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PubMed1984

Use of experimental designs with quantitative ELISA.

Precise use of enzyme-linked immunosorbent assay (ELISA) as a quantitative technique depends on repeatability of color development and its measurement. Variation in measured response among wells, within and among microtiter plates, often precludes such precision. For example, plates with all wells treated uniformly exhibited unacceptable optical density differences in excess of 0.35 and 0.25 O.D. U among row and column averages, respectively. Arrangement of samples on plates according to classical experimental designs, with compact blocking features and two-dimensional control over spatial patterns, provides a possible remedy. Analysis of variations over uniformly treated plates demonstrated the potential for increased precision when such designs are used instead of random arrangements. Retrospective analysis of more than 100 tests performed with various experimental designs confirmed that this potential was realized when using Youden square and lattice square designs. Several designs appropriate for microtiter plates are presented and their conduct described.

Analysis of Variance↗
PubMed1998

Statistical approaches to determine analytical variability and specifications: application of experimental design and variance component analysis.

Assessment of analytical variability is recognized as an important factor for the establishment of specifications. Estimation of the variance for an analytical procedure can be accomplished using a variety of approaches. The approach of variance component analysis was applied retrospectively, as well as prospectively, to estimate analytical variance. The prospective approach also included the use of experimental design. Recent new drug substance examples illustrating these approaches are presented. In these examples, the analytical property of potency was evaluated. Factors examined in the experimental design include laboratory, day, analyst, instrument and column. Process variability can also be determined by variance component analysis. For a stable drug substance, combining the analytical and process variances provides an estimate on the total variance for the analytical property of potency. With the total variability statistically derived, an appropriate specification that is consistent with process and analytical capability can be established.

Analysis of Variance↗
PubMed1999

Optimal experimental design for event-related fMRI.

An important challenge in the design and analysis of event-related or single-trial functional magnetic resonance imaging (fMRI) experiments is to optimize statistical efficiency, i.e., the accuracy with which the event-related hemodynamic response to different stimuli can be estimated for a given amount of imaging time. Several studies have suggested that using a fixed inter-stimulus-interval (ISI) of at least 15 sec results in optimal statistical efficiency or power and that using shorter ISIs results in a severe loss of power. In contrast, recent studies have demonstrated the feasibility of using ISIs as short as 500 ms while still maintaining considerable efficiency or power. Here, we attempt to resolve this apparent contradiction by a quantitative analysis of the relative efficiency afforded by different event-related experimental designs. This analysis shows that statistical efficiency falls off dramatically as the ISI gets sufficiently short, if the ISI is kept fixed for all trials. However, if the ISI is properly jittered or randomized from trial to trial, the efficiency improves monotonically with decreasing mean ISI. Importantly, the efficiency afforded by such variable ISI designs can be more than 10 times greater than that which can be achieved by fixed ISI designs. These results further demonstrate the feasibility of using identical experimental designs with fMRI and electro-/magnetoencephalography (EEG/MEG) without sacrificing statistical power or efficiency of either technique, thereby facilitating comparison and integration across imaging modalities.

Hemodynamics↗
PubMed2004

Selecting appropriate animal models and experimental designs for endocrine disruptor research and testing studies.

Evidence that chemicals in the environment may cause developmental and reproductive abnormalities in fish and wildlife by disrupting normal endocrine functions has increased concern about potential adverse human health effects from such chemicals. US laws have now been enacted that require the US Environmental Protection Agency (EPA) to develop and validate a screening program to identify chemicals in food and water with potential endocrine-disrupting activity. EPA subsequently proposed an Endocrine Disruptor Screening Program that uses in vitro and in vivo test systems to identify chemicals that may adversely affect humans and ecologically important animal species. However, the endocrine system can be readily modulated by many experimental factors, including diet and the genetic background of the selected animal strain or stock. It is therefore desirable to minimize or avoid factors that cause or contribute to experimental variation in endocrine disruptor research and testing studies. Standard laboratory animal diets contain high and variable levels of phytoestrogens, which can modulate physiologic and behavioral responses similar to both endogenous estrogen as well as exogenous estrogenic chemicals. Other studies have determined that some commonly used outbred mice and rats are less responsive to estrogenic substances than certain inbred mouse and rat strains for various estrogen-sensitive endpoints. It is therefore critical to select appropriate biological models and diets for endocrine disruptor studies that provide optimal sensitivity and specificity to accomplish the research or testing objectives. An introduction is provided to 11 other papers in this issue that review these and other important laboratory animal experimental design considerations in greater detail, and that review laboratory animal and in vitro models currently being used or evaluated for endocrine disruptor research and testing. Selection of appropriate animal models and experimental design parameters for endocrine disruptor research and testing will minimize confounding experimental variables, increase the likelihood of replicable experimental results, and contribute to more reliable and relevant test systems.

Animals↗
PubMed1985

Treatment effectiveness in an adolescent chemical dependency treatment program: a quasi-experimental design.

This study utilizes a waiting-list control group experimental design to empirically assess the effectiveness of a residential adolescent chemical dependency treatment program. Mailed questionnaires and telephone follow-up procedures were used to collect outcome data. Treatment can be classified as an "AA-Family" model, combining behavior modification and psychoanalytic techniques. Complete abstinence from alcohol and/or drugs was used as a criterion for success. The abstinence rate for the treatment group sample (65.5%) was significantly higher than the abstinence rate for the waiting-list control group (14.3%) at the .001 level of probability.

Adolescent↗
PubMed1987

Single-case experimental designs in neuropsychological rehabilitation.

It is becoming accepted that single-case studies can offer important contributions to theoretical aspects of neuropsychology. Such recognition has not been so forthcoming in the field of rehabilitation, where single-case studies can be employed to evaluate neuropsychological treatments. This paper describes behavioural approaches to treatment of the neurologically impaired which include single-case experimental designs that have originated in the field of behavioural psychology. Examples of behaviour programmes for the treatment of apraxia and alexia are provided together with examples of single-case experimental designs used to evaluate memory therapy. The paper concludes with a brief discussion of the role of statistics in single-case studies.

Adult↗
PubMed2006

A comparison of experimental designs for selection in breeding trials with nested treatment structure.

Plant breeders frequently evaluate large numbers of entries in field trials for selection. Generally, the tested entries are related by pedigree. The simplest case is a nested treatment structure, where entries fall into groups or families such that entries within groups are more closely related than between groups. We found that some plant breeders prefer to plant close relatives next to each other in the field. This contrasts with common experimental designs such as the alpha-design, where entries are fully randomized. A third design option is to randomize in such a way that entries of the same group are separated as much as possible. The present paper compares these design options by simulation. Another important consideration is the type of model used for analysis. Most of the common experimental designs were optimized assuming that the model used for analysis has fixed treatment effects. With many entries that are related by pedigree, analysis based on a model with random treatment effects becomes a competitive alternative. In simulations, we therefore study the properties of best linear unbiased predictions (BLUP) of genetic effects based on a nested treatment structure under these design options for a range of genetic parameters. It is concluded that BLUP provides efficient estimates of genetic effects and that resolvable incomplete block designs such as the alpha-design with restricted or unrestricted randomization can be recommended.

Breeding↗
PubMed2003

Strategy for developing and optimizing liquid chromatography methods in pharmaceutical development using computer-assisted screening and Plackett-Burman experimental design.

We describe a three-step method development/optimization strategy for HPLC assay/impurity methods for pharmaceuticals, which include multiple-column/mobile phase screening using a system equipped with a column-switching device, further optimization of separation by using multiple organic modifiers in the mobile phase, and multiple-factor method optimization using Plackett-Burman experimental designs. In the first two steps, commercially available chromatography optimization software, DryLab, was used to perform computer simulations. This allows the method developer to evaluate each condition (one column/mobile phase combination) with retention data from two scouting gradient runs. This approach significantly reduces the number of runs in method development. After a satisfactory separation was obtained, we used a method optimization step with Plackett-Burman experimental designs. The purpose of the 16-injection set experiments was to evaluate nine method factors with regard to method precision, accuracy, sensitivity and specificity. The results provided logical justifications in selecting method parameters such as column temperature, detection wavelength, injection volume, and sample solvent, etc. In data analysis, instead of the traditional mathematical manipulations, we used the graphical methods to examine and present data by creating the so-called main effect plots. Because replicates of design points were not run, the data did not allow the testing of statistical significance. However, it provided visual presentations in a way that is easy to understand for the method developer and end user alike.

Chromatography, High Pressure Liquid↗
PubMed2006

A simulation study comparing different experimental designs for estimating uptake and elimination rates.

The design of ecotoxicological studies requires decisions about the number and spacing of exposure groups tested, the number of replications, the spacing of sampling times, the duration of the study, and other considerations. For example, geometric spacing of sampling times or toxicant concentrations is often used as a default design. Optimal design methods in statistics can suggest alternative spacing of sampling times that yield more precise estimates of regression coefficients. In this study, we use a computer simulation to explore the impact of the spacing of sampling times and other factors on the estimation of uptake and elimination rate constants in an experiment addressing the bioaccumulation of a contaminant. Careful selection of sampling times can result in smaller standard errors for the parameter estimates, thereby allowing the construction of smaller, more precise confidence intervals. Thus, the effort invested in constructing an optimal experimental design may result in more precise inference or in a reduction of replications in an experimental design.

Animals↗
PubMed2001

Experimental design methodology applied to the study of channel dimensions on the elution of red blood cells in gravitational field flow fractionation.

Field flow fractionation (FFF) separation techniques have gained considerable success with micron-sized species. Living red blood cells (RBCs) of any origin have emerged as ideal models for cell separation development. Their elution mode is now described as "Lift-Hyperlayer". Certain separator dimension parameters are known to play a key role in the separation and band spreading process. Systematic studies of channel dimensions effects on RBC retention, band spreading, peak capacity and on a novel parameter described as "Particle Selectivity" were set up by means of a two-level factorial experimental design. From experimental results and statistical calculations it is confirmed that channel thickness plays a major role in retention ratio, peak variance, peak capacity and particle selectivity. Channel breadth strongly influences plate height, with lower impact on peak capacity and particle selectivity. Retention ratio, peak variance and peak capacity observed results are modulated by second-order interactions between channel dimensions. Preliminary rules for channel configurations are therefore set up and depend on separation goals. It is shown that a very polydisperse population is best disentangled in a thin and narrow channel whatever its length. If a mixture of many different micron-sized species is considered (each of limited polydispersities); a thick and broad channel should be preferred, with length modulating peak capacity to disentangle this polymodal mixture.

Cell Separation↗
PubMed2000

Experimental design of FPD made of all-ceramics and fibre-reinforced composite.

OBJECTIVES: This study was carried out to combine flexural properties of FRC materials with aesthetic values of ceramics. METHODS: The bonding strength of fibre-reinforced composite to ceramic was determined. Afterwards, 8 three unit and 8 four unit FPDs (fixed partial dentures) were manufactured based on the experimental design and were then adhesively luted onto human molars. After thermal cycling and mechanical loading in an artificial environment, the fracture strength and marginal adaptation was determined. FPDs made of FRC (fibre-reinforced composite) materials were used as a control. RESULTS: The most reliable bonding strength of ceramic to FRC material was achieved using acid etching in combination with adhesive luting techniques. Median fracture strength values of 575 N for three unit FPD and 876 N for four unit FPD were established. More than 85% of the experimental FPDs showed a perfect margin while less than 15% revealed a marginal gap, even after thermal cycling and mechanical loading (TCML). The strongest influence of TCML on the marginal adaptation of the experimental design FPD was determined within the four unit system showing approximately a 10% change in marginal gap and perfect margin. SIGNIFICANCE: Assuming an improvement in adhesive bonding between the ceramic and the FRC material and, in addition, an enhancement of the contact surface between pontic and abutment, the hybrid technique could represent an interesting procedure for further investigations and, eventually, clinical implication.

Acid Etching, Dental↗
PubMed1986

Construction of social value or utility-based health indices: the usefulness of factorial experimental design plans.

Global indices, which aggregate multiple health or function attributes into a single summary indicator, are useful measures in health research. Two key issues must be addressed in the initial stages of index construction from the universe of possible health and function attributes, which ones should be included in a new index? and how simple can the statistical model be to combine attributes into a single numeric index value? Factorial experimental designs were used in the initial stages of developing a function index for evaluating a program for the care of young handicapped children. Beginning with eight attributes judged important to the goals of the program by clinicians, social preference values for different function states were obtained from 32 parents of handicapped children and 32 members of the community. Using category rating methods each rater scored 16 written multi-attribute case descriptions which contained information about a child's status for all eight attributes. Either a good or poor level of each function attribute and age 3 or 5 years were described in each case. Thus, 2(8) = 256 different cases were rated. Two factorial design plans were selected and used to allocate case descriptions to raters. Analysis of variance determined that seven of the eight clinician selected attributes were required in a social value based index for handicapped children. Most importantly, the subsequent steps of index construction could be greatly simplified by the finding that a simple additive statistical model without complex attribute interaction terms was adequate for the index. We conclude that factorial experimental designs are an efficient, feasible and powerful tool for the initial stages of constructing a multi-attribute health index.

Activities of Daily Living↗
PubMed2005

Experimental design and analysis of antibody microarrays: applying methods from cDNA arrays.

Protein expression microarrays, also called antibody arrays, represent a new technology that allows the expression level of proteins to be assessed directly. As is also the case with gene expression microarrays, it is hoped that protein expression microarrays will aid in biomarker discovery, predicting disease outcomes and response to treatments, and detecting molecular mechanisms and/or pathways associated with a particular disease state. However, accurately achieving these aims is dependent upon suitable experimental designs, normalization procedures that eliminate systematic bias, and appropriate statistical analyses to assess differential expression or expose expression patterns. In the last five years, a large amount of research has been devoted to two-color cDNA arrays to improve experimental design, normalization and statistical analyses to assess differential expression and classification. These methods are directly applicable to two-color antibody arrays. The objective of this article is to discuss statistical methods that have been developed for cDNA arrays and describe how the methods can be directly applied to antibody arrays.

Antibodies↗
PubMed1985

Multiwell chamber chemotaxis assays: improved experimental design and data analysis.

The chemotaxis assay using the Boyden transfilter technique has become widely used in recent years for assessing migratory responses of a wide variety of cell types. In the study reported here we examined the migratory responses of mouse peritoneal macrophages using a multiwell chamber. The experiments were designed to analyze the components of variance in the assay method, to optimize the experimental design, and to develop objective statistical criteria for choosing among experiments with disparate results. Cell counts were obtained with the aid of an image analyzer coupled to a light microscope. Microcomputer software was developed to drive the image analyzer, collect data and conduct statistical analyses. Nested analysis of variance (ANOVA, either 2- or 3-level) was employed to partition the components of variance and F-tests were used to determine their significance. Significant sources of experimental error were identified both within and among wells and were attributed mostly to variability in the chamber/filter assembly and counting procedure. Statistical analyses demonstrated that there was significant variation among assays conducted in different multiwell chambers on the same day, among assays where the same agent was tested on different days in the same chamber, and among replicate counts of the same assay. The following recommendations were made: use ANOVA to distinguish differences due to biological effects from those due to experimental error, design experiments so that all relevant comparisons are included in the same chamber and the same assay, avoid pooling data from different assays unless ANOVA treatment variances are comparable, and when replicate assays yield disparate results choose the assay with the lowest percentage of variation due to experimental error.

Animals↗
PubMed1994

Reduction of animal use: experimental design and quality of experiments.

Poorly designed and analysed experiments can lead to a waste of scientific resources, and may even reach the wrong conclusions. Surveys of published papers by a number of authors have shown that many experiments are poorly analysed statistically, and one survey suggested that about a third of experiments may be unnecessarily large. Few toxicologists attempted to control variability using blocking or covariance analysis. In this study experimental design and statistical methods in 3 papers published in toxicological journals were used as case studies and were examined in detail. The first used dogs to study the effects of ethanol on blood and hepatic parameters following chronic alcohol consumption in a 2 x 4 factorial experimental design. However, the authors used mongrel dogs of both sexes and different ages with a wide range of body weights without any attempt to control the variation. They had also attempted to analyse a factorial design using Student's t-test rather than the analysis of variance. Means of 2 blood parameters presented with one decimal place had apparently been rounded to the nearest 5 units. It is suggested that this experiment could equally well have been done in 3 blocks using 24 instead of 46 dogs. The second case study was an investigation of the response of 2 strains of mice to a toxic agent causing bladder injury. The first experiment involved 40 treatment combinations (2 strains x 4 doses x 5 days) with 3-6 mice per combination. There was no explanation of how the experiment involving approximately 180 mice had actually been done, but unequal subclass numbers suggest that the experiment may have been done on an ad hoc basis rather than being properly designed. It is suggested that the experiment could have been done as 2 blocks involving 80 instead of about 180 mice. The third study again involved a factorial design with 4 dose levels of a compound and 2 sexes, with a total of 80 mice. Open field behaviour was examined. The author incorrectly used the t-test to analyse the data, and concluded that there was no dose effect, when a correct analysis showed this to be highly significant. In all case studies the scientists presented means +/- standard deviations or standard errors involving only the animals contributing to that mean, rather than the much better estimates that would be obtained with a pooled estimate of error. This is virtually a universal practice.(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthetics↗
PubMed2003

Aldose reductase and the importance of experimental design.

Kinetic studies on the AR (aldose reductase) protein have shown that it does not behave as a classical enzyme in relation to ring aldose sugars. As with non-enzymatic glycation reactions, there is probably a free-radical element involved derived from monosaccharide autoxidation. In the case of AR, there is free radical oxidation of NADPH by autoxidizing monosaccharides, which is enhanced in the presence of the NADPH-binding protein. Thus any assay for AR based on the oxidation of NADPH in the presence of autoxidizing monosaccharides is invalid, and tissue AR measurements based on this method are also invalid, and should be reassessed. AR exhibits broad specificity for both hydrophilic and hydrophobic aldehydes that suggests that the protein may be involved in detoxification. The last thing we would want to do is to inhibit it. ARIs (AR inhibitors) have a number of actions in the cell which are not specific, and which do not involve them binding to AR. These include peroxy-radical scavenging and effects of metal ion chelation. The AR/ARI story emphasizes the importance of correct experimental design in all biocatalytic experiments. Developing the use of Bayesian utility functions, we have used a systematic method to identify the optimum experimental designs for a number of kinetic model data sets. This has led to the identification of trends between kinetic model types, sets of design rules and the key conclusion that such designs should be based on some prior knowledge of K (m) and/or the kinetic model. We suggest an optimal and iterative method for selecting features of the design such as the substrate range, number of measurements and choice of intermediate points. The final design collects data suitable for accurate modelling and analysis and minimizes the error in the parameters estimated, and is suitable for simple or complex steady-state models.

Aldehyde Reductase↗
PubMed2000

Data and knowledge based experimental design for fermentation process optimization.

A novel method for the sequential experimental design in order to optimize fed-batch fermentations was applied to a hyaluronidase fermentation by Streptococcus agalactiae. A Lambda-optimal design was introduced to minimize the model parameter estimation error and to maximize the performance of the fermentation process. The method employs hybrid models that contain mechanistic, fuzzy and neural network components.

Journal Article↗
PubMed1979

Comparison and evaluation of some experimental designs for use in carcinogen screening.

The development and evaluation of experimental designs for routine in vivo screening of chemicals for potential carcinogenic activity were considered. Such designs have played an important role in the Carcinogenesis Bloassay Program of the National Cancer Institute (NCI). In particular, the current one-stage 50-animal/group screen used by the NCI was considered. A specific two-stage alternative was proposed in which 35 animals/group were used; this alternative allowed for retesting of equivocal compounds. The proposed designs were evaluated in terms of sensitivity, specificity, and throughout. Despite the large number of tests made for each compound, the false-positive rate was found to be less than 0.07 for the current screen and less than 0.05 for the proposed two-stage alternative. The power of the one-stage and two-stage screens was comparable. The two-stage screen was shown to make about 30% more decisions per test period with a savings of around 28% in the expected number of animals needed per compound tested.

Animals↗