Nested method design

The nested designs can be used to perform a ruggedness test following the definition of the US Pharmacopeia [7] or the second level requirements of the Canadian Acceptable Methods [14]. However, to our knowledge this methodology has not been applied yet for this purpose. 

Wernimont reported an example of a nested design, which is an example of fractional replication. It was desired to evaluate an interlaboratory study of a method of acetyl determination. Results obtained by two analysts in each of eight laboratories were compared by having each analyst perform two tests on each of 3 days. The design was... 

Many validation studies use a nested or hierarchical design (Figure 5). These studies usually involve several laboratories that independently conduct the same alternative method on all the substances in an RSTS. There are four sources of variability in such studies. These include variation in the test substances, variation within experiments within a laboratory (intraexperiment variability), variation between experiments within a laboratory (intralaboratory variability), and variation between laboratories (interlaboratory variability). Reviewed next is the nature and importance of each. The differences between chemicals are ignored in this discussion since they can generally be minimized with well-controlled test article distribution and storage. Attention is concentrated on the variability in results obtained by testing a single chemical in a number of different laboratories. 

An important extension of our large validation studies involves the use of data bases from field studies in the development of improved statistical methods for a variety of problems in quantitative applications of immunoassays. These problems include the preparation and analysis of calibration curves, treatment of "outliers" and values below detection limits, and the optimization of resource allocation in the analytical procedure. This last area is a difficult one because of the multiple level nested designs frequently used in large studies such as ours (22.). We have developed collaborations with David Rocke and Davis Bunch (statisticians and numerical analysts at Davis) in order to address these problems within the context of working assays. Hopefully we also can address the mathematical basis of using multiple immunoassays as biochemical "tasters" to approach multianalyte situations. 

Fig. 4,11, Bar-graph presentation of results obtained in the certification of lead in mussel tissue BCR-CRM 278. The horizontal dotted line signifies the standard deviation of the set of data and the vertical dotted line the certified value (mean of means). The figure shows the that the SD of the DPASV and of the AAS methods are much larger than those obtained with IDMS. These differences would influence the evaluation of the homogeneity of the material through a two-stage nested design as proposed by ISO Guide 35.

It is based on methods, i.e., F-tests for nested models, that were designed to test pre-specified hypotheses. 

In 2003, I wrote a book, Applied Statistical Designs for the Researcher (Marcel Dekker, Inc.), in which I covered experimental designs commonly encountered in the pharmaceutical, applied microbiological, and healthcare-product-formulation industries. It included two sample evaluations, analysis of variance, factorial, nested, chi-square, exploratory data analysis, nonpara-metric statistics, and a chapter on linear regression. Many researchers need more than simple linear regression methods to meet their research needs. It is for those researchers that this regression analysis book is written. 

A nested design, which is sometimes referred to as a hierarchical design, is used for an experiment in which there is an interest in a set of treatments and the experimental units are subsampled (Fig. 9.4). It has become a practical design or an approach to study and to evaluate method performance criteria that include accuracy expressed as overall recovery, intermediate precision, and... 

Figure 5. The concurrent nested strategy (Creswell, J. W. Research Design, Qualitative, Quantitative, and Mixed Methods Approaches 2nd ed. p, 213, copyright 2003 by Sage Publications, Inc. Reprinted by Permission of Sage...

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