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 effects of spatial and temporal heterogeneity on the population dynamics of four animal species in a Danish landscape

Background: Variation in carrying capacity and population return rates is generally ignored in traditional studies of population dynamics. Variation is hard to study in the field because of difficulties controlling the environment in order to obtain statistical replicates, and because of the scale and expense of experimenting on populations. There may also be ethical issues. To circumvent these problems we used detailed simulations of the simultaneous behaviours of interacting animals in an accurate facsimile of a real Danish landscape. The models incorporate as much as possible of the behaviour and ecology of skylarks Alauda arvensis, voles Microtus agrestis, a ground beetle Bembidion lampros and a linyphiid spider Erigone atra. This allows us to quantify and evaluate the importance of spatial and temporal heterogeneity on the population dynamics of the four species. Results: Both spatial and temporal heterogeneity affected the relationship between population growth rate and population density in all four species. Spatial heterogeneity accounted for 23–30% of the variance in population growth rate after accounting for the effects of density, reflecting big differences in local carrying capacity associated with the landscape features important to individual species. Temporal heterogeneity accounted for 3–13% of the variance in vole, skylark and spider, but 43% in beetles. The associated temporal variation in carrying capacity would be problematic in traditional analyses of density dependence. Return rates were less than one in all species and essentially invariant in skylarks, spiders and beetles. Return rates varied over the landscape in voles, being slower where there were larger fluctuations in local population sizes. Conclusion: Our analyses estimated the traditional parameters of carrying capacities and return rates, but these are now seen as varying continuously over the landscape depending on habitat quality and the mechanisms of density dependence. The importance of our results lies in our demonstration that the effects of spatial and temporal heterogeneity must be accounted for if we are to have accurate predictive models for use in management and conservation. This is an area which until now has lacked an adequate theoretical framework and methodology.

The tissue-specific processing of pro-opiomelanocortin

It is just over 30 years since the definitive identification of the adrenocorticotrophin (ACTH) precursor, pro-opiomelanocotin (POMC). Although first characterised in the anterior and intermediate lobes of the pituitary, POMC is also expressed in a number of both central and peripheral tissues including the skin, central nervous tissue and placenta. Following synthesis, POMC undergoes extensive post-translational processing producing not only ACTH, but also a number of other biologically active peptides. The extent and pattern of this processing is tissue-specific, the end result being the tissue dependent production of different combinations of peptides from the same precursor. These peptides have a diverse range of biological roles ranging from pigmentation to adrenal function to the regulation of feeding. This level of complexity has resulted in POMC becoming the archetypal model for prohormone processing, illustrating how a single protein combined with post-translational modification can have a diverse number of roles.

Estimating the hidden number of scrapie affected holdings in great Britain using a simple, truncated count model allowing for heterogeneity

None of the current surveillance streams monitoring the presence of scrapie in Great Britain provide a comprehensive and unbiased estimate of the prevalence of the disease at the holding level. Previous work to estimate the under-ascertainment adjusted prevalence of scrapie in Great Britain applied multiple-list capture-recapture methods. The enforcement of new control measures on scrapie-affected holdings in 2004 has stopped the overlapping between surveillance sources and, hence, the application of multiple-list capture-recapture models. Alternative methods, still under the capture-recapture methodology, relying on repeated entries in one single list have been suggested in these situations. In this article, we apply one-list capture-recapture approaches to data held on the Scrapie Notifications Database to estimate the undetected population of scrapie-affected holdings with clinical disease in Great Britain for the years 2002, 2003, and 2004. For doing so, we develop a new diagnostic tool for indication of heterogeneity as well as a new understanding of the Zelterman and Chao's lower bound estimators to account for potential unobserved heterogeneity. We demonstrate that the Zelterman estimator can be viewed as a maximum likelihood estimator for a special, locally truncated Poisson likelihood equivalent to a binomial likelihood. This understanding allows the extension of the Zelterman approach by means of logistic regression to include observed heterogeneity in the form of covariates-in case studied here, the holding size and country of origin. Our results confirm the presence of substantial unobserved heterogeneity supporting the application of our two estimators. The total scrapie-affected holding population in Great Britain is around 300 holdings per year. None of the covariates appear to inform the model significantly.

Aluminium in human breast tissue

Aluminium is omnipresent in everyday life and increased exposure is resulting in a burgeoning body burden of this non-essential metal. Personal care products are potential contributors to the body burden of aluminium and recent evidence has linked breast cancer with aluminium-based antiperspirants. We have used graphite furnace atomic absorption spectrometry (GFAAS) to measure the aluminium content in breast biopsies obtained following mastectomies. The aluminium content of breast tissue and breast tissue fat were in the range 4-437 nmol/g dry wt. and 3-192 nmol/g oil, respectively. The aluminium content of breast tissue in the outer regions (axilla and lateral) was significantly higher (P = 0.033) than the inner regions (middle and medial) of the breast. Whether differences in the regional distribution of aluminium in the breast are related to the known higher incidence of tumours in the outer upper quadrant of the breast remains to be ascertained. (c) 2007 Elsevier Inc. All rights reserved.

A comparison of three different models for estimating relative risk in meta-analysis of clinical trials under unobserved heterogeneity

We focus on the comparison of three statistical models used to estimate the treatment effect in metaanalysis when individually pooled data are available. The models are two conventional models, namely a multi-level and a model based upon an approximate likelihood, and a newly developed model, the profile likelihood model which might be viewed as an extension of the Mantel-Haenszel approach. To exemplify these methods, we use results from a meta-analysis of 22 trials to prevent respiratory tract infections. We show that by using the multi-level approach, in the case of baseline heterogeneity, the number of clusters or components is considerably over-estimated. The approximate and profile likelihood method showed nearly the same pattern for the treatment effect distribution. To provide more evidence two simulation studies are accomplished. The profile likelihood can be considered as a clear alternative to the approximate likelihood model. In the case of strong baseline heterogeneity, the profile likelihood method shows superior behaviour when compared with the multi-level model. Copyright (C) 2006 John Wiley & Sons, Ltd.

Isolation and partial characterisation of acid phosphatase isozymes from dormant oilseed of Corylus avellana L.

The acid phosphatase (orthophosphoric-monoester phosphohydrolase, EC 3.1.3.2) complement from dormant hazel (Corylus avellana L.) seeds was found to exhibit significant electrophoretic heterogeneity partially attributable to the presence of distinct molecular forms. In axiferous tissue, total acid phosphatase activity increased in a biphasic fashion during chilling, a treatment necessary to alleviate seed dormancy. Three acid phosphatase isozymes were isolated from cotyledons of dormant hazel seeds by successive ammonium sulphate precipitation, size-exclusion, Concanavalin A affinity, cation- and anion-exchange chromatographies resulting in 75-, 389- and 191-fold purification (APase1, APase2, APase3, respectively). The three glycosylated isoforms were isolated to catalytic homogeneity as determined by electrophoretic, kinetic and heat-inactivation studies. The native acid phosphatase complement of hazel seeds had an apparent Mr of 81.5±3.5 kDa as estimated by size-exclusion chromatography, while the determined pI values were 5.1 (APase1), 6.9 (APase2) and 7.3 (APase3). The optimum pH for p-nitrophenyl phosphate hydrolysis was pH 3 (APase1), pH 5.6 (APase2) and pH 6 (APase3). The hazel isozymes hydrolysed a variety of phosphorylated substrates in a non-specific manner, exhibiting low Km and the highest specificity constant (Vmax/Km) for pyrophosphate. They were not primary phytases since they could not initiate phytic acid hydrolysis, while APase2 and APase3 had significant phospho-tyrosine phosphatase activity. Inorganic phosphate was a competitive inhibitor, while activity was significantly impaired in the presence of vanadate and fluoride.

A phylogenetic mixture model for detecting pattern-heterogeneity in gene sequence or character-state data

We describe a general likelihood-based 'mixture model' for inferring phylogenetic trees from gene-sequence or other character-state data. The model accommodates cases in which different sites in the alignment evolve in qualitatively distinct ways, but does not require prior knowledge of these patterns or partitioning of the data. We call this qualitative variability in the pattern of evolution across sites "pattern-heterogeneity" to distinguish it from both a homogenous process of evolution and from one characterized principally by differences in rates of evolution. We present studies to show that the model correctly retrieves the signals of pattern-heterogeneity from simulated gene-sequence data, and we apply the method to protein-coding genes and to a ribosomal 12S data set. The mixture model outperforms conventional partitioning in both these data sets. We implement the mixture model such that it can simultaneously detect rate- and pattern-heterogeneity. The model simplifies to a homogeneous model or a rate- variability model as special cases, and therefore always performs at least as well as these two approaches, and often considerably improves upon them. We make the model available within a Bayesian Markov-chain Monte Carlo framework for phylogenetic inference, as an easy-to-use computer program.

Conformational heterogeneity of tripeptides containing Boc-Leu-Aib as corner residues in the solid state

A critical analysis of single crystal X-ray diffraction studies on a series of terminally protected tripeptides containing a centrally positioned Aib (alpha-aminoisobutyric acid) residue has been reported. For the tripeptide series containing Boc-Ala-Aib as corner residues, all the reported peptides formed distorted type II beta-turn structures. Moreover, a series of Phe substituted analogues ( tripeptides with Boc-Phe-Aib) have also shown different beta-turn conformations. However, the Leu-modified analogues (tripeptides with Boc-Leu-Aib) disrupt the concept of beta-turn formation and adopt various conformations in the solid state. X-ray crystallography sheds some light on the conformational heterogeneity at atomic resolution. (c) 2007 Elsevier Ltd. All rights reserved.

Absorption, tissue distribution and excretion of pelargonidin and its metabolites following oral administration to rats

Recent reports have demonstrated various cardiovascular and neurological benefits associated with the consumption of foods rich in anthocyanidins. However, information regarding absorption, metabolism, and especially, tissue distribution are only beginning to accumulate. In the present study, we investigated the occurrence and the kinetics of various circulating pelargonidin metabolites, and we aimed at providing initial information with regard to tissue distribution. Based on HPLC and LC-MS analyses we demonstrate that pelargonidin is absorbed and present in plasma following oral gavage to rats. In addition, the main structurally related pelargonidin metabolite identified in plasma and urine was pelargonidin glucuronide. Furthermore, p-hydroxybenzoic acid, a ring fission product of pelargonidin, was detected in plasma and urine samples obtained at 2 and 18 h after ingestion. At 2 h post-gavage, pelargonidin glucuronide was the major metabolite detected in kidney and liver, with levels reaching 0.5 and 0.15 nmol pelargonidin equivalents/g tissue, respectively. Brain and lung tissues contained detectable levels of the aglycone, with the glucuronide also present in the lungs. Other tissues, including spleen and heart, did not contain detectable levels of pelargonidin or ensuing metabolites. At 18 h post-gavage, tissue analyses did not reveal detectable levels of the aglycone nor of pelargonidin glucuronides. Taken together, our results demonstrate that the overall uptake of the administered pelargonidin was 18 % after 2 h, with the majority of the detected levels located in the stomach. However, the amounts recovered dropped to 1.2 % only 18 h post-gavage, with the urine and faecal content constituting almost 90 % of the total recovered pelargonidin.

The differential tissue distribution of the citrus flavanone naringenin following gastric instillation

Citrus flavonoids have been investigated for their biological activity, with both anti-inflammatory and -carcinogenic effects being reported. However, little information is known on the bioavailability of these compounds in vivo. The objectives of this study were to determine the tissue distribution of naringenin after gastric gavage of [H-3]-naringenin to rats. Unlabelled naringenin was also used to quantify the levels of naringenin and its major metabolites in tissues and eliminated in the urine and faeces. Significant radioactivity was detected in the plasma as well as all tissues examined 2 h post-gavage. After 18 h, higher levels of radioactivity were retained in plasma and tissues (55% of the administered radioactivity). Investigation of the nature of metabolites, using unlabelled naringenin, revealed that the glucuronides were the major components in plasma, tissues and urine, in addition to the colonic metabolite 3-(4- hydroxyphenyl) propionic acid, detected in the urine. The aglycone was the form extensively retained in tissues after 18 h post-gavage. Total identified metabolites detected after 18 h in most tissues were only 1-5% of the levels detected after 2 h. However, the brain, lungs and heart retained 27, 20 and 11%, respectively, relative to the total metabolites detected at 2 h. While radioactive detection suggests increased levels of breakdown products of naringenin after 18 h versus 2 h, the products identified using unlabelled naringenin are not consistent with this, suggesting that a predominant proportion of the naringenin breakdown products at 18 h are retained as smaller decomposition molecules which cannot yet be identified.

Linguistic heterogeneity in Williams syndrome

Williams syndrome (WS) is a rare genetic disorder resulting from a deletion on chromosome 7. A number of studies have shown that individuals with WS have a superior linguistic profile compared to their non-verbal abilities, however the evidence has been inconclusive, as many studies have disputed such a profile. The vast majority of studies on WS have assumed a single, homogeneous WS linguistic profile in order to support various theoretical viewpoints. The present study investigated the linguistic profiles of 5 individuals with WS on a number of standardized verbal measures and in conversational settings. The results indicated substantially variable performance in all aspects of the verbal domain, which supports the view that WS, linguistically, is a rather heterogeneous condition and this should be taken into consideration when referring to it in theoretical accounts of language acquisition and debates on modularity.

Modeling the effects of node heterogeneity on the performance of a real grid application

The performance benefit when using Grid systems comes from different strategies, among which partitioning the applications into parallel tasks is the most important. However, in most cases the enhancement coming from partitioning is smoothed by the effect of the synchronization overhead, mainly due to the high variability of completion times of the different tasks, which, in turn, is due to the large heterogeneity of Grid nodes. For this reason, it is important to have models which capture the performance of such systems. In this paper we describe a queueing-network-based performance model able to accurately analyze Grid architectures, and we use the model to study a real parallel application executed in a Grid. The proposed model improves the classical modelling techniques and highlights the impact of resource heterogeneity and network latency on the application performance.

Modeling the effects of node heterogeneity on the performance of grid applications

The performance benefit when using grid systems comes from different strategies, among which partitioning the applications into parallel tasks is the most important. However, in most cases the enhancement coming from partitioning is smoothed by the effects of synchronization overheads, mainly due to the high variability in the execution times of the different tasks, which, in turn, is accentuated by the large heterogeneity of grid nodes. In this paper we design hierarchical, queuing network performance models able to accurately analyze grid architectures and applications. Thanks to the model results, we introduce a new allocation policy based on a combination between task partitioning and task replication. The models are used to study two real applications and to evaluate the performance benefits obtained with allocation policies based on task replication.