Futility analysis

Suits and Bueche conclude their case-histories with a superb analysis of the sources, tactics and uses of applied research, and make the comment The case histories just summarised show, first of all, the futility of trying to label various elements of the research and development process as basic , applied or development . Given almost any definition of these terms, one can find variations or exceptions among the examples. ... 

As might be expected, improved spectrographie equipment is leading to an extension of x-ray emission as a technique for analysis, and this extension in turn points up opportunities for further improvement. One result is that we find ourselves in a period marked by rapidly changing equipment that soon becomes obsolescent. Description of all the equipment currently available is therefore futile. We shall accordingly restrict ourselves (with one exception see Section 9.9) to a representative list of products manufactured in the United States. 

However, this might not be possible. The analyte of interest may very well be naturally present in the soil. Thus, trying to find the point where the analyte does not exist in the soil would be futile. In many cases, samples need to be taken from a point where only background or natural levels of the component of interest are present to another point where the same conditions exist. Knowledge of the background levels of components of interest is thus essential in all soil sampling and analysis. 

Whether the parent drug or metabolite (or both) is chosen for analysis depends on the preliminary study. In principle, analysis for the parent compound should always be carried out however, there are situations (e.g., rapid metabolism) when this is quite futile and a major retained metabolite should be used. Covalently bound metabolites are addressed in a later section. 

However, FBA in itself is not sufficient to uniquely determine intracellular fluxes. In addition to the ambiguities with respect to the choice of the objective function, flux balance analysis is not able to deal with the following rather common scenarios [248] (i) Parallel metabolic routes cannot be resovled. For example, in the simplest case of two enzymes mediating the same reaction, the optimization procedure can only assign the sum of a flux of both routes, but not the flux of each route, (ii) Reversible reaction steps can not be resolved, only the sum of both directions, that is, the net flux, (iii) Cyclic fluxes cannot be resolved as they have no impact on the overall network flux, (iv) Futile cycles, which are common in many organisms, are not present in the FBA solution, because they are usually not optimal with respect to any optimization criterion. These shortcomings necessitate a direct experimental approach to metabolic fluxes, as detailed in the next section. 

It is also possible to stop trials for reasons other than overwhelming efficacy, for example for futility, where at an interim stage it is clear that if the trial were to continue it would have little chance of giving a positive result. We will say more about interim analysis in a later chapter and in particular consider the practical application of these methods. 

In addition to looking for overwhelming efficacy there is also the possibility of stopping the trial for futility at an interim stage. It may be, for example, that the analysis of the interim data is not at all in favour of the test treatment and were the trial to continue there would simply be no real possibility of obtaining a... 

This method of calculating the conditional power assumes that the observed difference between the treatments at the interim stage is the true difference, termed the conditional power under the current trend. It is also possible to calculate conditional power under other assumptions, for example, that the true treatment difference in the remaining part of the trial following the interim analysis is equal to d. These calculations under different assumptions about how the future data should behave will provide a broad basis on which to make judgements about terminating the trial for futility. 

It is not a requirement that a trial must have an interim analysis, either for efficacy or for futility. In most long-term trials, however, where there is the opportunity for an interim evaluation then it may be something worth putting in place. The interim can involve only efficacy, only futility, or both and may indeed involve some other things as well, such as a re-evaluation of sample size (see Section 8.5.3). 

In line with this, the interim analysis plan was revised and only one interim was to be conducted for both efficacy and futility after 40 per cent of the patients had completed 3 months of follow-up. Since the two proposed analyses were not equally spaced, a spending functions were needed to revise the adjusted significance levels and these turned out to be 0.0007 and 0.0497. 

The trial was, in fact, stopped at the interim analysis due to futility the conditional power, was well below 30 per cent. In addition, even though the formal boundary for safety was not crossed, the trend was in the direction of excess deaths in the ancrod group. 

The futility of an effective mass analysis, alluded to above, may be demonstrated by referring to the thermopower and susceptibility. Each of these quantities may be used to determine an effective mass if calculation and measurement are reconciled by varying m /m. One finds that x requires m /m > 1, while c requires m /m <1. A more sophisticated approach is doubtless needed. 

Stimulated by this recognition, multi-scale analysis and simulation have received unprecedented attention in recent years, as shown by the dramatic increase in related publications. However, measurement technology focused on multi-scale structures, particularly, on meso-scale phenomena, has not been sufficiently tackled. Without breakthroughs in this aspect, theories and simulations could not be verified and validated, and upgrading the knowledge base for chemical engineering would be futile. 

Like the examples mentioned above, most examples of metabolic flux analysis by metabolite balancing have redox balances as a central constraint used in the determination of the flux distribution. However, the redox balance is, especially under aerobic conditions, subject to uncertainties which make it less suitable for estimation of the fluxes. Part of the reason for this is to be found in futile cycles, e. g., oxidation of sulfides to disulfides, where reductive power is needed to reduce the disulfides. The net result of this reaction is reduction of molecular oxygen to water, and oxidation of NADPH to NADP+. Since the consumption rate of oxygen of these specific reactions is impossible to measure, the result may be that the NADPH consumption is underestimated. This is in accordance with the finding that when the NADPH-producing reactions are estimated independently of the NADPH-consuming reactions, there is usually a large excess of NADPH that needs to be oxidized by reactions not included in the network, e. g., futile cycles [11-13]. 

If several days have elapsed before the body is discovered, there is a tendency to tiiink that analysis for volatile poisons would be futile. In fact it should be one of the first groups to be checked. The presence of alcohols, toluene, and halogenated hydrocarbons... 

Scheme 4.17 presents a couple of other strange-looking cationic species which were discovered in studies in a related field. In connection with the problem of dodecahedrane synthesis via the isomerization of pagodane 34 (cf. data in Schemes 4.10 and 4.11), Olah s and Prinzbach s groups engaged in studies of the behavior of pagodane derivatives under superacid conditions. Their hope was to force the cationic isomerization of 34 to 3. Despite all attempts, this route was unworkable. As a reward for these apparently futile efforts they were able to observe the unexpected formation of a very stable cationic species, the pagodane dication 55 (Scheme 4.17). The pattern of its NMR spectra combined with the nature of its quenching adduct 56, and the theoretical analysis of possible alternatives, enabled the authors to ascribe to this dication the unprecedented four-center/two-electron delocalized bis-homoaromatic structure.

All of the aforementioned steps are an exercise in futility if the situations hypothesized are not usable by problem solvers. At this point in the analysis, it is infeasible to consider systematic observation of individuals as they develop full schemas, because such development takes an extended period of time and probably requires an entirely new curriculum of study. It is premature to invest time and resources in this new curriculum until the fundamental premise about situation recognition is tested. Such a study of schema development will certainly be necessary at a later time, but the initial question concerns only whether the basic identifications can be made. Thus, at this juncture we ask only whether individuals can acquire and use basic situation knowledge. That is... 

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