Using intervention time series analyses to assess the effects of imperfectly identifiable natural events: A general method and example

BACKGROUND: Intervention time series analysis (ITSA) is an important method for analysing the effect of sudden events on time series data. ITSA methods are quasi-experimental in nature and the validity of modelling with these methods depends upon assumptions about the timing of the intervention and the response of the process to it. METHOD: This paper describes how to apply ITSA to analyse the impact of unplanned events on time series when the timing of the event is not accurately known, and so the problems of ITSA methods are magnified by uncertainty in the point of onset of the unplanned intervention. RESULTS: The methods are illustrated using the example of the Australian Heroin Shortage of 2001, which provided an opportunity to study the health and social consequences of an abrupt change in heroin availability in an environment of widespread harm reduction measures. CONCLUSION: Application of these methods enables valuable insights about the consequences of unplanned and poorly identified interventions while minimising the risk of spurious results.

Reflections on the development and implementation of an early warning system for ecstasy and related drug markets in Australia

Regular and systematic monitoring of drug markets provides the basis for evidence-based policy. In Australia, trends in ecstasy and related drug (ERD) markets have been monitored in selected jurisdictions since 2000 and nationally since 2003, by the Party Drugs Initiative (PDI). The PDI maximises the validity of conclusions by triangulating information from (a) interviews with regular ecstasy users (REU), (b) interviews with key experts and (c) indicator data. There is currently no other system in Australia for monitoring these markets systematically; however, the value of the PDI has been constrained by the quality of available data. Difficulties in recruiting and interviewing appropriate consumers (REU) and key experts have been experienced, but largely overcome. Limitations of available indicator data from both health and law enforcement continue to present challenges and there remains considerable scope for enhancing existing routine data collection systems, to facilitate monitoring of ERD markets. With an expanding market for ecstasy and related drugs in Australia, and in the context of indicator data that continue to be limited in scope and detail, there is a strong argument for the continued collection of annual, comparable data from a sentinel group of REU, such as those recruited for the PDI.

A survey of regular ecstasy users' knowledge and practices around determining pill content and purity: Implications for policy and practice.

Objective: To examine the methods used by a sample of regular ecstasy users to determine the content and purity of ecstasy pills, their knowledge of the limitations of available pill testing methods, and how pill test results would influence their drug use behaviour. Method: Data were collected from regular ecstasy users (n = 810) recruited from all eight capital cities of Australia. Data were analysed using multiple logistic regression and chi-square (chi(2)) tests of association. Open-ended responses were coded for themes. Results: The majority of the sample(84%) reported attempting to find out the content and purity of ecstasy at least some of the time, most commonly asking friends or dealers. Less than one quarter (22%) reported personal use of testing kits. There was a moderate level of awareness of the limitations of testing kits among those who reported having used them. Over half (57%) of those reporting personal use of testing kits reported that they would not take a pill if test results indicated that it contained ketamine and over three quarters (76%) reported that they would not take an "unknown" pill (producing no reaction in a reagent test). Finally, a considerable majority (63%) expressed interest in pill testing should it be more widely available. Conclusions: The majority of regular ecstasy users sampled in this Australian study report previous attempts to determine the content and purity of pills sold as ecstasy. Although only a small proportion have used testing kits, many report that they would do so if they were more widely available. The results of pill tests may influence drug use if they indicate that pills contain substances which ecstasy users do not want to ingest or are of unknown content. More detailed research examining ways in which pill testing may influence drug use is required to inform evidence-based policy. (c) 2006 Elsevier B.V. All rights reserved.

Comparative cost-effectiveness of policy instruments for reducing the global burden of alcohol, tobacco and illicit drug use

Alcohol, tobacco and illicit drug use together pose a formidable challenge to international public health. Building on earlier estimates of the demonstrated burden of alcohol, tobacco and illicit drug use at the global level, this review aims to consider the comparative cost-effectiveness of evidence-based interventions for reducing the global burden of disease from these three risk factors. Although the number of published cost-effectiveness studies in the addictions field is now extensive ( reviewed briefly here) there are a series of practical problems in using them for sector-wide decision making, including methodological heterogeneity, differences in analytical reference point and the specificity of findings to a particular context. In response to these limitations, a more generalised form of cost-effectiveness analysis (CEA) is proposed, which enables like-with-like comparisons of the relative efficiency of preventive or individual-based strategies to be made, not only within but also across diseases or their risk factors. The application of generalised CEA to a range of personal and non-personal interventions for reducing the burden of addictive substances is described. While such a development avoids many of the obstacles that have plagued earlier attempts and in so doing opens up new opportunities to address important policy questions, there remain a number of caveats to population-level analysis of this kind, particularly when conducted at the global level. These issues are the subject of the final section of this review.

Gene expression in human alcoholism: Microarray analysis of frontal cortex

Background: Changes in brain gene expression are thought to be responsible for the tolerance, dependence, and neurotoxicity produced by chronic alcohol abuse, but there has been no large scale study of gene expression in human alcoholism. Methods: RNA was extracted from postmortem samples of superior frontal cortex of alcoholics and nonalcoholics. Relative levels of RNA were determined by array techniques. We used both cDNA and oligonucleotide microarrays to provide coverage of a large number of genes and to allow cross-validation for those genes represented on both types of arrays. Results: Expression levels were determined for over 4000 genes and 163 of these were found to differ by 40% or more between alcoholics and nonalcoholics. Analysis of these changes revealed a selective reprogramming of gene expression in this brain region, particularly for myelin-related genes which were downregulated in the alcoholic samples. In addition, cell cycle genes and several neuronal genes were changed in expression. Conclusions: These gene expression changes suggest a mechanism for the loss of cerebral white matter in alcoholics as well as alterations that may lead to the neurotoxic actions of ethanol.

Lifetime suicide risk in major depression: sex and age determinants

Background: Recent work has demonstrated that the lifetime suicide risk for patients with DSM IV Major Depression cannot mathematically approximate the accepted figure of 15%. Gender and age significantly affect both the prevalence of major depression and suicide risk, Methods: Gender and age stratified calculations were made on the entire population of the USA in 1994 using a mathematical algorithm. Sex specific corrections for under-reporting were incorporated into the design. Results: The lifetime suicide risks for men and women were 7% and 1%, respectively. The combined risk was 3.4%. The male:female ratio for suicide risk in major depression was 10:1 for youths under 25, and 5.6:1 for adults. Conclusions: Suicide in major depression is predominantly a male problem, although complacency towards female sufferers is to be avoided. Diagnosis of major depression is of limited help in predicting suicide risk compared to case specific factors. The male experience of depression that leads to suicide is often not identified as a legitimate medical complaint by either sufferers or professionals. Increasing help-accessing by males is a priority. Clinical implications: Patients with a history of hospitalisation; comorbidity, especially for substance abuse; and who are male, require greater vigilance for suicide risk. It may be that for males che threshold for diagnosing and treating major depression needs to be lowered. Limitations: This research is based on a mathematical algorithm to approximate a life-long longitudinal study that identifies community cases of depression. Our findings therefore rely on the validity of the statistics used. Extrapolation is limited to populations with an actual suicide rate of 17/100,000 or less and a lifetime prevalence of major depression of 17% or more. (C) 1999 Elsevier Science B.V. All rights reserved.

Comorbidity and genotype modify receptor expression in human alcoholics

Chronic alcohol misuse leads to both widespread and localized damage in human cerebral cortex. The latter, as neuronal loss, is marked in superior frontal cortex (SFC) but milder in primary motor cortex (PMC) and elsewhere. Quantitative morphometry by Harper et al showed that neuronal loss is greater in alcoholics with comorbidity (Wernicke Korsakoff syndrome, liver cirrhosis). Previous work revealed a paradox: the marked differences in GABAA receptor density, pharmacology, and expression between alcoholics without cormorbidity and controls are muted or absent in cirrhotic alcoholics. This concurs with work by the Butterworth group on hepatic encephalopathy cases — most of whom had an alcoholic ætiology — who show only minor differences from controls. Glutamate receptor differences are muted in many autopsy studies, though we have evidence that NMDA site pharmacology may vary in cirrhotic alcoholics. Here we used Real-Time PCR normalized to GAPDH deltaCT to quantify NMDA NR1, NR2A and NR2B subunit expression in SFC and PMC samples obtained at autopsy from alcoholics with and without comorbid cirrhosis and matched controls. Overall subunit transcript expression was signifi cantly lower in alcoholic cirrhotics than in either of the other groups (F2,42 = 12.942, P < 0.001). The effect was most marked for the NR1 subunit; males differed from females, particularly in SFC. The data suggest that if excitotoxicity mediates neuronal loss in SFC, it may be implemented differently: passively in uncomplicated alcoholics, by altered GABAergic transmission; actively in cirrhotic alcoholics, by altered glutamatergic transmission. We also subdivided cases on a panel of genetic markers. Different genotypes interacted with NMDA and GABAA pharmacology and expression. Cirrhotic and uncomplicated alcoholics may differ pathogenically because of inherent characteristics in addition to possible neurotoxic sequelæ to the liver damage.

Detection of elevated protein modification in human cerebellum in alcoholic cerebellar degeneration

Modification of proteins by reactive ethanol metabolites has been known for some time to occur in the liver, the main site of ethanol metabolism. In more recent studies of laboratory animals, similar modifications have been detected in organs with lesser ability to metabolize ethanol, such as skeletal and cardiac muscle and brain. Such modification may alter protein function or form a neoantigen, making it a target for immune attack. We now report an analysis of protein modification derived from ethanol metabolites in human brain tissue by ELISA using adduct-specific antibodies. We obtained autopsy cerebellum samples from 10 alcoholic cerebellar degeneration cases and 10 matched controls under informed written consent from the next of kin and clearance from the UQ Human Ethics Committee. Elevated levels of protein modifications derived from acetaldehyde (unreduced-acetaldehyde and acetaldehyde-advanced glycation end-product adducts), from malondialdehyde (malondialdehyde adducts) and from combined adducts (malondialdehydeacetaldehyde (MAA) adducts) were detected in alcoholic cerebellar degeneration samples when compared to controls. Other adduct types found in liver samples, such as reduced-acetaldehyde and those derived from hydroxyethyl radicals, were not detected in brain samples. This may reflect the different routes of ethanol metabolism in the two tissues. This is the first report of elevated protein modification in alcoholic cerebellar degeneration, and suggests that such modification may play a role in the pathogenesis of brain injury. Supported by NIAAA under grant NIH AA12404 and the NHMRC (Australia) under grant #981723.

Bayesian population pharmacokinetic analysis of sirolimus

Objective: It is usual that data collected from routine clinical care is sparse and unable to support the more complex pharmacokinetic (PK) models that may have been reported in previous rich data studies. Informative priors may be a pre-requisite for model development. The aim of this study was to estimate the population PK parameters of sirolimus using a fully Bayesian approach with informative priors. Methods: Informative priors including prior mean and precision of the prior mean were elicited from previous published studies using a meta-analytic technique. Precision of between-subject variability was determined by simulations from a Wishart distribution using MATLAB (version 6.5). Concentration-time data of sirolimus retrospectively collected from kidney transplant patients were analysed using WinBUGS (version 1.3). The candidate models were either one- or two-compartment with first order absorption and first order elimination. Model discrimination was based on computation of the posterior odds supporting the model. Results: A total of 315 concentration-time points were obtained from 25 patients. Most data were clustered at trough concentrations with range of 1.6 to 77 hours post-dose. Using informative priors, either a one- or two-compartment model could be used to describe the data. When a one-compartment model was applied, information was gained from the data for the value of apparent clearance (CL/F = 18.5 L/h), and apparent volume of distribution (V/F = 1406 L) but no information was gained about the absorption rate constant (ka). When a two-compartment model was fitted to the data, the data were informative about CL/F, apparent inter-compartmental clearance, and apparent volume of distribution of the peripheral compartment (13.2 L/h, 20.8 L/h, and 579 L, respectively). The posterior distribution of the volume distribution of central compartment and ka were the same as priors. The posterior odds for the two-compartment model was 8.1, indicating the data supported the two-compartment model. Conclusion: The use of informative priors supported the choice of a more complex and informative model that would otherwise have not been supported by the sparse data.