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PubMed2000

Fast development of separation methods for the chiral analysis of amino acid derivatives using capillary electrophoresis and experimental designs.

The use of experimental design in method development was studied for the chiral separation of several amino acid derivatives with capillary electrophoresis. The aim of this study was to define rapidly experimental conditions under which the enantiomers can be sufficiently separated for quantification and to derive a methodology for the separation of new compounds. Three modified cyclodextrins (CDs) were used as chiral selectors: hydroxypropyl-beta-cyclodextrin, carboxymethyl-beta-CD and sulfobutylether-beta-CD. The following factors were examined: the type of cyclodextrin, the CD concentration, the pH and the % of organic modifier (methanol) of the electrolyte. Two types of fractional factorial design were used depending on the type of analyte and on the number of factors selected: a 3(4-2) fractional factorial design (4 factors studied at 3 different levels) and a 2(3-1) fractional factorial design (3 factors at 2 different levels). From the 14 compounds investigated, 12 could be separated with one or another CD and not more than 9 experiments were required. No generalisation of the best analysis conditions was possible within this family of compounds. Specific analysis conditions must be defined for each analyte. Experimental designs have shown to be very useful to determine rapidly conditions under which each enantiomer can be separated with an acceptable resolution.

Amino Acids↗
PubMed2005

Empirical investigation of experimental design properties of discrete choice experiments in health care.

Experimental design is critical to valid inference from the results of discrete choice experiments (DCEs). In health economics, DCEs have placed limited emphasis on experimental design, typically employing relatively small fractional factorial designs, which allow only strictly linear additive utility functions to be estimated. The extensive literature on optimal experimental design outside health economics has proposed potentially desirable design properties, such as orthogonality, utility balance and level balance. However, there are trade-offs between these properties and emphasis on some properties may increase the random variability in responses, potentially biasing parameter estimates.This study investigates empirically the design properties of DCEs, in particular, the optimal method of combining alternatives in the choice set. The study involves a forced choice between two alternatives (treatment and non-treatment for a hypothetical health care condition), each with three, four-level, alternative-specific attributes. Three experimental design approaches are investigated: a standard six-attribute, orthogonal main effects design; a design that combines alternatives to achieve utility balance, ensuring no alternatives are dominated; and a design that combines alternatives randomly. The different experimental designs did not impact on the underlying parameter estimates, but imposing utility balance increases the random variability of responses.

Adolescent↗
PubMedDate not supplied

Single-case experimental designs. 1: Using idiographic research.

The single-case experimental design is an example of idiographic research which involves establishing causality. The reasons for using idiographic research in nursing are discussed and important differences between nomothetic and idiographic designs are highlighted in this article. Single-case experimental designs are recommended in situations where both true experimental and quasi-experimental designs are difficult or impossible to use for practical or ethical reasons. Single-case experimental designs are ideal for nursing care situations because they study individual cases, making it possible to give individualized nursing care while simultaneously studying the outcomes of specific patients.

Humans↗
PubMed2002

Experimental design issues for the early detection of disease: novel designs.

This paper investigates two experimental designs which have been used to evaluate the benefit of the early detection of breast cancer. They have some advantages over a classical design (the screening program versus usual medical care) in that subjects in a control group may benefit by participating in the study. We refer to the two experimental designs as the up-front (UFD) and close-out (COD) designs. The UFD consists of offering an initial exam to all participants. Then they can be randomized to a usual care group or a screening group receiving one or more special examinations. If the outcome of the initial examination is included in the analysis, then the study can answer the question of the benefit of an additional screening program after an initial examination. If the analysis excludes all the cases diagnosed at the initial examination, then the analysis evaluates the benefit of a screening program after elimination of the prevalent cases. These prevalent cases are most likely to be affected by length bias sampling and consequently will tend to have less aggressive disease and live longer. As a result, the UFD can answer two scientific questions. The COD consists of randomizing subjects to a usual care group and a screened group. However, the usual care group receives an examination which coincides at the time of the last exam in the study group. In this paper the power of these two designs have been evaluated. In both cases the power is severely reduced compared to the usual control group receiving no special exams. The power is a function of the sensitivity of the exam, the number and spacings of the exams given to the screened group as well as the sample size, disease incidence of the population and the survival distribution. The theoretical results on power are applied to the Canadian National Breast Cancer Study (ages 40-49) which used an UFD and the Stockholm Mammography Breast Cancer Screening Trial which utilized a COD.

Journal Article↗
PubMed1985

Multiple-objective criteria for optimal experimental design: application to ferrokinetics.

Optimal experimental design is used to predict the experimental conditions that will allow the "best" estimates of model parameters. A variety of criteria must be considered before an optimal design is chosen. Maximizing the determinant of the information matrix (D optimality), which tends to produce the most precise simultaneous estimates of all parameters, is commonly considered as the primary criterion. To complement this criterion, we present another whose effect is to reduce the interaction among the parameter estimates so that changes in any one parameter can be more distinct. This new criterion consists of maximizing the determinant of an appropriately scaled information matrix (M optimality). These criteria are applied jointly in a multiple-objective function. To illustrate the use of these concepts, we develop an optimal experimental design of blood sampling schedules using a detailed ferrokinetic model.

Humans↗
PubMed1990

DESIGN: computerized optimization of experimental design for estimating Kd and Bmax in ligand binding experiments. II. Simultaneous analysis of homologous and heterologous competition curves and analysis blocking and of "multiligand" dose-response surfaces.

We have developed a computer program, DESIGN, for optimization of ligand binding experiments to minimize the "average" uncertainty in all unknown parameters. An earlier report [G. E. Rovati, D. Rodbard, and P. J. Munson (1988) Anal. Biochem. 174, 636-649] described the application of this program to experiments involving a single homologous or heterologous dose-response curve. We now present several advanced features of the program DESIGN, including simultaneous optimization of two or more binding competition curves optimization of a "multiligand" experiment. Multiligand designs are those which use combinations of two (or more) ligands in each reaction tube. Such designs are an important and natural extension of the popular method of "blocking experiments" where an additional ligand is used to suppress one or more classes of sites. Extending the idea of a dose-response curve, the most general multiligand design would result in a "dose-response surface". One can now optimize the design not only for a single binding curve, but also for families of curves and for binding surfaces. The examples presented in this report further demonstrate the power and utility of the program DESIGN and the nature of D-optimal designs in the context of more complex binding experiments. We illustrate D-optimal designs involving one radioligand and two unlabeled ligands; we consider one example of homogeneous and several examples of heterogeneous binding sites. Further, to demonstrate the virtues of the dose-response surface experiment, we have compared the optimal surface design to the equivalent design restricted to traditional dose-response curves. The use of DESIGN in conjunction with multiligand experiments can improve the efficiency of estimation of the binding parameters, potentially resulting in reduction of the number of observations needed to obtain a desired degree of precision in representative cases.

Binding Sites↗
PubMed1996

A new dietary model to study colorectal carcinogenesis: experimental design, food preparation, and experimental findings.

Experimental dietary studies of human colorectal carcinogenesis are usually based on the AIN-76A diet, which is dissimilar to human food in source, preparation, and content. The aims of this study were to examine the feasibility of preparing and feeding rats the diet of a specific human population at risk for colorectal neoplasia and to determine whether changes in the colonic morphology and metabolic contents would differ from those resulting from a standard rat diet. The mean daily food intake composition of a previously evaluated adenoma patient case-control study was used for the "human adenoma" (HA) experimental diet. Foods were prepared as for usual human consumption and processed by dehydration to the physical characteristics of an animal diet. Sixty-four female Sprague-Dawley rats were randomized and fed ad libitum the HA or the AIN-76A diet. Every eight weeks, eight rats from each group were sacrificed, and the colons and contents were examined. Analysis of the prepared food showed no significant deleterious changes; food intake and weight gain were similar in both groups. Compared with the controls, the colonic contents of rats fed the HA diet contained significantly less calcium, concentrations of neutral sterols, total lipids, and cholic and deoxycholic acids were increased, and there were no colonic histological changes other than significant epithelial hyperproliferation. This initial study demonstrated that the HA diet can be successfully processed for feeding to experimental animals and is acceptable and adequate for growth but induces significant metabolic and hyperproliferative changes in the rat colon. This dietary model may be useful for studies of human food, narrowing the gap between animal experimentation and human nutritional research.

Adenoma↗
PubMedDate not supplied

Experimental designs, statistics and interpretation.

The Working Group on Experimental Designs, Statistics and Interpretation considered the use of statistics in combination toxicology, the terminology used to describe the interaction(s) of chemicals, the use of efficient experimental designs to minimize animal use, the diverse interests and goals covered by combination toxicology and approaches useful for complex mixtures. The importance of the use of appropriate experimental designs and statistical methodology was recognized. Given the present lack of consensus on terminology and methodology, it is recommended that investigators provide in their publications the definition of additivity and the mathematical model being used.

Animal Testing Alternatives↗
PubMed1999

Medium optimization for spore production of coniothyrium minitans using statistically-based experimental designs

Statistically-based experimental designs were used to optimize a chemically defined solid medium for the spore production of Coniothyrium minitans. In the first optimization step the influence of starch, urea, phosphate, magnesium, calcium, thiamin and trace elements on spore production was evaluated using a fractional factorial design. Starch and trace elements influenced spore production positively while urea affected spore production negatively. The other components had no significant influence on spore production. In the second and third steps the concentrations of starch, urea and trace elements were further optimized using central composite designs and response surface analysis. This optimization strategy allowed the spore production to be increased by a factor 7 from 4 x 10(9) to almost 3 x 10(10) spores per Petri dish of 9 cm diameter. Copyright 1999 John Wiley & Sons, Inc.

Journal Article↗
PubMed1997

A trial-based experimental design for fMRI.

An experimental design for functional MRI (fMRI) is presented whose conceptual units of analysis are behavioral trials, in contrast to blocks of trials. This type of design is referred to as a trial-based (TB) fMRI design. It is explained how TB designs can afford the ability to: (1) randomize the presentation of behavioral trials and (2) utilize intertrial variance in uncontrolled behavioral measures to examine their functional correlates. A particular type of TB design that involves modeling trial-evoked fMRI responses with one or more shifted impulse response functions is described. This design is capable of discriminating functional changes occurring during temporally separated behavioral subcomponents within trials. An example of such a design is implemented and its statistical specificity, functional sensitivity, and functional specificity are tested.

Adult↗
PubMed2005

Optimisation of high performance liquid chromatography separation of neuroprotective peptides. Fractional experimental designs combined with artificial neural networks.

The study of experimental design conjunction with artificial neural networks for optimisation of isocratic ion-pair reverse phase HPLC separation of neuroprotective peptides is reported. Different types of experimental designs (full-factorial, fractional) were studied as suitable input and output data sources for ANN training and examined on mixtures of humanin derivatives. The independent input variables were: composition of mobile phase, including its pH, and column temperature. In case of a simple mixture of two peptides, the retention time of the most retentive component and resolution were used as the dependent variables (outputs). In case of a complex mixture with unknown number of components, number of peaks, sum of resolutions and retention time of ultimate peak were considered as output variables. Fractional factorial experimental design has been proved to produce sufficient input data for ANN approximation and thus further allowed decreasing the number of experiments necessary for optimisation. After the optimal separation conditions were found, fractions with peptides were collected and their analysis using off-line matrix assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF-MS) was performed.

Amino Acid Substitution↗
PubMed2005

Evaluation of experimental designs for two-color cDNA microarrays.

The major goal of two-color cDNA microarray experiments is to measure the relative gene expression level (i.e., relative amount of mRNA) of each gene between samples in studies of gene expression. More specifically, given an N-sample experiment, we need all N(N - 1)/2 relative expression levels of all sample pairs of each gene for identification of the differentially expressed genes and for clustering of gene expression patterns. However, the intensities observed from two-color cDNA microarray experiments do not simply represent the relative gene expression level. They are composed of signal (gene expression level), noise, and other factors. In discussions on the experimental design of two-color cDNA microarray experiments, little attention has been given to the fact that different combinations of test and control samples will produce microarray intensities data with varying intrinsic composition of factors. As a consequence, not all experimental designs for two-color cDNA microarray experiments are able to provide all possible relative gene expression levels. This phenomenon has never been addressed. To obtain all possible relative gene expression levels, a novel method for two-color cDNA microarray experimental design evaluation is necessary that will allow the making of an accurate choice. In this study, we propose a model-based approach to illustrate how the factor composition of microarray intensities changed with different experimental designs in two-color cDNA microarray experiments. By analyzing 12 experimental designs (including 5 general forms), we demonstrate that not all experimental designs are able to provide all possible relative gene expression levels due to the differences in factor composition. Our results indicate that whether an experimental design can provide all possible relative expression levels of all sample pairs for each gene should be the first criterion to be considered in an evaluation of experimental designs for two-color cDNA microarray experiments.

Animals↗
PubMed1996

A re-examination of the experimental design for nursing research.

This paper will present a case for the re-examination of the experimental design for contemporary nursing research. It is an attempt to re-dress the academic 'romance' with the new found orientation towards exploratory descriptive research. To make the case, there is a need to make explicit some of the erroneous assumptions regarding the philosophical origins of the experimental design. By ignoring the contribution of the experimental design, there is the risk of overlooking certain areas of potential nursing knowledge. This is particularly pertinent in the current political climate, where the need to provide cost-effective outcomes is reliant upon the principles of causality and certainty inherent in experimental designs.

Causality↗
PubMed2003

Multifactorial experimental design and the transitivity of ratios with spotted DNA microarrays.

BACKGROUND: Multifactorial experimental designs using DNA microarrays are becoming increasingly common, but the extent of the transitivity of cDNA microarray expression measurements across multiple samples has yet to be explored. RESULTS: A strong correlation between direct and transitive inference for significantly differentially expressed genes is demonstrated, using subsets of a dye-swap loop design. CONCLUSIONS: In experimental design, opportunities for transitive inference should be exploited, while always ensuring that comparisons of greatest interest comprise direct hybridizations.

Gene Expression Profiling↗
PubMed2003

Development of a multidose formulation for a humanized monoclonal antibody using experimental design techniques.

The purpose of this study was to identify optimal preservatives for a multidose formulation of a humanized monoclonal antibody using experimental design techniques. The effect of antimicrobial parenteral preservatives (benzyl alcohol, chlorobutanol, methylparaben, propylparaben, phenol, and m-cresol) on protein stability was assessed using size-exclusion chromatography, differential scanning calorimetry, right-angle light scattering, UV spectroscopy, and potency testing using a cell-based fluorescence-activated cell sorting method. A quick, cost-effective preservative screening test was designed. Combinations of preservatives were examined using an I-optimal experimental design. The protein was most stable in the presence of methylparaben and propylparaben, and was compatible with benzyl alcohol and chlorobutanol at low concentrations. Phenol and m-cresol were not compatible with the protein. The I-optimal experimental design indicated that as an individual preservative, benzyl alcohol was promising. The model also indicated several effective combinations of preservatives that satisfied the antimicrobial efficacy and physical stability constraints. The preservative screening test and the experimental design approach were effective in identifying optimal concentrations of antimicrobial preservatives for a multidose protein formulation; (1) benzyl alcohol, and (2) the combination of methylparaben and chlorobutanol were screened as potential candidates to satisfy the regulatory requirements of various preservative efficacy tests.

Anti-Infective Agents↗
PubMed2002

Experimental design and the relative sensitivity of BOLD and perfusion fMRI.

This paper compares the statistical power of BOLD and arterial spin labeling perfusion fMRI for a variety of experimental designs within and across subjects. Based on theory and simulations, we predict that perfusion data are composed of independent observations in time under the null hypothesis, in contrast to BOLD data, which possess marked autocorrelation. We also present a method (sinc subtraction) of generating perfusion data from its raw source signal that minimizes the presence of oxygen-sensitive signal changes and can be used with any experimental design. Empirically, we demonstrate the absence of autocorrelation in perfusion noise, examine the shape of the hemodynamic response function for BOLD and perfusion, and obtain a measure of signal to noise for each method. This information is then used to generate a model of relative sensitivity of the BOLD and perfusion methods for within-subject experimental designs of varying temporal frequency. It is determined that perfusion fMRI provides superior sensitivity for within-subject experimental designs that concentrate their power at or below approximately 0.009 Hz (corresponding to a "blocked" experimental design of 60-s epochs). Additionally, evidence is presented that across-subject hypothesis tests may be more sensitive when conducted using perfusion imaging, despite the better within-subject signal to noise obtained in some cases with BOLD.

Adult↗
PubMed1995

Application of chemometric experimental designs in capillary electrophoresis: a review.

Various chemometric experimental designs have been employed for the optimisation of capillary electrophoresis (CE) methods. Similar designs have been utilised in the assessment of the robustness of CE methods. The designs employed include central composites, fractional factorials, Plackett-Burman, simplex and overlapping-resolution mapping. Optimisation studies have largely concentrated on the use of these designs on selection of the optimal electrolyte composition. The robustness testing studies performed have involved the use of screening designs to identify the critical parameters affecting responses such as migration times and resolution. Further designs such as central composites have then been employed to set method limits following robustness studies. It is concluded that the use of experimental designs and statistical data evaluation in conjunction with personal computer-controlled CE autosamplers and instruments are of great benefit in the optimisation and robustness evaluation of CE methods.

Electrophoresis, Capillary↗