that such dysregulation provides early warning signs of a broad range of comorbidities.

Aged↗

A tale of two continents: a multilevel comparison of the determinants of child nutritional status from selected African and Indian regions.

This paper compares individual and household predictors of underweight among young children in sub-Saharan Africa and India, while also assessing the impact of clustering of weight for age z-scores at the household, community and regional levels. Multilevel statistical models are employed to compare the strength of the correlates of underweight (using weight-for-age z-scores) in six sub-Saharan African countries and four Indian states. The multilevel approach controls for correlation among children resulting from clustering within families, communities, or regions and in addition enables tests for differences in the regional, community and household effects for children from families of different socio-economic characteristics. Findings demonstrate the importance of individual and household level predictors such as age, the size of child at birth, prolonged breast-feeding, recent diarrhoea episodes, and maternal education as predictors of low weight-for-age z-scores across regions. Strong family effects are observed as well as significant community and regional random effects on variation in weight for age z-scores. In some regions, socio-economic characteristics of the household result in significant differences in the household or community level variance in weight for age z-scores, suggesting that the impact of the geographical context varies by socio-economic status of the household.

Africa South of the Sahara↗

A review on the design and reporting of studies on drug-gene interaction.

OBJECTIVE: Methodological standards for clinical pharmacogenetic studies should be developed to improve reporting of studies and facilitate their inclusion in systematic reviews. The essence of these studies lies within the concept of effect modification. STUDY DESIGN AND SETTING: A narrative review discussing methodological issues in the design and reporting of pharmacogenetic studies. RESULTS: Studying effect modification within a trial leads to the comparison of subgroups based on genotype. Differences in effect based on genotype should preferably be expressed in absolute terms (risk differences) to facilitate clinical decisions on treatment. Information on the distribution of potential effect modifiers or prognostic factors should be available to prevent a biased comparison of differences in effect between genotypes. The distribution of genotypes should also be presented and compared to Hardy-Weinberg equilibrium to check for selection bias. Additional points of interest include the possibility of selective nonavailability of biomaterial and the choice of a statistical model to study effect modification. CONCLUSION: Additional methodological issues should be taken into account when designing and reporting pharmacogenetic studies, to ensure high study quality. We present several important issues for future studies investigating drug-gene interactions that can serve as a basis for further discussion on methodology in pharmacogenetics.

Genotype↗

The automated counting of spots for the ELISpot assay.

An automated method for counting spot-forming units in the ELISpot assay is described that uses a statistical model fit to training data that is based on counts from one or more experts. The method adapts to variable background intensities and provides considerable flexibility with respect to what image features can be used to model expert counts. Point estimates of spot counts are produced together with intervals that reflect the degree of uncertainty in the count. Finally, the approach is completely transparent and "open source" in contrast to methods embedded in current commercial software. An illustrative application to data from a study of the reactivity of T-cells from healthy human subjects to a pool of immunodominant peptides from CMV, EBV and flu is presented.

Algorithms↗