Multiple-Comparisons Issue

Hypothesis-driven study and the results are easy to interpret small sample size requirement simple analysis no multiple comparison issue low cost easy to validate... 

In summary, there is not much to be gained in using one-way analysis of variance with multiple treatment groups. A simpler analysis structuring the appropriate pairwise comparisons will more directly answer the questions of interest. One final word of caution though undertaking multiple comparisons in this way raises another problem, that of multiplicity. For the time being we will put that issue to one side we will, however, return to it in Chapter 10. 

Multiple confounding issues make interpretation and comparison of these results difficult. Differences in MTX dose and schedule clearly may limit the reproducibility of studies. Furthermore, incomplete ascertainment of toxicity, particularly when performed retrospectively, may impact on study validity. Finally, modest and heteregenous sample sizes clearly limit the available statistical power to detect clinically meaningful differences in treatment response. 

In Chapter 11 we discussed the issue of multiple comparisons and multiplicity in the context of pairwise treatment comparisons following a significant omnibus F test. When we adopt the 5% significance level (a = 0.05), by definition it is likely that a type 1 error will occur when 20 separate comparisons are made. That is, a statistically significant result will be "found" by chance alone. The greater the number of objectives presented in a study protocol, the greater the number of comparisons that will be... 

This approach reduces the number of study participants necessary to achieve the required statistical power in two ways. If the three individual components of the MACE composite endpoint (or the higher number of individual components in a MACE-plus composite endpoint) were compared separately between treatment groups, the numbers of events in each case would be lower than the total number of composite endpoint events. Moreover, a statistical correction would need to be made to address the issue of multiplicity as more comparisons are made, the chances of finding a statistically significant difference that does not in fact exist, i.e., committing a type I error, increase (recall discussions in Chap. 4). To counter this possibility, the alpha level (typically 0.05 for a single comparison) used for each of the multiple comparisons must be lowered. 

The fifth and final chapter, on Parallel Force Field Evaluation, takes account of the fact that the bulk of CPU time spent in MD simulations is required for evaluation of the force field. In the first paper, BOARD and his coworkers present a comparison of the performance of various parallel implementations of Ewald and multipole summations together with recommendations for their application. The second paper, by Phillips et AL., addresses the special problems associated with the design of parallel MD programs. Conflicting issues that shape the design of such codes are identified and the use of features such as multiple threads and message-driven execution is described. The final paper, by Okunbor Murty, compares three force decomposition techniques (the checkerboard partitioning method. 

A critical methodological issue for a proper meta-analysis is the choice of studies. It is important that all studies meet reasonable criteria otherwise, a potential bias is introduced. We chose only those studies that had an appropriate control group, which provided a standard by which a drug s effects could be measured. By contrast, there have been meta-analyses of multiple studies on psychotherapy, all done without comparison groups or with invalid comparison groups. Combining the... 

Classical trajectory studies of the association reactions M+ + H20 and M+ + D20 with M = Li, Na, K (Hase et al. 1992 Hase and Feng 1981 Swamy and Hase 1982,1984), Li+(H20) + H20 (Swamy and Hase 1984), Li+ + (CH3)20 (Swamy and Hase 1984 Vande Linde and Hase 1988), and Cl- + CH3C1 (Vande Linde and Hase 1990a,b) are particularly relevant to cluster dynamics. In these studies, the occurrence of multiple inner turning points in the time dependence of the association radial coordinate was taken as the criterion for complex formation. A critical issue (Herbst 1982) is whether the collisions transfer enough energy from translation to internal motions to result in association. Comparison of association probabilities from various studies leads to the conclusion that softer and/or floppier ions and molecules that have low frequency vibrations typically recombine the most efficiently. Thus, it has been found that Li+ + (CH3)20 association is more likely than Li+ + H20 association, and similarly H20 association with Li(H20)+ is more likely than with the bare cation Li+. The authors found a nonmonotonic dependence of association probability on the assumed HaO bend frequency and also a dependence on the impact parameter, the rotational temperature, and the orientation of the H20 dipole during the collision. 

Then, a comparison of complex formation constants which are tackled in the colloquial manner affords a numerical value which corresponds to an average fractionation capacity of that mixture or biomass sample with respect to metal ions. Yet the scope is broader toxicity issues in comparison of various heavy metals or other biochemical properties such as biocatalytic efficiency can be addressed in the same way as simple accumulation or fractionation (including the fact that fractionation may be amplified relative to differences of complex stabihties by multiple speciation events or by transmembrane transports). 

The IND differs in a number of ways from its European counterparts. First, it is much longer a typical IND is of at least 1000 pages, and for dmgs with foreign human experience, often many multiples of this number. The UK Clinical Trials Certificate, used very rarely for this reason, and not the Clinical Trials Exemption ( CTX ), would be the nearer comparison. Second, an IND is required for all human exposure to INDs, and this includes normal volunteer studies. Third, all being well, there is only a 30-day wait between filing and commencement of the clinical study no news from FDA after this time period has elapsed is presumptive evidence that the study may proceed (most FDA divisions will, in fact, issue affirmative letters that this is the case, within 30 days). Fourth, once an IND has become active, there is no subsequent 30-day wait when further clinical protocols are submitted. 

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