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PubMed1985

Experimental design considerations: a determinant of acute neonatal toxicity.

Few studies have investigated the potential developmental differences resulting from treating neonatal rat pups in either split-litter or whole-litter (nested) experimental designs. We directly compared rat pups dosed with triethyl lead (TEL) via both split-litter (representing all dosage groups within a single litter) and nested (all pups randomly assigned to a single litter receive the same dose) designs. The nested design was chosen to produce a uniform behavioral pattern across pups within each litter, whereas the split-litter design was chosen to promote pup competition and differential maternal care. On postpartum day 5, pups were administered either 12, 13, 14, or 15 mg/kg TEL, with each design represented by 12 litters. Although the LD50 values for the two designs were not significantly different, there were significantly more deaths in the 12 mg/kg dosage group within the split-litter design than in the nested design group. Preweaning survival times for split-litter dosed animals were also decreased. In addition, significant growth reduction (7-16%) was observed in the split-litter group, relative to the nested design animals during the preweaning period. These results suggest that neonatal toxicity is not independent from experimental design considerations, and that the factors of littermate competition and/or pup-induced maternal care deserve further study.

Animals↗
PubMed2005

Experimental design methodology for the preparation of carbonaceous sorbents from sewage sludge by chemical activation--application to air and water treatments.

The objective of this study is to optimize experimental conditions of sorbent preparation from sewage sludge using experimental design methodology. Series of carbonaceous sorbents have been prepared by chemical activation with sulfuric acid. The sorbents produced were characterized, and their properties (surface chemistry, porous and adsorptive properties) were analyzed as a function of the experimental conditions (impregnation ratio, activation temperature and time). Carbonaceous sorbents developed from sludge allow copper ion, phenol and dyes (Acid Red 18 and Basic Violet 4) to be removed from aqueous solution as well as VOC from gas phase. Indeed, according to experimental conditions, copper adsorption capacity varies from 77 to 83 mg g(-1), phenol adsorption capacity varies between 41 and 53 mg g(-1) and VOC adsorption capacities (acetone and toluene) range from 12 to 54 mg g(-1). Each response has been described by a second-order model that was found to be appropriate to predict most of the responses in every experimental region. The most influential factors on each experimental design response have been identified. Regions in which optimum values of each factor were achieved for preparation of activated carbons suitable for use in wastewater and gas treatments have been determined using response surfaces methodology. In order to have a high mass yield and to minimize the energetic cost of the process, the following optimal conditions, 1.5 g of H2SO4 g(-1) of sludge, 700 degrees C and 145 min are more appropriate for use of activated carbon from sludge in water and gas treatments.

Adsorption↗
PubMed1999

Rapid development of the enantiomeric separation of beta-blockers by capillary electrophoresis using an experimental design approach.

A rapid method for determining the separation conditions for chiral resolution of eleven beta-blocking drug substances by capillary electrophoresis is described, using an experimental design approach. An acidic phosphate-triethanolamine buffer and an uncoated fused-silica capillary were used for all experiments. Several modified cyclodextrins were applied as chiral selectors: sulfobutyl ether beta-cyclodextrin (SBE-beta CD), dimethyl beta-cyclodextrin (DM-beta CD), carboxymethyl beta-cyclodextrin (CM-beta CD), and hydroxypropyl beta-cyclodextrin (HP-beta CD). Two different fractional factorial experimental designs were applied: (1) a design examining four factors at three levels (3(4-2)) and (2) one examining three factors at two levels (2(3-1)). The factors studied were: type of cyclodextrin, cyclodextrin concentration, pH of the background electrolyte and percentage of organic modifier. Enough resolution for the separation of the enantiomers and even for their quantification was reached. The same scheme is proposed when a fast chiral separation method needs to be developed for other drug families.

Adrenergic beta-Antagonists↗
PubMed1996

Single-case experimental designs in medical education: an innovative research method.

This paper presents an argument for more extensive use of single-case experimental research designs in medical education research. Single-case experimental designs consist of a group of experimental techniques that are widely used in the social sciences but are just beginning to be utilized by medical researchers. The method emphasizes reliable observations of behavior, repeated measurements of outcome, and individualized tailoring of objectives for each subject; all of these occur within a system that allows an experimental analysis to be conducted. Single-case designs are particularly useful when only small numbers of participants are available for a relatively long period of time. Trends in medical education toward individualized instruction, adult-centered learning, and fine-grained analyses of medical skills and knowledge make this field especially amenable to single-case experimental designs. Issues of internal and external validity, generality, practicality, and ethics are discussed, and several typical designs are illustrated. While the emergence of qualitative research methods in medical education may prove useful, single-case designs can maintain experimental science's emphasis on methodologic rigor, while allowing the flexibility often needed to conduct research in applied settings.

Education, Medical↗
PubMed2000

Meal fatty acid uptake in human adipose tissue: technical and experimental design issues.

The adipose tissue uptake of dietary fat has been studied using fatty acid radiotracers incorporated into a meal, followed by adipose tissue biopsies. A number of experimental design issues, including the use of isotopic tracers to measure meal fatty acid oxidation and plasma appearance of tracer, as well as the heterogeneity of adipose tissue fatty acid uptake, have been addressed. We examined these questions in a study of 24 volunteers (12 men and 12 women) who consumed a meal containing [(3)H]triolein and [(14)C]triolein. Slight differences in the purity of [(3)H]triolein vs. [(14)C]triolein were found, which could affect the apparent adipose tissue uptake of meal fatty acids. The adipose tissue triglyceride specific activity from bilateral biopsy sites agreed well, implying that a unilateral biopsy is satisfactory for measuring tracer uptake. Meal fatty acid oxidation measured using [(3)H]triolein and [(14)C]triolein was well correlated (r = 0.79, P < 0.0001). The peak tracer appearance in plasma chylomicrons occurred 1 h after the ingestion of a second, unlabeled meal. Our findings have implications for the experimental design of future meal fatty acid tracer/adipose tissue biopsy studies.

Adipose Tissue↗
PubMed2002

Optimisation of carbomer viscous eye drops: an in vitro experimental design approach using rheological techniques.

The optimisation of the in vitro interaction between several poly(acrylic acid) derivatives (Carbopol 1342P NF, Carbopol 974P and Carbopol 980 NF) and mucin was performed by an analysis technique combining oscillatory shear rheology and experimental design in order to improve the formulation of carbomer viscous eye drops.First, standard oscillation procedures were used to characterise the polyacrylic acid and mucin dispersions, and to investigate the influence of several polymer-related factors (concentration, preparation, type of polymer used) on the rheological properties. Second, an experimental plan design was developed to investigate the effect of polymer-related factors on the mucoadhesive indexes (MAI(G') and MAI(G")) which were calculated using the viscoelastic data obtained from polymer/mucin, polymer/tearfluid and mucin/tearfluid mixtures. Optimal mucoadhesive interactions were determined based on the experimental design results. Finally, the optima were fully characterised rheologically to further verify the mucoadhesive capacity. The main conclusion is that the factor influencing most explicitly the mucoadhesive interaction of the viscous eye drop is the mucin concentration and neither the type of polyacrylic acid, nor its concentration.

Acrylates↗
PubMed1988

Pregnancy outcome associated with natural family planning (NFP): scientific basis and experimental design for an international cohort study.

Although natural family planning (NFP) is a form of contraception without ostensible maternal risks (other than pregnancy), potential fetal risks could exist if aging gametes are involved in inadvertent fertilization. In the following report, we first review animal studies firmly establishing that aging sperm and aging oocytes (delayed fertilization) cause chromosomal abnormalities in mammals and other species. We next review human studies associating decreased coital frequency with trisomy and studies of NFP populations that generally show no increased frequency of anomalous offspring or spontaneous abortions. Our rationale for initiating an international cohort study is presented, along with the experimental design selected. Preliminary findings indicate that the experimental design chosen will indeed provide information allowing NFP safety to be assessed definitively.

Aging↗
PubMed1988

Experimental design for the C3H/10T1/2 CL8 cell transformation assay.

The C3H/10T1/2 CL8(10T1/2) cell transformation assay has been used as an important in vitro tool for screening potential carcinogens. In this paper we describe an experimental design that increases the sensitivity and specificity of the assay. One half of the total dishes was allocated to the solvent control and the other half was equally subdivided into four treatment dose groups of low to high cytotoxic effects. The transformation frequency was calculated on the basis of the number of dishes with Type III foci. Each treatment group, as well as the pooled treatment groups, was compared to the solvent control using Fisher's exact test. The sensitivity of our design, as evaluated by power analyses, greatly exceeded that of a standard test design in which about 20 dishes are allocated to each of the control and treatment groups. Furthermore, our use of an expanded number of control and treatment dishes reduces the chance for both false positive and false negative responses. Our experimental design is illustrated with data from experiments in which the transforming potential of two drugs, dimenhydrinate and SC-32006, was examined.

Animals↗
PubMed1975

Oral nitroglycerin as a prophylactic antianginal drug: clinical, physiologic, and statistical evidence of efficacy based on a three-phase experimental design.

With the use of a three-phase experimental design, the efficacy of oral nitroglycerin has been evaluated in a total of 53 patients with documented angina pectoris due to coronary artery disease. The study were a double-blind, randomized, and cross-over comparison of controlled-release nitroglycerin (2.6 mg. tablets administered three times daily) and an indistinguishable placebo. Sixteen patients recorded anginal symptoms by the diary method over a 6 month trial of randomly sequenced 1 month periods of drug or placebo. In 15 patients, ST segments were monitored with a Holter dynamic electrocardiograph for periods of 10 to 12 hours under normal life style and evaluated by matching activities during periods of drug and placebo. In 22 patients, a multistage treadmill exercise test was conducted to an endpoint of anginal pain. The three phases of the investigation were run in succession; each phase was completed before the next one was begun. Oral nitroglycerin reduced the incidence and severity of anginal attacks by 47.2 and 49.4 per cent, respectively, and decreased the number of sublingual nitroglycerin tablets used by 51.1 per cent in comparison to placebo (p less than 0.001). Eleven of 16 patients (69 per cent) decreased their need for sublingual nitroglycerin by over 50 per cent. Based on a polynomial trend analysis over a period of 8 weeks, no tolerance to the therapeutic effects of the drug was found. With DCG monitoring, drug decreased the ST segment depression from 1.76 mm. on placebo to 1.12 mm, with a significant difference of 0.64 mm. (p less than 0.001). ST segment depression was decreased more than 0.5 mm. by drug in comparison to placebo in 10 of 15 patients (66 per cent). Larger depressions of the ST segment noted with placebo at heart rates greater than 80 beats per minute were prevented by administration of the drug. During treadmill exercise, drug delayed the onset of pain by 83 seconds (64 per cent) over placebo (p less than 0.001) and decreased the duration of pain by 70 seconds (49 per cent) in comparison to placebo (p less than 0.001). Drug did not affect heart rate or systolic blood pressure at rest or after exercise, as well as rate-pressure product for production of angina following exercise (p less than 0.05). There was no side effects reported caused by the drug. The data demonstrate that oral nitroglycerin, given as controlled-release tablets, was absorbed from the gastrointestinal tract in quantities sufficient to provide statistically significant clinical improvement of angina pectoris.

Activities of Daily Living↗
PubMedDate not supplied

Strong quasi-experimental designs for research on the effectiveness of rehabilitation.

Medical rehabilitation needs better understanding of the effectiveness of its treatments and of patient characteristics most responsive to alternative intervention strategies. The goal of this paper is to improve understanding of research design in medical rehabilitation. More specifically, it describes two potentially rigorous but infrequently used "quasi-experimental" research designs--the regression-discontinuity design and the multiple interrupted time-series design. These are contrasted with the strongest research design--the randomized experiment--and to weaker designs, such as the nonequivalent group designs. Pre-experimental research, including qualitative, descriptive, and predictive studies, should not be confused with experimental research designs. More frequent use of randomized experimental and strong quasi-experimental designs can provide knowledge that will augment the effectiveness of rehabilitation practice.

Humans↗
PubMed2003

Experimental design and sample size determination for testing synergism in drug combination studies based on uniform measures.

In anticancer drug development, the combined use of two drugs is an important strategy to achieve greater therapeutic success. Often combination studies are performed in animal (mostly mice) models before clinical trials are conducted. These experiments on mice are costly, especially with combination studies. However, experimental designs and sample size derivations for the joint action of drugs are not currently available except for a few cases where strong model assumptions are made. For example, Abdelbasit and Plackett proposed an optimal design assuming that the dose-response relationship follows some specified linear models. Tallarida et al. derived a design by fixing the mixture ratio and used a t-test to detect the simple similar action. The issue is that in reality we usually do not have enough information on the joint action of the two compounds before experiment and to understand their joint action is exactly our study goal. In this paper, we first propose a novel non-parametric model that does not impose such strong assumptions on the joint action. We then propose an experimental design for the joint action using uniform measure in this non-parametric model. This design is optimal in the sense that it reduces the variability in modelling synergy while allocating the doses to minimize the number of experimental units and to extract maximum information on the joint action of the compounds. Based on this design, we propose a robust F-test to detect departures from the simple similar action of two compounds and a method to determine sample sizes that are economically feasible. We illustrate the method with a study of the joint action of two new anticancer agents: temozolomide and irinotecan.

Animals↗
PubMed1991

Experimental design for drug development: a Bayesian approach.

The Bayesian approach to inference and decision making provides an integrated way of addressing the various aspects of drug development, from the early preclinical study of compounds through the clinical and postmarketing phases. In particular, it provides a natural, convenient way for choosing among experimental designs. An essential aspect of the process of evaluating design strategies is the ability to calculate predictive probabilities of potential results. I describe a Bayesian approach to experimental design and illustrate it by considering a particular type of clinical trial. Also, I compare Bayesian and classical statistical attitudes toward design.

Bayes Theorem↗
PubMed2005

Experimental design for functional MRI of scene memory encoding.

The use of functional imaging to identify encoding-related areas in the medial temporal lobe has previously been explored for presurgical evaluation in patients with temporal lobe epilepsy. Optimizing sensitivity in such paradigms is critical for the reliable detection of regions most closely engaged in memory encoding. A variety of experimental designs have been used to detect encoding-related activity, including blocked, sparse event-related, and rapid event-related designs. Although blocked designs are generally more sensitive than event-related designs, design and analysis advantages could potentially overcome this difference. In the present study, we directly contrast different experimental designs in terms of the intensity, extent, and lateralization of activation detected in healthy subjects. Our results suggest that although improved design augments the sensitivity of event-related designs, these benefits are not sufficient to overcome the sensitivity advantages of traditional blocked designs.

Adolescent↗
PubMed2000

Experimental design for fermentation media development: statistical design or global random search?

The diversity of combinatorial interactions of medium components with the metabolism of cells as well as the large number of medium constituents necessary for cellular growth and production do not permit satisfactory detailed modelling. For this reason, experimental search procedures in simultaneous shaking flask experiments are used to optimise fermentation media. As an alternative to the methods of statistical experimental design employed in this field for many decades, the use of stochastic search procedures has been evaluated recently, since these require neither the unimodality of the response surface nor limitations in the number of medium components under consideration. Genetic algorithms were selected due to their basic capability for efficient exploration of large variable spaces. Using a genetic algorithm, it has been experimentally verified, with the aid of process examples, that process improvements can be achieved both for microbial and enzymatic conversions and for cell cultures despite the large number of medium components under simultaneous consideration (about 10 or more). In exploring a new variable space, process improvements of more than 100% were generally achieved. For initial reaction conditions previously 'optimised' via standard procedures it has been possible in most cases to achieve a further improvement of 20-40% of the target quantity. Although the genetic algorithm can be very efficient for exploration of large variable spaces, it is improbable that a 'global optimum' can be precisely identified because of the relatively small number of shaking flask experiments usually performed. As a consequence, a combination of highly directed random searches to explore the n-dimensional variable space with the genetic algorithm and subsequent application of classical statistical experimental design is recommended for media development.

Journal Article↗
PubMed1995

Virtual kinetics: using statistical experimental design for rapid analysis of enzyme inhibitor mechanisms.

Modern automated drug-screening can generate hundreds of inhibitor leads from diverse chemical sources in a short period of time. Traditional methods of inhibitor analysis are resource intensive and limit the number of inhibitors that can be analyzed for their mechanism of inhibition. This paper presents methods we have developed for rapid estimation of both potency and mechanism of potential inhibitor leads for a biochemically complex screening target (protein kinase C) using commercially available computer programs for statistical experimental design. Our findings indicate that, with careful choice of factor levels, statistical experimental design clearly identifies the various interactions of the assay components with inhibitors. Suitably plotted, the data can be used to examine the competitive nature of the inhibitor and can provide estimates of IC50 and Michaelis constants useful for planning further kinetic work. The techniques used are amenable to automation and should be useful for identifying inhibitors that may have only marginal potency, but exhibit desirable mechanistic profiles suitable for structural analoging efforts.

Antifungal Agents↗
PubMed2002

WEXTOR: a Web-based tool for generating and visualizing experimental designs and procedures.

WEXTOR is a Javascript-based experiment generator and teaching tool on the World-Wide Web that can be used to design laboratory and Web experiments in guided step-by-step process. It dynamically creates the customized Web pages and Javascripts needed for the experimental procedure and provides experimenters with a print-ready visual display of their experimental design. WEXTOR flexibly supports complete and incomplete factorial designs with between-subjects, within-subjects, and quasi-experimental factors, as well as mixed designs. The software implements client-side response time measurement and contains a content wizard for creating interactive materials, as well as dependent measures (graphical scales, multiple-choice items, etc.), on the experiment pages. However, it does not aim to replace a full-fledged HTML editor. Several methodological features specifically needed in Web experimental design have been implemented in the Web-based tool and are described in this paper. WEXTOR is platform independent. The created Web pages can be uploaded to any type of Web server in which data may be recorded in logfiles or via a database. The current version of WEXTOR is freely available for educational and noncommercial purposes. Its Web address is http://www.genpsylab.unizh.ch/wextor/index.html.

Internet↗
PubMed1995

Measuring diversity: experimental design of combinatorial libraries for drug discovery.

Screening synthetic combinatorial libraries, such as mixtures of oligo(N-substituted)glycines, facilitates rapid drug lead discovery and optimization by vastly increasing the number of candidate molecules made and tested. Discovery efficiency and productivity can be further improved by using experimental design to maximize molecular diversity for a given library size or to bias the library with key features for a specific receptor. We describe new methods to quantify molecular diversity using descriptors that characterize lipophilicity, shape and branching, chemical functionality, and specific binding features. Experimental design methods select sets of side chains that are diverse in these properties, and "flower plots" allow the diversity to be graphically compared. We also quantify the overall diversity accessible to different families of combinatorial chemistry.

Drug Design↗
PubMed2003

Spherical coordinate representations of solvent composition for liquid chromatography method development using experimental design.

One of the major techniques used for the method development of ternary and quaternary high performance liquid chromatography (HPLC) systems has been to use mixture designs, often referred to as "Glajch's Triangle". This technique does not allow for the systematic and simultaneous optimization of other factors such as gradient time, pH and temperature that affect the quality of separations. An alternative approach is to use experimental designs. The condition, however, that the composition of all components of the mobile phase must total 100% presents a problem when trying to mathematically represent ranges of each mobile phase constituent of a ternary or quaternary system. A method is described here, based on spherical coordinate representations, that adheres to the constraints of the mobile phase composition and allows experimental designs, such as central composite and factorial designs, to be applied to the simultaneous optimization of the mobile phase composition. Other factors, in particular temperature and gradient time, can then be included in the design. As a result of applying these designs to the HPLC separation of phenols and corticosteroids, it was found necessary to include three-way interactions between experimental factors in the model. The significance of these interactions shows that they need to be considered in HPLC method development.

Adrenal Cortex Hormones↗