Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral combination therapy

Objective: To assess the evidence for the effectiveness of increasing numbers of drugs in antiretroviral combination therapy.

Design: Systematic review, meta-analysis, and meta-regression of fully reported randomised controlled trials. All studies included compared quadruple versus triple therapy, triple versus double therapy, double versus monotherapy, or monotherapy versus placebo or no treatment.

Participants: Patients with any stage of HIV infection who had not received antiretroviral therapy.

Main outcome measures: Changes in disease progression or death (clinical outcomes); CD4 count and plasma viral load (surrogate markers).
Search strategy: Six electronic databases, including Medline, Embase, and the Cochrane Library, searched up to February 2001.

Results: 54 randomised controlled trials, most of good quality, with 66 comparison groups were included in the analysis. For both the clinical outcomes and surrogate markers, combinations with up to and including three (triple therapy) were progressively and significantly more effective. The odds ratio for disease progression or death for triple therapy compared with double therapy was 0.6 (95% confidence interval 0.5 to 0.8). Heterogeneity in effect sizes was present in many outcomes but was largely related to the drugs used and trial quality.

Conclusions: Evidence from randomised controlled trials supports the use of triple therapy. Research is needed on the effectiveness of quadruple therapies and the relative effectiveness of specific combinations of drugs.

Democracy and economic growth : a meta-analysis

Despite a sizeable theoretical and empirical literature, no firm conclusions have been drawn regarding the impact of political democracy on economic growth. This article challenges the consensus of an inconclusive relationship through a quantitative assessment of the democracy-growth literature. It applies meta-regression analysis to the population of 483 estimates derived from 84 studies on democracy and growth. Using traditional meta-analysis estimators, the bootstrap, and Fixed and Random Effects meta-regression models, it derives several robust conclusions. Taking all the available published evidence together, it concludes that democracy does not have a direct impact on economic growth. However, democracy has robust, significant, and positive indirect effects through higher human capital, lower inflation, lower political instability, and higher levels of economic freedom. Democracies may also be associated with larger governments and less free international trade. There also appear to be country- and region-specific democracy-growth effects. Overall, democracy's net effect on the economy does not seem to be detrimental.

The robust result in meta-analysis of aid effectiveness : a response to Mekasha and Tarp

In this response to Mekasha and Tarp (2013) we show that contrary to what they state, their study validates our basic analysis. They confirm that the literature finds that aid is of little economic importance in generating growth. The results also show that the literature systematically selects control variables for their effect on aid effectiveness. We argue that their choice of the random effects model is not appropriate for the problem at hand, and that the way they use multiple meta-regression analysis contradicts the robust results reached at the basic analysis.

Effectiveness of interventions to promote physical activity among socioeconomically disadvantaged women : a systematic review and meta-analysis

Physical activity is important for preventing weight gain and obesity, but women experiencing socioeconomic disadvantage are at high risk of inactivity. This study aimed to determine the effectiveness of interventions to increase physical activity among women experiencing disadvantage, and the intervention factors (i.e. physical activity measure, delivery mode, delivery channel, setting, duration, use of theory, behavioural techniques, participant age, risk of bias) associated with effectiveness. We conducted a meta-analysis of controlled trials using random-effects models and meta-regression. Seven databases were searched for trials among healthy women (18–64 years), which included a physical activity intervention, any control group, and statistical analyses of a physical activity outcome at baseline and post-intervention. Nineteen studies were included (n = 6,339). Because of substantial statistical heterogeneity (χ2 = 53.61, df = 18, P < 0.0001, I2 = 66%), an overall pooled effect is not reported. In subgroup analyses, between-group differences were evident for delivery mode, which modestly reduced heterogeneity (to 54%). Studies with a group delivery component had a standardized mean difference of 0.38 greater than either individual or community-based delivery. Programs with a group delivery mode significantly increase physical activity among women experiencing disadvantage, and group delivery should be considered an essential element of physical activity promotion programs targeting this population group.

Procedural learning deficits in specific language impairment (SLI): a meta-analysis of serial reaction time task performance

Meta-analysis and meta-regression were used to evaluate whether evidence to date demonstrates deficits in procedural memory in individuals with specific language impairment (SLI), and to examine reasons for inconsistencies of findings across studies. The Procedural Deficit Hypothesis (PDH) proposes that SLI is largely explained by abnormal functioning of the frontal-basal ganglia circuits that support procedural memory. It has also been suggested that declarative memory can compensate for at least some of the problems observed in individuals with SLI. A number of studies have used Serial Reaction Time (SRT) tasks to investigate procedural learning in SLI. In this report, results from eight studies that collectively examined 186 participants with SLI and 203 typically-developing peers were submitted to a meta-analysis. The average mean effect size was .328 (CI95: .071, .584) and was significant. This suggests SLI is associated with impairments of procedural learning as measured by the SRT task. Differences among individual study effect sizes, examined with meta-regression, indicated that smaller effect sizes were found in studies with older participants, and in studies that had a larger number of trials on the SRT task. The contributions of age and SRT task characteristics to learning are discussed with respect to impaired and compensatory neural mechanisms in SLI.

Adipokines as emerging depression biomarkers: a systematic review and meta-analysis

Adiponectin, leptin and resistin may play a role in the pathophysiology of major depressive disorder (MDD). However, differences in peripheral levels of these hormones are inconsistent across diagnostic and intervention studies. Therefore, we performed meta-analyses of diagnostic studies (i.e., MDD subjects versus healthy controls) and intervention investigations (i.e., pre-vs. post-antidepressant treatment) in MDD. Adiponectin (N=1278; Hedge's g=-0.35; P=0.16) and leptin (N=893; Hedge's g=-0.018; P=0.93) did not differ across diagnostic studies. Meta-regression analyses revealed that gender and depression severity explained the heterogeneity observed in adiponectin diagnostic studies, while BMI and the difference in BMI between MDD individuals and controls explained the heterogeneity of leptin diagnostic studies. Subgroup analyses revealed that adiponectin peripheral levels were significantly lower in MDD participants compared to controls when assayed with RIA, but not ELISA. Leptin levels were significantly higher in individuals with mild/moderate depression versus controls. Resistin serum levels were lower in MDD individuals compared to healthy controls (N=298; Hedge's g=-0.25; P=0.03). Leptin serum levels did not change after antidepressant treatment. However, heterogeneity was significant and sample size was low (N=108); consequently meta-regression analysis could not be performed. Intervention meta-analyses could not be performed for adiponectin and resistin (i.e., few studies met inclusion criteria). In conclusion, this systematic review and meta-analysis underscored that relevant moderators/confounders (e.g., BMI, depression severity and type of assay) should be controlled for when considering the role of leptin and adiponectin as putative MDD diagnostic biomarkers.

Peripheral vascular endothelial growth factor as a novel depression biomarker: a meta-analysis

BACKGROUND: The neurotrophic hypothesis of major depressive disorder (MDD) postulates that the pathology of this illness incorporates a down-regulation of neurotrophin signaling. Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophic mediator regarding the neurobiology of MDD. Nevertheless, emerging evidence has implicated the multi-competent angiogenic and neurogenic molecule - vascular endothelial growth factor (VEGF) - in hippocampal neurogenesis and depression pathophysiology. OBJECTIVE: To compare peripheral levels of VEGF between individuals with MDD and healthy controls. METHODS: We performed a systematic review and meta-analysis of original studies measuring peripheral levels of VEGF in participants with MDD compared to healthy controls. We searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases for studies published in any language through December 16th, 2014. RESULTS: Fourteen studies met eligibility criteria (N=1633). VEGF levels were significantly elevated in individuals with MDD when compared to healthy controls (Hedges's g=0.343; 95% CI: 0.146-0.540; P<0.01). Funnel plot inspection and the Egger's test did not provide evidence of publication bias. A significant degree of heterogeneity was observed (Q=38.355, df=13, P<0.001; I(2)=66.1%), which was explored through meta-regression and subgroup analyses. Overall methodological quality, sample for assay (plasma versus serum), as well as the matching of MDD and control samples for age and gender emerged as significant sources of heterogeneity. CONCLUSIONS: Taken together, extant data indicate that VEGF shows promise as a biomarker for MDD, and supports that this mediator may be involved in neuroplasticity mechanisms underlying the pathophysiology of MDD.

A systematic review and meta-analysis on the longitudinal relationship between eating pathology and depression.

OBJECTIVE: Undertake a meta-analysis to provide a quantitative synthesis of longitudinal studies that assessed the direction of effects between eating pathology and depression. A second aim was to use meta-regression to account for heterogeneity in terms of study-level effect modifiers. METHOD: A systematic review was conducted on 42 studies that assessed the longitudinal relationship between eating pathology and depression. Of these 42 studies, multilevel random-effects meta-analyses were conducted on 30 eligible studies. RESULTS: Meta-analysis results showed that eating pathology was a risk factor for depression (rm  = 0.13) and that depression was a risk factor for eating pathology (rm  = 0.16). Meta-regression analyses showed that these effects were significantly stronger for studies that operationalized eating pathology as an eating disorder diagnosis versus eating pathology symptoms, and for studies that operationalized the respective outcome measure as a categorical variable (e.g., a diagnosis of a disorder or where symptoms were "present"/"absent") versus a continuous measure. Results also showed that in relation to eating pathology type, the effect of an eating disorder diagnosis and bulimic symptoms on depression was significantly stronger for younger participants. DISCUSSION: Eating pathology and depression are concurrent risk factors for each other, suggesting that future research would benefit from identifying factors that are etiological to the development of both constructs. RESUMEN OBJETIVO: Llevar a cabo un meta-análisis para proporcionar una síntesis cuantitativa de los estudios longitudinales que evaluaron la dirección de los efectos entre la alimentación patológica y la depresión. Un segundo objetivo fue utilizar la meta-regresión para dar cuenta de la heterogeneidad en términos de modificadores del efecto a nivel de estudio. MÉTODO: Una revisión sistemática se llevó a cabo en 42 estudios que evaluaron la relación longitudinal entre la alimentación patológica y la depresión. De estos 42 estudios, se realizaron meta-análisis de multinivel de efectos aleatorios en 30 estudios elegibles. RESULTADOS: Los resultados del meta-análisis mostraron que la alimentación patológica era un factor de riesgo para depresión (rm=0.13) y que la depresión era un factor de riesgo para la alimentación patológica (rm=0.16). Los análisis de meta-regresión mostraron que estos efectos eran significativamente más fuertes para estudios que operacionalizaban la alimentación patológica como un diagnóstico de trastorno de la conducta alimentaria versus síntomas de alimentación patológica, y para los estudios que operacionalizaban la medida respectiva de resultado como una variable categórica (e.g., un diagnóstico de trastorno o cuando los síntomas estaban "presentes"/"ausentes") versus una medida continua. Los resultados mostraron que en relación al tipo de alimentación patológica, el efecto de un diagnóstico de trastorno de la conducta alimentaria y síntomas bulímicos en la depresión era significativamente más fuerte para participantes más jóvenes. DISCUSIÓN: La alimentación patológica y la depresión son factores de riesgo concurrentes uno para el otro, lo que sugiere que la investigación futura se beneficiaría de identificar factores que son etiológicos al desarrollo de ambos constructos. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2016;49:439-454).

Neither fixed nor random: weighted least squares meta-analysis

This study challenges two core conventional meta-analysis methods: fixed effect and random effects. We show how and explain why an unrestricted weighted least squares estimator is superior to conventional random-effects meta-analysis when there is publication (or small-sample) bias and better than a fixed-effect weighted average if there is heterogeneity. Statistical theory and simulations of effect sizes, log odds ratios and regression coefficients demonstrate that this unrestricted weighted least squares estimator provides satisfactory estimates and confidence intervals that are comparable to random effects when there is no publication (or small-sample) bias and identical to fixed-effect meta-analysis when there is no heterogeneity. When there is publication selection bias, the unrestricted weighted least squares approach dominates random effects; when there is excess heterogeneity, it is clearly superior to fixed-effect meta-analysis. In practical applications, an unrestricted weighted least squares weighted average will often provide superior estimates to both conventional fixed and random effects.

C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis

BACKGROUND: Inflammatory processes and neural-immune interactions have been implicated in the pathogenesis of psychiatric conditions, but studies in bipolar disorder are inconclusive so far. We aimed to investigate whether peripheral concentrations of C-reactive protein (CRP), an acute-phase response protein of inflammatory activity, are increased in bipolar disorder across the mood spectrum. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, the Cochrane Library, Scopus, and Web of Knowledge from database inception to Aug 14, 2016, for studies that measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls. We extracted data from published reports. We did three between-group meta-analyses comparing CRP concentrations in patients in mania, depression, or euthymia, with those in healthy controls (cross-sectional studies), and two within-group meta-analyses comparing changes in CRP concentrations before and after treatment of an index manic or depressive episode (longitudinal studies). We used Hedges' adjusted g to calculate effect sizes and pooled results using random-effect models. We also did meta-regression analyses by mood state to investigate possible moderators of CRP concentrations. FINDINGS: We identified 27 studies representing 2161 patients with bipolar disorder and 81 932 healthy controls. Compared with healthy individuals, CRP concentrations were moderately increased in people with bipolar disorder during depression (g 0·67, 95% CI 0·23 to 1·11; p=0·003) and euthymia (0·65, 0·40 to 0·90; p<0·0001) and more substantially increased during mania (0·87, 0·58 to 1·15; p<0·0001). The extent of the increases in CRP concentrations in mania and depression was not related to symptom severity (p=0·256 for mania and p=0·626 for depression). CRP concentrations were moderately decreased after resolution of an index manic episode (-0·36, -0·66 to -0·05; p=0·022) and slightly decreased after resolution of an index depressive episode (-0·18, -0·30 to -0·07; p=0·002). INTERPRETATION: CRP concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania.

Publication bias in union-productivity research?

This paper develops and applies several meta-analytic techniques to investigate the presence of publication bias in industrial relations research, specifically in the union-productivity effects literature. Publication bias arises when statistically insignificant results are suppressed or when results satisfying prior expectations are given preference. Like most fields, research in industrial relations is vulnerable to publication bias. Unlike other fields such as economics, there is no evidence of publication bias in the union-productivity literature, as a whole. However, there are pockets of publication selection, as well as negative autoregression, confirming the controversial nature of this area of research. Meta-regression analysis reveals evidence of publication bias (or selection) among US studies.

Economic freedom and economic growth: Does specification make a difference?

In this paper we apply meta-analytic techniques to the literature on the impact of economic freedom on economic growth and find an overall positive direct association between economic freedom and economic growth. A positive indirect effect of economic freedom on economic growth through the stimulation of physical capital is also identified. However, the literature is affected by specification bias with respect to controls for physical capital. The omission of physical capital results in larger estimates of the economic freedom–economic growth association. Further, the use of panel data leads to smaller estimates of the impact of economic freedom on economic growth. The meta-analysis is confirmed by primary cross-sectional and panel data analysis of 82 countries for the period 1970–1999.

Picture this : a simple graph that reveals much ado about research

Funnel graphs provide a simple, yet highly effective, means to identify key features of an empirical literature. This paper illustrates the use of funnel graphs to detect publication selection bias, identify the existence of genuine empirical effects and discover potential moderator variables that can help to explain the wide variation routinely found among reported research findings. Applications include union–productivity effects, water price elasticities, common currency-trade effects, minimum-wage employment effects, efficiency wages and the price elasticity of prescription drugs.