User bias

The method used to align molecules is still an area of contention. Applications like MOE-FlexAlign (30,39) and FlexS (37) are used to help discover different alignment configurations or to ensure that user bias has not entered the alignment scheme. Methods like MOE-FlexAlign and CoMFA s Field Fit (4) are useful if one knows the bioactive conformation or if the molecules of inter-... 

The inclusion of the protein active site can add an important steric or shape constraint to the search, limiting the size of the selected molecules appropriately, as shown by application to the thyroid hormone receptor [75]. However, the real power of such methods comes from the ability to search receptor-based pharmacophores with only a limited user bias on the points to be used. This has been implemented via partial-match searching [103], available within UNITY, which marks a molecule as a hit if it matches 4 out of 20 possible pharmacophoric features in the site. Additional constraints on the solutions can be imposed by grouping the pharmacophore points and limiting matches to one or more points from each group, a feature of the THINK program [78]. In this way, molecules can be selected that explore several areas of the binding site. 

As mentioned Sec. 1, a pharmacophore represents an objective description of what is required for activity, and pharmacophore discovery should represent an objective way of determining that pharmacophore. It is difficult to discern how objective this process has been in the applications Sec. 5.5 (i.e., to determine how much user bias was injected into selecting which of the many pharmacophores consistent with the SAR was chosen). User bias is not necessarily bad —in the hands of a skilled practitioner, this allows judgments to be made based on data from a variety of sources. But, ultimately, this field will best advance if different noncommunicating users applying the same method to the same data achieve the same final result. 

Such techniques have the distinct advantage that once the elements are selected, the method is not subject to user-bias, beyond the choice of the number of factors to be included in the varimax rotation. The resulting factors are truly independent of each other, and faithfully reflect the composition of the original data set, within certain transparent... 

Eliminate user bias by employing objective measures of user satisfaction and workload. 

Handheld Accurate Inexpensive No continuous monitoring Not apphcable to manufacturing Invasive User bias... 

Flush mount Continuous monitoring Applicable to manufacturing Noninvasive No user bias Biased by conduction from barrel... 

Immersion May be accurate Continuous monitoring Applicable to manufacturing Relatively inexpensive No user bias May disrupt flow stream Shear effects... 

Thermal imaging May be accurate Continuous monitoring Noninvasive Expensive User bias Environmental factors... 

While a systematic potential energy scan can be beneficial in cases where little is known about the system in advance and as a way to reduce user bias in exploring possible binding sites, it is not always necessary. High-symmetry,... 

The result of the Back-to-Basics series is an accumulation of some 50 separate but interrelated expositions of mass spectrometric principles and apparatus. Some areas of mass spectrometry, such as ion cyclotron resonance and ion trap instruments, have not been covered except for passing references. This decision has not been due to any bias by the authors or Micromass but simply reflects the large amount of writing that had to be done and the needs of the greatest proportion of users. 

Both approaches are subjected to criticisms and to errors. The stipulation of the model constitutes a bias in favour of one among several possible alternatives, and the conclusions will suffer if the choice was not appropriate. All the models, by definition, are subjected to failures of this kind, and it rests with the users to exert their acumen to deeide if the model is applicable to the case under examination. 

Theoretically IQC should be the front-line approach to quality. If a method has been adequately validated and shown to meet the requirements of the user and kept in analytical control with IQC to detect intrusion of bias or imprecision, then the EQA needs to provide the occasional, independent, objective reassurance. In practice however, the EQA is likely to play an equal role with IQC, both in confirming problems brought to the attention of the analyst by the IQC and in stimulating further action. 

The user supplied weighting constant, (>0), should have a large value during the early iterations of the Gauss-Newton method when the parameters are away from their optimal values. As the parameters approach the optimum, should be reduced so that the contribution of the penalty function is essentially negligible (so that no bias is introduced in the parameter estimates). 

The highest quality reference materials are certified for the concentration values of the constituent(s) of interest, reflecting high confidence in the value s accuracy and the thorough investigation of all known or suspected sources of bias. Used appropriately (e.g., Roper et al., 2001 Zschunke, 2000), these certified values provide an effective means to ensure comparability (both among laboratories and over time). It is not always practical, however, to undertake the work required to produce a certified value in many such cases, a value can be carefully determined, but insufficient information exists to assess the associated uncertainty. This information value is nevertheless of substantial interest to other users of the reference material. It can, for example, allow laboratories to compare results even though full traceability is impractical. 

The study of the precision of a method is often the most time and resource consuming part of a method validation program, particularly for methods that are developed for multiple users. The precision is a measure of the random bias of the method. It has contributions fi om the repeatability of various steps in the analytical method, such as sample preparation and sample injection for HPLC [5-9], and from reproducibility of the whole analytical method fiom analyst to analyst, fiom instrument to instrument and fiom laboratory to laboratory. As a reproducibility study requires a large commitment of time and resources it is reasonable to ensure the overall ruggedness of the method before it is embarked upon. 

Subsequent research by Herschel (1971), Kikuchi and Softer (1977), and Frieden (Chapter 8) has refined the concept in a way that provides an explicit and sensible accounting for noise contributions. This work also provides solutions that incorporate a type of prior knowledge not used before. In particular, the users may express their bias by proposing a prior spectrum or guess as to what the true spectrum o(x) might look like. Furthermore, they may express their relative confidence in the guess by specifying a probability of occurrence for each value that may be assumed by an element of the estimate o(x). Both the prior spectrum and its associated user-conviction probability function may be obtained from past experience by statistical analysis. In Chapter 8, Frieden examines the possibilities of maximum and minimum conviction in connection with the types of prior... 

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