Parameter identifiability is required in pooled data methods

In pooled data methods such as naive pooled data methods and NONMEM, the number of sample points per individual may be less than the number of unknown parameters so that the values of the parameters are not estimable in individuals. However, for the moments of the distributions of the parameters to be estimable, the basic parameters must be identifiable.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45052/1/10928_2006_Article_BF02353673.pd

Balance studies on compartmental systems with stochastic inputs

For a population of identical one compartment systems with daily inputs which are random samples from a stationary distribution the mean of the daily balance (balance = input minus excretion) taken over the population of compartments or over days for one compartment is linearly dependent on input with a slope which is independent of the distribution of the inputs and an intercept which depends only on the mean of the distribution of intakes. Analytical and simulation studies on a model with three daily inputs gives essentially similar results. Even if the inputs are not from a stationary distribution but the inputs to a population of compartments are all from the same distribution, one still obtains a linear regression of the mean of the daily balance over the population of compartments, on intake for any particular day but this no longer holds from day to day. This provides a theoretical basis for the interpretation of balance studies on populations of individuals when the daily intakes of an element under study cannot be kept constant.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33422/1/0000824.pd

Diagnosis. II. Diagnostic models based on attribute clusters: A proposal and comparisons

A new discrimination procedure based on the formation of clusters of dependent attributes, and estimation of the joint probability distribution as the product of the probabilities of the disjoint clusters is proposed and investigated. The major advantages of this method are a substantial reduction of the number of probability estimates that must be made, the ability to include symptom dependencies, and the ease and flexibility of its implementation.Comparisons with other discrimination procedures are obtained using Monte Carlo techniques. Results indicate that the proposed model is robust and may lead to gains over the independence and actuarial models, especially for small sample sizes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22084/1/0000508.pd

Effects of Standardized Ileal Digestible Valine:Lysine Ratio on the Growth Performance and Economics of Finishing Pigs from 55 to 100 lb

The objective of these experiments was to determine the effects of SID Val:Lys ratio in low CP and low lysine diets on the growth performance and economics of finishing pigs from 55 to 100 lb. In Exp. 1, a total of 1,134 gilts (PIC 337 × 1050, initially 68.8 lb BW) were used in a 19-d growth trial with 27 pigs per pen and seven pens per treatment in a randomized complete block design with pens blocked by initial average BW. There was a total of six dietary treatments: 59.0, 62.5, 65.9, 69.6, 73.0, and 75.5% SID Val:Lys ratio. In Exp. 2, a total of 2,100 gilts (PIC 327 × 1050, initially 56.6 lb BW) were used in a 22-d growth trial with 25 pigs per pen and 12 pens per treatment in a randomized complete block design with pens blocked by initial average BW. There was a total of seven dietary treatments: 57.0, 60.6, 63.9, 67.5, 71.1, 74.4, and 78.0% SID Val:Lys ratio. In both experiments, the intermediate Val:Lys levels were obtained by blending different proportions of the low and high Val:Lys diets. Responses measured at the pen level were analyzed using general linear and non-linear mixed models. Competing statistical models were: a broken-line linear ascending (BLL) model, a broken-line quadratic ascending (BLQ) model, and a quadratic polynomial (QP). Competing models were compared using Bayesian information criteria (BIC). In Exp. 1, ADG increased linearly (P = 0.009) with increasing SID Val:Lys ratio whereas ADFI only marginally increased (linear, P = 0.098) with no evidence for differences on F/G. Feed cost per pig, feed cost per lb of gain, and total revenue per pig increased (linear, P \u3c 0.009) with increasing SID Val:Lys ratio without evidence for differences in IOFC. In Exp. 2, ADG and ADFI increased (P \u3c 0.002) with increasing SID Val:Lys ratio resulting in an improvement in F/G (P \u3c 0.001). Similarly, increasing SID Val:Lys ratio increased feed cost per pig (quadratic, P \u3c 0.001), feed cost per lb of gain (linear, P \u3c 0.001), total revenue (quadratic, P \u3c 0.001), and IOFC (quadratic, P \u3c 0.001). In conclusion, the SID Val:Lys ratio to optimize performance ranged from 71.0% for minimum F/G to 74.4% for maximum ADG. However, feed cost per lb of gain was minimized at less than 57% SID Val:Lys ratio and maximum income over feed cost was estimated at 62.3% SID Val:Lys ratio with a plateau thereafter. Therefore, 99% of the optimum ADG and F/G were estimated at approximately 69% and 65% SID Val:Lys ratio, respectively

Visualization and exploratory analysis of epidemiologic data using a novel space time information system

Abstract Background Recent years have seen an expansion in the use of Geographic Information Systems (GIS) in environmental health research. In this field GIS can be used to detect disease clustering, to analyze access to hospital emergency care, to predict environmental outbreaks, and to estimate exposure to toxic compounds. Despite these advances the inability of GIS to properly handle temporal information is increasingly recognised as a significant constraint. The effective representation and visualization of both spatial and temporal dimensions therefore is expected to significantly enhance our ability to undertake environmental health research using time-referenced geospatial data. Especially for diseases with long latency periods (such as cancer) the ability to represent, quantify and model individual exposure through time is a critical component of risk estimation. In response to this need a STIS – a Space Time Information System has been developed to visualize and analyze objects simultaneously through space and time. Results In this paper we present a "first use" of a STIS in a case-control study of the relationship between arsenic exposure and bladder cancer in south eastern Michigan. Individual arsenic exposure is reconstructed by incorporating spatiotemporal data including residential mobility and drinking water habits. The unique contribution of the STIS is its ability to visualize and analyze residential histories over different temporal scales. Participant information is viewed and statistically analyzed using dynamic views in which values of an attribute change through time. These views include tables, graphs (such as histograms and scatterplots), and maps. In addition, these views can be linked and synchronized for complex data exploration using cartographic brushing, statistical brushing, and animation. Conclusion The STIS provides new and powerful ways to visualize and analyze how individual exposure and associated environmental variables change through time. We expect to see innovative space-time methods being utilized in future environmental health research now that the successful "first use" of a STIS in exposure reconstruction has been accomplished.http://deepblue.lib.umich.edu/bitstream/2027.42/112824/1/12942_2004_Article_41.pd

Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin

A four compartment mechanistic mathematical model is developed for the pharmacokinetics of the commonly used anti-malarial drug artesunate and its principle metabolite dihydroartemisinin following oral administration of artesunate. The model is structurally unidentifiable unless additional constraints are imposed. Combinations of mechanistically derived constraints are considered to assess their effects on structural identifiability and on model fits. Certain combinations of the constraints give rise to locally or globally identifiable model structures. Initial validation of the model under various combinations of the constraints leading to identifiable model structures was performed against a dataset of artesunate and dihydroartemisinin concentration–time profiles of 19 malaria patients. When all the discussed constraints were imposed on the model, the resulting globally identifiable model structure was found to fit reasonably well to those patients with normal drug absorption profiles. However, there is wide variability in the fitted parameters and further investigation is warranted

Alpha-aminoisobutyric acid uptake in primary cultures of astrocytes

Homotypically pure cultures of rat brain astrocytes were used to examine some aspects of non-neuronal A-system (alanine preferring) amino acid uptake. The Asystem specific probe, alpha-aminoisobutyric acid is transported rapidly, and a steady state distribution ratio of 9–25 is reached after 30 minute incubations. Kinetic estimates derived from uptake progress curves indicated a K m of 1.35 mM and a V max of 133 nmol/min/mg protein. Uptake is reduced in the absence of either Na + or K + . Elevations in extracellular K + , a putative metabolic modulator of neuroglia, did not affect uptake.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45428/1/11064_2004_Article_BF00965086.pd

Global, local and focused geographic clustering for case-control data with residential histories

BACKGROUND: This paper introduces a new approach for evaluating clustering in case-control data that accounts for residential histories. Although many statistics have been proposed for assessing local, focused and global clustering in health outcomes, few, if any, exist for evaluating clusters when individuals are mobile. METHODS: Local, global and focused tests for residential histories are developed based on sets of matrices of nearest neighbor relationships that reflect the changing topology of cases and controls. Exposure traces are defined that account for the latency between exposure and disease manifestation, and that use exposure windows whose duration may vary. Several of the methods so derived are applied to evaluate clustering of residential histories in a case-control study of bladder cancer in south eastern Michigan. These data are still being collected and the analysis is conducted for demonstration purposes only. RESULTS: Statistically significant clustering of residential histories of cases was found but is likely due to delayed reporting of cases by one of the hospitals participating in the study. CONCLUSION: Data with residential histories are preferable when causative exposures and disease latencies occur on a long enough time span that human mobility matters. To analyze such data, methods are needed that take residential histories into account

Use of parallel erlang density functions to analyze first-pass pulmonary uptake of multiple indicators in dogs

The gamma and Erlang density functions describe a large class of lagged, right-skewed distributions. The Erlang distribution has been shown to be the analytic solution for a chain of compartments with identical rate constants. This relationship makes it useful for the analysis of first-pass pulmonary drug uptake data following intravenous bolus administration and the incorporation of this analysis into an overall systemic drug disposition model. However, others have shown that one Erlang density function characterizes the residence time distribution of solutes in single tissues with significant systematic error. We propose a model of two Erlang density functions in parallel that does characterize well the arterial appearance of indocyanine green, antipyrine, and alfentanil administered simultaneously by right atrial bolus injection. We derive the equations that permit calculation of the higher order moments of a system consisting of two parallel Erlang density functions and use the results of these calculations from the data for all three indicators to estimate pulmonary capillary blood volume and mean transit time in the dog.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45054/1/10928_2006_Article_BF02353481.pd