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.

Case study part 1: how to calculate appropriate deterministic long-term toxicity to exposure rates (TERs) for birds and mammals

In the European Union, first-tier assessment of the long-term risk to birds and mammals from pesticides is based on calculation of a deterministic long-term toxicity/exposure ratio(TERlt). The ratio is developed from generic herbivores and insectivores and applied to all species. This paper describes two case studies that implement proposed improvements to the way long-term risk is assessed. These refined methods require calculation of a TER for each of five identified phases of reproduction (phase-specific TERs) and use of adjusted No Observed Effect Levels (NOELs)to incorporate variation in species sensitivity to pesticides. They also involve progressive refinement of the exposure estimate so that it applies to particular species, rather than generic indicators, and relates spraying date to onset of reproduction. The effect of using these new methods on the assessment of risk is described. Each refinement did not necessarily alter the calculated TER value in a way that was either predictable or consistent across both case studies. However, use of adjusted NOELs always reduced TERs, and relating spraying date to onset of reproduction increased most phase-specific TERs. The case studies suggested that the current first-tier TERlt assessment may underestimate risk in some circumstances and that phase-specific assessments can help identify appropriate risk-reduction measures. The way in which deterministic phase-specific assessments can currently be implemented to enhance first-tier assessment is outlined.

The effect of doubled CO2 and model basic state biases on the monsoon-ENSO system. I: Mean response and interannual variability

The impact of doubled CO2 concentration on the Asian summer monsoon is studied using a coupled ocean-atmosphere model. Both the mean seasonal precipitation and interannual monsoon variability are found to increase in the future climate scenario presented. Systematic biases in current climate simulations of the coupled system prevent accurate representation of the monsoon-ENSO teleconnection, of prime importance for seasonal prediction and for determining monsoon interannual variability. By applying seasonally varying heat flux adjustments to the tropical Pacific and Indian Ocean surface in the future climate simulation, some assessment can be made of the impact of systematic model biases on future climate predictions. In simulations where the flux adjustments are implemented, the response to climate change is magnified, with the suggestion that systematic biases may be masking the true impact of increased greenhouse gas forcing. The teleconnection between ENSO and the Asian summer monsoon remains robust in the future climate, although the Indo-Pacific takes on more of a biennial character for long periods of the flux-adjusted simulation. Assessing the teleconnection across interdecadal timescales shows wide variations in its amplitude, despite the absence of external forcing. This suggests that recent changes in the observed record cannot be distinguished from internal variations and as such are not necessarily related to climate change.

Effect of dietary supplementation of different oils during the first or second half of pregnancy on the glucose tolerance of the sow

Poor glucose tolerance may be an under-researched contributory factor in the high (10% to 20%) pre-weaning mortality rate observed in pigs. Insulin resistance commences at around week 12 of gestation in the sow, although there are conflicting reports in the literature about the extent to which insulin resistance is modulated by maternal diet. The aim of the study was to determine the effects of supplementing the maternal diet with different dietary oils during either the first half or the second half of gestation on the glucose tolerance of the sow. Sows were offered the control (C: n = 5) diet as pellets or the C diet plus 10% extra energy (h = 16 per group) derived from either. (i) extra pellets; (ii) palm oil; (iii) olive oil; (iv) sunflower oil; or (v) fish oil. Experimental diets were fed during either the first (G1) or second (G2) half of gestation. A glucose tolerance test (GTT) was conducted on day 108 of gestation by administering 0.5g/kg glucose i.v. Blood samples were taken every 5 to 10 min for 90 min post administration. The change in body weight and backfat thickness during gestation was similar but both type and timing of dietary supplementation influenced litter size and weight. With the exception of the sunflower oil group, supplementing the maternal diet in G1 resulted in larger and heavier litters, particularly in mothers offered palm oil. Basal blood glucose concentrations tended to be more elevated in G1 than G2 groups, whilst plasma insulin concentrations were similar Following a GTT, the adjusted area under the curve was greater in G1 compared to G2 sows, despite no differences in glucose clearance. Maternal diet appeared to influence the relationship between glucose curve characteristics following a GTT and litter outcome. In conclusion, the degree of insulin sensitivity can be altered by both the period during which maternal nutritional supplementation is offered and the fatty acid profile of the diet.

Including a time-of-year effect in the analysis of a matched case-control study

Motivated by a matched case-control study to investigate potential risk factors for meningococcal disease amongst adolescents, we consider the analysis of matched case-control studies where disease incidence, and possibly other risk factors, vary with time of year. For the cases, the time of infection may be recorded. For controls, however, the recorded time is simply the time of data collection, which is shortly after the time of infection for the matched case, and so depends on the latter. We show that the effect of risk factors and interactions may be adjusted for the time of year effect in a standard conditional logistic regression analysis without introducing any bias. We also show that, if the time delay between data collection for cases and controls is constant, provided this delay is not very short, estimates of the time of year effect are approximately unbiased. In the case that the length of the delay varies over time, the estimate of the time of year effect is biased. We obtain an approximate expression for the degree of bias in this case. Copyright © 2004 John Wiley & Sons, Ltd.

The effect of intensive case management on the relatives of patients with severe mental illness

Objective: Relatives play a vital role in caring for patients with severe mental illness but receive inadequate support from psychiatric services. Evidence suggests that although intensive case management is directed primarily at patients, relatives may benefit a's well. This study examined whether relatives of patients who were receiving intensive case management had more contact with mental health professionals than relatives of patients who were receiving standard case management. It also examined whether relatives of patients receiving intensive case management appraised caregiving less negatively and experienced less psychological distress than relatives of patients receiving standard case management. Methods: The sample was drawn from the pool of patients participating in the UK700 randomized controlled trial of intensive case management. Prospective data on contact between case managers and the relatives of 146 patients were collected over a two-year period. At a two-year follow-up assessment, relatives of 116 patients were. interviewed with the Experience of Caregiving Inventory and the 12-item General Health Questionnaire. Results: Considerably more relatives of patients receiving intensive case management had contact with a case manager during the study period than relatives of patients receiving standard case management (70 percent compared with 45 percent). However, relatives of patients receiving intensive case management did not-appraise caregiving less negatively or experience less psychological distress than relatives of patients who were receiving. standard case management. Conclusions: Reducing case managers' caseloads alone. will not guarantee adequate support for relatives.. Instead, providing more support will need to be an explicit aim, and staff will require specific additional training to achieve it.

Effect of processed and red meat on endogenous nitrosation and DNA damage

Haem in red meat (RM) stimulates the endogenous production of mutagenic nitroso compounds (NOC). Processed (nitrite-preserved red) meat additionally contains high concentrations of preformed NOC. In two studies, of a fresh RM versus a vegetarian (VEG) diet (six males and six females) and of a nitrite-preserved red meat (PM) versus a VEG diet (5 males and 11 females), we investigated whether processing of meat might increase colorectal cancer risk by stimulating nitrosation and DNA damage. Meat diets contained 420 g (males) or 366 g (females) meat/per day. Faecal homogenates from day 10 onwards were analysed for haem and NOC and asso- ciated supernatants for genotoxicity. Means are adjusted for differ- ences in male to female ratios between studies. Faecal NOC concentrations on VEG diets were low (2.6 and 3.5 mmol/g) but significantly higher on meat diets (PM 175 ± 19 nmol/g versus RM 185 ± 22 nmol/g; P 5 0.75). The RM diet resulted in a larger pro- portion of nitrosyl iron (RM 78% versus PM 54%; P < 0.0001) and less nitrosothiols (RM 12% versus PM 19%; P < 0.01) and other NOC (RM 10% versus PM 27%; P < 0.0001). There was no statis- tically significant difference in DNA breaks induced by faecal water (FW) following PM and RM diets (P 5 0.80). However, PM re- sulted in higher levels of oxidized pyrimidines (P < 0.05). Surpris- ingly, VEG diets resulted in significantly more FW-induced DNA strand breaks than the meat diets (P < 0.05), which needs to be clarified in further studies. Meats cured with nitrite have the same effect as fresh RM on endogenous nitrosation but show increased FW-induced oxidative DNA damage.

Effect of polymorphisms in the PPARGC1A gene on body fat in Asian Indians

OBJECTIVE: To evaluate whether polymorphisms in the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PPARGC1A) gene were related to body fat in Asian Indians. METHODS: Three polymorphisms of PPARGC1A gene, the Thr394Thr, Gly482Ser and +A2962G, were genotyped on 82 type 2 diabetic and 82 normal glucose tolerant (NGT) subjects randomly chosen from the Chennai Urban Rural Epidemiology Study using PCR-RFLP, and the nature of the variants were confirmed using direct sequencing. Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies using an expectation-maximization algorithm. Visceral, subcutaneous and total abdominal fat were measured using computed tomography, whereas dual X-ray absorptiometry was used to measure central abdominal and total body fat. RESULTS: None of the three polymorphisms studied were in LD. The genotype (0.59 vs 0.32, P=0.001) and allele (0.30 vs 0.17, P=0.007) frequencies of Thr394Thr polymorphism were significantly higher in type 2 diabetic subjects compared to those in NGT subjects. The odds ratio for diabetes (adjusted for age, sex and body mass index) for the susceptible genotype, XA (GA+AA) of Thr394Thr polymorphism, was 2.53 (95% confidence intervals: 1.30-5.04, P=0.009). Visceral and subcutaneous fat were significantly higher in NGT subjects with XA genotype of the Thr394Thr polymorphism compared to those with GG genotype (visceral fat: XA 148.2+/-46.9 vs GG 106.5+/-51.9 cm(2), P=0.001; subcutaneous fat: XA 271.8+/-167.1 vs GG 181.5+/-78.5 cm(2), P=0.001). Abdominal (XA 4521.9+/-1749.6 vs GG 3445.2+/-1443.4 g, P=0.004), central abdominal (XA 1689.0+/-524.0 vs GG 1228.5+/-438.7 g, P<0.0001) and non-abdominal fat (XA 18763.8+/-8789.4 vs GG 13160.4+/-4255.3 g, P<0.0001) were also significantly higher in the NGT subjects with XA genotype compared to those with GG genotype. The Gly482Ser and +A2962G polymorphisms were not associated with any of the body fat measures. CONCLUSION: Among Asian Indians, the Thr394Thr (G --> A) polymorphism is associated with increased total, visceral and subcutaneous body fat.

Environmental and ecological economics in the 21st century: an age adjusted citation analysis of the influential articles, journals, authors and institutions

We investigate the influence of articles, authors, journals and institutions in the field of environmental and ecological economics. We depart from studies that investigated the literature until 2001 and include a time period that has witnessed an enormous increase of importance in the field. We adjust for the age effect given the huge impact of the year of an article's publication on its influence and we show that this adjustment does make a substantial difference — especially for disaggregated units of analysis with diverse age characteristics such as articles or authors. We analyse 6597 studies on environmental and ecological economics published between 2000 and 2009. We provide rankings of the influential articles, authors, journals and institutions and find that Ecological Economics, Energy Economics and the Journal of Environmental Economics and Management have the most influential articles, they publish very influential authors and their articles are cited most. The University of Maryland, Resources for the Future, the University of East Anglia and the World Bank appear to be the most influential institutions in the field of environmental and ecological economics.

The effect of proteolysis on the induction of cell death by monomeric alpha-lactalbumin.

α-Lactalbumin (α-la) is a major whey protein found in milk. Previous data suggested that α-la has antiproliferative effects in human adenocarcinoma cell lines such as Caco-2 and HT-29. However, the cell death inducing α-la was not a naturally occurring monomer but either a multimeric variant or an α-la:oleic acid complex (HAMLET/BAMLET). Proteolysis showed that both human and bovine α-la are susceptible to digestion. ELISA assays assessing cell death with the native undigested α-la fractions showed that undigested protein fractions did have a significant cell death effect on CaCo-2 cells. Bovine α-la was also more effective than human α-la. A reduction in activity corresponded with lower concentrations of the protein and partial digestion and fragmentation of the protein using trypsin and pepsin. This suggests that the tertiary structure is vital for the apoptotic effect.

Environmental and ecological economics in the 21st century: an age adjusted citation analysis of the most influential articles, journals, authors and institutions

We investigate the influence of articles, authors, journals and institutions in the field of environmental and ecological economics. We depart from studies that investigated the literature until 2001 and include a time period that has witnessed an enormous increase of importance in the field. We adjust for the age effect given the huge impact of the year of an article's publication on its influence and we show that this adjustment does make a substantial difference — especially for disaggregated units of analysis with diverse age characteristics such as articles or authors. We analyse 6597 studies on environmental and ecological economics published between 2000 and 2009. We provide rankings of the influential articles, authors, journals and institutions and find that Ecological Economics, Energy Economics and the Journal of Environmental Economics and Management have the most influential articles, they publish very influential authors and their articles are cited most. The University of Maryland, Resources for the Future, the University of East Anglia and the World Bank appear to be the most influential institutions in the field of environmental and ecological economics.