Endpoint choice

An example the hippocampus in Alzheimer s disease The mechanistic aim of pharmacology Hippocampus-specific endpoints Choice of representative subjects Conclusion Perspectives... 

Time is a critical measure for clinical trial analysis. Time is captured in clinical trial databases in a study day variable. Study day can be defined as the number of days from therapeutic intervention to any given time point or event. By defining study day, you create a common metric for measuring time across a population of patients in a clinical trial. There can be a study day calculation for any time point of interest. Adverse event start, study termination, and clinical endpoint event date all make good choices for study day calculations. The study day calculation is performed with one of the two following approaches. 

The selection of suitable single species and protocols is not a trivial task and may be dependent on various factors. Some of these include simplicity, low cost, or modest material and equipment demand. However, a higher sensitivity than other species to toxicants may be decisive in this choice in order to serve as warning systems. Table 1 shows the sensitivity in terms of effective concentration (EC50), which is the toxicity endpoint for the organisms (bacteria, crustaceans, algae, and fish) selected for the toxicity bioassays. These toxicity bioassays are usually classified according to the test species involved. 

These databases are a rich source of information, yet they do not capture an element of interest, namely the biological endpoint there is no searchable field to identify, in a quantitative manner, what is the target-related activity of a particular compound. Such information is important if one considers that (a) not all chemotypes indexed in patent databases are indeed active - some are just patent claims with no factual basis and that (b) not aU chemotypes disclosed as active are equally active, or selective for that matter, on the target of choice. Furthermore, should one decide to pursue a certain interaction hotspot in a given ligand-receptor structure (assuming good structure-activity models are available), it would be very convenient to mine structure-activity databases for similar chemotypes to use as potential bioisosteric replacements. 

It is important when choosing a particular measurement scale to answer a number of questions. Is the choice that is made of clinical relevance How is the endpoint to be measured Can we measure the clinical endpoint directly, or must we choose an indirect approach Is the choice that is made sensitive enough to measure real treatment effects Having collected the information how are we to analyse it Some of these issues are illustrated in the following sections. 

Questions 2 and 3 imply a choice between expressing effects in terms of magnitude, frequency, and certainty. In practice, the assessment endpoint may often need to be dehned in terms of 2 or 3 of these dimensions. For example, it may be desirable to estimate the proportion of species (frequency) that will experience different levels of mortality (magnitude), and to provide confidence limits (certainty). Indeed, the risk manager s questions may imply an assessment endpoint with more than 3 dimensions, for example, if it is desired to express frequency in terms of space (e.g., number of hectares) and time (proportion of years). The dimensionality of the assessment endpoint will have major implications for all aspects of the analysis and for communication of results, so it is essential to discuss it carefully with the risk manager at the outset to ensure it meets their needs. 

The choice of assessment scenario, like the assessment endpoint, is likely to be implied by the management goal and should be made in close consultation with the risk manager, to ensure it meets their needs. 

When the analysis is based on a continuous outcome there is commonly the choice of whether to use the raw outcome variable or the change from baseline as the primary endpoint. Whichever of these endpoints is chosen, the baseline value should be included as a covariate in the primary analysis. The use of change from baseline without adjusting for baseline does not generally constitute an appropriate covariate adjustment. Note that when the baseline is included as a covariate in the model, the estimated treatment effects are identical for both change from baseline and the raw outcome analysis. ... 

The primary endpoint is that endpoint which provides the best measure of treatment response/success and such choices are based on clinical arguments rather than statistical ones. It seems unlikely that a change in this could be justified. 

Finally most therapeutic specific guidelines contain recommendations that directly impact on statistical considerations, for example in terms of the definition of endpoints, the requirement for more than one primary endpoint, the definition of analysis sets and the choice of A. In a particular therapeutic setting it is self-evident that the requisite guidelines should be studied carefully in order to extract relevant information for statistical aspects of design and analysis. 

There are two types of Karl Fisher titrations volumetric and coulometric. Volumetric titration is used to determine relatively large amounts of water (1 to 100. ig) and can be performed using the single- or two-component system. Most commercially available titrators make use of the one-component titrant, which can be purchased in two strengths 2 mg of water per milliliter of titrant and the 5 mg of water per milliliter of titrant. The choice of concentration is dependent on the amount of water in the sample and any sample size limitations. In both cases, the sample is typically dissolved in a methanol solution. The iodine/SCVpyridine (imidazole) required for the reaction is titrated into the sample solution either manually or automatically. The reaction endpoint is generally detected bivoltametrically. 

A number of practical considerations affect the choice of experimental approaches to address a specific question. In general, these practical considerations tend to have a greater impact on applications to toxicology (where specific endpoints may not be measurable in all cell types) than studies of xenobiotic metabolism (where the principal requirement is enzyme activity). However, applications to toxicology should be considered when making a choice of an experimental approach as specific toxicological issues may develop from the metabolism studies or in other aspects of the safety assessment processes. 

The choice of titration protocol to determine the TA of a sample is dependent primarily on the color of the sample. The colorimetric titration uses phenolphthalein indicator solution to determine the endpoint of the titration. Phenolphthalein indicator solution turns from colorless to pink upon reaching the endpoint therefore, if the color of the sample interferes with this color change, the potentiometric titration is the best method. However, when using colorimetric titration, it is also common to titrate to an endpoint of pH 8.2, the endpoint of the phenolphthalein solution. 

Weyers, A. and Vollmer, G. (2000) Algal growth inhibition effect of the choice of growth rate or biomass as endpoint on the classification and labelling of new substances notified in the EU, Chemosphere 41 (7), 1007-1010. 

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