Meta-analysis: a unifying meta-likelihood approach framing unobserved heterogeneity, study covariates, publication bias, and study quality

OBJECTIVES: This contribution provides a unifying concept for meta-analysis integrating the handling of unobserved heterogeneity, study covariates, publication bias and study quality. It is important to consider these issues simultaneously to avoid the occurrence of artifacts, and a method for doing so is suggested here. METHODS: The approach is based upon the meta-likelihood in combination with a general linear nonparametric mixed model, which lays the ground for all inferential conclusions suggested here. RESULTS: The concept is illustrated at hand of a meta-analysis investigating the relationship of hormone replacement therapy and breast cancer. The phenomenon of interest has been investigated in many studies for a considerable time and different results were reported. In 1992 a meta-analysis by Sillero-Arenas et al. concluded a small, but significant overall effect of 1.06 on the relative risk scale. Using the meta-likelihood approach it is demonstrated here that this meta-analysis is due to considerable unobserved heterogeneity. Furthermore, it is shown that new methods are available to model this heterogeneity successfully. It is argued further to include available study covariates to explain this heterogeneity in the meta-analysis at hand. CONCLUSIONS: The topic of HRT and breast cancer has again very recently become an issue of public debate, when results of a large trial investigating the health effects of hormone replacement therapy were published indicating an increased risk for breast cancer (risk ratio of 1.26). Using an adequate regression model in the previously published meta-analysis an adjusted estimate of effect of 1.14 can be given which is considerably higher than the one published in the meta-analysis of Sillero-Arenas et al. In summary, it is hoped that the method suggested here contributes further to a good meta-analytic practice in public health and clinical disciplines.

The significance of insecure attachment and disorganization in the development of children's externalizing behavior: A meta-analytic study

This study addresses the extent to which insecure and disorganized attachments increase risk for externalizing problems using meta-analysis. From 69 samples (N = 5,947), the association between insecurity and externalizing problems was significant, d = 0.31 (95% CI: 0.23, 0.40). Larger effects were found for boys (d = 0.35), clinical samples (d = 0.49), and from observation-based outcome assessments (d = 0.58). Larger effects were found for attachment assessments other than the Strange Situation. Overall, disorganized children appeared at elevated risk (d = 0.34, 95% CI: 0.18, 0.50), with weaker effects for avoidance (d = 0.12, 95% CI: 0.03, 0.21) and resistance (d = 0.11, 95% CI: −0.04, 0.26). The results are discussed in terms of the potential significance of attachment for mental health.

Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

Interactions between uncoupling protein 2 gene polymorphisms, obesity and alcohol intake on liver function: a large meta-analysed population-based study

BACKGROUND AND OBJECTIVE: Given the role of uncoupling protein 2 (UCP2) in the accumulation of fat in the hepatocytes and in the enhancement of protective mechanisms in acute ethanol intake, we hypothesised that UCP2 polymorphisms are likely to cause liver disease through their interactions with obesity and alcohol intake. To test this hypothesis, we investigated the interaction between tagging polymorphisms in the UCP2 gene (rs2306819, rs599277 and rs659366), alcohol intake and obesity traits such as BMI and waist circumference (WC) on alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in a large meta-analysis of data sets from three populations (n=20 242). DESIGN AND METHODS: The study populations included the Northern Finland Birth Cohort 1966 (n=4996), Netherlands Study of Depression and Anxiety (n=1883) and LifeLines Cohort Study (n=13 363). Interactions between the polymorphisms and obesity and alcohol intake on dichotomised ALT and GGT levels were assessed using logistic regression and the likelihood ratio test. RESULTS: In the meta-analysis of the three cohorts, none of the three UCP2 polymorphisms were associated with GGT or ALT levels. There was no evidence for interaction between the polymorphisms and alcohol intake on GGT and ALT levels. In contrast, the association of WC and BMI with GGT levels varied by rs659366 genotype (Pinteraction=0.03 and 0.007, respectively; adjusted for age, gender, high alcohol intake, diabetes, hypertension and serum lipid concentrations). CONCLUSION: In conclusion, our findings in 20 242 individuals suggest that UCP2 gene polymorphisms may cause liver dysfunction through the interaction with body fat rather than alcohol intake.

Revisiting youden’s index as a useful measure of the misclassification error in meta-analysis of diagnostic studies

The paper considers meta-analysis of diagnostic studies that use a continuous score for classification of study participants into healthy or diseased groups. Classification is often done on the basis of a threshold or cut-off value, which might vary between studies. Consequently, conventional meta-analysis methodology focusing solely on separate analysis of sensitivity and specificity might be confounded by a potentially unknown variation of the cut-off value. To cope with this phenomena it is suggested to use, instead, an overall estimate of the misclassification error previously suggested and used as Youden’s index and; furthermore, it is argued that this index is less prone to between-study variation of cut-off values. A simple Mantel–Haenszel estimator as a summary measure of the overall misclassification error is suggested, which adjusts for a potential study effect. The measure of the misclassification error based on Youden’s index is advantageous in that it easily allows an extension to a likelihood approach, which is then able to cope with unobserved heterogeneity via a nonparametric mixture model. All methods are illustrated at hand of an example on a diagnostic meta-analysis on duplex doppler ultrasound, with angiography as the standard for stroke prevention.

Revisiting Youden's index as a useful measure of the misclassification error in meta-analysis of diagnostic studies

The paper considers meta-analysis of diagnostic studies that use a continuous Score for classification of study participants into healthy, or diseased groups. Classification is often done on the basis of a threshold or cut-off value, which might vary between Studies. Consequently, conventional meta-analysis methodology focusing solely on separate analysis of sensitivity and specificity might he confounded by a potentially unknown variation of the cut-off Value. To cope with this phenomena it is suggested to use, instead an overall estimate of the misclassification error previously suggested and used as Youden's index and; furthermore, it is argued that this index is less prone to between-study variation of cut-off values. A simple Mantel-Haenszel estimator as a summary measure of the overall misclassification error is suggested, which adjusts for a potential study effect. The measure of the misclassification error based on Youden's index is advantageous in that it easily allows an extension to a likelihood approach, which is then able to cope with unobserved heterogeneity via a nonparametric mixture model. All methods are illustrated at hand of an example on a diagnostic meta-analysis on duplex doppler ultrasound, with angiography as the standard for stroke prevention.

Strategies to prevent falls and fractures in hospitals and care homes and effect of cognitive impairment: systematic review and meta-analyses

OBJECTIVES: To evaluate the evidence for strategies to prevent falls or fractures in residents in care homes and hospital inpatients and to investigate the effect of dementia and cognitive impairment. DESIGN: Systematic review and meta-analyses of studies grouped by intervention and setting (hospital or care home). Meta-regression to investigate the effects of dementia and of study quality and design. DATA SOURCES: Medline, CINAHL, Embase, PsychInfo, Cochrane Database, Clinical Trials Register, and hand searching of references from reviews and guidelines to January 2005. RESULTS: 1207 references were identified, including 115 systematic reviews, expert reviews, or guidelines. Of the 92 full papers inspected, 43 were included. Meta-analysis for multifaceted interventions in hospital (13 studies) showed a rate ratio of 0.82 (95% confidence interval 0.68 to 0.997) for falls but no significant effect on the number of fallers or fractures. For hip protectors in care homes (11 studies) the rate ratio for hip fractures was 0.67 (0.46 to 0.98), but there was no significant effect on falls and not enough studies on fallers. For all other interventions (multifaceted interventions in care homes; removal of physical restraints in either setting; fall alarm devices in either setting; exercise in care homes; calcium/vitamin D in care homes; changes in the physical environment in either setting; medication review in hospital) meta-analysis was either unsuitable because of insufficient studies or showed no significant effect on falls, fallers, or fractures, despite strongly positive results in some individual studies. Meta-regression showed no significant association between effect size and prevalence of dementia or cognitive impairment. CONCLUSION: There is some evidence that multifaceted interventions in hospital reduce the number of falls and that use of hip protectors in care homes prevents hip fractures. There is insufficient evidence, however, for the effectiveness of other single interventions in hospitals or care homes or multifaceted interventions in care homes.

Effects of beverage alcohol taxes and prices on drinking: a meta-analysis of 1003 estimates from 112 studies

Aims: We conducted a systematic review of studies examining relationships between measures of beverage alcohol tax or price levels and alcohol sales or self-reported drinking. A total of 112 studies of alcohol tax or price effects were found, containing 1003 estimates of the tax/price–consumption relationship. Design: Studies included analyses of alternative outcome measures, varying subgroups of the population, several statistical models, and using different units of analysis. Multiple estimates were coded from each study, along with numerous study characteristics. Using reported estimates, standard errors, t-ratios, sample sizes and other statistics, we calculated the partial correlation for the relationship between alcohol price or tax and sales or drinking measures for each major model or subgroup reported within each study. Random-effects models were used to combine studies for inverse variance weighted overall estimates of the magnitude and significance of the relationship between alcohol tax/price and drinking. Findings: Simple means of reported elasticities are -0.46 for beer, -0.69 for wine and -0.80 for spirits. Meta-analytical results document the highly significant relationships (P < 0.001) between alcohol tax or price measures and indices of sales or consumption of alcohol (aggregate-level r = -0.17 for beer, -0.30 for wine, -0.29 for spirits and -0.44 for total alcohol). Price/tax also affects heavy drinking significantly (mean reported elasticity = -0.28, individual-level r = -0.01, P < 0.01), but the magnitude of effect is smaller than effects on overall drinking. Conclusions: A large literature establishes that beverage alcohol prices and taxes are related inversely to drinking. Effects are large compared to other prevention policies and programs. Public policies that raise prices of alcohol are an effective means to reduce drinking.

A meta analysis of real estate fund performance

This paper provides evidence regarding the risk-adjusted performance of 19 UK real estate funds in the UK, over the period 1991-2001. Using Jensen’s alpha the results are generally favourable towards the hypothesis that real estate fund managers showed superior risk-adjusted performance over this period. However, using three widely known parametric statistical procedures to jointly test for timing and selection ability the results are less conclusive. The paper then utilises the meta-analysis technique to further examine the regression results in an attempt to estimate the proportion of variation in results attributable to sampling error. The meta-analysis results reveal strong evidence, across all models, that the variation in findings is real and may not be attributed to sampling error. Thus, the meta-analysis results provide strong evidence that on average the sample of real estate funds analysed in this study delivered significant risk-adjusted performance over this period. The meta-analysis for the three timing and selection models strongly indicating that this out performance of the benchmark resulted from superior selection ability, while the evidence for the ability of real estate fund managers to time the market is at best weak. Thus, we can say that although real estate fund managers are unable to outperform a passive buy and hold strategy through timing, they are able to improve their risk-adjusted performance through selection ability.

Fertilisers and insect herbivores: a meta-analysis

Despite the importance of a thorough understanding of the effect of synthetic fertiliser on insect population dynamics, existing literature is conflicting and an area of intense debate. Here, a categorical random-effects meta-analysis and a vote count meta-analysis are employed to examine the effects of nitrogen(N), phosphorus (P), potassium (K) and NPK fertiliser on insect population dynamics. In agreement with the general consensus, insects were found to respond positively, overall, to fertilisers. Sucking insects showed a much stronger response to fertilisers than chewing insects. The environment in which a study is conducted can have a marked effect on insect responses to fertiliser, with natural environments showing the potential for buffering effects of nitrogen fertilisers in particular. As well as highlighting the potential shortfall in the amount of research investigating particularly the effects of potassium and phosphorus, this study provides an invaluable flag post in the ongoing research investigating fertiliser effects on ecosystems.

Magnetic resonance imaging of a randomized controlled trial investigating predictors of recovery following psychological treatment in adolescents with moderate to severe unipolar depression: study protocol for Magnetic Resonance - Improving Mood with Psychoanalytic and Cognitive Therapies (MR-IMPACT)

Background Major depressive disorders (MDD) are a debilitating and pervasive group of mental illnesses afflicting many millions of people resulting in the loss of 110 million working days and more than 2,500 suicides per annum. Adolescent MDD patients attending NHS clinics show high rates of recurrence into adult life. A meta-analysis of recent research shows that psychological treatments are not as efficacious as previously thought. Modest treatment outcomes of approximately 65% of cases responding suggest that aetiological and clinical heterogeneity may hamper the better use of existing therapies and discovery of more effective treatments. Information with respect to optimal treatment choice for individuals is lacking, with no validated biomarkers to aid therapeutic decision-making. Methods/Design Magnetic resonance-Improving Mood with Psychoanalytic and Cognitive Therapies, the MR-IMPACT study, plans to identify brain regions implicated in the pathophysiology of depressions and examine whether there are specific behavioural or neural markers predicting remission and/or subsequent relapse in a subsample of depressed adolescents recruited to the IMPACT randomised controlled trial (Registration # ISRCTN83033550). Discussion MR-IMPACT is an investigative biomarker component of the IMPACT pragmatic effectiveness trial. The aim of this investigation is to identify neural markers and regional indicators of the pathophysiology of and treatment response for MDD in adolescents. We anticipate that these data may enable more targeted treatment delivery by identifying those patients who may be optimal candidates for therapeutic response.

Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI

Before the advent of genome-wide association studies (GWASs), hundreds of candidate genes for obesity-susceptibility had been identified through a variety of approaches. We examined whether those obesity candidate genes are enriched for associations with body mass index (BMI) compared with non-candidate genes by using data from a large-scale GWAS. A thorough literature search identified 547 candidate genes for obesity-susceptibility based on evidence from animal studies, Mendelian syndromes, linkage studies, genetic association studies and expression studies. Genomic regions were defined to include the genes ±10 kb of flanking sequence around candidate and non-candidate genes. We used summary statistics publicly available from the discovery stage of the genome-wide meta-analysis for BMI performed by the genetic investigation of anthropometric traits consortium in 123 564 individuals. Hypergeometric, rank tail-strength and gene-set enrichment analysis tests were used to test for the enrichment of association in candidate compared with non-candidate genes. The hypergeometric test of enrichment was not significant at the 5% P-value quantile (P = 0.35), but was nominally significant at the 25% quantile (P = 0.015). The rank tail-strength and gene-set enrichment tests were nominally significant for the full set of genes and borderline significant for the subset without SNPs at P < 10(-7). Taken together, the observed evidence for enrichment suggests that the candidate gene approach retains some value. However, the degree of enrichment is small despite the extensive number of candidate genes and the large sample size. Studies that focus on candidate genes have only slightly increased chances of detecting associations, and are likely to miss many true effects in non-candidate genes, at least for obesity-related traits.

Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study

BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. METHODS: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. FINDINGS: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). INTERPRETATION: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.

Meta-analysis of relationships between enteric methane yield and milk fatty acid profile in dairy cattle

Various studies have indicated a relationship between enteric methane (CH4) production and milk fatty acid (FA) profiles of dairy cattle. However, the number of studies investigating such a relationship is limited and the direct relationships reported are mainly obtained by variation in CH4 production and milk FA concentration induced by dietary lipid supplements. The aim of this study was to perform a meta-analysis to quantify relationships between CH4 yield (per unit of feed and unit of milk) and milk FA profile in dairy cattle and to develop equations to predict CH4 yield based on milk FA profile of cows fed a wide variety of diets. Data from 8 experiments encompassing 30 different dietary treatments and 146 observations were included. Yield of CH4 measured in these experiments was 21.5 ± 2.46 g/kg of dry matter intake (DMI) and 13.9 ± 2.30 g/ kg of fat- and protein-corrected milk (FPCM). Correlation coefficients were chosen as effect size of the relationship between CH4 yield and individual milk FA concentration (g/100 g of FA). Average true correlation coefficients were estimated by a random-effects model. Milk FA concentrations of C6:0, C8:0, C10:0, C16:0, and C16:0-iso were significantly or tended to be positively related to CH4 yield per unit of feed. Concentrations of trans-6+7+8+9 C18:1, trans-10+11 C18:1, cis- 11 C18:1, cis-12 C18:1, cis-13 C18:1, trans-16+cis-14 C18:1, and cis-9,12 C18:2 in milk fat were significantly or tended to be negatively related to CH4 yield per unit of feed. Milk FA concentrations of C10:0, C12:0, C14:0-iso, C14:0, cis-9 C14:1, C15:0, and C16:0 were significantly or tended to be positively related to CH4 yield per unit of milk. Concentrations of C4:0, C18:0, trans-10+11 C18:1, cis-9 C18:1, cis-11 C18:1, and cis- 9,12 C18:2 in milk fat were significantly or tended to be negatively related to CH4 yield per unit of milk. Mixed model multiple regression and a stepwise selection procedure of milk FA based on the Bayesian information criterion to predict CH4 yield with milk FA as input (g/100 g of FA) resulted in the following prediction equations: CH4 (g/kg of DMI) = 23.39 + 9.74 × C16:0- iso – 1.06 × trans-10+11 C18:1 – 1.75 × cis-9,12 C18:2 (R2 = 0.54), and CH4 (g/kg of FPCM) = 21.13 – 1.38 × C4:0 + 8.53 × C16:0-iso – 0.22 × cis-9 C18:1 – 0.59 × trans-10+11 C18:1 (R2 = 0.47). This indicated that milk FA profile has a moderate potential for predicting CH4 yield per unit of feed and a slightly lower potential for predicting CH4 yield per unit of milk. Key words: methane , milk fatty acid profile , metaanalysis , dairy cattle

Casein-derived lactotripeptides reduce systolic and diastolic blood pressure in a meta-analysis of randomised clinical trials

There is an urgent need to treat individuals with high blood pressure (BP) with effective dietary strategies. Previous studies suggest a small, but significant decrease in BP after lactotripeptides (LTP) ingestion, although the data are inconsistent. The study aim was to perform a comprehensive meta-analysis of data from all relevant randomised controlled trials (RCT). Medline, Cochrane library, EMBASE and Web of Science were searched until May 2014. Eligibility criteria were RCT that examined the effects of LTP on BP in adults, with systolic BP (SBP) and diastolic BP (DBP) as outcome measures. Thirty RCT met the inclusion criteria, which resulted in 33 sets of data. The pooled treatment effect for SBP was −2.95 mmHg (95% CI: −4.17, −1.73; p < 0.001), and for DBP was −1.51 mmHg (95% CI: −2.21, −0.80; p < 0.001). Sub-group analyses revealed that reduction of BP in Japanese studies was significantly greater, compared with European studies (p = 0.002 for SBP and p < 0.001 for DBP). The 24-h ambulatory BP (AMBP) response to LTP supplementation was statistically non-significant (p = 0.101 for SBP and p = 0.166 for DBP). Both publication bias and “small-study effect” were identified, which shifted the treatment effect towards less significant SBP and non-significant DBP reduction after LTP consumption. LTP may be effective in BP reduction, especially in Japanese individuals; however sub-group, meta-regression analyses and statistically significant publication biases suggest inconsistencies.