Population studies

In Section 4D.2 we introduced two probability distributions commonly encountered when studying populations. The construction of confidence intervals for a normally distributed population was the subject of Section 4D.3. We have yet to address, however, how we can identify the probability distribution for a given population. In Examples 4.11-4.14 we assumed that the amount of aspirin in analgesic tablets is normally distributed. We are justified in asking how this can be determined without analyzing every member of the population. When we cannot study the whole population, or when we cannot predict the mathematical form of a population s probability distribution, we must deduce the distribution from a limited sampling of its members. 

Information on the toxic effects of molybdenum in humans is scarce. A high incidence of gout was reported in a locale in Armenia where the soil contained exceptionally high levels of both molybdenum and copper (15). However, the significance of the suggested correlation is questionable because of the lack of information on the study population and the absence of a control group. 

Central to epidemiology is the use of rates to express the health experience of populations. Rates arc important because epidemiology is inherently a comparative discipline. An epidemiologist is constantly attempting to compare the disease experience of a study population with that of a comparison population, A rate is nothing more than a specialized proportion in which the counts of people with a particular disease are placed over a denominator that is composed of people who are at risk, i,e, who have a chance of dcr cloping the disease. Men, for example, would not be included in the denominator used to calculate the prevalence or incidence of uterine cancer,... 

Please describe planned study population. Choice of participants should be appropriate for the indication proposed. Subjects should not have enrolled in a clinical trial during the preceding 12 weeks. Please describe how special populations such as women of childbearing age, children and the elderly will be handled in this study. Please comment on the special need for close monitoring due to safety considerations. 

The determination of the laser-generated populations rij t) is infinitely more delicate. Computer simulations can certainly be applied to study population relaxation times of different electronic states. However, such simulations are no longer completely classical. Semiclassical simulations have been invented for that purpose, and the methods such as surface hopping were proposed. Unfortunately, they have not yet been employed in the present context. Laser spectroscopic data are used instead the decay of the excited state populations is written n (t) = exp(—t/r ), where Xj is the experimentally determined population relaxation time. The laws of chemical kinetics may also be used when necessary. Proceeding in this way, the rapidly varying component of AS q, t) can be determined. 

Fig. 3.6 Map of Texas coast and adjacent Mexican sites from Ambrosia psilostachys (Ap) study. Populations of Ambrosia cumanensis are represted by Ac. ...

Stroke patients who require mechanical ventilation are not necessarily destined for a poor outcome. In a study by Santoli et al., 58 patients underwent mechanical ventilation and 16 survived. Eleven achieved a Barthel Index (BI) score of 60, indicating a good outcome. Within this study population, those patients with bilaterally absent comeal and pupillary reflexes had uniformly poor outcomes, underscoring the need for careful assessment of brainstem reflexes in intubated stroke patients. Other factors that have been associated with poor outcome in intubated stroke patients are advanced age and lower Glasgow Coma Score (GCS) at the time of intubation, as well as seizures and pulmonary edema. ... 

An update of a previous study (Axelson et al. 1978), Axelson (1986) evaluated an expanded cohort of 1,424 men (levels of trichloroethylene exposure inferred from measured urinary metabolite concentrations) and found a significant increase in incidences of bladder cancer and lymphomas, and a lower than expected incidence of total cancer mortality. A further update of this work (Axelson et al. 1994) expanded the cohort to include 249 women, tracking cancer morbidity over 30 years, and found no correlation between exposure concentration or exposure time and cancer incidence at any site. The highest standardized incidence ratio noted in this study was 1.56 (95% Cl of 0.51-3.64) for 5 cases of non-Hodgkin s lymphoma observed in men. Although four of these cases occurred in persons exposed for at least 2 years, and 3 cases had a latency of 10 years or more, urinary levels of TCA showed that 4 of the 5 cases were exposed to the lowest levels of trichloroethylene (urinary levels of TCA 0-49 mg/L). The study authors mentioned that a urinary TCA level below 50 mg/L corresponds to a trichloroethylene exposure concentration of about 20 ppm. The study authors concluded that "this study provides no evidence that trichloroethylene is a human carcinogen, i.e., when the exposure is as low as for this study population."... 

More recently, large human intervention trials were undertaken with P-carotene alone, or in combination with non-dietary amounts of vitamin E. These trials were undertaken because of promising animal studies that suggested that these antioxidants could offer chemo-preventive action against oxidative stress. The results, which are summarised in Table 11.1, were disappointing. Although the study population in two of the studies (ATBC and CARET)... 

Phase 1 trials are the first in man studies of a new drug in humans. These studies are usually carried out on small samples of subjects. The idea here is to determine the safety of the drug in a small and usually healthy volunteer study population. 

Phase 3 trials are large-scale clinical trials on populations numbering in the hundreds to thousands of patients. These are the critical trials that the drug maker runs to show that its new drug is both safe and efficacious in the target study population. If the phase 3 trials are successful, they will form the keystone elements of a New Drug Application... 

Concomitant or prior medications may be used in either safety or efficacy analyses. The presence of specific medications may be used as covariates for inferential analyses. Also, medications are often summarized to show that the therapies under study come from medically comparable populations. Medications may be used to determine protocol compliance and to help define a protocol-compliant study population. Concomitant medications may be examined to determine whether they interact with study therapy or whether they can explain the presence of certain adverse events. From a CDISC perspective, prior medications would be considered a finding while concomitant medications would be considered an intervention. 

The randomization scheme assigns a therapy randomly across a study population based on various stratification factors such as site, blocking factor, and perhaps subject demographics. There is no actual patient assignment information in this data table. Here is an example of a randomization scheme with a block size of four and a treatment ratio of 2 2 ... 

Key Concepts for Creating Analysis Data Sets 84 Defining Variables Once 84 Defining Study Populations 85 Defining Baseline Observations 85 Last Observation Carried Forward (LOCF) 86 Defining Study Day 89 Windowing Data 91 Transposing Data 94... 

Get data This step involves pulling the data to be used into SAS. It often requires merging treatment or study population data with analysis data sets or some other data to be summarized/listed. 

Mineral Oil Hydraulic Fluids. There is limited information on the toxicity of mineral oil hydraulic fluids in humans. A single case report of a child accidentally ingesting a single dose of automotive transmission fluid provides limited information on death and systemic effects. A case-control study provides some information on the carcinogenicity of mineral oil hydraulic fluids. The study population was exposed via inhalation and dermal routes. An occupational exposure study provides information on neurotoxicity following chronic dermal exposure. Information on the toxicity of mineral oil hydraulic fluids is limited to a series of inhalation, oral, and dermal acute-duration exposures. These studies provide information on death, systemic effects, and neurotoxicity by inhalation, oral, and dermal routes, and immunotoxicity following dermal exposure. 

In a study of 102 cases of occupational lead poisoning, 17 cases of clinically verified chronic nephropathy were found (Lilis et al. 1968). Endogenous creatinine clearance was <80 pg/dL. The mean PbB level for the entire study population was 80 pg/dL (range, 42-141 pg/dL). Nephropathy was more common among those exposed to lead for more than 10 years than among those exposed for less than 10 years. 

The BCS has been developed primarily for regulatory applications, although its use has been extended beyond this area (as discussed in more detail below). The aim of the BCS in a regulatory context is to provide a basis for replacing certain bioequivalence studies by equally or more accurate in vitro dissolution tests. This could reduce costs and time in the development process as well as reducing unnecessary drug exposure in healthy volunteers, which is normally the study population in bioequivalence studies. 

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