POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders.

PURPOSE: To review our clinical experience and determine if there are appropriate signs and symptoms to consider POLG sequencing prior to valproic acid (VPA) dosing in patients with seizures. METHODS: Four patients who developed VPA-induced hepatotoxicity were examined for POLG sequence variations. A subsequent chart review was used to describe clinical course prior to and after VPA dosing. RESULTS: Four patients of multiple different ethnicities, age 3-18 years, developed VPA-induced hepatotoxicity. All were given VPA due to intractable partial seizures. Three of the patients had developed epilepsia partialis continua. The time from VPA exposure to liver failure was between 2 and 3 months. Liver failure was reversible in one patient. Molecular studies revealed homozygous p.R597W or p.A467T mutations in two patients. The other two patients showed compound heterozygous mutations, p.A467T/p.Q68X and p.L83P/p.G888S. Clinical findings and POLG mutations were diagnostic of Alpers-Huttenlocher syndrome. CONCLUSION: Our cases underscore several important findings: POLG mutations have been observed in every ethnic group studied to date; early predominance of epileptiform discharges over the occipital region is common in POLG-induced epilepsy; the EEG and MRI findings varying between patients and stages of the disease; and VPA dosing at any stage of Alpers-Huttenlocher syndrome can precipitate liver failure. Our data support an emerging proposal that POLG gene testing should be considered in any child or adolescent who presents or develops intractable seizures with or without status epilepticus or epilepsia partialis continua, particularly when there is a history of psychomotor regression.

Rationale for reading fluconazole MICs at 24 hours rather than 48 hours when testing Candida spp. by the CLSI M27-A2 standard method.

We investigated if CLSI M27-A2 Candida species breakpoints for fluconazole MIC are valid when read at 24 h. Analysis of a data set showed good correlation between 48- and 24-h MICs, as well as similar outcomes and pharmacodynamic efficacy parameters, except for isolates in the susceptible dose-dependent category, such as Candida glabrata.

Estimating the mean and standard deviation of concentration distributions using censored samples

Environmental data sets of pollutant concentrations in air, water, and soil frequently include unquantified sample values reported only as being below the analytical method detection limit. These values, referred to as censored values, should be considered in the estimation of distribution parameters as each represents some value of pollutant concentration between zero and the detection limit. Most of the currently accepted methods for estimating the population parameters of environmental data sets containing censored values rely upon the assumption of an underlying normal (or transformed normal) distribution. This assumption can result in unacceptable levels of error in parameter estimation due to the unbounded left tail of the normal distribution. With the beta distribution, which is bounded by the same range of a distribution of concentrations, $\rm\lbrack0\le x\le1\rbrack,$ parameter estimation errors resulting from improper distribution bounds are avoided. This work developed a method that uses the beta distribution to estimate population parameters from censored environmental data sets and evaluated its performance in comparison to currently accepted methods that rely upon an underlying normal (or transformed normal) distribution. Data sets were generated assuming typical values encountered in environmental pollutant evaluation for mean, standard deviation, and number of variates. For each set of model values, data sets were generated assuming that the data was distributed either normally, lognormally, or according to a beta distribution. For varying levels of censoring, two established methods of parameter estimation, regression on normal ordered statistics, and regression on lognormal ordered statistics, were used to estimate the known mean and standard deviation of each data set. The method developed for this study, employing a beta distribution assumption, was also used to estimate parameters and the relative accuracy of all three methods were compared. For data sets of all three distribution types, and for censoring levels up to 50%, the performance of the new method equaled, if not exceeded, the performance of the two established methods. Because of its robustness in parameter estimation regardless of distribution type or censoring level, the method employing the beta distribution should be considered for full development in estimating parameters for censored environmental data sets. ^

Cost-benefit analysis: The ``gold standard'' re-examined

The dissertation reviews the recommendations of the Panel on Cost Effectiveness in Health and Medicine (Panel) convened by the US Public Health Service in 1993 in four areas: aggregation of costs and benefits, methods of estimating resources used, definition of population impacted and perspective used in cost benefit analysis. Financial data from a clinical trial was used to test whether different approaches in each of the above four areas would change the net benefit resulting from a cost benefit analysis. Differences in aggregation of cost and benefit resulted in the same net benefit, but not the same cost/benefit ratios. Differences in resource use estimation methods, population subgroups definitions and perspectives all produced different net benefits. Difference in perspective resulted in different and often opposing decisions as to whether the proposed intervention from the clinical trial should be implemented. ^