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PubMed2006

A meta-analysis of safety and effectiveness of perioperative beta-blocker use for the prevention of cardiac events in different types of noncardiac surgery.

OBJECTIVE: Perioperative beta-blocker therapy has been proposed to improve outcome. Most of the trials conducted, however, lacked statistical power to evaluate the incidence of hard cardiac events and the relationship to the type of surgery. Therefore, we conducted a meta-analysis of all randomized controlled trials in which beta-blocker therapy was evaluated. METHODS: An electronic search of published reports on Medline was undertaken to identify studies published between January 1980 and November 2004 in English language journals. All studies reported on at least one of three endpoints: perioperative myocardial ischemia, perioperative nonfatal myocardial infarction, and cardiac mortality. Type of surgery, defined as low, intermediate, and high risk according to the American College of Cardiology/American Heart Association guidelines, was noted. RESULTS: In total, 15 studies were identified, which enrolled 1,077 patient. No significant differences were observed in baseline clinical characteristics between patients randomized to beta-blocker therapy and control/placebo. Beta-blocker therapy was associated with a 65% reduction in perioperative myocardial ischemia (11.0% vs. 25.6%; odds ratio 0.35, 95% confidence interval 0.23-0.54; P<0.001). Furthermore, a 56% reduction in myocardial infarction (0.5% vs. 3.9%, odds ratio 0.44, 95% confidence interval 0.20-0.97; P=0.04) and a 67% reduction (1.1% vs. 6.1%, odds ratio 0.33, 95% confidence interval 0.17-0.67; P=0.002) in the composite endpoint of cardiac death and nonfatal myocardial infarction were observed. No statistical evidence was observed for heterogeneity in the treatment effect in subgroups according to type of surgery (P for heterogeneity 0.2). CONCLUSION: This meta-analysis shows that beta-blocker use in noncardiac surgical procedures is associated with a significant reduction of perioperative cardiac adverse events.

Adrenergic beta-Antagonists↗
PubMed1988

Prognostic indices in stroke.

Two hundred and six patients with acute stroke admitted consecutively to District General Hospitals, were studied for a period of six months. Significance tests conducted singly detected 21 factors present during the first 48 h of stroke, which were related to outcome six months later in terms of both mortality and functional recovery. Among these significant factors were various measures of perceptual dysfunction, including Albert's Test. Multivariate statistical analysis which included discriminant analysis and linear logistic modelling, revealed six factors (Albert's Test Score, leg function, level of consciousness, arm power, weighted mental score and ECG changes) which were significantly and independently related to outcome. A statistical model based on these factors predicted functional outcome with an overall accuracy of 67 per cent and mortality with an accuracy of 83 per cent. This model provides a useful basis for stratification in future randomized controlled trial in stroke, and may have a role in the management of the individual stroke patient.

Acute Disease↗
PubMed2004

Whole genome DNA copy number changes identified by high density oligonucleotide arrays.

Changes in DNA copy number are one of the hallmarks of the genetic instability common to most human cancers. Previous microarray-based methods have been used to identify chromosomal gains and losses; however, they are unable to genotype alleles at the level of single nucleotide polymorphisms (SNPs). Here we describe a novel algorithm that uses a recently developed high-density oligonucleotide array-based SNP genotyping method, whole genome sampling analysis (WGSA), to identify genome-wide chromosomal gains and losses at high resolution. WGSA simultaneously genotypes over 10,000 SNPs by allele-specific hybridisation to perfect match (PM) and mismatch (MM) probes synthesised on a single array. The copy number algorithm jointly uses PM intensity and discrimination ratios between paired PM and MM intensity values to identify and estimate genetic copy number changes. Values from an experimental sample are compared with SNP-specific distributions derived from a reference set containing over 100 normal individuals to gain statistical power. Genomic regions with statistically significant copy number changes can be identified using both single point analysis and contiguous point analysis of SNP intensities. We identified multiple regions of amplification and deletion using a panel of human breast cancer cell lines. We verified these results using an independent method based on quantitative polymerase chain reaction and found that our approach is both sensitive and specific and can tolerate samples which contain a mixture of both tumour and normal DNA. In addition, by using known allele frequencies from the reference set, statistically significant genomic intervals can be identified containing contiguous stretches of homozygous markers, potentially allowing the detection of regions undergoing loss of heterozygosity (LOH) without the need for a matched normal control sample. The coupling of LOH analysis, via SNP genotyping, with copy number estimations using a single array provides additional insight into the structure of genomic alterations. With mean and median inter-SNP euchromatin distances of 244 kilobases (kb) and 119 kb, respectively, this method affords a resolution that is not easily achievable with non-oligonucleotide-based experimental approaches.

Cell Line, Tumor↗
PubMed2002

Mapping multiple genes for quantitative or complex traits.

Models for complex and quantitative traits that involve multiple, possibly interacting, genes are described. Methods of linkage analysis are developed that utilize special features of these models, and their power is compared with that of simple genome scans that ignore these special features. Our calculations show that for family-based nonparametric linkage analysis in human genetics, in contrast to experimental genetics, there are limits to the increase in power that can be achieved by correctly modeling gene-gene interactions. In particular, the noncentrality parameter of likelihood-based statistics to detect single gene effects involves both single gene and interaction components of variance, so even when the interaction components of variance are relatively large, the incremental power from a statistic designed to detect both single gene and interaction effects is often quite modest. We carry out our analysis with the assistance of a parameterization that allows us to compute score statistics, noncentrality parameters, and Fisher information matrices reasonably explicitly.

Alleles↗
PubMed2003

QSAR studies in substituted 1,2,3,4,6,7,12,12a-octa-hydropyrazino[2',1':6,1]pyrido[3,4-b]indoles--a potent class of neuroleptics.

A series of nineteen substituted 1,2,3,4,6,7,12,12a-octahydropyrazino[2',1':6,1]pyrido[3, 4-b]indoles analogues of neuroleptic drug, Centbutindole have been studied using quantitative structure-activity relationship analysis. The derived models display good fits to the experimental data (r>or=0.75) having good predictive power (r(cv)>or=0.688). The best model describes a high correlation between predicted and experimental activity data (r=0.967). Statistical analysis of the equation populations indicates that hydrophobicity (as measured by pi(R), logP(o/w) and SlogP_VSA8), dipole y and structural parameters in terms of indicator variable, (In(1)) and globularity are important variables in describing the variation in the neuroleptic activity in the series.

Animals↗
PubMed2004

Linkage analysis: principles and methods for the analysis of human quantitative traits.

Currently, mapping genes for complex human traits relies on two complementary approaches, linkage and association analyses. Both suffer from several methodological and theoretical limitations, which can considerably increase the type-1 error rate and reduce the power to map human quantitative trait loci (QTL). This review focuses on linkage methods for QTL mapping. It summarizes the most common linkage statistics used, namely Haseman-Elston-based methods, variance components, and statistics that condition on trait values. Methods developed more recently that accommodate the X-chromosome, parental imprinting and allelic association in linkage analysis are also summarized. The type-I error rate and power of these methods are discussed. Finally, rough guidelines are provided to help guide the choice of linkage statistics.

Genetic Linkage↗
PubMedDate not supplied

Spatiotemporal analysis of environmental exposure-health effect associations.

The goal of this work is to discuss a general methodology for studying associations between environmental exposures and health effect by means of the spatiotemporal random field theory. This theory is the tool of choice for rigorously accounting for important spatiotemporal variations and uncertainties related to exposures and effect. Within the framework of the random field theory, the Bayesian maximum entropy model neatly synthesizes various sources of physical and epidemiological knowledge into spatiotemporal analysis. Therefore, unlike technical statistics, this approach relies on the blending of substantive physical knowledge with powerful mathematical techniques and a coherent rationale. Given the well-founded fact that certain health effects may be caused by environmental exposures, the significance of these exposures is assessed in terms of a criterion that is based on the joint stochastic representation of exposure and health-effect distributions in space/time. In view of this criterion, the strength and consistency of the exposure-effect association are evaluated on the basis of the health-effect predictions that the combined physico-epidemiologic analysis generates in space/time. The main features of the approach are demonstrated by a simulation example and a real case study involving mortality and cold temperatures in North Carolina. The studies demonstrated the practical usefulness of the stochastic human exposure analysis in assessing the exposure-effect association. The results reported here emphasize the links between spatiotemporal models of physical systems and population health-effect distributions, thus suggesting directions for improving the current understanding of quantitative "exposure-health effect" functions.

Cold Temperature↗
PubMed2005

Detecting protein-protein interaction in live yeast by flow cytometry.

BACKGROUND: The yeast Saccharomyces cerevisiae is the most commonly used organism for studying protein- protein interactions. In this report we demonstrate the use of flow cytometry in observing fluorescence resonance energy transfer (FRET) between cyan and yellow fluorescent fusion proteins (CFP and YFP, respectively) as a marker for protein interaction in live yeast cells. Probability binning is also employed to provide a statistical confirmation of our observations. METHODS: We coexpressed CFP and YFP fusions containing the N-terminal transmembrane domain (NTM) of Tom70p in yeast and analyzed FRET in live cells with a multilaser flow cytometer. The Tom70p NTM was previously shown to be sufficient for mitochondrial localization and protein-protein interaction (Millar and Shore, 1994, J Biol Chem 269:12229-12232). RESULTS: FRET was observed only in cells that expressed CFP and YFP fusions that each contained the wild-type NTM. The introduction of mutations previously shown to disrupt NTM interaction eliminated FRET. Probability binning confirmed that differences between the FRET channels of experimental and control samples were statistically and physiologically significant. CONCLUSION: Flow cytometric analysis of FRET in yeast is a powerful technique for studying protein-protein interactions. The use of flow cytometry allows FRET data to be gathered from a large number of individual cells, thus providing important advantages unavailable to other techniques. Its application to yeast presents a new method to a popular system widely used in proteomic studies.

Bacterial Proteins↗
PubMed2001

Randomized controlled trial of 50 and 100 mcg of misoprostol for induction of labor at term.

To compare the safety and efficacy of two different regimens of misoprostol for labor induction at term, we conducted a randomized controlled trial on women presenting for induction of labor at > or =37 weeks' gestation. Eligible women were randomized to receive intravaginal misoprostol 50 microg every 4 h or 100 microg every 6 h until any of the following: 1) adequate contraction pattern (3 contractions/10 min); 2) dilatation >3 cm; 3) artificial rupture of membranes; or 4) signs of uterine hyperstimulation. Use of oxytocin during labor was at the discretion of the managing clinician. The main outcome variable considered for analysis was cesarean section rate. Secondary outcome measures were induction to delivery interval and neonatal outcome (Apgar scores, meconium staining, and umbilical artery pH). A total of 58 women were randomized to receive either misoprostol 100 microg (n=26) or 50 microg (n=32). The 100 and 50 microg groups had similar mean Bishop's scores at induction (4.0+/-2.3 vs 4.1+/-2.2, p=0.87), rates of nulliparity, use of epidural anesthesia, and oxytocin augmentation. The number of doses of misoprostol used was similar in the two groups (1.4+/-0.6 vs 1.8+/-1.2). The mean+/-standard deviation time to delivery (hours) (11.9+/-7.3 vs 14.3+/-9.6 h, p=0.30) and cesarean section rate (35% vs 19%, p=0.30, relative risk: 1.8, 95% confidence interval 0.7-5.4) were not different in the 100 vs 50 microg group. Power analysis demonstrated that 132 women would be required in each group to achieve statistical significance in the primary outcome measure (alpha=0.05, beta=0.80). Similarly, rates of 5-minute Apgar scores <7 (4% vs 3%, p=1.0), and of meconium passage (17% vs 25%, p=0.73) were not significantly different between the two groups.

Administration, Intravaginal↗
PubMed1986

A hand-held decision-aid system designed for rural health workers.

A great part of the world's population is cared for by rural health workers who are also collecting data for epidemiological studies. These workers have a low level of medical training and are working in a poor technical environment. At the request of an international humanitarian and medical organization (Médecins Sans Frontières), we have developed an integrated (hardware and software) system, TROPICAID, based on a hand-held computer and designed to increase rural health workers' efficiency. The software is easy to use and enables users to get information from an internal data base on 60 drugs. The decision-making module analyzes the patient's parameters (460 different symptoms are recognized) and indicates possible diagnoses (the system knows 210) and relevant treatments. In addition, the system facilitates the collection of medical data for elementary statistical analysis. The computer, which is lightweight (1.5 kg) and compact, runs on battery power for up to a week in normal use. The program which is written in Pascal and data are stored in high-capacity EPROMs. An early trial in Chad with Médecins sans Frontières has shown the value of such a project as well as a few weaknesses to be overcome.

Chad↗
PubMed2002

Identifying disease modifying genes in multiple sclerosis.

Evidence is mounting that genetic variation influences not only susceptibility to multiple sclerosis (MS), but also its course and severity. Identification of disease modifying genes, however, poses unique challenges, especially on how to classify the course and outcome of the disease in ways that may be relevant to analysis of biological factors that might be influenced by genes. The power of the statistical approaches to detect small effects of individual genes in complex disorders such as MS is problematic, and approaches to estimate power must be appropriate for the data. Nonetheless, using contemporary schemes of classification, genetic variants that influence disease course have been found; in fact, a small number have been confirmed to influence disease course in two or more independent studies. This review addresses strategies relevant to identification of disease modifying genes in MS, and summarizes and critically evaluates the current state of knowledge in this area.

Apolipoproteins E↗
PubMed2000

Mach's phenomenalism and the British reception of Mendelism.

The assimilation of Mendel's paper into Britain took place in an Edwardian social context. This paper concentrates on the interplay of empirical and philosophical issues in this reception. A feature of the British reception of mendelism, not duplicated elsewhere, was the role of phenomenalist philosophies of science as developed by the physicist-mathematician and scientific methodologist Karl Pearson from the philosophical positions of Austrian physicist Ernst Mach and British mathematician William Clifford. Pearson's philosophy of science forms the background to his subsequent collaboration with the zoologist W.F.R. Weldon. In this collaborative work, Pearson developed powerful statistical techniques for analyzing Weldon's empirical data on organic variation. Pearson's statistical analysis of causation and his rejection of hidden entities and causes in the explanation of evolutionary change formed the philosophical component of this program. The arguments of Pearson and Weldon were first brought to bear against the pre-Mendel 'discontinuist' analyses of variation of William Bateson. The introduction of Mendel's paper into these empirical and methodological debates consequently resulted in mathematically sophisticated attacks on Mendel's claims by Pearson and Weldon. This paper summarizes this history and argues for the creative importance of this biometrical resistance to Mendelism.

Animals↗
PubMedDate not supplied

Effect modification in epidemiologic studies of low-level neurotoxicant exposures and health outcomes.

Little attention has been invested in exploring the possibility that the nature or magnitude of a neurotoxicant's health impact on children depends on host characteristics (e.g., sex, age) or contextual factors (e.g., socioeconomic status, other chemical exposures). Such effect modification is a property of a true association, and should be distinguished from confounding. In epidemiologic studies of children, most efforts to identify effect modification have been unsystematic, pursued as part of data analysis rather than of study design. As a result, most samples have insufficient statistical power to characterize effect modification with adequate precision. This may contribute to an inconsistency in results across studies. Failure to assess effect modification adequately may also lead to invalid inferences. If the magnitude of an association between a neurotoxicant exposure and a particular end point varies across strata of a third factor, an estimate that summarizes the association across strata of this factor will be inappropriate, overestimating the association in a stratum in which the association is absent, and underestimating it in a stratum in which it is present. Until such dependencies are identified, our understanding of the mechanism(s) of a compound's neurotoxicity will remain incomplete, as will the knowledge base required to formulate public policy that adequately protects the most sensitive subgroups of the population.

Child↗
PubMed2002

EEG mapping in patients with restless legs syndrome as compared with normal controls.

Restless legs syndrome (RLS) is a sensorimotor movement and sleep disorder with a high prevalence. While the sleep disturbance due to RLS has been studied quite well polysomnographically, little is known about the electrophysiological function during daytime. The aim of the present study was to investigate the diurnal quantitative EEG and clinical symptomatology in 33 drug-free RLS patients as compared with age- and sex-matched normal controls. Investigations comprised brain mapping of the vigilance-controlled EEG as well as completion of the Zung Self-Rating Depression Scale, the Zung Self-Rating Anxiety Scale, the Quality of Life Index, the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale for evaluation of clinical symptomatology. Statistical analysis demonstrated an increase in absolute delta and absolute and relative alpha-2 power, a decrease in absolute and relative alpha-1 power, an acceleration of the dominant frequency and the alpha centroid, and a slowing of the delta/theta centroid, as well as a non-significant attenuation in total power. These findings are characteristic of dissociated vigilance changes described in depression. Indeed, RLS patients demonstrated significantly higher depression and anxiety scores, lower quality of life and deteriorated sleep quality. The score of the Epworth Sleepiness Scale was not elevated, in contrast to the increased daytime sleepiness observed in other highly prevalent organic sleep disorders (e.g. sleep apnea). In conclusion, daytime EEG mapping revealed neurophysiological correlates of depression in RLS, which was confirmed by self-ratings at the symptomatological level.

Adult↗
PubMed2000

Prediction of bone strength of distal forearm using radius bone mineral density and phalangeal speed of sound.

This investigation compares quantitative ultrasound (QUS) measurement of the phalanges with peripheral quantitative computed tomography (pQCT) and dual X-ray absorptiometry (DXA) measurement of the forearm, to estimate the strength of the distal radius in 13 cadaveric forearms. The cadavers were scanned at the distal radius by pQCT and DXA for bone mineral density (BMD) and at the approximate phalanges by QUS for speed of sound (SOS). The distal radii were subjected to a simulated Colles fracture produced with a materials testing machine. The load at which the distal radius was fractured was considered as a representation of bone strength. The bone strength correlated significantly with SOS at different phalanges (r = 0.63-0.72), BMD at different regions of interest by DXA (r = 0.67-0.75), and cortical BMD at different sites by pQCT (r = 0.61-0.67). Standard stepwise regression analysis showed that adding phalangeal SOS into forearm densitometric variables significantly enhanced the statistical power for prediction of the strength of the distal radius. Our results suggest that, for assessment of site-specific distal forearm strength, QUS measurement of the phalanges is comparable to forearm densitometry. Phalangeal QUS may add clinical value if distal forearm strength has a high priority.

Aged↗
PubMed2000

Idiopathic and allergic rhinitis show a similar inflammatory response

HYPOTHESIS: Idiopathic and allergic rhinitics have similar mucosal mast cell and IgE+ cell distribution. INTRODUCTION: The pathophysiology of idiopathic rhinitis (IR) is unknown but patients differ from those with allergic rhinitis (AR) in that they do not express IgE. Our study is novel because we investigated: (1) three study groups chosen prospectively using strict selection criteria over a 4-year period; and (2) mast cell and IgE+ cell counts were on full-thickness, full-length inferior turbinate mucosa. METHODS: Patient groups: allergic (n = 17); idiopathic: (n = 16); and normal controls (n = 9). Immunohistochemistry: mast cell and IgE+ cell detection using anti-mast cell tryptase and anti-IgE antibodies with an avidin-biotin (peroxidase) complex on paraffin processed tissue. Morphometry: sections were divided into three strata comprising an epithelial layer and two submucosal layers. Statistics: Mann-Whitney non-parametric analysis. alpha = 0.05, beta = 0.2. RESULTS: The power of the study was 89%. Mast cells (P = 0.03) and IgE+ cells (P < 0.05) were significantly increased in the epithelium of idiopahtic and allergic rhinitis mucosa compared to the normal control. More IgE+ cells were counted in the AR and IR groups compared to the controls in all three strata. CONCLUSION: Mast cells and IgE+ cells are involved in the pahtophysiology of IR. We propose that IR may be a variant form of AR involving a localized IgE-mediated inflammatory response.

Journal Article↗
PubMed2003

Comparing nutrient intake from food to the estimated average requirements shows middle- to upper-income pregnant women lack iron and possibly magnesium.

OBJECTIVE: To determine whether nutrient intake from food alone was adequate across trimesters for middle- to upper-income pregnant women when compared with estimated average requirements (EAR), and to determine whether food intake exceeded the tolerable upper intake level (UL) for any nutrient. DESIGN: Observational study in which pregnant women completed 3-day diet records each month during their pregnancy. Records were analyzed for nutrient content, and usual intake distributions were determined. SUBJECTS/SETTING: Subjects were low-risk women in their first trimester of pregnancy (living in middle- to upper-income households). Ninety-four women were recruited, and sixty-three participated. STATISTICAL ANALYSIS PERFORMED: Nutrient intake data were adjusted to achieve normality by using a power transformation. A mixed model method was used to assess trends in intake over time, and to estimate mean intake and within-subjects and between-subjects variance. The usual intake distribution for each nutrient was determined and compared with the EAR and UL. RESULTS: The probabilities of usual nutrient intake from food being less than the EAR were highest for iron (.91), magnesium (.53), zinc (.31), vitamin B6 (.21), selenium (.20), and vitamin C (.12). Women were not at risk of exceeding the UL from food intake for any nutrient studied. APPLICATIONS/CONCLUSIONS: Study participants did not consume adequate amounts of iron from food to meet the needs of pregnancy, and therefore iron supplementation is warranted in this population. Intake of magnesium was suboptimal using the EAR as a cut-point for adequacy.

Adult↗
PubMed2004

In vivo positron-emission tomography imaging of progression and transformation in a mouse model of mammary neoplasia.

Imaging mouse models of human cancer promises more effective analysis of tumor progression and reduction of the number of animals needed for statistical power in preclinical therapeutic intervention trials. This study utilizes positron emission tomography imaging of 2-[18F]-fluoro-deoxy-D-glucose to monitor longitudinal development of mammary intraepithelial neoplasia outgrowths in immunocompetent FVB/NJ mice. The mammary intraepithelial neoplasia outgrowth tissues mimic the progression of breast cancer from premalignant ductal carcinoma in situ to invasive carcinoma. Progression of disease is clearly evident in the positron emission tomography images, and tracer uptake correlates with histological evaluation. Furthermore, quantitative markers of disease extracted from the images can be used to track proliferation and progression in vivo over multiple time points.

Animals↗