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PubMed2002

The use of the Box-Behnken experimental design in the optimisation and robustness testing of a capillary electrophoresis method for the analysis of ethambutol hydrochloride in a pharmaceutical formulation.

Box-Behnken experimental designs do not appear to be extensively used in optimisation of analytical methods using capillary electrophoresis (CE). This paper describes the use of the Box-Behnken experimental design to optimise the factors affecting the separation of ethambutol hydrochloride (EB), its impurity 2-amino-1-butanol and the internal standard (phenylephrine hydrochloride) in a CE method for a pharmaceutical tablet assay. The three factors studied simultaneously were: buffer pH, buffer concentration and applied electric field, each at three levels. The method was optimised with respect to three responses: resolution between peaks, theoretical plate count and the migration time of the EB peak. A statistical programme, which applies a multiple response optimisation algorithm, was used to calculate and optimise the three responses simultaneously. The optimum conditions were established to be 58.0 mM sodium borate buffer at pH 9.50 and an applied electric field of 412 V/cm. The robustness of the method was also determined and confirmed using a second Box-Behnken design, as part of the validation exercise. System suitability values for the method were derived from the regression surface analysis. The CE method for a pharmaceutical tablet formulation was further validated according to current regulatory requirements, with respect to linearity and range, precision, specificity, accuracy and limit of quantitation. The optimised method gives a fast and efficient separation under 4 min, with complete resolution between the three peaks, and represents an improvement over the existing USP method. It can be concluded that the Box-Behnken experimental design provides a suitable means of optimising and testing the robustness of a CE pharmaceutical method.

Amino Alcohols↗

PubMed1998

Phylogenetic information and experimental design in molecular systematics.

Despite the widespread perception that evolutionary inference from molecular sequences is a statistical problem, there has been very little attention paid to questions of experimental design. Previous consideration of this topic has led to little more than an empirical folklore regarding the choice of suitable genes for analysis, and to dispute over the best choice of taxa for inclusion in data sets. I introduce what I believe are new methods that permit the quantification of phylogenetic information in a sequence alignment. The methods use likelihood calculations based on Markov-process models of nucleotide substitution allied with phylogenetic trees, and allow a general approach to optimal experimental design. Two examples are given, illustrating realistic problems in experimental design in molecular phylogenetics and suggesting more general conclusions about the choice of genomic regions, sequence lengths and taxa for evolutionary studies.

Animals↗

PubMed2001

Experimental design for gene expression microarrays.

We examine experimental design issues arising with gene expression microarray technology. Microarray experiments have multiple sources of variation, and experimental plans should ensure that effects of interest are not confounded with ancillary effects. A commonly used design is shown to violate this principle and to be generally inefficient. We explore the connection between microarray designs and classical block design and use a family of ANOVA models as a guide to choosing a design. We combine principles of good design and A-optimality to give a general set of recommendations for design with microarrays. These recommendations are illustrated in detail for one kind of experimental objective, where we also give the results of a computer search for good designs.

Journal Article↗

PubMed2005

BrainMap taxonomy of experimental design: description and evaluation.

Coordinate-based, voxel-wise meta-analysis is an exciting recent addition to the human functional brain mapping literature. In view of the critical importance of selection criteria for any valid meta-analysis, a taxonomy of experimental design should be an important tool for aiding in the design of rigorous meta-analyses. The coding scheme of experimental designs developed for and implemented within the BrainMap database provides a candidate taxonomy. In this study, the BrainMap experimental-design taxonomy is described and evaluated by comparing taxonomy fields to data-filtering choices made by subject-matter experts carrying out meta-analyses of the functional imaging literature. Fifteen publications reporting a total of 46 voxel-wise meta-analyses were included in this assessment. Collectively these 46 meta-analyses pooled data from 351 publications, selected for experimental similarity within each meta-analysis. Filter implementations within BrainMap were graded by ease-of-use (A-C) and by stage-of-use (1-3). Quality filters and content filters were tabulated separately. Quality filters required for data entry into BrainMap were classed as mandatory (five filters), being above the use grading system. All authors spontaneously adopted the five mandatory filters in constructing their meta-analysis, indicating excellent agreement on data quality among authors and between authors and the BrainMap development team. Two non-mandatory quality filters (group size and imaging modality) were applied by all authors; both were Stage 1, Grade A filters. Field-of-view filters were the least-accessible quality filters (Stage 3, Grade C); two field-of-view filters were applied by six and four authors, respectively. Authors made a total of 115 content-filter choices. Of these, 78 (68%) were Stage 1, Grade A filters; 16 (14%) were Stage 2, Grade A; and 21 (18%) were Stage 2, Grade C. No author-applied filter was absent from the taxonomy.

Brain Mapping↗

PubMed1987

Evaluating health promotion: a longitudinal quasi-experimental design.

A quasi-experimental research design is used to evaluate Carolina Healthstyle, a health promotion project for South Carolina state employees. A 10% stratified random sample of employees was surveyed in the Spring of 1983 and again in 1984. Eighteen agencies were intervention agencies and the rest comparison that year. This article reports changes with simple before-after comparisons in the intervention agencies and matched pair analysis and randomized block designs to compare intervention and comparison agencies. Results are reported for smoking, exercise safety, nutrition, stress, and alcohol. Significant increases in exercise were found in both intervention and comparison agencies. The number of smokers decreased in intervention from 30%-26% with no change in comparison agencies. Safety practices changed at similar rates in both intervention and comparison groups. Consumption of chicken increased significantly only in the intervention agencies. Few other diet or stress changes were found. There were changes in alcohol consumption in intervention agencies only. The presence of the comparison group helps to separate the program effects from secular trends.

Adolescent↗

PubMed1996

Inhalation experiments with mixtures of hydrocarbons. Experimental design, statistics and interpretation of kinetics and possible interactions.

The paper describes experimental and statistical methods for toxicokinetic evaluation of mixtures in inhalation experiments. Synthetic mixtures of three C9 n-paraffinic, naphthenic and aromatic hydrocarbons (n-nonane, trimethylcyclohexane and trimethylbenzene, respectively) were studied in the rat after inhalation for 12h. The hydrocarbons were mixed according to principles for statistical experimental design using mixture design at four vapour levels (75, 150, 300 and 450 ppm) to support an empirical model with linear, interaction and quadratic terms (Taylor polynome). Immediately after exposure, concentrations of hydrocarbons were measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat. Multivariate data analysis and modelling were performed with PLS (projections to latent structures). The best models were obtained after removing all interaction terms, suggesting that there were no interactions between the hydrocarbons with respect to absorption and distribution. Uptake of paraffins and particularly aromatics is best described by quadratic models, whereas the uptake of the naphthenic hydrocarbons is nearly linear. All models are good, with high correlation (r2) and prediction properties (Q2), the latter after cross validation. The concentrations of aromates in blood were high compared to the other hydrocarbons. At concentrations below 250 ppm, the naphthene reached higher concentrations in the brain compared to the paraffin and the aromate. Statistical experimental design, multivariate data analysis and modelling have proved useful for the evaluation of synthetic mixtures. The principles may also be used in the design of liquid mixtures, which may be evaporated partially or completely.

Adipose Tissue↗

PubMed2003

[A review of experimental designs of compound compatibility law of traditional Chinese medicine].

The paper discussed a variety of experimental designs of compound compatibility law of traditional Chinese medicine (TCM): study of whole formula and different ingredients of formula. The latter includes study of single ingredient, study of functional ingredient group, orthogonal design, clustering analysis, homogeneous design, factorial analysis and so on. It was proposed that experimental designs of formula should be based on the theory of TCM, and combined with modern sciences.

China↗

PubMed1985

Experimental design of bioassays for screening and low dose extrapolation.

Relatively high doses of chemicals generally are employed in animal bioassays to detect potential carcinogens with relatively small numbers of animals. The problem investigated here is the development of experimental designs which are effective for high to low dose extrapolation for tumor incidence as well as for screening (detecting) carcinogens. Several experimental designs are compared over a wide range of different dose response curves. Linear extrapolation is used below the experimental data range to establish an upper bound on carcinogenic risk at low doses. The goal is to find experimental designs which minimize the upper bound on low dose risk estimates (i.e., maximize the allowable dose for a given level of risk). The maximum tolerated dose (MTD) is employed for screening purposes. Among the designs investigated, experiments with doses at the MTD, 1/2 MTD, 1/4 MTD, and controls generally provide relatively good data for low dose extrapolation with relatively good power for detecting carcinogens. For this design, equal numbers of animals per dose level perform as well as unequal allocations.

Animals↗

PubMed2004

A new experimental design for screening Chinese medicine formula.

In this paper, an appropriate scale screening for traditional Chinese medicine formula was developed in according to verified pharmacological experiments with uniform optimized experimental design and orthogonal optimized experimental design. Meanwhile, a most appropriate match of prescription dosage for curing vascular disease was got, which was based on NO value of pharmacodynamics experimental data and the endothelial cells configuration which would changed in a degree when damaged by hydration diamine. The appropriate scale of the formula was Ginkgo extraction: substance A:B:C = 100:20:50:0.01. This formula was more optimized and effective than other formula compared by pharmacological and validated experiments.

Cells, Cultured↗

PubMed1997

Literature review and analysis of biological complexity in model stream ecosystems: influence of size and experimental design.

A meta-analysis of more than 150 model stream ecosystem studies employed in hazard assessment was conducted to assess the effect of model ecosystem size on biological complexity and experimental design. Test system length was highly correlated to duration of colonization and chemical exposure period; however, size was generally unrelated to taxa richness, diversity, abundance, or biomass for algal, protozoan, and invertebrate assemblages. Fish were usually caged and not free-roaming, even in the relatively large (> 10 m) systems. Experimental designs, especially in recent years, have been less concerned with pseudoreplication, resulting in studies emphasizing numerous treatments with few or no replicates. Test systems have evolved that emphasize flow through exposures, use of natural source waters, and regression-style experimental designs. These factors collectively reduce problems historically associated with pseudoreplication. Larger model ecosystems (> 6 m) are advantageous for increasing the ability to sample more intensively through time and space without imposing sampling artifacts. Fish (caged and free-roaming) are also more often used in larger systems. Several model ecosystem studies that were compared with natural field-based communities demonstrated a high degree of correspondence for biological complexity attributes. Well-designed model stream ecosystems have a high degree of biological complexity and reasonable levels of variability for ecologically relevant endpoints. The use of small application factors (approximately equal to 1) is applicable to ecotoxicological results from these studies for risk assessment.

Animals↗

PubMedDate not supplied

Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models.

Considerable effort has been placed into the identification of new antineoplastic agents to treat breast cancer and other malignant diseases. The basic approaches, in terms of model selection, endpoints, and data analysis, have changed in the previous few decades. This article deals with many of the issues associated with designing in vivo studies to investigate the activity of experimental and established compounds and their potential interactions. Endpoints for both in situ and excision assays are described, including approaches for determining cell kill, tumor growth delay, survival, and other estimates of activity. Suggestions for approaches that may limit the number of animals also are included, as are possible alternatives for death as an experimental endpoint. Other concerns, such routes for drug administration, drug dosage, and preliminary assessments of toxicity also are addressed. Statistical considerations are only briefly discussed, since these are addressed in detail in the accompanying article by Hanfelt (Hanfelt JJ, Breast Cancer Res Treat 46:279-302, 1997). The approaches suggested within this article are presented to draw attention to many of the key issues in experimental design and are not intended to exclude other approaches.

Animals↗

PubMed1996

Application of experimental design techniques to optimize a competitive ELISA.

This paper describes the application of experimental design techniques to optimize a sensitive ELISA for a hapten molecule with a calibration range of 0-1000 pg/ml. Ten factors that were expected to affect the assay performance were initially screened, followed by factorial experiments to delineate the effects of the critical factors identified at the screening stage. Assay performance was evaluated using a unique rating system based on standard curve reproducibility, assay detection limits and the use of desirability functions. This rating system allowed multiple responses to be evaluated simultaneously. It was found that the substrate incubation time and enzyme label lot played an important role, while dilutions of the enzyme label and the anti-hapten antibody showed significant interaction. These observations were in good agreement with optimal assay conditions based on historical data collected over a period of two to three years. Application of experimental design techniques enabled us to confirm the significance of the factors affecting the assay within a three month period, with a minimum number of experiments. In addition, information on interaction between factors were determined.

Animals↗

PubMed1990

A knowledge-based experimental design system for nucleic acid engineering.

Presented in this paper is a knowledge-based experimental design system that incorporates the domain expertise used in nucleic acid engineering, thus automating the processing of error-prone, laborious low-level work, and many decision-making steps, and guiding the biologist toward a workable plan. This allows the biologist to work at a higher abstraction level, concentrating on more fundamental, difficult and challenging problems directly related to protein structure - function relationships. Cassette-based site-directed mutagenesis and synthetic gene designs are used as examples to illustrate the utility of the knowledge-based system approach to experimental design.

Algorithms↗

PubMed2001

Investigation of pharmaceutical high-performance liquid chromatography assay bias using experimental design.

This article presents a systematic approach to investigate, document, and eliminate pharmaceutical HPLC assay bias using experimental design. This is the first article to describe the application of experimental design in the area of assay bias. It is found that both formulation and analytical variables can contribute to pharmaceutical HPLC assay bias using model compounds and formulations.

Chromatography, High Pressure Liquid↗

PubMed1989

A quasi-experimental design based on regional variations: discussion of a method for evaluating outcomes of medical practice.

A large proportion of common medical practices are subject to substantial regional variation resulting in numerous natural experiments. Opportunities are thereby provided for outcome evaluation through quasi-experimental design. If patients treated in different regions were comparable a natural experiment involving alternative treatments could be regarded as 'pseudo randomised', but empirical investigations are needed to verify this prerequisite. This paper discusses the role of quasi-experimental designs in assessment of medical care with evaluation of outcomes after hysterectomy in Denmark as an example. The design is developed and the comparability of selected groups of patients is elucidated from administrative data, while the outcome results are not presented in this context. One indication for hysterectomy is carcinoma in situ of the cervix uteri which may be treated with either hysterectomy, or conisation. A study group of patients was selected from departments where hysterectomy was the treatment of choice for this indication while the reference group was drawn from departments in which conisation was generally preferred. The comparability of the populations, effects and information for the two groups are elicited from administrative data. We conclude that it is possible to establish a quasi-experimental design based on regional variations and that the comparability of the groups included may be assessed through registry data. The importance of technology diffusion for the prospects of performing quasi randomised studies is emphasised. In this attempt to evaluate hysterectomy, it was not possible to identify groups of patients, which were sufficiently comparable to justify a study of soft outcomes.

Adult↗

PubMed1999

Usefulness of statistic experimental designs in enzymology: example with recombinant hCYP3A4 and 1A2.

First, the effects of 10 incubation factors were screened altogether on nifedipine dehydrogenase (NIF) and methoxyresorufin O-deethylase (MROD) activities catalyzed by recombinant human CYP3A4 and 1A2, respectively. Using a statistic experimental design, only 36 assays were needed to be exhaustive. Eight factors influenced CYP3A4-mediated NIF activity: buffer type, pH, temperature, Mg/EDTA, cytochrome b5, NADPH-P450 reductase, NADH, and solvent. Two factors had no significant effect: total ionic concentration and catalase/reduced glutathione. Six factors influenced CYP1A2-mediated MROD rates: buffer type, pH, temperature, Mg/EDTA, NADH, and glycerol. Four factors had no significant effect: total ionic concentration, cytochrome b5, reductase, and NAD+. Secondly, the combined effects of ionic strength and Mg concentration on NIF/CYP3A4 were studied and easily modeled using another statistic experimental design. The effect of Mg was strong at a constant ionic strength of 100 mM and negligible at a constant ionic strength of 500 mM. Thirdly, the effects of influencing factors and their interactions on MROD/CYP1A2 were modeled after 40 assays using a third statistic experimental design. Later experiments confirmed the predictivity of the models and the efficiency of optimized conditions. This approach can be applied to other biochemistry areas.

Biometry↗

PubMed1994

Toxic responses to defined chemical mixtures: mathematical models and experimental designs.

The problem and relevance of assessing biological responses to chemical mixtures is presented with reference to the literature on this problem and its possible solutions. This review is intended for a general audience as an introduction to, and comment on, assessing the interactions of defined mixtures of xenobiotics. The focus is on experimental toxicology, however, the methods are also applicable to pharmacology. Much of the literature on this topic is quite specialized in statistics, theory, or specific applications. This may deter a significant portion of the growing number of investigators in this field from using this literature, and may partially account for the persistent use of methods which have been shown to permit precarious conclusions. References are given for some of the most comprehensive and recent work and reviews on the subject. The reader is given some familiarity with this topic's basic problems and ideas, and the controversy on terminology. One example is presented of a popular experimental design and data analysis method which while applicable in some situations, has been shown to lead to precarious and even erroneous conclusions. Eight other methods of data analysis are briefly presented and some of their advantages, disadvantages, assumptions, and limitations are discussed. These methods were selected to illustrate similarities and differences in the various approaches taken in addressing this problem. Three basic types of experimental design appropriate to these kinds of studies are outlined. General considerations, suggested guidelines, and possible pitfalls in experimental design, and data analysis of biological responses to chemical mixtures are discussed.

Chemical Phenomena↗

PubMedDate not supplied

Optimal replication and the importance of experimental design for gel-based quantitative proteomics.

Quantitative proteomic studies, based on two-dimensional gel electrophoresis, are commonly used to find proteins that are differentially expressed between samples or groups of samples. These proteins are of interest as potential diagnostic or prognostic biomarkers, or as proteins associated with a trait. The complexity of proteomic data poses many challenges, so while experiments may reveal proteins that are differentially expressed, these are often not significant when subjected to rigorous statistical analysis. However, this can be addressed through appropriate experimental design. A good experimental design considers the impact of different sources of variation, both analytical and biological, on the statistical importance of the results. The design should address the number of samples that must be analyzed and the number of replicate gels per sample, in the context of a particular minimum difference that one is seeking to achieve. In this study, we explore the ways to improve the quality of protein expression data from 2-DE gels, and describe an approach for defining the number of samples required and the number of gels per sample. It has been developed for the simplest of situations, two groups of samples with variation at two levels: between samples and between gels. This approach will also be useful as a guide for more complex designs involving more than two groups of samples. We describe some Internet-accessible tools that can assist in the design of proteomic studies.

Algorithms↗