Estimation of a Relative Risk Effect Size when Using Continuous Outcomes Data: An Application of Methods in the Prevention of Major Depression and Eating Disorders.

INTRODUCTION: The raw mean difference (RMD) and standardized mean difference (SMD) are continuous effect size measures that are not readily usable in decision-analytic models of health care interventions. This study compared the predictive performance of 3 methods by which continuous outcomes data collected using psychiatric rating scales can be used to calculate a relative risk (RR) effect size. METHODS: Three methods to calculate RR effect sizes from continuous outcomes data are described: the RMD, SMD, and Cochrane conversion methods. Each conversion method was validated using data from randomized controlled trials (RCTs) examining the efficacy of interventions for the prevention of depression in youth (aged ≤17 years) and adults (aged ≥18 years) and the prevention of eating disorders in young women (aged ≤21 years). Validation analyses compared predicted RR effect sizes to actual RR effect sizes using scatterplots, correlation coefficients ( r), and simple linear regression. An applied analysis was also conducted to examine the impact of using each conversion method in a cost-effectiveness model. RESULTS: The predictive performances of the RMD and Cochrane conversion methods were strong relative to the SMD conversion method when analyzing RCTs involving depression in adults (RMD: r = 0.89-0.90; Cochrane: r = 0.73; SMD: r = 0.41-0.67) and eating disorders in young women (RMD: r = 0.89; Cochrane: r = 0.96). Moderate predictive performances were observed across the 3 methods when analyzing RCTs involving depression in youth (RMD: r = 0.50; Cochrane: r = 0.47; SMD: r = 0.46-0.46). Negligible differences were observed between the 3 methods when applied to a cost-effectiveness model. CONCLUSION: The RMD and Cochrane conversion methods are both valid methods for predicting RR effect sizes from continuous outcomes data. However, further validation and refinement are required before being applied more broadly.

A new improved graphical and quantitative method for detecting bias in meta-analysis.

Detection of publication and related biases remains suboptimal and threatens the validity and interpretation of meta-analytical findings. When bias is present, it usually differentially affects small and large studies manifesting as an association between precision and effect size and therefore visual asymmetry of conventional funnel plots. This asymmetry can be quantified and Egger's regression is, by far, the most widely used statistical measure for quantifying funnel plot asymmetry. However, concerns have been raised about both the visual appearance of funnel plots and the sensitivity of Egger's regression to detect such asymmetry, particularly when the number of studies is small. In this article, we propose a new graphical method, the Doi plot, to visualize asymmetry and also a new measure, the LFK index, to detect and quantify asymmetry of study effects in Doi plots. We demonstrate that the visual representation of asymmetry was better for the Doi plot when compared with the funnel plot. We also show that the diagnostic accuracy of the LFK index in discriminating between asymmetry due to simulated publication bias versus chance or no asymmetry was also better with the LFK index which had areas under the receiver operating characteristic curve of 0.74-0.88 with simulations of meta-analyses with five, 10, 15, and 20 studies. The Egger's regression result had lower areas under the receiver operating characteristic curve values of 0.58-0.75 across the same simulations. The LFK index also had a higher sensitivity (71.3-72.1%) than the Egger's regression result (18.5-43.0%). We conclude that the methods proposed in this article can markedly improve the ability of researchers to detect bias in meta-analysis.

A generalized pairwise modelling framework for network meta-analysis.

Indirect comparison methods are used to measure the effect of two treatments that were each compared against a similar control group in a meta-analysis. The network meta-analysis method extends this to multiple treatments which are assessed simultaneously. Currently, there exist Bayesian and multivariate modelling approaches to these analyses, but these are computationally intensive and rely on assumptions that may not be valid in practice. Here we introduce a generalized pairwise modelling (GPM) framework for network meta-analysis, so named as it is based on the repeated application of adjusted indirect comparisons, also known as the Bucher method. The validity of this method hinges on the sufficient similarity of the common control node (transitivity), and for the application in the GPM framework this requirement extends to all common nodes used to make an indirect comparison estimate. Apart from the assumption of sufficient similarity, the GPM framework assumes only standard arithmetic and statistical rules making it more robust when compared with existing methods for network meta-analysis. A software program (MetaXL; www.epigear.com) is available to run this framework, so it is easily accessible to researchers.

Comparative effectiveness of malaria prevention measures: a systematic review and network meta-analysis.

BACKGROUND: Malaria causes significant morbidity and mortality worldwide. There are several preventive measures that are currently employed, including insecticide-treated nets (ITNs, including long-lasting insecticidal nets and insecticidal-treated bed nets), indoor residual spraying (IRS), prophylactic drugs (PD), and untreated nets (UN). However, it is unclear which measure is the most effective for malaria prevention. We therefore undertook a network meta-analysis to compare the efficacy of different preventive measures on incidence of malaria infection. METHODS: A systematic literature review was undertaken across four medical and life sciences databases (PubMed, Cochrane Central, Embase, and Web of Science) from their inception to July 2016 to compare the effectiveness of different preventive measures on malaria incidence. Data from the included studies were analysed for the effectiveness of several measures against no intervention (NI). This was carried out using an automated generalized pairwise modeling (GPM) framework for network meta-analysis to generate mixed treatment effects against a common comparator of no intervention (NI). RESULTS: There were 30 studies that met the inclusion criteria from 1998-2016. The GPM framework led to a final ranking of effectiveness of measures in the following order from best to worst: PD, ITN, IRS and UN, in comparison with NI. However, only ITN (RR: 0.49, 95% CI: 0.32-0.74) showed precision while other methods [PD (RR: 0.24, 95% CI: 0.004-15.43), IRS (RR: 0.55, 95% CI: 0.20-1.56) and UN (RR: 0.73, 95% CI: 0.28-1.90)] demonstrating considerable uncertainty associated with their point estimates. CONCLUSION: Current evidence is strong for the protective effect of ITN interventions in malaria prevention. Even though ITNs were found to be the only preventive measure with statistical support for their effectiveness, the role of other malaria control measures may be important adjuncts in the global drive to eliminate malaria.

Population cost-effectiveness of the Triple P parenting programme for the treatment of conduct disorder: an economic modelling study.

Parenting programmes are the recommended treatments of conduct disorders (CD) in children, but little is known about their longer term cost-effectiveness. This study aimed to evaluate the population cost-effectiveness of one of the most researched evidence-based parenting programmes, the Triple P-Positive Parenting Programme, delivered in a group and individual format, for the treatment of CD in children. A population-based multiple cohort decision analytic model was developed to estimate the cost per disability-adjusted life year (DALY) averted of Triple P compared with a 'no intervention' scenario, using a health sector perspective. The model targeted a cohort of 5-9-year-old children with CD in Australia currently seeking treatment, and followed them until they reached adulthood (i.e., 18 years). Multivariate probabilistic and univariate sensitivity analyses were conducted to incorporate uncertainty in the model parameters. Triple P was cost-effective compared to no intervention at a threshold of AU$50,000 per DALY averted when delivered in a group format [incremental cost-effectiveness ratio (ICER) = $1013 per DALY averted; 95% uncertainty interval (UI) 471-1956] and in an individual format (ICER = $20,498 per DALY averted; 95% UI 11,146-39,470). Evidence-based parenting programmes, such as the Triple P, for the treatment of CD among children appear to represent good value for money, when delivered in a group or an individual face-to-face format, with the group format being the most cost-effective option. The current model can be used for economic evaluations of other interventions targeting CD and in other settings.

Meta-analysis in evidence-based healthcare: a paradigm shift away from random effects is overdue.

Each year up to 20 000 systematic reviews and meta-analyses are published whose results influence healthcare decisions, thus making the robustness and reliability of meta-analytic methods one of the world's top clinical and public health priorities. The evidence synthesis makes use of either fixed-effect or random-effects statistical methods. The fixed-effect method has largely been replaced by the random-effects method as heterogeneity of study effects led to poor error estimation. However, despite the widespread use and acceptance of the random-effects method to correct this, it too remains unsatisfactory and continues to suffer from defective error estimation, posing a serious threat to decision-making in evidence-based clinical and public health practice. We discuss here the problem with the random-effects approach and demonstrate that there exist better estimators under the fixed-effect model framework that can achieve optimal error estimation. We argue for an urgent return to the earlier framework with updates that address these problems and conclude that doing so can markedly improve the reliability of meta-analytical findings and thus decision-making in healthcare.

The modeled cost-effectiveness of family-based and adolescent-focused treatment for anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a prevalent, serious mental disorder. We aimed to evaluate the cost-effectiveness of family-based treatment (FBT) compared to adolescent-focused individual therapy (AFT) or no intervention within the Australian healthcare system. METHOD: A Markov model was developed to estimate the cost and disability-adjusted life-year (DALY) averted of FBT relative to comparators over 6 years from the health system perspective. The target population was 11-18 year olds with AN of relatively short duration. Uncertainty and sensitivity analyses were conducted to test model assumptions. Results are reported as incremental cost-effectiveness ratios (ICER) in 2013 Australian dollars per DALY averted. RESULTS: FBT was less costly than AFT. Relative to no intervention, the mean ICER of FBT and AFT was $5,089 (95% uncertainty interval (UI): dominant to $16,659) and $51,897 ($21,591 to $1,712,491) per DALY averted. FBT and AFT are 100% and 45% likely to be cost-effective, respectively, at a threshold of AUD$50,000 per DALY averted. Sensitivity analyses indicated that excluding hospital costs led to increases in the ICERs but the conclusion of the study did not change. CONCLUSION: FBT is the most cost-effective among treatment arms, whereas AFT was not cost-effective compared to no intervention. Further research is required to verify this result.

The modelled cost-effectiveness of cognitive dissonance for the prevention of anorexia nervosa and bulimia nervosa in adolescent girls in Australia.

BACKGROUND: Eating disorders (EDs), including anorexia nervosa (AN) and bulimia nervosa (BN), are prevalent disorders that carry substantial economic and social burden. The aim of the current study was to evaluate the modelled population cost-effectiveness of cognitive dissonance (CD), a school-based preventive intervention for EDs, in the Australian health care context. METHOD: A population-based Markov model was developed to estimate the cost per disability adjusted life-year (DALY) averted by CD relative to no intervention. We modelled the cases of AN and BN that could be prevented over a 10-year time horizon in each study arm and the subsequent reduction in DALYs associated with this. The target population was 15-18 year old secondary school girls with high body-image concerns. This study only considered costs of the health sector providing services and not costs to individuals. Multivariate probabilistic and one-way sensitivity analyses were conducted to test model assumptions. RESULTS: Findings showed that the mean incremental cost-effectiveness ratio at base-case for the intervention was $103,980 per DALY averted with none of the uncertainty iterations falling below the threshold of AUD$50,000 per DALY averted. The evaluation was most sensitive to estimates of participant rates with higher rates associated with more favourable results. The intervention would become cost-effective (84% chance) if the effect of the intervention lasted up to 5 years. CONCLUSION: As modelled, school-based CD intervention is not a cost-effective preventive intervention for AN and BN. Given the burden of EDs, understanding how to improve participation rates is an important opportunity for future research.

Psychosocial therapies for the adjunctive treatment of bipolar disorder in adults: network meta-analysis.

BackgroundFew trials have compared psychosocial therapies for people with bipolar affective disorder, and conventional meta-analyses provided limited comparisons between therapies.AimsTo combine evidence for the efficacy of psychosocial interventions used as adjunctive treatment of bipolar disorder in adults, using network meta-analysis (NMA).MethodSystematic review identified studies and NMA was used to pool data on relapse to mania or depression, medication adherence, and symptom scales for mania, depression and Global Assessment of Functioning (GAF).ResultsCarer-focused interventions significantly reduced the risk of depressive or manic relapse. Psychoeducation alone and in combination with cognitive-behavioural therapy (CBT) significantly reduced medication non-adherence. Psychoeducation plus CBT significantly reduced manic symptoms and increased GAF. No intervention was associated with a significant reduction in depression symptom scale scores.ConclusionsOnly interventions for family members affected relapse rates. Psychoeducation plus CBT reduced medication non-adherence, improved mania symptoms and GAF. Novel methods for addressing depressive symptoms are required.

Prevention of eating disorders: A systematic review and meta-analysis.

OBJECTIVE: To systematically review and quantify the effectiveness of Eating Disorder (ED) prevention interventions. METHODS: Electronic databases (including the Cochrane Controlled Trial Register, MEDLINE, PsychInfo, EMBASE, and Scopus) were searched for published randomized controlled trials of ED prevention interventions from 2009 to 2015. Trials prior to 2009 were retrieved from prior reviews. RESULTS: One hundred and twelve articles were included. Fifty-eight percent of trials had high risk of bias. Findings indicated small to moderate effect sizes on reduction of ED risk factors or symptoms which occurred up to three-year post-intervention. For universal prevention, media literacy (ML) interventions significantly reduced shape and weight concerns for both females (-0.69, confidence interval (CI): -1.17 to -0.22) and males (-0.32, 95% CI -0.57 to -0.07). For selective prevention, cognitive dissonance (CD) interventions were superior to control interventions in reducing ED symptoms (-0.32, 95% CI -0.52 to -0.13). Cognitive behavioural therapy (CBT) interventions had the largest effect size (-0.40, 95% CI -0.55 to -0.26) on dieting outcome at 9-month follow-up while the healthy weight intervention reduced ED risk factors and body mass index. No indicated prevention interventions were found to be effective in reducing ED risk factors. CONCLUSIONS: There are a number of promising preventive interventions for ED risk factors including CD, CBT and ML. Whether these actually lower ED incidence is, however, uncertain. Combined ED and obesity prevention interventions require further research.

Contribution of Trans-Fatty Acid Intake to Coronary Heart Disease Burden in Australia: A Modelling Study.

Trans-fatty acids (TFAs) intake has been consistently associated with a higher risk of coronary heart disease (CHD) mortality. We provided an updated assessment of TFA intake in Australian adults in 2010 and conducted modeling to estimate CHD mortality attributable to TFA intake. Data of the 2011-2012 National Nutrition and Physical Activity Survey was used to assess TFA intake. The CHD burden attributable to TFA was calculated by comparing the current level of TFA intake to a counterfactual setting where consumption was lowered to a theoretical minimum distribution of 0.5% energy. The average TFA intake among adults was 0.59% energy, and overall 10% of adults exceeded the World Health Organization (WHO) recommended limit of 1% energy. Education and income were moderately and inversely associated with TFA intake (p-value ≤ 0.001), with one in seven adults in the lowest income and education quintile having >1% energy from TFA. Australia had 487 CHD deaths (95% uncertainty interval, 367-615) due to TFA exposure, equivalent to 1.52% (95% uncertainty limits: 1.15%-1.92%) of all CHD mortality. The relative impact of TFA exposure on CHD mortality in Australia is limited, but, in absolute terms, still substantial. Policies aimed at reducing industrial TFA exposure can reduce socioeconomic inequalities in health and may therefore be desirable.

Advances in the meta-analysis of heterogeneous clinical trials II: The quality effects model.

This article examines the performance of the updated quality effects (QE) estimator for meta-analysis of heterogeneous studies. It is shown that this approach leads to a decreased mean squared error (MSE) of the estimator while maintaining the nominal level of coverage probability of the confidence interval. Extensive simulation studies confirm that this approach leads to the maintenance of the correct coverage probability of the confidence interval, regardless of the level of heterogeneity, as well as a lower observed variance compared to the random effects (RE) model. The QE model is robust to subjectivity in quality assessment down to completely random entry, in which case its MSE equals that of the RE estimator. When the proposed QE method is applied to a meta-analysis of magnesium for myocardial infarction data, the pooled mortality odds ratio (OR) becomes 0.81 (95% CI 0.61-1.08) which favors the larger studies but also reflects the increased uncertainty around the pooled estimate. In comparison, under the RE model, the pooled mortality OR is 0.71 (95% CI 0.57-0.89) which is less conservative than that of the QE results. The new estimation method has been implemented into the free meta-analysis software MetaXL which allows comparison of alternative estimators and can be downloaded from www.epigear.com.

Advances in the meta-analysis of heterogeneous clinical trials I: The inverse variance heterogeneity model.

This article examines an improved alternative to the random effects (RE) model for meta-analysis of heterogeneous studies. It is shown that the known issues of underestimation of the statistical error and spuriously overconfident estimates with the RE model can be resolved by the use of an estimator under the fixed effect model assumption with a quasi-likelihood based variance structure - the IVhet model. Extensive simulations confirm that this estimator retains a correct coverage probability and a lower observed variance than the RE model estimator, regardless of heterogeneity. When the proposed IVhet method is applied to the controversial meta-analysis of intravenous magnesium for the prevention of mortality after myocardial infarction, the pooled OR is 1.01 (95% CI 0.71-1.46) which not only favors the larger studies but also indicates more uncertainty around the point estimate. In comparison, under the RE model the pooled OR is 0.71 (95% CI 0.57-0.89) which, given the simulation results, reflects underestimation of the statistical error. Given the compelling evidence generated, we recommend that the IVhet model replace both the FE and RE models. To facilitate this, it has been implemented into free meta-analysis software called MetaXL which can be downloaded from www.epigear.com.

The burden of selected congenital anomalies amenable to surgery in low and middle-income regions: cleft lip and palate, congenital heart anomalies and neural tube defects.

OBJECTIVE: To quantify the burden of selected congenital anomalies in low and middle-income countries (LMICs) that could be reduced should surgical programmes cover the entire population with access to quality care. DESIGN: Burden of disease and epidemiological modelling. SETTING: LMICs from all global regions. POPULATION: All prevalent cases of selected congenital anomalies at birth in 2010. MAIN OUTCOME MEASURES: Disability-adjusted life years (DALYs). INTERVENTIONS AND METHODS: Surgical programmes for three congenital conditions were analysed: clefts (lip and palate); congenital heart anomalies; and neural tube defects. Data from the Global Burden of Disease 2010 Study were used to estimate the combination of fatal burden that could be addressed by surgical care and the additional long-term non-fatal burden associated with increased survival. RESULTS: Of the estimated 21.6 million DALYs caused by these three conditions in LMICs, 12.4 million DALYs (57%) are potentially addressable by surgical care among the population born with such conditions. Neural tube defects have the largest potential with 76% of burden amenable by surgery, followed by clefts (59%) and congenital heart anomalies (49%). Sub-Saharan Africa and South Asia have the greatest proportion of surgically addressable burden for clefts (68%), North Africa and Middle East for congenital heart anomalies (73%), and South Asia for neural tube defects (81%). CONCLUSIONS: There is an important and neglected role surgical programmes can play in reducing the burden of congenital anomalies in LMICs.

Burden of injuries avertable by a basic surgical package in low- and middle-income regions: a systematic analysis from the Global Burden of Disease 2010 Study.

BACKGROUND: Injuries accounted for 11 % of the global burden of disease in 2010. This study aimed to quantify the burden of injury in low- and middle-income countries (LMICs) that could be averted if basic surgical services were made available and accessible to the entire population. METHODS: We examined all causes of injury from the Global Burden of Disease 2010 Study. We split the disability-adjusted life years (DALYs) for these conditions between surgically "avertable" and "nonavertable" burdens. For estimating the avertable fatal burden, we applied the lowest fatality rates among the 21 epidemiologic regions to each LMIC region, assuming that the differences in death rates between each region and the lowest rates reflect the gap in surgical care. We adjusted for fatal cases that occur prior to reaching hospitals as they are not surgically avertable. Similarly, we applied the lowest nonfatal burden per case to each LMIC region. RESULTS: Overall, 21 % of the injury burden in LMICs was potentially avertable by basic surgical care (52.3 million DALYs). The avertable proportion was greater for deaths than for nonfatal burden (23 vs. 20 %), suggesting that surgical services for injuries more effectively save lives than ameliorate disability. Sub-Saharan Africa had the largest proportion of potentially avertable burden (25 %). South Asia had the highest total avertable DALYs (17.4 million). Road injury comprised the largest total avertable burden in LMICs (16.1 million DALYs). CONCLUSIONS: Basic surgical care has the potential to play a major role in reducing the injury-related burden in LMICs.

Surgically avertable burden of digestive diseases at first-level hospitals in low and middle-income regions.

BACKGROUND: To quantify the burden of digestive diseases avertable by surgical care at first-level hospitals in low- and middle-income countries (LMICs). METHODS: We examined 4 digestive diseases from the Global Burden of Disease (GBD) 2010 STUDY: Appendicitis, intestinal obstruction, inguinal and femoral hernia, and gallbladder and bile duct disease. Using demographic and epidemiologic data from the GBD 2010 STUDY, we calculated the potential decrease in burden of digestive diseases if quality surgical services were available universally and accessible at first-level hospitals. The lowest case fatality rates for each age and sex grouping from all GBD regions were assumed to reflect the best possible state of full surgical coverage and treatment. These best scenario rates were applied to the GBD 2010 results from all LMIC regions to estimate surgically avertable burden. RESULTS: Overall, 4.8 million disability-adjusted life-years (DALYs) or 65% of burden related to the 4 digestive diseases are avertable potentially with first-level surgical care in LMICs. Sub-Saharan Africa has the greatest avertable burden in absolute DALYs (1.7 million) and avertable proportion (83%). Intestinal obstruction accounted for the largest portion of avertable burden among the 4 digestive diseases (2.2 million DALYs; 64% avertable). CONCLUSION: Improving the capacity of surgical services at first-level hospitals is essential for averting the burden of digestive diseases in LMICs. Practicable strategies for scaling up surgical capacities in rural districts are available potentially, which must be given due attention.

Was there really any evidence that rosiglitazone increased the risk of myocardial infarction or death from cardiovascular causes?

Rosiglitazone has previously been widely used to treat patients with type 2 diabetes mellitus, but its safety in terms of cardiovascular morbidity and mortality had been called into question. Recently, there have been doubts raised about the meta-analytic evidence with the regulatory authorities relaxing its restrictions. We hypothesized that the original analyses may have produced exaggerated results because of the small baseline risks involved. To demonstrate this, we replicated the meta-analysis of four randomized trials of greater than 12-month follow-up that made use of a randomized control group not receiving rosiglitazone and reported outcome data for all occurrences of the complementary outcomes (no myocardial infarction, no death from cardiovascular causes, and no heart failure). Data were combined by means of a fixed-effects model. In the rosiglitazone group, as compared with the control group, the relative risk for no myocardial infarction was 0.997 (95% confidence interval [CI], 0.994 to 1.000), and the relative risk for no death from cardiovascular causes was 1.001 (95%CI, 0.999 to 1.003). Finally, no heart failure had a relative risk of 0.995 (95%CI, 0.993 to 0.998). Rosiglitazone does not seem to have any significant increase in the risk of myocardial infarction or of death from cardiovascular causes associated with its use. Regulatory authorities should revisit this issue of the appropriate measure for reporting of adverse events with low baseline risks as this has implications well beyond rosiglitazone.