Screening methods performance/limitations

Local sensitivity analysis is of limited value when the chemical system is non-linear. In this case global methods, which vary the parameters over the range of their possible values, are preferable. Two global uncertainty methods have been used in this work, a screening method, the so-called Morris One-At-A-Time (MOAT) analysis and a Monte Carlo analysis with Latin Hypercube Sampling (Saltelli et al., 2000 Zador et al., submitted, 20041). The analyses were performed by varying rate parameters, branching ratios and constrained concentrations within their uncertainty interval,... 

It is also desirable that a screening test should have a low incidence of false positive results. (False positives will occur if the test is sensitive to other, similar compounds - such as natural substances in the tissue - or metabolites.) A high incidence of false positives will limit the cost-effectiveness of the screening method because unnecessary and often costly confirmatory tests will need to be performed. 

In the EU, and also in other countries that have adopted regulations or guidelines based on the EU approach, the interpretation of analytical results and regulatory decisions is made on the basis of those results that depend on the method performance characteristics known as the detection capability and the decision limit. The detection capability (CCfi) is defined in point 1.12 of the Annex to Commission Decision 2002/657/EC. CCP as the smallest content of the analyte that may be detected, identified, and/or quantified in a sample with an error probability of p. The P error is the probability that the tested sample is truly non-compliant even though a compliant measurement has been obtained. For screening tests the P error (the false-compliant rate) should be <5%. 

The other important aspect is the reliability of retrospective validations. Careful validations are critical to ascertain whether a proposed virtual screening technique will perform well when applied prospectively. This requires benchmarks that mimic key features of prospective virtual screens, including database size and the number of putative hits that can be tested in vitro. Unfortunately, our ability to generate retrospective tests that accurately capture the difficulty of prospective applications of virtual screening methods is still very limited [20]. Furthermore, the virtual lack of blind tests has contributed to the overfitting of current retrospective benchmarks by virtual screening techniques and thus to an overestimation of their prospective performance [25]. Regrettably, retrospective validations that do not address the... 

Synthesis. Exploratory research has produced a wide variety of odorants based on natural stmctures, chemicals analogous to naturals, and synthetic materials derived from available raw materials and economical processing. As in most areas of the chemical industry, the search for new and useful substances is made difficult by the many materials that have been patented and successfully commercialized (4). In the search for new aroma chemicals, many new materials are prepared for screening each year. Chemists who perform this work are involved in a creative exercise that takes its direction from the commercial sector in terms of desirable odor types and specific performance needs. Because of economic limitations, considerations of raw material costs and available processing methods may play a role eady in the exploratory work. 

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