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PubMed2006

A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS.

BACKGROUND: The combination of a small pool of patients at any given time with the availability of many potential neuroprotective agents to be tested in ALS requires efficient phase II trial designs. OBJECTIVE: To describe the design of the Clinical Trial of High Dose Coenzyme Q10 (CoQ10) in ALS (QALS study)--a phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial. METHODS: The study design features two stages. The first stage (dose selection) identifies which of two doses of CoQ10 (1800 mg or 2700 mg) is preferred using a selection procedure rather than a formal hypothesis test. The second stage (early efficacy test) compares the preferred dose of CoQ10 against placebo using a non-superiority or futility design. Data from patients assigned to the preferred dose of CoQ10 in the first stage are also used in the second stage. The primary outcome measure is the decline in Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRSr) score from baseline to 9 months. RESULTS: The total sample size required is 185 patients, as compared to a much larger sample size estimated to be necessary using a conventional superiority design (total: 852 patients). The authors report a bias correction made necessary by the inclusion of patient data from the first stage in the second stage. CONCLUSIONS: Several features of the Clinical Trial of High Dose Coenzyme Q10 in ALS study design promote efficiency. These features may be beneficial in phase II trials in amyotrophic lateral sclerosis and other fields.

Adult↗
PubMed1983

Confirmatory and exploratory analysis applied to pharmaco-EEG and related study data: contradiction or useful enrichment?

Besides hypothesis testing, which should be done as sparingly as possible, the measured or observed data should be described as extensively as possible. The traditional reliance on profiles of the mean responses may neglect useful information, and such profiles may also be misleading. With the aid of exploratory data analysis, different aspects of the structure of a data set can be considered. 'Data snooping' may discover coherences, non-trivial structures and peculiarities, which lead to a new hypothesis or to new mathematical-statistical models. It is, in our opinion, a necessity to consider exploratory and confirmatory data analyses in conjunction. This will be illustrated by examples taken from pharmaco-EEG studies.

Aged↗
PubMed2006

Estimation of bias between 2 analytical methods at clinically important ranges.

An approach for estimating bias between 2 analytical methods at different clinical ranges is introduced in this article. The approach models replicated data obtained from the reference and the test method in terms of repeatability and trueness bias. The latter can be partitioned into constant and proportional bias. The approach is based on maximum likelihood estimation and can accommodate normal as well as Poisson and binomial distributions that apply to hematology applications and/or other laboratory methods that count particles per unit of volume and/or time. A full spectrum of statistical inference in the form of confidence intervals for each estimate as well as any statistical hypothesis testing is provided. At the same time these estimates can be practically interpreted and related to any clinical important range or decision point. We recommend this approach as an alternative to the National Committee for Clinical Laboratory Standards (NCCLS) EP9-A2 approach in cases where the application of the NCCLS standard is not appropriate.

Bias↗
PubMed1999

Sample size considerations for superiority trials in systemic lupus erythematosus (SLE).

For reasons of efficiency and ethics, sample size calculations are an important part of the design of all clinical trials. This paper highlights the statistical issues inherent to the estimation of sample size requirements in superiority trials particular to SLE. Calculations based on statistical power for testing hypotheses have historically been the method of choice for sample size determination in clinical trials. The advantages of using confidence intervals (CI's) rather than P-values in reporting results of clinical trials is now well established. Since the design of a trial should match the analysis that will eventually be performed, sample size methods based on ensuring accurate estimation of important parameters via sufficiently narrow CI widths should be preferred to methods based on hypothesis testing. Methods and examples are given for sample size calculations for continuous and dichotomous outcomes from both a power and confidence interval width viewpoint. An understanding of sample size calculations in association with expert statistical consultation will result in better designed clinical trials that accurately estimate clinically relevant differences between treatment outcomes, thereby furthering the treatment of patients with SLE.

Confidence Intervals↗
PubMed1992

Statistical aspects of bioequivalence--a review.

1. Over the past 20 years a number of statistical methods have been proposed for use in bioequivalence testing. This review examines these methods and reflects current thinking of regulatory authorities. 2. The standard bioequivalence study is conducted as a controlled, single-dose crossover design in a small number of healthy male adults. Blood and/or urine samples are taken at predetermined times for drug/metabolite assay from which pharmacokinetic parameters are derived and compared statistically. Sample size calculations should be determined by the error variance associated with the primary characteristic to be studied, the significance level, the power of the test and the deviation from the reference product compatible with safety and efficacy. 3. In general, bioequivalence is assessed using three parameters namely, Cmax, tmax and AUC. Urinary excretion data may also be used if the amount excreted unchanged is significant. These parameters are best obtained using a simple model-independent approach. 4. The parameters of Cmax and AUC should be logarithmically transformed prior to analysis. For tmax, parametric statistical procedures are not appropriate. 5. Classical hypothesis testing using the power approach is not applicable to the practical problem under consideration in bioequivalence trials. 6. Classical 90% confidence limits and the 2 one-sided t-test approach are operationally identical and are the methods of choice for assessing bioequivalence (Cmax and AUC). When tmax is an important parameter from the clinical point of view then the use of non-parametric confidence intervals is recommended.

Adult↗
PubMed2004

A sample size computation method for non-linear mixed effects models with applications to pharmacokinetics models.

We propose a simple method to compute sample size for an arbitrary test hypothesis in population pharmacokinetics (PK) studies analysed with non-linear mixed effects models. Sample size procedures exist for linear mixed effects model, and have been recently extended by Rochon using the generalized estimating equation of Liang and Zeger. Thus, full model based inference in sample size computation has been possible. The method we propose extends the approach using a first-order linearization of the non-linear mixed effects model and use of the Wald chi(2) test statistic. The proposed method is general. It allows an arbitrary non-linear model as well as arbitrary distribution of random effects characterizing both inter- and intra-individual variability of the mixed effects model. To illustrate possible uses of the method we present tables of minimum sample sizes, in particular, with an illustration of the effect of sampling design on sample size. We demonstrate how (D-)optimal or frequent sampling requires fewer subjects in comparison to a sparse sampling design. We also present results from Monte Carlo simulations showing that the computed sample size can produce the desired power. The proposed method greatly reduces computing times compared with simulation-based methods of estimating sample sizes for population PK studies.

Black People↗
PubMed2004

Levator ani thickness variations in symptomatic and asymptomatic women using magnetic resonance-based 3-dimensional color mapping.

OBJECTIVE: This study was undertaken to develop and test a 3-dimensional (3D) color thickness mapping technique on levator ani imaged with magnetic resonance imaging (MRI). METHODS: Supine MRI datasets from 30 women were studied: 10 asymptomatic, 10 with urodynamic stress incontinence, and 10 with pelvic organ prolapse. Levators were manually outlined, and thickness mapping applied. Three-dimensional models were colored topographically, reflecting levator thickness. Thickness and occurrences of absent levator substance (gaps) were compared across the 3 groups, using nonparametric statistical tests. RESULTS: Color thickness mapping was successful in all subjects. There were statistically significant differences in thickness and gap percentages among the 3 groups of women, with thicker, bulkier levators in asymptomatic women, compared with women with prolapse or urodynamic stress incontinence. CONCLUSION: Color thickness mapping is feasible. It may be used to compare levators in symptomatic and asymptomatic women, to study relationships between levator thickness and pelvic floor dysfunction. This technique can be used in larger studies for hypothesis testing.

Adult↗
PubMed1997

Differential ethanol sensitivity of subpopulations of GABAA synapses onto rat hippocampal CA1 pyramidal neurons.

The actions of ethanol on gamma-aminobutyric acid-A (GABAA) receptor-mediated synaptic transmission in rat hippocampal CA1 neurons remain controversial. Recent studies have reported that intoxicating concentrations of ethanol (10-100 mM) can potentiate, inhibit, or have no effect on GABAA receptor-mediated synaptic responses in this brain region. The essential determinants of ethanol sensitivity have not been defined; however, GABAA receptor subunit composition, as well as posttranslational modifications of these receptors, have been suggested as important factors in conferring ethanol sensitivity to the GABAA receptor complex. Multiple types of GABAA receptor-mediated synaptic responses have been described within individual hippocampal CA1 neurons. These responses have been shown to differ in some of their physiological and pharmacological properties. In the present study we tested hypothesis that some of the disparate findings concerning the effects of ethanol may have resulted from differences in the ethanol sensitivity of GABAA receptor-mediated synapses on single CA1 pyramidal cells. Electrical stimulation adjacent to the stratum pyramidale (proximal) and within the stratum lacunosum-moleculare (distal) activated nonoverlapping populations of GABAA receptors on rat hippocampal CA1 neurons. Proximal inhibitory postsynaptic currents (IPSCs) decayed with a single time constant and were significantly potentiated by ethanol at all concentrations tested (40, 80, and 160 mM). Distal IPSCs had slower decay rates that were often described better by the sum of two exponentials and were significantly less sensitive to ethanol at all concentrations tested. Three other allosteric modulators of GABAA receptor function with well-defined GABAA receptor subunit requirements, pentobarbital, flunitrazepam, and zolpidem, potentiated proximal and distal GABAA IPSCs to the same extent. These results demonstrate that the ethanol sensitivity of GABAA receptors can differ, not only between brain regions but within single neurons. These findings offer a possible explanation for the conflicting results of previous studies on ethanol modulation of GABAA receptor-mediated synaptic transmission in rat hippocampal CA1 neurons.

Animals↗
PubMed2003

Support, shape and number of replicate samples for tree foliage analysis.

Many fundamental features of a sampling program are determined by the heterogeneity of the object under study and the settings for the error (alpha), the power (beta), the effect size (ES), the number of replicate samples, and sample support, which is a feature that is often overlooked. The number of replicates, alpha, beta, ES, and sample support are interconnected. The effect of the sample support and its shape on the required number of replicate samples was investigated by means of a resampling method. The method was applied to a simulated distribution of Cd in the crown of a Salix fragilis L. tree. Increasing the dimensions of the sample support results in a decrease in the variance of the element concentration under study. Analysis of the variance is often the foundation of statistical tests, therefore, valid statistical testing requires the use of a fixed sample support during the experiment. This requirement might be difficult to meet in time-series analyses and long-term monitoring programs. Sample supports have their largest dimension in the direction with the largest heterogeneity, i.e. the direction representing the crown height, and this will give more accurate results than supports with other shapes. Taking the relationships between the sample support and the variance of the element concentrations in tree crowns into account provides guidelines for sampling efficiency in terms of precision and costs. In terms of time, the optimal support to test whether the average Cd concentration of the crown exceeds a threshold value is 0.405 m3 (alpha = 0.05, beta = 0.20, ES = 1.0 mg kg(-1) dry mass). The average weight of this support is 23 g dry mass, and 11 replicate samples need to be taken. It should be noted that in this case the optimal support applies to Cd under conditions similar to those of the simulation, but not necessarily all the examinations for this tree species, element, and hypothesis test.

Cadmium↗
PubMed2005

Microhardness and Ca:P ratio of carious and Carisolv treated caries-affected dentine using an ultra-micro-indentation system and energy dispersive analysis of x-rays--a pilot study.

BACKGROUND: This study aimed to evaluate microhardness and chemical analysis of carious and caries-affected dentine. The hypothesis tested was that calcium:phosphorous (Ca:P) ratios correlate with microhardness values. METHODS: Four carious human third molars were sectioned through the caries lesion in the mesiodistal longitudinal plane. One half of each lesion underwent carious dentine removal using Carisolv gel. The cut surfaces were polished, microhardness tested using an Ultra-Micro-Indentation System (UMIS) and elemental analysis performed using energy dispersive analysis of x-rays (EDAX). RESULTS: The microhardness of carious dentine decreased gradually towards the cavity floor, but that for caries-affected dentine showed more variation with depth, having a mean hardness of (0.63 +/- 0.18) GPa. Ca:P ratios of carious dentine varied among the four specimens. The mean Ca:P ratio of caries-affected dentine was 1:2.03 +/- 0.08. The hypothesis was accepted for active lesions. CONCLUSIONS: The use of Carisolv to excavate carious tissue can be as effective as rotary instrumentation.

Adult↗
PubMed1994

Cognitive appraisal of stress events: measuring the personal schema of childbirth.

The purpose of this study was to theoretically base, develop, and test items for the Childbirth Schema Scale. The scale was designed to obtain an understanding of schema formation and revision with the known stressor of childbirth. The psychometric properties of the instrument were assessed using a sample of childbearing women, surveyed before and after birth. A principal components analysis with varimax rotation resulted in a four-factor solution supporting the theoretical factors of emotions of outcome, sensations of work, time, and preparation for control. Construct validity was assessed by hypothesis testing that women whose prebirth schemas were least like their real experience would use more review than women whose schemas were closer. A significant t test between the two groups provided some evidence of validity. The factors were used to form subscales. Internal consistency scores for each subscale were .73, .70, .84, and .65, respectively.

Adult↗
PubMed2003

Ethnic/racial differences in psychiatric disorders: a test of four hypotheses.

OBJECTIVES: Ethnic/racial differences in the prevalence of psychiatric disorders have been reported in hospital studies conducted in the United States, but general population studies find little or no evidence of higher rates of disorder in Black communities than White communities. Thus, ethnic/racial differences in the prevalence of psychiatric disorders in treated samples may be due to biased estimates. Aside from sampling bias, 4 hypothetical models of ethnic/racial differences may account for such bias: sociocultural, self-selection, social selection, and clinician bias. The present article reviews and performs limited tests of these 4 models. DESIGN: Paranoia is considered a key symptom in biases associated with ethnic/racial differences in psychiatric disorders. Black, Latino, and White community and patient samples are compared, via secondary analysis of data from an epidemiologic study, in terms of their expression of a range of paranoid symptoms. PARTICIPANTS: The study sample consisted of 404 community residents, 96 patients with major depression, and 65 patients with nonorganic, nonaffective psychotic disorder (mainly DSM III schizophrenia). MAIN OUTCOME MEASURES: Hypothesis-testing involved 2 approaches: 1) standard significance tests of mean differences between groups; and 2) an analysis of the patterns of mean scores across the paranoia scales from the Psychiatric Epidemiology Research Interview by ethnic/racial group and diagnostic category. RESULTS: The results of this study favor the sociocultural explanation of bias associated with ethnic/racial differences in psychiatric disorders. CONCLUSION: To reduce disparities in ethnic/racial patterns of psychiatric hospitalizations, the biases associated with differences in the sociocultural backgrounds of providers and patients need to be addressed.

Adult↗
PubMed1996

Comparative study of visual and verbal short-term memory in English and Spanish speakers: testing a linguistic hypothesis.

It has been proposed that differences in digit span performance between English and Spanish speakers are due to the greater number of syllables per digit in the Spanish language. To test this hypothesis, we studied the performance of 30 English- and 30 Spanish-speaking elders on the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Span Subtest, a modified digit span test that was linguistically comparable for both languages, and the Corsi Block Test. Consistent with previous reports, we found that English speakers scored significantly higher than Spanish speakers on WAIS-R Digit Span Forward. Group differences were reduced on the modified Digit Span Forward, but remained significant. English and Spanish speakers scored comparably on Digit Span Backward (WAIS-R and modified) and Visual Span. We suggest that although differences in the number of syllables per digit string are in part responsible for the lower performance of Spanish speakers on Digit Span Forward, cultural and educational issues also contribute to the observed differences between English and Spanish speakers.

Adult↗
PubMed1997

Comparative sensitivity of human erythrocytes and lymphocytes to sonolysis by 1-MHz ultrasound.

Many studies of ultrasonic hemolysis have used erythrocytes; other blood cells are less well studied. The hypothesis tested was that human lymphocytes, being large and relatively fragile, are more sensitive to sonolysis than are erythrocytes at equivalent cell concentrations. Human lymphocytes (RPMI 1788) grown in vitro and erythrocytes obtained by venipuncture were used at a nominal cell concentration of 2.5 x 10(6) cells/mL. Cells were contained in rotated (200 rpm) exposure vessels and were exposed/sham-exposed to 1-MHz continuous-wave ultrasound for 60 s. Cell lysis was determined by hemacytometer counts of aliquots taken before/after treatment. The hypothesis was supported; the mean levels of lysis in insonated lymphocyte and erythrocyte preparations were 89.8% +/- 0.6% and 78.9% +/- 3.1%, respectively. This difference was significant at p < 0.005.

Cells, Cultured↗
PubMed1996

Morphological field emission-SEM study of the effect of six phosphoric acid etching agents on human dentin.

OBJECTIVES: This study evaluated the effects of six phosphoric acid-etching agents on dentin, the independent variables being two acid concentrations (10% and 32%-37%) and three thickener conditions (no thickener, silica, and polymer). The tested hypothesis was that the use of different etchants with similar concentrations of phosphoric acid would result in similar depths of dentin demineralization. METHODS: Thirty dentin disks were obtained from extracted human teeth by microtome sectioning. The dentin surfaces were etched with one of the etching agents, fixed, dehydrated and dried. The specimens were observed using a FE-SEM. The mean deepest demineralization of intertubular dentin was measured from fracture surfaces of the disks. These values were analyzed by ANOVA and Duncan's Test. The morphological appearance of the dentin surfaces was compared using the following observation criteria: 1) Presence of a cuff of peritubular dentin; 2) Relative thickness of the layer containing residual collagen or smear layer particles; and 3) Formation of a submicron hiatus at the bottom of the exposed collagen network. The pH of each of the etching agents was measured. A correlation analysis was made of the pH vs. the depth of dentin demineralization. RESULTS: Silica-thickened etchants did not demineralize dentin as deeply as did polymer-thickened etchants and unthickened etchants. High magnifications revealed three distinct zones within the demineralized dentin layer; an upper porous zone of residual smear layer or denatured collagen and residual silica particles (in groups etched with silica-thickened etchants), an intermediate area with randomly oriented collagen fibers, and a lower zone with submicron hiatus, few collagen fibers, and scattered hydroxyapatite inclusions. This hiatus was observable in all the specimens etched with the polymer-thickened etchants, in 90% of the specimens etched with the unthickened phosphoric acid liquids, and in 60% of the specimens etched with the silica-thickened gels. SIGNIFICANCE: The results obtained suggest that similar concentrations of phosphoric acid etchants containing distinct thickeners result in different demineralization depths as well as different morphology of etched dentin.

Acid Etching, Dental↗
PubMed2006

[Fat tissue distribution and metabolic alterations in boys with primary hypertension].

UNLABELLED: Metabolic alterations related to obesity are regarded as significant risk factor for target organ damage in hypertensive patients. Fat tissue distribution seems to play significant role in metabolic alterations related to cardiovascular damage. The aim of the study was to test hypothesis that fat tissue distribution and excess of visceral fat is related to cardiovascular damage and metabolic cardiovascular risk factors in obese boys with yet untreated, primary hypertension. PATIENTS: 40 boys (14.8 +/- 3.0 yrs) with untreated essential hypertensions. METHODS: amount of visceral (VAT), intraperitoneal visceral (ipVAT), extraperitoneal visceral (epVAT) and subcutaneous fat (SAT) was measured by nuclear magnetic imaging (NMR). Carotic intima media thickness (cIMT), fenoral intima media thickness (fIMT) and left ventricular mass index (LVMi) were evaluated by sonography. Oral glucose loading test was done, lipids, homocysteine, CRP, uric acid, microalbuminuria, adipocytokines, IGF-1 and IGF binding proteins (IGFBP) were determined. RESULTS: The ratio of VAT to epVAT (V/Ve) correlated with carotid IMT (p=0.0001; r=0.561), standard deviation from median of the norm of cIMT (cIMT-SDS) (p=0.0001; r=0.681), femoral IMT (p=0.015; r=0.480) and fIMT-SDS (p=0.002; r=0.579). SAT correlated negatively with cIMT (p=0.0016; r=-0.355) and cIMT-SDS (p=0.01; r=-0.391). Waist to hip ratio (WHR) correlated with cIMT-SDS (p=0.03; r=0.401). VAT correlated positively and SAT negatively with HDL, apoA1, uric acid concentration and HOMA-IR value. VAT/epVAT correlated with HOMA-IR (p=0.02; r=0.402), free IGF-1 (p=0.001; r=0.478). epVAT also correlated with free IGF-1 (p=0.006; r=-0.494) and IGFBP3 (p=0.02; r=-0.471). Step-wise regression analysis revealed that relative excess of intraperitoneal visceral fat (VAT/epVAT) and WHR were independent predictors of cIMT-SDS(p=0.022, R2=0.755). CONCLUSIONS: Fat tissue distribution correlates with early vascular injury and metabolic alterations in boys with primary hypertension. Relative excess of visceral fat assessed by NMR and truncal obesity expressed as WHR are independent risk factors for early vascular damage in overweight boys with primary hypertension.

Adolescent↗
PubMed2005

The bootstrap: a technique for data-driven statistics. Using computer-intensive analyses to explore experimental data.

BACKGROUND: The concept of resampling data--more commonly referred to as bootstrapping--has been in use for more than three decades. Bootstrapping has considerable theoretical advantages when it is applied to non-Gaussian data. Most of the published literature is concerned with the mathematical aspects of the bootstrap but increasingly this technique is being utilized in medical and other fields. METHODS: I reviewed the published literature following a 1994 publication assessing the transfer of technology, including the bootstrap, to the biomedical literature. RESULTS: In the ten-year period following that 1994 paper there were 1679 published references to the technique in Medline. In that same time period the following citations were found in the four major medical journals-British Medical Journal (48), JAMA (51), Lancet (52) and the New England Journal of Medicine (45). CONTENT: I introduce the basic theory of the bootstrap, the jackknife, and permutation tests. The bootstrap is used to estimate the accuracy of an estimator such as the standard error, a confidence interval, or the bias of an estimator. The technique may be useful for analysing smallish expensive-to-collect data sets where prior information is sparse, distributional assumptions are unclear, and where further data may be difficult to acquire. Some of the elementary uses of bootstrapping are illustrated by considering the calculation of confidence intervals such as for reference ranges or for experimental data findings, hypothesis testing such as comparing experimental findings, linear regression, and correlation when studying association and prediction of variables, non-linear regression such as used in immunoassay techniques, and ROC curve processing. CONCLUSIONS: These techniques can supplement current nonparametric statistical methods and should be included, where appropriate, in the armamentarium of data processing methodologies.

Computers↗
PubMed2004

The effectiveness of neurofeedback and stimulant drugs in treating AD/HD: part II. Replication.

This study replicated T. R. Rossiter and T. J. La Vaque (1995) with a larger sample, expanded age range, and improved statistical analysis. Thirty-one ADIHD patients who chose stimulant drug (MED) treatment were matched with 31 patients who chose a neurofeedback (EEG) treatment program. EEG patients received either office (n = 14) or home (n = 17) neurofeedback. Stimulants for MED patients were titrated using the Test of Variables of Attention (TOVA). EEG (effect size [ES] = 1.01-1.71) and MED (ES = 0.80-1.80) groups showed statistically and clinically significant improvement on TOVA measures of attention, impulse control, processing speed, and variability in attention. The EEG group demonstrated statistically and clinically significant improvement on behavioral measures (Behavior Assessment System for Children, ES = 1.16-1.78, and Brown Attention Deficit Disorder Scales, ES = 1.59). TOVA gain scores for the EEG and MED groups were not significantly different. More importantly, confidence interval and nonequivalence null hypothesis testing confirmed that the neurofeedback program produced patient outcomes equivalent to those obtained with stimulant drugs. An effectiveness research design places some limitations on the conclusions that can be drawn.

Adolescent↗