A note on confidence intervals with extended least squares parameter estimates.

It has previously been shown that the extended least squares (ELS) method for fitting pharmacokinetic models behaves better than other methods when there is possible heteroscedasticity (unequal error variance) in the data. Confidence intervals for pharmacokinetic parameters, at the target confidence level of 95%, computed in simulations with several pharmacokinetic and error variance models, using a theoretically reasonable approximation to the asymptotic covariance matrix of the ELS parameter estimator, are found to include the true parameter values considerably less than 95% of the time. Intervals with the ordinary least squares method perform better.

Some clarifications regarding moments of residence times with pharmacokinetic models.

The stochastic formulation of linear kinetic models is elaborated in order to introduce some new concepts and help clarify the meaning and role of residence time moments. Certain conditional moments are introduced. Multicompartment and steady-state dosing within the stochastic context are considered.

Enterolith ileus resulting from small bowel diverticulosis.

Small intestine diverticula are infrequent. These acquired pulsion diverticula are postulated to be a result of intestinal dyskinesis. Usually asymptomatic, they can produce a variety of disorders such as malabsorption, hemorrhage, diverticulitis, and perforation.

Evaluation of a Bayesian regression-analysis computer program for predicting phenytoin concentration.

A microcomputer program using Bayesian regression analysis to predict serum phenytoin concentrations was evaluated. Phenytoin concentration-time data from nine healthy male volunteers and one male patient were obtained from published studies. For two different dosage regimens that each subject received, the last available predose concentration on the sixth day of the regimen was predicted using observed predose concentrations on both the morning of the third day and on each of the first three days of phenytoin administration.

Flow cytometric analysis of lymphocyte phenotypes in AIDS using monoclonal antibodies and simultaneous dual immunofluorescence.

Simultaneous dual immunofluorescence and flow cytometry was used to study sixteen lymphocyte phenotypes in 209 men including: healthy homosexuals, lymphadenopathy patients (LAN), and AIDS patients. Significant differences between the distribution of lymphocytes in healthy homosexuals and healthy heterosexuals were decreased percentages of helper/inducer T cells (Leu 3), increased cytotoxic/suppressor T cells (Leu 2), and consequently a decreased Leu 3/Leu 2 ratio. The increased Leu 2 cells were identified as functionally cytotoxic subset Leu 2+ 15- phenotype rather than suppressor cells which are Leu 15+.

Sudden infant death syndrome: epidemiological comparisons between South Australia and communities with a different incidence.

Comparison of perinatal, environmental and infant care factors in communities with different Sudden Infant Death Syndrome (SIDS) incidences could reveal ways of reducing SIDS frequency in the higher incidence community. The incidence of SIDS in Sweden is much lower than that in Adelaide. Several factors known to be significant in SIDS are less common in Sweden: teenage mothers, low birthweight and the failure to immunize infants.

Renewal and release of hemopoietic stem cells: does clonal succession exist?

The term "clonal succession" was proposed 20 years ago by Kay to characterize the release of stem cells from their primary pool, followed by the expansion of each cell to a clone and the succession of new clones as the mature cells of each clone are lost because of their finite life span. The authors point out that the events described by Kay as clonal succession are necessary features of hemopoietic proliferation. Clonal succession is equivalent to the universally recognized existence of a self-replicating primary stem cell pool that continuously supplies cells for amplification and maturation to subsequent compartments.

Long-term disability associated with flail chest injury.

Twenty-two trauma victims who had sustained flail chest as their only significant injury were evaluated to determine the final outcome. Fourteen patients (63.9 percent) were found to have long-term sequelae.

The usefulness of preoperative laboratory screening.

We assessed the usefulness of routine laboratory screening of preoperative patients. Computer-readable laboratory, demographic, and discharge diagnostic data were assembled for 2,000 patients undergoing elective surgery over a four-month period, and randomly selected samples of patients were studied. Several tests ordered by protocol and performed by the laboratory at the time of admission were examined in these samples, including complete blood cell count, differential cell count, prothrombin time, partial thromboplastin time, platelet count, six-factor automated multiple analysis, and glucose level.

Pharmacokinetic parameter estimates from several least squares procedures: superiority of extended least squares.

The precision of pharmacokinetic parameter estimates from several least squares parameter estimation methods are compared. The methods can be thought of as differing with respect to the way they weight data. Three standard methods, Ordinary Least Squares (OLS-equal weighting), Weighted Least Squares with reciprocal squared observation weighting [WLS(y-2)], and log transform OLS (OLS(ln))--the log of the pharmacokinetic model is fit to the log of the observations--are compared along with two newer methods, Iteratively Reweighted Least Squares with reciprocal squared prediction weighting (IRLS,(f-2)), and Extended Least Squares with power function "weighting" (ELS(f-xi)--here xi is regarded as an unknown parameter).

Extended least squares nonlinear regression: a possible solution to the "choice of weights" problem in analysis of individual pharmacokinetic data.

It is often difficult to specify weights for weighted least squares nonlinear regression analysis of pharmacokinetic data. Improper choice of weights may lead to inaccurate and/or imprecise estimates of pharmacokinetic parameters. Extended least squares nonlinear regression provides a possible solution to this problem by allowing the incorporation of a general parametric variance model.

Relationship of urinary polyamines to tumor activity and tumor volume in patients.

Serially obtained urinary polyamine levels were determined for 192 patients during a specified time period. The number of patient urine samples totaled 938. The patients had tumors of either the breast, stomach, prostate, or female genital tract, or metastatic carcinomas of unknown origin.

Population pharmacokinetic data and parameter estimation based on their first two statistical moments.

A statistical model is set forth that can be taken as a very general description of most data sets that arise from population pharmacokinetic studies. A (nontraditional) method for estimating the parameters of the model--called the NONMEM method in previously published papers--is described. This method involves a linearization of the model.

Computation of the explicit solution to the Michaelis-Menten equation.

An explicit solution to the Michaelis-Menten differential equation with bolus and zero-order input is presented. This solution involves certain simple functions whose values are not readily available. Efficient algorithms for computing values of these functions to any desired degree of accuracy and FORTRAN codes for implementing them are also given.

Evaluation of methods for estimating population pharmacokinetic parameters. III. Monoexponential model: routine clinical pharmacokinetic data.

Individual pharmacokinetic parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean kinetics, interindividual kinetic variability, and residual variability, including intraindividual variability and measurement error. Individual pharmacokinetics are estimated by fitting a pharmacokinetic model to individual data. Population pharmacokinetic parameters have traditionally been estimated by doing this separately for each individual, and then combining the individual parameter estimates, the Standard Two Stage (STS) approach.

Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-Bayesian methods.

One may attempt to individualize drug dosage by estimating an individual's pharmacokinetic parameters. Information useful for this purpose consists of certain population pharmacokinetic parameters (notably those describing the typical relationship between dosage and drug concentrations) and also measured drug concentrations from the individual of concern. Both types of information should be used.

Further evidence for the use of polyamines as biochemical markers for malignant tumors.

One hundred ninety patients with a variety of tumor presented within a specified time period and fit a specified protocol. Multiple serial urinary putrescine, spermidine, and spermine levels were obtained in these patients, and their disease activity over time, defined as either active or nonactive, was determined by clinical examination, the results of laboratory tests, and radiological criteria. Twenty-four-hr urine collections were used for analysis of polyamine levels.

On the solution to the Michaelis-Menten equation.

An "explicit" solution to the Michaelis-Menten differential equation is presented. Instead of involving the exponential function, the solution involves another simple function. A table for this function is presented.

Estimating population kinetics.

This paper will review the methods that have been advanced for the estimation of parameters of models quantifying the population characteristics of the kinetic behavior of endogenous and exogenous substances in individuals of the population. Such methods are used frequently, for example, in pharmacokinetic studies. In certain populations, especially biological ones, considerable kinetic variability between population members is present.

Evaluation of methods for estimating population pharmacokinetic parameters. II. Biexponential model and experimental pharmacokinetic data.

Individual pharmacokinetic parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean-kinetics, interindividual variability, and residual variability, including intraindividual variability and measurement error. Individual pharmacokinetics are estimated by fitting individual data to a pharmacokinetic model. Population pharmacokinetic parameters have been estimated either by fitting all individuals' data together as though there were no individual kinetic difference, the naive pooled data (NPD) approach, or by fitting each individuals' data separately and then combining the individual parameter estimates, the two stage (TS) approach.

Some suggestions for measuring predictive performance.

The performance of a prediction or measurement model is often evaluated by computing the correlation coefficient and/or the regression of predictions on true (reference) values. These provide, however, only a poor description of predictive performance. The mean square prediction error (precision) and the mean prediction error (bias) provide better descriptions of predictive performance.

Evaluation of methods for estimating population pharmacokinetics parameters. I. Michaelis-Menten model: routine clinical pharmacokinetic data.

Individual pharmacokinetic par parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean kinetics, interindividual variability, and residual intraindividual variability plus measurement error. Individual pharmacokinetics are estimated by fitting individual data to a pharmacokinetic model. Population pharmacokinetic parameters are estimated either by fitting all individual's data together as though there was no individual kinetic differences (the naive pooled data approach), or by fitting each individual's data separately, and then combining the individual parameter estimates (the two-stage approach).

Sudden infant death syndrome.

The death of an infant has always resulted in grief and distress to the family involved. When this death occurs in an apparently healthy infant without warning and for no apparent reason, the grief can be magnified and complicated by feelings of confusion, self-recrimination, guilt and fear. Some of these complications can be avoided by early and adequate explanation, and the assurance that while the specific cause of Sudden Infant Death Syndrome is not known, a great deal is known about the condition and this information is available to parents.