Biomedical subjects

Dietrich von Rosen

Publications and source records attributed to Dietrich von Rosen.

5 recordsLinked to original sources

PubMed2006

Comparing experimental designs for benchmark dose calculations for continuous endpoints.

The BMD (benchmark dose) method that is used in risk assessment of chemical compounds was introduced by Crump (1984) and is based on dose-response modeling. To take uncertainty in the data and model fitting into account, the lower confidence bound of the BMD estimate (BMDL) is suggested to be used as a point of departure in health risk assessments. In this article, we study how to design optimum experiments for applying the BMD method for continuous data. We exemplify our approach by considering the class of Hill models. The main aim is to study whether an increased number of dose groups and at the same time a decreased number of animals in each dose group improves conditions for estimating the benchmark dose. Since Hill models are nonlinear, the optimum design depends on the values of the unknown parameters. That is why we consider Bayesian designs and assume that the parameter vector has a prior distribution. A natural design criterion is to minimize the expected variance of the BMD estimator. We present an example where we calculate the value of the design criterion for several designs and try to find out how the number of dose groups, the number of animals in the dose groups, and the choice of doses affects this value for different Hill curves. It follows from our calculations that to avoid the risk of unfavorable dose placements, it is good to use designs with more than four dose groups. We can also conclude that any additional information about the expected dose-response curve, e.g., information obtained from studies made in the past, should be taken into account when planning a study because it can improve the design.

Animals↗

PubMed2005

Identification of a critical dose level for risk assessment: developments in benchmark dose analysis of continuous endpoints.

The benchmark dose (BMD) method has been recommended to replace the no-observed-adverse-effect-level (NOAEL) approach in health risk assessment of chemical substances. In the present article, developments in BMD analysis from continuous experimental data are proposed. The suggested approach defines the BMD as the dose at which the slope of the S-shaped dose-response relationship changes the most in the low-dose region. This dose resides in a region where the sensitivity to chemical exposure may start to change noticeably. It is shown that the response (defined as a percent change relative to the magnitude, or size, of response) corresponding to the dose where the slope changes the most depends on the geometrical shape of the dose-response curve; the response becomes lower as the curve becomes more asymmetrical and threshold-like in the low-dose region. Given a symmetrical case, described by the Hill function, the response associated with the critical dose level becomes 21% (defined as a percent change relative to the magnitude, or size, of response). According to a limiting case of asymmetry and threshold-like characteristics, reflected by a Gompertz curve, the response corresponding to the dose of interest becomes as low as 7.3% (defined as a percent change relative to the magnitude, or size, of response). Use of a response in the range of 5-10% when estimating the BMD conservatively accounts for uncertainties associated with the proposed strategy, and may be appropriate in a risk assessment point of view. The present investigation also indicated that a BMD defined according to the suggested procedure may be estimated more precisely relative to BMDs defined under other approaches for continuous data.

Animals↗

PubMed2004

Dose-response modeling and benchmark calculations from spontaneous behavior data on mice neonatally exposed to 2,2',4,4',5-pentabromodiphenyl ether.

In this paper the benchmark dose (BMD) method was introduced for spontaneous behavior data observed in 2-, 5-, and 8-month-old male and female C57Bl mice exposed orally on postnatal day 10 to different doses of 2,2',4,4',5-pentabromodiphenyl ether (PBDE 99). Spontaneous behavior (locomotion, rearing, and total activity) was in the present work quantified in terms of a fractional response defined as the cumulative response after 20 min divided by the cumulative response produced over the whole 1-h test period. The fractional response contains information about the time-response profile (which differs between the treatment groups) and has appropriate statistical characteristics. In the analysis, male and female mice could be characterized by a common dose-response model (i.e., they responded equally to the exposure to PBDE 99). As a primary approach, the BMD was defined as the dose producing a 5 or 10% change in the mean fractional response. According to the Hill model, considering a 10% change the lower bound of the BMD for rearing, locomotion, and total activity was 1.2, 0.85, and 0.31 mg PBDE 99/kg body weight, respectively. A probability-based procedure for BMD modeling was also considered. Using this methodology, the BMD was defined as corresponding to an excess risk of 5 or 10% of falling below cutoff points representing adverse levels of fractional response.

Algorithms↗

PubMed2003

ECT of major depressed patients in relation to biological and clinical variables: a brief overview.

The knowledge that spontaneous or induced convulsions can improve mental disorders has been present for several centuries. electroconvulsive therapy (ECT) has undergone fundamental changes since its introduction, and in the last 15-20 years there has been a legitimate renewal of interest for this therapy. Today the indications for use of ECT seem well codified, and its technique and practices have evolved considerably. It is now firmly established as an important and effective method of treating certain severe forms of depression. However, still very little is known about the mechanism of ECT. In this paper, first, we will give a short overview as to how far we have got concerning ECT in relation to various clinical and biological variables. Second, we will describe ECT in relation to electroencephalographic (EEG) technique and clinical outcome as well as give some proposals as to how to go on with the data analysis of EEG. In conclusion, the superior effect of ECT compared to other antidepressives in severe depression may depend on neurochemical and neurobiological cascade effects initiated by repeated treatments. Above all, ECT offers a unique experimental opportunity to study how neuromodulation of the major transmitter systems may be involved in brain dynamics and alteration of connectivity.

Animals↗

PubMed2003

Benchmark calculations in risk assessment using continuous dose-response information: the influence of variance and the determination of a cut-off value.

A benchmark dose (BMD) is the dose of a chemical that corresponds to a predetermined increase in the response (the benchmark response, BMR) of a health effect. In this article, a method (the hybrid approach) for benchmark calculations from continuous dose-response information is investigated. In the formulation of the methodology, a cut-off value for an adverse health effect has to be determined. It is shown that the influence of variance on the hybrid model depends on the choice of determination of the cut-off point. If the cut-off value is determined as corresponding to a specified tail proportion of the control distribution, P(0), the BMD becomes biased upward when the variance is biased upward. On the contrary, if the cut-off value is directly determined to some level of the continuous response variable, the BMD becomes biased upward when the variance is biased downward. A simulation study was also performed in which the accuracy and precision of the BMD was compared for the two ways of determining the cut-off value. In general, considering BMRs of 1, 5, and 10% (additional risk) the precision of the BMD became higher when the cut-off value was estimated by specifying P(0), relative to the case with a direct determination. Use of the square-root of the maximum-likelihood estimator of the variance in BMD estimation may provide a bias that is reflected by the cut-off formulation (downward bias if specifying P(0), and upward bias if specifying the cut-off, c, directly). This feature may be reduced if an unbiased estimator of the standard deviation is used in the calculations.

Analysis of Variance↗