Significance, statistical

Assess tolerance Describe or define pharmacokinetics (PK) and pharmacodynamics (PD) Explore drug metabolism and drug interactions Estimate [biological] activity Dose tolerance studies Single- and multiple-dose PK and/or PD studies Drug interaction studies 

Explore use for the targeted indication Estimate dosage for subsequent studies Provide basis for confirmatory study design, endpoints, methodologies Earliest trials of relatively short duration in well-defined narrow patient populations using surrogate of pharmacological endpoints or clinical measures Dose-response exploration studies 

Demonstrate/confirm efficacy Establish safety profile Provide an adequate basis for assessing benefit-Hisk relationship to support licensing [marketing approval] Establish dose-response relationship Adequate and well-controUed studies to establish efficacy Randomized parallel dose-response studies Clinical safety studies Large simple trials Comparative studies 

Refine understanding of benefit-risk relationship in general or special populations and/or environments. Identify less common adverse reactions Refine dosing recommendation Comparative effectiveness studies Studies of mortality-morbidity outcomes Studies of additional endpoints Large simple trials Pharmacoeconomics studies 

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The excess chemiccil potential is thus determined from the average of exp[—lT (r )/fe In ensembles other than the canonical ensemble the expressions for the excess chem potential are slightly different. The ghost particle does not remain in the system and the system is unaffected by the procedure. To achieve statistically significant results m Widom insertion moves may be required. However, practical difficulties are encounte when applying the Widom insertion method to dense fluids and/or to systems contain molecules, because the proportion of insertions that give rise to low values of y f, dramatically. This is because it is difficult to find a hole of the appropriate size and sha... 

Analytical chemists make a distinction between error and uncertainty Error is the difference between a single measurement or result and its true value. In other words, error is a measure of bias. As discussed earlier, error can be divided into determinate and indeterminate sources. Although we can correct for determinate error, the indeterminate portion of the error remains. Statistical significance testing, which is discussed later in this chapter, provides a way to determine whether a bias resulting from determinate error might be present. 

Effects are shown with their 95% confidence intervals. Effects that are similar than their interval are not statistically significant and ate shown with an asterisk. 

Clinical trials for r-IEN-y in RA indicated that the dmg is well tolerated (52). Consistent improvement in tender and swollen joint scores was observed, but a large number of patients were needed in the trial to show statistical significance for r-IEN-y treatment. In certain individuals, responses were remarkable. An additive effect between r-IEN-y and penicillamine was detected. Efficacy was lower when r-IEN-y was combined with gold therapy. Research is continuing. 

Phase III Dmg samples are made available to select clinicians for use on large numbers of patients to obtain statistically significant data for safety and efficacy. 

In defining acute level toxicity foi the purposes of comparing different materials, the LD q itself is not sufficient but the LD q and the 95% confidence limits should be quoted as a minimum. For example, and as demonstrated in Figure 8, two materials (A and B) with different LD q values, but overlapping 95% confidence limits, ate to be considered not statistically significantly different with respect to mortahty at the 50% level this it based on the fact that there is a statistical probabiUty that the LD q of one material could He in the 95% confidence limits of the other, and vice versa. Conversely, when there is no overlap in 95% confidence limits, as shown with material C, it may be concluded that the LD q values ate statistically significantly different. 

Fig. 8. Comparison of three materials on the basis of LD q and 95% confidence internal data. Materials A and B are not statistically significantly different.

Material C, however, has 95% confidence limits at the LD q level which do not overlap those of A or B it is statistically significantly mote lethaHy toxic... 

Fig. 9. The two materials, A and B, have overlapping 95% confidence limits at the LD q level. Because the slopes of the dose—mortahty regression lines for both materials are similar, there is no statistically significant difference in mortahty at the LD q and LD q levels. Both materials may be assumed to be lethahy equitoxic over a wide range of doses, under the specific conditions of the test.

When the data as a whole are reviewed for studies on humans exposed to ethylene oxide, no conclusion can be made that there is an increase in mortahty associated with those exposed to ethylene oxide. Two Swedish studies (247,248) indicated an increase in leukemia for workers exposed to multiple chemicals including ethylene oxide however, in a recent larger Swedish study (249) of workers exposed to only ethylene oxide, there was no association of any type of cancer increase for these workers. In a recent study sponsored by NIOSH, there was no significant increase in mortahty observed for cancer when all types are combined or for certain individual types of cancer, even for those people who worked the longest and were observed the longest. However, a statistically significant increase in mortahty from certain types of lymphoma was observed for male workers. This is contrary to the results observed for female workers. In addition, four other cohort studies of ethylene oxide-exposed workers have been pubhshed (250—253), but no unequivocal increase in the risk of cancer was observed. 

There have been suggestions of alterations in sex ratios following accidental environmental exposure to dioxin in Seveso, Italy, in 1976. Between 1977 and 1984, 74 births occurred in the most heavily contaminated zone which showed an excess of females (26 males and 48 females born). Preliminary evidence suggests that the excess was associated with high dioxin exposure in both parents. Over a later period, between 1985 and 1994, the ratio declined (60 males and 64 females) and was no longer statistically significant. 

The differences for cancer were not statistically significant, but those for the other two categories of disease were (p < 0.05 i.e. only a 1 in 20 chance that the difference was accidental). For all causes, p < 0.001 i.e. only a 1 in 1000 chance that the difference was accidental. 

Computer simulation is an experimental science to the extent that calculated dynamic properties are subject to systematic and statistical errors. Sources of systematic error consist of size dependence, poor equilibration, non-bond interaction cutoff, etc. These should, of course, be estimated and eliminated where possible. It is also essential to obtain an estimate of the statistical significance of the results. Simulation averages are taken over runs of finite length, and this is the main cause of statistical imprecision in the mean values so obtained. 

The optimal sequence obtained, called FSD-1 for full sequence design, is shown in Table 17.2 and compared with the sequence of the template Zif 268. A search of the FSD-1 sequence against protein databases did not reveal a statistically significant similarity with any other protein, including zinc finger proteins. 

Representativeness can be examined from two aspects statistical and deterministic. Any statistical test of representativeness is lacking becau.se many histories are needed for statistical significance. In the absence of this, PSAs use statistical methods to synthesize data to represent the equipment, operation, and maintenance. How well this represents the plant being modeled is not known. Deterministic representativeness can be answered by full-scale tests on like equipment. Such is the responsibility of the NSSS vendor, but for economic reasons, recourse to simplillcd and scaled models is often necessary. System success criteria for a PSA may be taken from the FSAR which may have a conservative bias for licensing. Realism is more expensive than conservatism. 

The pump data is broken down into pump types (each is treated separately) and failure modes (start versus run). The MOV data is separated into MOVs inside the drywell versus those outside the drywell (statistically significant differences exist in observed failure rates). The MOV data also reflects failure to open versus failure to close. The large electrical breaker (4160 V, 480 V) data shows significant differences from both the WASH-1400 and IEEE Std.500 data, i.e., 3 failures in 34,333 demands for 4160 V breakers and 6 failures in 11,238 demands for 480 V breakers. 

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