The Study Design

To summarize, the three main scientific questions we wished to answer were  

Are changes in the secondary structure of the proteins detectable by SFTIRM  

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Do target populations exist, such as children, that require particular attention in the study design ... 

In the development of the study design for an LSMBS, it is worthwhile to keep in mind that regulatory authorities have no established protocols or guidance for this type of study. If the results of the study will be submitted to a regulatory authority, it is advisable to meet with staff of the authority prior to finalization of the protocol, so that mutual understanding and consensus can be reached on the design. 

QA is an important aspect of any technical study. It is particularly crucial in an LSMBS, because several hundred participants, widely separated geographically, are involved. The analytical laboratories typically have standard provisions for QA inspections and reviews, and the field phase management organization is also likely to have standard provisions for QA inspection and review. Shoppers, however, are typically external to study management and analytical laboratories and, thus, are not directly covered by existing QA systems. The study design must include a means by which the field phase, i.e., sample collection and shipment by the shoppers, is made to comply with QA requirements. 

The quantity of QC samples to be collected is dependent on the study design, but Aeld blanks and held replicates should represent approximately 5-10% of the groundwater samples collected for the study. QC samples should be collected on the same day, using the same supplies and equipment, and be stored and shipped under the same conditions as the groundwater samples collected for pesticide analysis. Document all procedures, equipment, and reference chemicals used to generate the QC samples. 

NO acts as an autocrine factor that mediates HIV-1 replication as at the molecular level, NO seems to stimulate long-terminal repeat-mediated transcription [125]. It was noted that exogenous NO increases replication of HIV-1 T-tropic isolates in primary T cells or T-cell lines, and inhibitors of iNOS partly block HIV-1 replication, especially that induced by tumor necrosis factor a [125]. The contrasting effects of exogenous NO, particularly NO donors, may depend on the type of NO donors, their releasing kinetics, and the dose used in the study design. 

Parameters of interest in the repeat-dose study can be considered as sets of measures, each with its own history, rationale, and requirements. It is critical to remember, however, that the strength of the study design as a scientific evaluation lies in the relationships and patterns of effects that are seen not in simply looking at each of these measures (or groups) as independent findings, but rather as integrated profiles of biological effects. 

The first precise or calculable aspect of experimental design encountered is determining sufficient test and control group sizes to allow one to have an adequate level of confidence in the results of a study (that is, in the ability of the study design with the statistical tests used to detect a true difference, or effect, when it is present). The statistical test contributes a level of power to such a detection. Remember that the power of a statistical test is the probability that a test results in rejection of a hypothesis, H0 say, when some other hypothesis, H, say, is valid. This is termed the power of the test with respect to the (alternative) hypothesis H. ... 

In the process of PK/PD modeling, it is important to describe, prospectively, the objectives of the modeling, the study design, and the available PK and PD data. The assumptions of the model can be related to dose-response, PK, PD, or one or more of the assumptions listed in Table 18.1. 

Model validation is a process that involves establishing the predictive power of a model during the study design as well as in the data analysis stages. The predictive power is estimated through simulation that considers distributions of PK, PD, and study-design variables. A robust study design will provide accurate and precise model-parameter estimations that are insensitive to model assumptions. 

The study design includes a discussion of the appropriateness of the research methods. 

Granulation and discoloration of kidneys and a decrease in kidney-to-brain-weight ratio was reported in minks fed 6.19 mg/kg/day of heptachlor daily for 28 days (Aulerich et al. 1990). Rats receiving 0.5 mg/kg/day of heptachlor in the diet in an intermediate-duration study showed a statistically significant increase in blood urea (Enan et al. 1982). Increased blood urea may indicate renal inefficiency in metabolism and clearance of protein by-products. This study is limited in that histologic examination was not included in the study design and insufficient dose levels were utilized to establish a dose response. 

Studies on health effects of PAEs in humans have remained controversial due to limitations of the study design. Some findings in human populations are consistent with animal data, suggesting that PAEs and their metabolites produce toxic effects in the reproductive system. Some studies associate monoesters PAEs with semen parameters, sperm DNA damage, and hormones in human population, but none of them are statistically significant. Urinary monomethyl phthalate (MMP), monobenzyl phthalate (MBzP), mono- -butyl phthalate (MBP), MEHP, and monoethyl phthalate (MEP) were associated with poor sperm morphology and vigor, and with low sperm concentration, motility, and linearity [31-35]. However, it is not yet possible to conclude whether phthalate exposure is harmful for human reproduction. 

Studies on health effects of PAEs in humans have remained controversial due to limitations of the study designs. Some findings in human populations are consistent with animal data suggesting that PAEs and their metabolites produce toxic effects in the reproductive system. However, it is not yet possible to conclude whether phthalate exposure is harmful for human reproduction [116]. 

Inclusion of a study does not imply acceptance of the adequacy of the study design or of the analysis and interpretation of the results, and limitations are clearly outlined in square brackets at the end of each study description. The reasons for not giving further consideration to an individual study are also indicated in square brackets. 

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