Petra L. Graham

Intensity of dementia through latent variable modelling (I-DeLV) in the AIBL cohort

69% of Mild Cognitively Impaired and 96% of AD. Conclusions: The described models provide accurate estimations of NAB based on demographic corrected cognitive test scores. If NAB is a predictor for progression to AD and given such models can accurately predict NAB, it follows that this work may lead to an effective and economical screen for early detection of individuals at risk of developing AD, in-turn providing justification for further confirmatory tests (e.g. PET) or to identify suitable participants for intervention or therapeutic trials.

Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis

Objective To systematically review the efficacy of steroids in the prevention of acute respiratory distress syndrome (ARDS) in critically ill adults, and treatment for established ARDS. Data sources Search of randomised controlled trials (1966-April 2007) of PubMed, Cochrane central register of controlled trials, Cochrane database of systematic reviews, American College of Physicians Journal Club, health technology assessment database, and database of abstracts of reviews of effects. Data extraction Two investigators independently assessed trials for inclusion and extracted data into standardised forms; differences were resolved by consensus. Data synthesis Steroid efficacy was assessed through a Bayesian hierarchical model for comparing the odds of developing ARDS and mortality (both expressed as odds ratio with 95% credible interval) and duration of ventilator free days, assessed as mean difference. Bayesian outcome probabilities were calculated as the probability that the odds ratio would be ≥1 or the probability that the mean difference would be ≥0. Nine randomised trials using variable dose and duration of steroids were identified. Preventive steroids (four studies) were associated with a trend to increase both the odds of patients developing ARDS (odds ratio 1.55, 95% credible interval 0.58 to 4.05; P(odds ratio ≥1)=86.6%), and the risk of mortality in those who subsequently developed ARDS (three studies, odds ratio 1.52, 95% credible interval 0.30 to 5.94; P(odds ratio ≥1)=72.8%). Steroid administration after onset of ARDS (five studies) was associated with a trend towards reduction in mortality (odds ratio 0.62, 95% credible interval 0.23 to 1.26; P(odds ratio ≥1)=6.8%). Steroid therapy increased the number of ventilator free days compared with controls (three studies, mean difference 4.05 days, 95% credible interval 0.22 to 8.71; P(mean difference ≥0)=97.9%). Steroids were not associated with increase in risk of infection. Conclusions A definitive role of corticosteroids in the treatment of ARDS in adults is not established. A possibility of reduced mortality and increased ventilator free days with steroids started after the onset of ARDS was suggested. Preventive steroids possibly increase the incidence of ARDS in critically ill adults.

Oxime therapy and outcomes in human organophosphate poisoning: an evaluation using meta-analytic techniques

Objective:The status of oximes in human organophosphate poisoning is controversial. This analysis compares the outcomes of therapy with or without oximes. Design:Quantitative analysis using meta-analytic techniques. Methods:Controlled trials of oximes in human organophosphate poisoning were identified by search of MEDLINE and TOXLINE (1966 to May 2005) and review of published articles. Measurements and Main Results:Of the 3,122 articles on organophosphate poisoning identified by electronic search, 116 related to oxime use in human organophosphate poisoning. Seven trials, including two randomized controlled trials, compared oximes with standard medical care. Varying dosage schedules of pralidoxime or obidoxime were used. The effects of oxime therapy on mortality rate, mechanical ventilation, incidence of intermediate syndrome, and need for intensive care therapy were analyzed and expressed as risk difference (positive values indicating oxime harm). The random effects estimator was reported because of underlying heterogeneity of treatment effects between study types. No statistically significant association of oxime therapy was demonstrated for either mortality (risk difference 0.09, 95% confidence interval −0.08 to 0.27), ventilatory requirements (risk difference 0.16, 95% confidence interval −0.07 to 0.38), or the incidence of intermediate syndrome (risk difference 0.16, 95% confidence interval −0.12 to 0.45), although point estimates of effect suggested harm. An increased need for intensive care therapy (risk difference 0.19, 95% confidence interval 0.01 to 0.36) was apparent with oxime therapy. Conclusions:Based on the current available data on human organophosphate poisoning, oxime was associated with either a null effect or possible harm. The lack of current prospective randomized controlled trials, with appropriate patient stratification, mandates ongoing assessment of the role of oximes in organophosphate poisoning.

Epidemiology of injuries in competition taekwondo: a meta-analysis of observational studies.

This paper aims to review and collate the epidemiological data of injuries in competition taekwondo as reported in the literature, make recommendations, and suggest further research. The electronic databases AMED, AusportMed, CINAHL, MEDLINE, PubMed, and SPORTDiscus were searched from inception to March 2008. Fourteen prospective cohort studies reporting the incidence of injuries in taekwondo were included. Two reviewers independently extracted data and assessed trial quality using the STROBE statement. Homogenous studies were combined in a pooled analysis using a Poisson random effects regression model. Poisson regression showed an overall mean injury rate of 79.3 per 1000 athlete-exposures (95% confidence interval 22.8, 275.4). Neither age, gender nor level of play were significant in the analysis. The most common injury location and type were found to be the lower limb and contusion, respectively, and were invariably associated with contact. Although taekwondo players are exposed to a substantial risk of sustaining injuries, the majority of injuries appeared to be of minimal severity. Modifications to the competition rules and protective equipment may be warranted. Future studies should adhere to recommended operational definitions, utilise a standardised injury classification system, and report injury rates using multiple denominators in order to facilitate inter- and cross-sport comparisons.

Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective

IntroductionCurrent low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock.MethodsRCTs were identified (1950-September 2008) by multiple data-base electronic search (MEDLINE via OVID, OVID PreMedline, OVID Embase, Cochrane Central Register of Controlled trials, Cochrane database of systematic reviews, Health Technology Assessment Database and Database of Abstracts of Reviews of Effects) and hand search of references, reviews and scientific society proceedings. Three investigators independently assessed trial inclusion and data extraction into standardised forms; differences resolved by consensus.ResultsCorticosteroid efficacy, compared with control, for hospital-mortality, proportion of patients experiencing shock-resolution, and infective and non-infective complications was assessed using Bayesian random-effects models; expressed as odds ratio (OR, (95% credible-interval)). Bayesian outcome probabilities were calculated as the probability (P) that OR ≥1. Fourteen RCTs were identified. High-dose (>1000 mg hydrocortisone (equivalent) per day) corticosteroid trials were associated with a null (n = 5; OR 0.91(0.31-1.25)) or higher (n = 4, OR 1.46(0.73-2.16), outlier excluded) mortality probability (P = 42.0% and 89.3%, respectively). Low-dose trials (<1000 mg hydrocortisone per day) were associated with a lower (n = 9, OR 0.80(0.40-1.39); n = 8 OR 0.71(0.37-1.10), outlier excluded) mortality probability (20.4% and 5.8%, respectively). OR for shock-resolution was increased in the low dose trials (n = 7; OR 1.20(1.07-4.55); P = 98.2%). Patient responsiveness to corticotrophin stimulation was non-determinant. A high probability of risk-related treatment efficacy (decrease in log-odds mortality with increased control arm risk) was identified by metaregression in the low dose trials (n = 9, slope coefficient -0.49(-1.14, 0.27); P = 92.2%). Odds of complications were not increased with corticosteroids.ConclusionsAlthough a null effect for mortality treatment efficacy of low dose corticosteroid therapy in severe sepsis and septic shock was not excluded, there remained a high probability of treatment efficacy, more so with outlier exclusion. Similarly, although a null effect was not excluded, advantageous effects of low dose steroids had a high probability of dependence upon patient underlying risk. Low dose steroid efficacy was not demonstrated in corticotrophin non-responders. Further large-scale trials appear mandated.

The efficacy of loop diuretics in acute renal failure: assessment using Bayesian evidence synthesis techniques.

Objective:To quantify the therapeutic efficacy of loop diuretics in acute renal failure using Bayesian evidence synthesis, because despite widespread use, the role of diuretics is controversial. Data Source:Randomized controlled trials or nonrandomized studies, 1966 to January 2007, identified from MEDLINE and EMBASE databases and manual bibliographic search. Study Selection:Studies with assessable predefined end points, exclusive of those pertaining to acute renal failure prophylaxis or chronic renal failure. Data Extraction:Data extraction was performed jointly by the first two authors; independent study assessment was via standard checklist, unblinded. Data Synthesis:The primary outcome was mortality; secondary outcomes were time to renal function normalization and total number of dialyses. Bayesian hierarchical random effects estimates of treatment effects were determined as risk ratio for mortality, incidence rate ratio for dialysis number, and mean difference for continuous measures. Bayesian outcome probabilities were calculated as probability (P) that risk ratio or incidence rate ratio of loop diuretics >1 and probability that mean difference >0. Five randomized controlled trials and eight nonrandomized studies were identified. Loop diuretics were not associated with decreased mortality in either randomized controlled trials or nonrandomized studies: overall risk ratio 1.10; 95% credible interval 0.85, 1.42; P (risk ratio >1) = 83.8%. The oliguric period was decreased by loop diuretics: overall mean difference −7.70 days; 95% credible interval −12.51, −2.08; P (mean difference >0) = 0.7%. Although the dialysis rate credible interval, loop diuretics vs. control, spanned unity (incidence rate ratio 0.71; 95% credible interval 0.47, 1.06), the probability that the incidence rate ratio exceeded unity indicated a substantial benefit: P (incidence rate ratio >1 = 4.1%. Uremic duration was not substantially different, loop diuretics vs. control: overall mean difference −1.54 days; 95% credible interval −5.62, 2.46; P [mean difference >0] = 17.8%). Conclusions:Loop diuretics were not associated with improved survival benefit in acute renal failure, despite reduction in oliguric period and high probability of a significant reduction in dialysis numbers. Further studies to clarify this dichotomy appear mandated.

Understanding sources of variation in syndromic surveillance for early warning of natural or intentional disease outbreaks

Daily counts of computer records of hospital emergency department arrivals grouped according to diagnosis (called here syndrome groupings) can be monitored by epidemiologists for changes in frequency that could provide early warning of bioterrorism events or naturally occurring disease outbreaks and epidemics. This type of public health surveillance is sometimes called syndromic surveillance. We used transitional Poisson regression models to obtain one-day-ahead arrival forecasts. Regression parameter estimates and forecasts were updated for each day using the latest 365 days of data. The resulting time series of recursive estimates of parameters such as the amplitude and location of the seasonal peaks as well as the one-day-ahead forecasts and forecast errors can be monitored to understand changes in epidemiology of each syndrome grouping. The counts for each syndrome grouping were autocorrelated and non-homogeneous Poisson. As such, the main methodological contribution of the article is the adaptation of Cumulative Sum (CUSUM) and Exponentially Weighted Moving Average (EWMA) plans for monitoring non-homogeneous counts. These plans were valid for small counts where the assumption of normally distributed one-day-ahead forecasts errors, typically used in other papers, breaks down. In addition, these adaptive plans have the advantage that control limits do not have to be trained for different syndrome groupings or aggregations of emergency departments. Conventional methods for signaling increases in syndrome grouping counts, Shewhart, CUSUM, and EWMA control charts of the standardized forecast errors were also examined. Shewhart charts were, at times, insensitive to shifts of interest. CUSUM and EWMA charts were only reasonable for large counts. We illustrate our methods with respiratory, influenza, diarrhea, and abdominal pain syndrome groupings.

Robust meta-analytic conclusions mandate the provision of prediction intervals in meta-analysis summaries

OBJECTIVES Results of meta-analyses typically conclude that future large studies may be mandated. However, the predictive ability of these estimates is deficient. We explored meta-analytic prediction intervals as means for providing a clear and appropriate future treatment summary reflecting current estimates. STUDY DESIGN A meta-epidemiological study of binary outcome critical care meta-analyses published between 2002 and 2010. Computation of 95% DerSimonian-Laird and Bayesian random-effects meta-analytic confidence intervals (CI) and 95% credible intervals (CrI), respectively, and frequentist (PI) and Bayesian (PrI) prediction intervals for odds ratio (OR) and risk ratio (RR) were undertaken. Bayesian calculations included the probability that the OR and RR point estimates ≥1. RESULTS Seventy-two meta-analyses from 70 articles were identified, containing between three and 80 studies each, with median nine studies. For both frequentist and Bayesian settings, 49-69% of the meta-analyses excluded the null. All significant CrI had high probabilities of efficacy/harm. The number of PI vs. PrI excluding 1 was 25% vs. 3% (OR), 26% vs. 3% (RR) of the total meta-analyses. Unsurprisingly, PI/PrI width was greater than CI/CrI width and increased with increasing heterogeneity and combination of fewer studies. CONCLUSION Robust meta-analytic conclusions and determination of studies warranting new large trials may be more appropriately signaled by consideration of initial interval estimates with prediction intervals. Substantial heterogeneity results in exceedingly wide PIs. More caution should be exercised regarding the conclusions of a meta-analysis.

Genetic algorithm with logistic regression for prediction of progression to Alzheimer's disease.

BackgroundAssessment of risk and early diagnosis of Alzheimers disease (AD) is a key to its prevention or slowing the progression of the disease. Previous research on risk factors for AD typically utilizes statistical comparison tests or stepwise selection with regression models. Outcomes of these methods tend to emphasize single risk factors rather than a combination of risk factors. However, a combination of factors, rather than any one alone, is likely to affect disease development. Genetic algorithms (GA) can be useful and efficient for searching a combination of variables for the best achievement (eg. accuracy of diagnosis), especially when the search space is large, complex or poorly understood, as in the case in prediction of AD development.ResultsMultiple sets of neuropsychological tests were identified by GA to best predict conversions between clinical categories, with a cross validated AUC (area under the ROC curve) of 0.90 for prediction of HC conversion to MCI/AD and 0.86 for MCI conversion to AD within 36 months.ConclusionsThis study showed the potential of GA application in the neural science area. It demonstrated that the combination of a small set of variables is superior in performance than the use of all the single significant variables in the model for prediction of progression of disease. Variables more frequently selected by GA might be more important as part of the algorithm for prediction of disease development.

Advances in the management of organophosphate poisoning

Organophosphate (OP) poisoning is commonly encountered in agricultural communities. The mainstay of therapy in OP poisoning is the use of atropine. However, several other therapies have been evaluated. Although oxime has been the most studied antidote, results in humans have been disappointing and limited by the lack of well-designed, prospective, randomised controlled trials. The key factor in determining outcomes in OP poisoning appears to be the timing of antidote administration. Other adjuvants, such as magnesium, fresh frozen plasma and haemoperfusion appear promising, and need to be explored further. A multi-faceted approach may be the answer to improving outcomes in OP poisoning. This review evaluates the advances in OP management over the last 20 years.