Design of long-term animal bioassay for low-dose extrapolation using a multistage model

Conventional designs of animal bioassays allocate the same number of animals into control and dose groups to explore the spontaneous and induced tumor incidence rates, respectively. The purpose of such bioassays are (a) to determine whether or not the substance exhibits carcinogenic properties, and (b) if so, to estimate the human response at relatively low doses. In this study, it has been found that the optimal allocation to the experimental groups which, in some sense, minimize the error of the estimated response for low dose extrapolation is associated with the dose level and tumor risk. The number of dose levels has been investigated at the affordable experimental cost. The pattern of the administered dose, 1 MTD, 1/2 MTD, 1/4 MTD,....., etc. plus control, gives the most reasonable arrangement for the low dose extrapolation purpose. The arrangement of five dose groups may make the highest dose trivial. A four-dose design can circumvent this problem and has also one degree of freedom for testing the goodness-of-fit of the response model.^ An example using the data on liver tumors induced in mice in a lifetime study of feeding dieldrin (Walker et al., 1973) is implemented with the methodology. The results are compared with conclusions drawn from other studies. ^

THE RELATIONSHIP BETWEEN DEGREE OF BLOOD PRESSURE REDUCTION AND MORTALITY AMONG HYPERTENSIVES IN THE HYPERTENSION DETECTION AND FOLLOW-UP PROGRAM

The relationship between degree of diastolic blood pressure (DBP) reduction and mortality was examined among hypertensives, ages 30-69, in the Hypertension Detection and Follow-up Program (HDFP). The HDFP was a multi-center community-based trial, which followed 10,940 hypertensive participants for five years. One-year survival was required for inclusion in this investigation since the one-year annual visit was the first occasion where change in blood pressure could be measured on all participants. During the subsequent four years of follow-up on 10,052 participants, 568 deaths occurred. For levels of change in DBP and for categories of variables related to mortality, the crude mortality rate was calculated. Time-dependent life tables were also calculated so as to utilize available blood pressure data over time. In addition, the Cox life table regression model, extended to take into account both time-constant and time-dependent covariates, was used to examine the relationship change in blood pressure over time and mortality.^ The results of the time-dependent life table and time-dependent Cox life table regression analyses supported the existence of a quadratic function which modeled the relationship between DBP reduction and mortality, even after adjusting for other risk factors. The minimum mortality hazard ratio, based on a particular model, occurred at a DBP reduction of 22.6 mm Hg (standard error = 10.6) in the whole population and 8.5 mm Hg (standard error = 4.6) in the baseline DBP stratum 90-104. After this reduction, there was a small increase in the risk of death. There was not evidence of the quadratic function after fitting the same model using systolic blood pressure. Methodologic issues involved in studying a particular degree of blood pressure reduction were considered. The confidence interval around the change corresponding to the minimum hazard ratio was wide and the obtained blood pressure level should not be interpreted as a goal for treatment. Blood pressure reduction was attributed, not only to pharmacologic therapy, but also to regression to the mean, and to other unknown factors unrelated to treatment. Therefore, the surprising results of this study do not provide direct implications for treatment, but strongly suggest replication in other populations. ^

THE MEASUREMENT OF HUMANISTIC AND DEHUMANISTIC BEHAVIORS IN HOSPITAL NURSING ENVIRONMENTS

The purpose of this investigation was to develop a reliable scale to measure the social environment of hospital nursing units according to the degree of humanistic and dehumanistic behaviors as perceived by nursing staff in hospitals. The study was based on a conceptual model proposed by Jan Howard, a sociologist. After reviewing the literature relevant to personalization of care, analyzing interviews with patients in various settings, and studying biological, psychological, and sociological frames of reference, Howard proposed the following necessary conditions for humanized health care. They were the dimensions of Irreplaceability, Holistic Selves, Freedom of Action, Status Equality, Shared Decision Making and Responsibility, Empathy, and Positive Affect.^ It was proposed that a scale composed of behaviors which reflected Howard's dimensions be developed within the framework of the social environment of nursing care units in hospitals. Nursing units were chosen because hospitals are traditionally organized around nursing care units and because patients spend the majority of their time in hospitals interacting with various levels of nursing personnel.^ Approximately 180 behaviors describing both patient and nursing staff behaviors which occur on nursing units were developed. Behaviors which were believed to be humanistic as well as dehumanistic were included. The items were classified under the dimensions of Howard's model by a purposively selected sample of 42 nurses representing a broad range of education, experience, and clinical areas. Those items with a high degree of agreement, at least 50%, were placed in the questionnaire. The questionnaire consisted of 169 items including six items from the Marlowe Crowne Social Desirability Scale (Short Form).^ The questionnaire, the Social Environment Scale, was distributed to the entire 7 to 3 shift nursing staff (603) of four hospitals including a public county specialty hospital, a public county general and acute hospital, a large university affiliated hospital with all services, and a small general community hospital. Staff were asked to report on a Likert type scale how often the listed behaviors occurred on their units. Three hundred and sixteen respondents (52% of the population) participated in the study.^ An item analysis was done in which each item was examined in relationship to its correlation to its own dimension total and to the totals of the other dimensions. As a result of this analysis, three dimensions, Positive Affect, Irreplaceability, and Freedom of Action were deleted from the scale. The final scale consisted of 70 items with 26 in Shared Decision Making and Responsibility, 25 in Holistic Selves, 12 in Status Equality, and seven in Empathy. The alpha coefficient was over .800 for all scales except Empathy which was .597.^ An analysis of variance by hospital was performed on the means of each dimension of the scale. There was a statistically significant difference between hospitals with a trend for the public hospitals to score lower on the scale than the university or community hospitals. That the scale scores should be lower in crowded, understaffed public hospitals was not unexpected and reflected that the scale had some discriminating ability. These differences were still observed after adjusting for the effect of Social Desirability.^ In summary, there is preliminary evidence based on this exploratory investigation that a reliable scale based on at least four dimensions from Howard's model could be developed to measure the concept of humanistic health care in hospital settings. ^