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PubMed1991

Quantifying lung structure. Experimental design and biologic variation in various models of lung injury.

The lung is a complex organ composed of a large number of different cell types of varying size and shape. Quantification of lung structure requires an understanding of how the distribution of specific cells and their characteristics affect the accuracy of measurement made on them and how to optimize experimental design for a morphometric study. We have studied lung structural modifications in a variety of lung injuries over the last decade. Extensive quantitative data from EM morphometric studies of pulmonary tissue have been collected. These data provide a unique opportunity to study the accuracy and efficiency of methods used to quantitate lung structure. We present and discuss novel computation-intensive methods for the estimation of biologic variability, sampling error, and measurement error. A new concept, unnested analysis of variance for stratified sampling and the use of computer-based methods for statistical analysis (the bootstrap method) and optimizing experimental design (nonlinear minimization procedure) are described in this report. Examples of experimental designs with their corresponding levels of accuracy and cost are also provided. The number of samples needed for a given level of precision is affected by the volume density of the structure being measured. The most important determinant for the overall accuracy of a morphometric study is the number of animals studied. Biologic variations between samples within an animal and among animals can vary significantly as a function of the model of injury studied.

Animals↗
PubMed2002

The application of analysis of variance (ANOVA) to different experimental designs in optometry.

Analysis of variance (ANOVA) is the most efficient method available for the analysis of experimental data. Analysis of variance is a method of considerable complexity and subtlety, with many different variations, each of which applies in a particular experimental context. Hence, it is possible to apply the wrong type of ANOVA to data and, therefore, to draw an erroneous conclusion from an experiment. This article reviews the types of ANOVA most likely to arise in clinical experiments in optometry including the one-way ANOVA ('fixed' and 'random effect' models), two-way ANOVA in randomised blocks, three-way ANOVA, and factorial experimental designs (including the varieties known as 'split-plot' and 'repeated measures'). For each ANOVA, the appropriate experimental design is described, a statistical model is formulated, and the advantages and limitations of each type of design discussed. In addition, the problems of non-conformity to the statistical model and determination of the number of replications are considered.

Analysis of Variance↗
PubMed1986

Flexibility of single-subject experimental designs. Part III: Using flexibility to design or modify experiments.

The purpose of this paper is to present clinical researchers with viable alternatives to basic, prototypical single-subject experimental designs. The availability of these alternatives is a product of the flexibility inherent in the application of these designs. Two general types of flexibility are discussed: a priori flexibility, as in combining designs in one study and ad hoc flexibility in which a design is modified during the course of a study. The flexibility afforded by the designs provides the opportunity to fashion individual experimental designs for specific research problems addressed. A review of the clinical research literature published during the last 10 years revealed that the flexibility of these designs has been underutilized. The benefits that can derive from using the potential flexibility of the designs are described, and specific suggestions are made for incorporating flexibility into clinical research.

Humans↗
PubMed2005

Application of model discriminating experimental design for modeling and development of a fermentative fed-batch L-valine production process.

A model discriminating experimental design approach for fed-batch processes has been developed and applied to the fermentative production of L-valine by a genetically modified Corynebacterium glutamicum strain possessing multiple auxotrophies as an example. Being faced with the typical situation of uncertain model information based on preliminary experiments, model discriminating design was successfully applied to improve discrimination between five competing models. Within the same modeling and experimental design framework, also the planning of an optimized production process with respect to the total volumetric productivity is shown. Simulation results were experimentally affirmed, yielding an increased total volumetric productivity of 6.2 mM L-valine per hour. However, also so far unknown metabolic mechanisms were observed in the optimized process, underlining the importance of process optimization during modeling to avoid problems of extreme extrapolation of model predictions during the final process optimization.

Biotechnology↗
PubMed2005

Box-Behnken experimental design in the development of a nasal drug delivery system of model drug hydroxyurea: characterization of viscosity, in vitro drug release, droplet size, and dynamic surface tension.

The purpose of the research was to investigate the changes in physicochemical properties and their influence on nasal formulation performance using 5-factor, 3-level Box-Behnken experimental design on the combined responses of viscosity, droplet size distribution (DSD), and drug release. Gel formulations of hydroxyurea (HU) with surface-active polymers (hydroxyethylcellulose [HEC] and polyethylene-oxide [PEO]) and ionic excipients (sodium chloride and calcium chloride) were prepared using Box-Behnken experimental design. The rheology and dynamic surface tension (DST) of the test formulations was investigated using LV-DV-III Brookfield rheometer and T60 SITA tensiometer, respectively. Droplet size analysis of nasal aerosols was determined by laser diffraction using the Malvern Spraytec with the InnovaSystems actuator. In vitro drug release studies were conducted on Franz diffusion cells. With PEO gel, calcium chloride increased the viscosity and DSD and retarded drug release, while sodium chloride decreased the viscosity, DST, and DSD and accelerated the release of HU. With HEC gel, the addition of the above salts resulted in less significant changes in viscosity, DSD, and DST, but both salts significantly increased the release of HU. Droplet size data obtained from a high viscosity nasal pump was dependent on type of polymer, polymer-excipient interactions, and solvent properties. The applications of Box-Behnken experimental design facilitated the prediction and identified major excipient influences on viscosity, DSD, and in vitro drug release.

Administration, Intranasal↗
PubMed2000

Experimental design and methods for school-based randomized trials. Experience from the Hutchinson Smoking Prevention Project (HSPP).

Nonadherence to accepted design principles for randomized trials has been a limitation of school-based intervention research. Designed to overcome these limitations, the Hutchinson Smoking Prevention Project (HSPP) is a 15-year randomized trial to determine the extent to which a school-based (grades 3-12) tobacco use prevention intervention can deter youth tobacco use throughout and beyond high school. This paper presents the HSPP experimental design, together with methods for its implementation, and an evaluation of the degree to which HSPP has adhered to principles of randomized trials. Results from the experimental design and its conduct include (1) a recruitment rate of 97.6% (40 of 41 targeted school districts), (2) full and active participation for the trial's duration by 100% of the 40 school districts recruited, (3) implementation by virtually all teachers (99%+), with 86% implementation fidelity, and (4) outcome determination for 94.3% (7910) of 8388 original study participants identified 12 years previously at baseline. The high degree of rigor achieved by the HSPP experimental design ensures confidence in the trial's soon-to-be available intervention effectiveness results. Equally important, for future school-based trials, the HSPP design and its execution have illustrated that school-based research can adhere to the principles of rigorous randomized trials, with high rates of implementation, and very high rates of recruitment, maintenance, and follow-up of study participants, even for studies with decade-long follow-up periods. Rigor in school-based trials can be achieved through a combination of (1) commitment to the principles of randomized trials, (2) attention to the special challenges of trials specific to the school setting, (3) adoption and meticulous execution of proven methods for trial conduct, and (4) establishment at the outset of principles for maintaining positive collaborative relationships with participating school districts for the duration of the trial. These findings are important in light of the great potential for using the nation's schools to access youth for health promotion/risk-factor prevention.

Adolescent↗
PubMed1985

The effects of visual feedback on hemispheric alpha asymmetries and reported processing strategies: a single-subject experimental design.

A double reversal single-subject experimental design was used to study the effects of visual feedback on the hemispheric alpha asymmetries of a male subject during a linguistic task. Results indicated that the subject demonstrated flexibility in hemispheric alpha and corresponding processing strategies employed when an alpha biofeedback procedure was used. These results provide further support for the notion that right and left hemispheric activation is associated with different, yet compatible, cognitive strategies and that both can be manipulated under conditions of feedback.

Adult↗
PubMedDate not supplied

Bioassay of a cigarette smoke fraction, II. Experimental design and potency estimations.

A series of experimental designs aimed at collecting and analyzing ciliostasis data in the most efficient and statistically valid manner was examined. The design that proved best for assessing water-soluble tobacco smoke samples in the hamster tracheal ring system utilized two dose levels of the University of Kentucky 1R1 reference cigarette (which functions as a reference as well as a continuing check on the dose-response relation in each experiment) plus several test tobacco smoke samples, each at a single dose level. A pair of animals formed the basis of a randomized block design, with one of the technician X sample preparation degrees of freedom confounded with animal differences within a pair. Assessment of the test samples can thus be expressed in terms of potency relative to the 1R1 reference. Control chart procedures were an essential facet of the system. Details of experiments and methods of data analysis are presented as examples of some of the steps required ot establish valid bioassay systems.

Analysis of Variance↗
PubMed1992

PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.

The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.

Benzamides↗
PubMed2005

The importance of experimental design in proteomic mass spectrometry experiments: some cautionary tales.

Proteomic expression patterns derived from mass spectrometry have been put forward as potential biomarkers for the early diagnosis of cancer and other diseases. This approach has generated much excitement and has led to a large number of new experiments and vast amounts of new data. The data, derived at great expense, can have very little value if careful attention is not paid to the experimental design and analysis. Using examples from surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) and matrix-assisted laser desorption-ionisation/time-of-flight (MALDI-TOF) experiments, we describe several experimental design issues that can corrupt a dataset. Fortunately, the problems we identify can be avoided if attention is paid to potential sources of bias before the experiment is run. With an appropriate experimental design, proteomics technology can be a useful tool for discovering important information relating protein expression to disease.

Biomarkers, Tumor↗
PubMed2002

Power of experimental design studies for the validation of pharmaceutical processes: case study of a multilayer tablet manufacturing process.

Experimental design studies (EDS) are already widely used in the pharmaceutical industry for drug formulation or process optimization. Rare are the situations in which this methodology is applied for validation purposes. The power of this statistical tool, key element of a global validation strategy, is demonstrated for a multilayer tablet manufacturing process. Applied to the Geomatrix system generally composed of one compression and three granulation processes, time and strictness gains are non-negligible. Experimental design studies are not used in this work for modeling. Introduced at each important step of the process development, they allow for the evaluation of process ruggedness at pilot scale and specifications for full production. A demonstration of the complete control of key process parameters is given, identified throughout preliminary studies.

Chemistry, Pharmaceutical↗
PubMed2004

A simulation study comparing the impact of experimental error on the performance of experimental designs and artificial neural networks used for process screening.

Many variables and their interactions can affect a biotechnological process. Testing a large number of variables and all their possible interactions is a cumbersome task and its cost can be prohibitive. Several screening strategies, with a relatively low number of experiments, can be used to find which variables have the largest impact on the process and estimate the magnitude of their effect. One approach for process screening is the use of experimental designs, among which fractional factorial and Plackett-Burman designs are frequent choices. Other screening strategies involve the use of artificial neural networks (ANNs). The advantage of ANNs is that they have fewer assumptions than experimental designs, but they render black-box models (i.e., little information can be extracted about the process mechanics). In this paper, we simulate a biotechnological process (fed-batch growth of baker's yeast) to analyze and compare the effect of random experimental errors of different magnitudes and statistical distributions on experimental designs and ANNs. Except for the situation in which the error has a normal distribution and the standard deviation is constant, it was not possible to determine a clear-cut rule for favoring one screening strategy over the other. Instead, we found that the data can be better analyzed using both strategies simultaneously.

Culture Media↗
PubMed2006

Experimental design principles for isotopically instationary 13C labeling experiments.

13C metabolic flux analysis (MFA) is a well-established tool in Metabolic Engineering that found numerous applications in recent years. However, one strong limitation of the current method is the requirement of an-at least approximate-isotopic stationary state at sampling time. This requirement leads to a principle lower limit for the duration of a 13C labeling experiment. A new methodological development is based on repeated sampling during the instationary transient of the 13C labeling dynamics. The statistical and computational treatment of such instationary experiments is a completely new terrain. The computational effort is very high because large differential equations have to be solved and, moreover, the intracellular pool sizes play a significant role. For this reason, the present contribution works out principles and strategies for the experimental design of instationary experiments based on a simple example network. Hereby, the potential of isotopically instationary experiments is investigated in detail. Various statistical results on instationary flux identifiability are presented and possible pitfalls of experimental design are discussed. Finally, a framework for almost optimal experimental design of isotopically instationary experiments is proposed which provides a practical guideline for the analysis of large-scale networks.

Carbon Isotopes↗
PubMedDate not supplied

Relationship between "growing pains" and foot posture in children: single-case experimental designs in clinical practice.

Many young children present to the podiatric physician with the complaint of aching legs. Many of these children are clinically assessed as having a pronated foot posture. This foot posture is thought to be deleterious and is often treated with in-shoe devices such as triplane wedges or orthoses. Intervention aiming to reduce the amount of foot pronation in both stance and gait has been reported by parents and children to reduce, and in many cases eliminate, the episodes of aching legs. To test this theory and establish a degree of causality, a single-case experimental design was used in conjunction with age-appropriate pain scores for the children and independent parental ratings. Single-case experimental design is a useful research tool for the clinical practice setting that can identify cause-effect relationships and obviates large sample sizes. Eight complete single-case experimental designs were performed in the clinical setting. The in-shoe intervention proved efficacious for children with a pronated foot posture and aching legs. These findings may provide the impetus for a more rigorous examination of the possible relationship between pronation and "growing pains."

Child↗
PubMed2003

Experimental design of Fenton and photo-Fenton reactions for the treatment of cellulose bleaching effluents.

Multivariate experimental design was applied to the treatment of a cellulose conventional bleaching effluent in order to evaluate the use of the Fenton reagent under solar light irradiation. The effluent was characterised by the general parameters total organic carbon (TOC), chemical oxygen demand and color, and it was analysed for chlorinated low molecular weight compounds using GC-MS. The main parameters that govern the complex reactive system: Fe(II) and H(2)O(2) initial concentration, and temperature were simultaneously studied. Factorial experimental design allowed to assign the weight of each variable in the TOC removal after 15 min of reaction. Temperature had an important effect in the organic matter degradation, especially when the ratio of Fenton reagents was not properly chosen. Fenton reagent under solar irradiation proved to be highly effective for these types of wastewaters. A 90% TOC reduction was achieved in only 15 min of treatment. In addition, the GC-MS analysis showed the elimination of the chlorinated organic compounds initially detected in the studied bleaching effluents.

Chlorine Compounds↗
PubMed1999

Prediction of chiral separations using a combination of experimental design and artificial neural networks.

In this work the advantages of using artificial neural networks (ANNs) combined with experimental design (ED) to optimize the separation of amino acids enantiomers, with alpha-cyclodextrin as chiral selector, were demonstrated. The results obtained with the ED-ANN approach were compared with those of either the partial least-squares (PLS) method or the response surface methodology where experimental design and the regression equation were used. The ANN approach is quite general, no explicit model is needed, and the amount of experimental work can be decreased considerably.

Amino Acids↗
PubMed2006

Effects of lower limb intensive mass practice in poststroke patients: single-subject experimental design with long-term follow-up.

OBJECTIVE: To investigate the effects of two weeks of intensive mass practice with a constraint-induced movement therapy approach for the lower extremity in five chronic poststroke patients, and the persistence of effects at three and six months. DESIGN: A single-subject experimental design (SSED) was used with an AB design and follow-ups three and six months later. SETTING: Outpatient rehabilitation at Torsby Hospital in Sweden. MAIN MEASURES: Motor function in lower extremity, mobility, dynamic balance, weight-bearing symmetry and walking ability were measured on six occasions during two weeks (A phase), with the Fugl-Meyer assessment for lower extremity, the Timed Up and Go, the Step Test, the Timed Walking Test and the Six-Minute Walk Test. During the intervention's B phase, six measurements were performed with the same time intervals as in the A phase. There were follow-ups three and six months later. INTERVENTION: The intervention (B phase) consisted of bicycling, training in water, strength training, standing weight-bearing, walking up and down stairs, walking indoors and outdoors and flexibility training of the lower extremity, on all weekdays, 6 h a day for two weeks. RESULTS: The results showed improvements in 23/30 variables (77%), 12 of them statistically significant (52%). At follow-up, 22/23 improvements persisted. For example, three of five subjects walked significantly further after the intervention and the follow-ups showed that they still walked further than before the intervention. CONCLUSION: Intensive mass practice with constraint-induced movement therapy for the lower extremity can improve motor function, mobility, dynamic balance, weight-bearing symmetry and walking ability in chronic poststroke patients. Long-term follow-up showed that the effects persisted for these five subjects.

Aged↗
PubMed2001

Experimental designs to investigate capillary electrophoresis-electrospray ionization-mass spectrometry enantioseparation with the partial-filling technique.

An experimental design approach is described to evaluate the main electrophoretic parameters involved in the enantioseparation of pharmaceuticals by capillary electrophoresis (CE) coupled to electrospray ionization-mass spectrometry (ESI-MS). For all experiments, the partial-filling technique was applied to avoid the chiral selector entering in the mass spectrometer ion source with a negative effect on the electrospray performance. To carry out enantioseparation, a volatile buffer constituted of 20 mM ammonium acetate at pH 4.0, and a polyvinyl alcohol-coated capillary were used. Methadone was employed as the model compound and three different cyclodextrins (CDs), namely sulfobutyl ether-beta-CD, carboxymethylated-beta-CD and hydroxypropyl-beta-CD, were selected in order to study the countercurrent process. Two different experimental designs were chosen: (i) a full-factorial design to examine the effects and significance of the investigated factors, and (ii) a central composite face-centered design to establish the mathematical model of the selected responses in function of experimental factors. The chiral selector concentration, percentage of the capillary filled with the chiral selector, and drying gas nebulization pressure were three relevant factors taken into consideration. For each CD, the methadone enantiomeric resolution, apparent selectivity, and migration time of the second enantiomer were established as responses. The latter were systematically related to experimental parameters with the help of multiple linear regression. It is noteworthy that the behaviour was different in function of the chiral selector charge. Results revealed that the nebulization pressure involved in the electrospray process and the CD concentration had a significant effect on the enantiomeric resolution, while the effect of the separation zone length was less pronounced. Finally, response surfaces were drawn from the mathematical model and experimental conditions were selected to allow a robust determination of methadone enantiomers by CE-MS.

Buffers↗