Detecting, quantifying and adjusting for publication bias in meta-analyses: protocol of a systematic review on methods.

BACKGROUND: Health professionals and policymakers aspire to make healthcare decisions based on the entire relevant research evidence. This, however, can rarely be achieved because a considerable amount of research findings are not published, especially in case of 'negative' results - a phenomenon widely recognized as publication bias. Different methods of detecting, quantifying and adjusting for publication bias in meta-analyses have been described in the literature, such as graphical approaches and formal statistical tests to detect publication bias, and statistical approaches to modify effect sizes to adjust a pooled estimate when the presence of publication bias is suspected. An up-to-date systematic review of the existing methods is lacking. METHODS/DESIGN: The objectives of this systematic review are as follows:âeuro¢ To systematically review methodological articles which focus on non-publication of studies and to describe methods of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses.âeuro¢ To appraise strengths and weaknesses of methods, the resources they require, and the conditions under which the method could be used, based on findings of included studies.We will systematically search Web of Science, Medline, and the Cochrane Library for methodological articles that describe at least one method of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses. A dedicated data extraction form is developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article. As this will be a qualitative systematic review, data reporting will involve a descriptive summary. DISCUSSION: Results are expected to be publicly available in mid 2013. This systematic review together with the results of other systematic reviews of the OPEN project (To Overcome Failure to Publish Negative Findings) will serve as a basis for the development of future policies and guidelines regarding the assessment and handling of publication bias in meta-analyses.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

EasyStrata: evaluation and visualization of stratified genome-wide association meta-analysis data.

The R package EasyStrata facilitates the evaluation and visualization of stratified genome-wide association meta-analyses (GWAMAs) results. It provides (i) statistical methods to test and account for between-strata difference as a means to tackle gene-strata interaction effects and (ii) extended graphical features tailored for stratified GWAMA results. The software provides further features also suitable for general GWAMAs including functions to annotate, exclude or highlight specific loci in plots or to extract independent subsets of loci from genome-wide datasets. It is freely available and includes a user-friendly scripting interface that simplifies data handling and allows for combining statistical and graphical functions in a flexible fashion. AVAILABILITY: EasyStrata is available for free (under the GNU General Public License v3) from our Web site www.genepi-regensburg.de/easystrata and from the CRAN R package repository cran.r-project.org/web/packages/EasyStrata/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Quantitative Ultrasound of the Heel and Fracture Risk Assessment: an Updated Meta-Analysis

Objectives: Quantitative ultrasound (QUS) is an attractive method for assessing fracture risk because it is portable, inexpensive, without ionizing radiation, and available in areas of the world where DXA is not readily accessible or affordable. However, the diversity of QUS scanners and variability of fracture outcomes measured in different studies is an important obstacle to widespread utilisation of QUS for fracture risk assessment. We aimed in this review to assess the predictive power of heel QUS for fractures considering different characteristics of the association (QUS parameters and fracture outcomes measured, QUS devices, study populations, and independence from DXA-measured bone density).Materials/Methods : We conducted an inverse-variance randomeffects meta-analysis of prospective studies with heel QUS measures at baseline and fracture outcomes in their follow-up. Relative risks (RR) per standard deviation (SD) of different QUS parameters (broadband ultrasound attenuation [BUA], speed of sound &SOS;, stiffness index &SI;, and quantitative ultrasound index [QUI]) for various fracture outcomes (hip, vertebral, any clinical, any osteoporotic, and major osteoporotic fractures) were reported based on study questions.Results : 21 studies including 55,164 women and 13,742 men were included with a total follow-up of 279,124 person-years. All four QUS parameters were associated with risk of different fractures. For instance, RR of hip fracture for 1 SD decrease of BUA was 1.69 (95% CI 1.43-2.00), SOS was 1.96 (95% CI 1.64-2.34), SI was 2.26 (95%CI 1.71-2.99), and QUI was 1.99 (95% CI 1.49-2.67). Validated devices from different manufacturers predicted fracture risks with a similar performance (meta-regression p-values>0.05 for difference of devices). There was no sign of publication bias among the studies. QUS measures predicted fracture with a similar performance in men and women. Meta-analysis of studies with QUS measures adjusted for hip DXA showed a significant and independent association with fracture risk (RR/SD for BUA =1.34 [95%CI 1.22-1.49]).Conclusions : This study confirms that QUS of the heel using validated devices predicts risk of different fracture outcomes in elderly men and women. Further research and international collaborations are needed for standardisation of QUS parameters across various manufacturers and inclusion of QUS in fracture risk assessment tools. Disclosure of Interest : None declared.

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis.

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure). Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21-90) and 61 (29-119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤600 mg versus >600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.

Meta-analysis and imputation refines the association of 15q25 with smoking quantity.

Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms.

Insults during the fetal period predispose the offspring to systemic cardiovascular disease, but little is known about the pulmonary circulation and the underlying mechanisms. Maternal undernutrition during pregnancy may represent a model to investigate underlying mechanisms, because it is associated with systemic vascular dysfunction in the offspring in animals and humans. In rats, restrictive diet during pregnancy (RDP) increases oxidative stress in the placenta. Oxygen species are known to induce epigenetic alterations and may cross the placental barrier. We hypothesized that RDP in mice induces pulmonary vascular dysfunction in the offspring that is related to an epigenetic mechanism. To test this hypothesis, we assessed pulmonary vascular function and lung DNA methylation in offspring of RDP and in control mice at the end of a 2-wk exposure to hypoxia. We found that endothelium-dependent pulmonary artery vasodilation in vitro was impaired and hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in vivo were exaggerated in offspring of RDP. This pulmonary vascular dysfunction was associated with altered lung DNA methylation. Administration of the histone deacetylase inhibitors butyrate and trichostatin A to offspring of RDP normalized pulmonary DNA methylation and vascular function. Finally, administration of the nitroxide Tempol to the mother during RDP prevented vascular dysfunction and dysmethylation in the offspring. These findings demonstrate that in mice undernutrition during gestation induces pulmonary vascular dysfunction in the offspring by an epigenetic mechanism. A similar mechanism may be involved in the fetal programming of vascular dysfunction in humans.

Modeling information in software languages

Ohjelmiston kehitystyökalut käyttävät infromaatiota kehittäjän tuottamasta lähdekoodista. Informaatiota hyödynnetään ohjelmistoprojektin eri vaiheissa ja eri tarkoituksissa. Moderneissa ohjelmistoprojekteissa käytetyn informaation määrä voi kasvaa erittäin suureksi. Ohjelmistotyökaluilla on omat informaatiomallinsa ja käyttömekanisminsa. Informaation määrä sekä erilliset työkaluinformaatiomallit tekevät erittäin hankalaksi rakentaa joustavaa työkaluympäristöä, erityisesti ongelma-aluekohtaiseen ohjelmiston kehitysprosessiin. Tässä työssä on analysoitu perusinformaatiometamalleja Unified Modeling language kielestä, Python ohjelmointikielestä ja C++ ohjelmointikielestä. Metainformaation taso on rajoitettu rakenteelliselle tasolle. Ajettavat rakenteet on jätetty pois. ModelBase metamalli on yhdistetty olemassa olevista analysoiduista metamalleista. Tätä metamallia voidaan käyttää tulevaisuudessa ohjelmistotyökalujen kehitykseen.

Meta-analysis of the effects of MI training on clinicians' behavior.

MI-based interventions are widely used with a number of different clinical populations and their efficacy has been well established. However, the clinicians' training has not traditionally been the focus of empirical investigations. We conducted a meta-analytic review of clinicians' MI-training and MI-skills findings. Fifteen studies were included, involving 715 clinicians. Pre-post training effect sizes were calculated (13 studies) as well as group contrast effect sizes (7 studies). Pre-post training comparisons showed medium to large ES of MI training, which are maintained over a short period of time. When compared to a control group, our results also suggested higher MI proficiency in the professionals trained in MI than in nontrained ones (medium ES). However, this estimate of ES may be affected by a publication bias and therefore, should be considered with caution. Methodological limitations and potential sources of heterogeneity of the studies included in this meta-analysis are discussed.

[Magnificentiores selectioresque Urbis Venetiarum prospectus quos olim Michael Marieschi, Venetus pictor et architectus in plerisque tabulis depinxit, nunc vero ab ipsomet acurate delineante, incidente, tyspisque mandante, iterum in sexdecim aereis tabulis in lucem aeduntur]. [3], Foscarorum ades ad levam, et e conspectu altera Balborum ambo praeter canalem magnum ; ubi etiam solemne nauticum certamen, et maxima prequentia cymbarum vel auro vel argento vel alio ornatu obductarum, fictasque formas exhibentium cernuntur, nec non lintres naviculariorum pro brabrio certantium. Inter easdem aedes exornata ad maiorem spectaculi dignitatm meta super acquas erigitur. : [estampe] / Mich.l Marieschi del.t et inci.t

Référence bibliographique : Toledano, Marieschi, 35d

Python as a programming language for the introductory programming courses

Tämä kandidaatintyö tutkii tietotekniikan perusopetuksessa keskeisen aiheen,ohjelmoinnin, alkeisopetusta ja siihen liittyviä ongelmia. Työssä perehdytään ohjelmoinnin perusopetusmenetelmiin ja opetuksen lähestymistapoihin, sekä ratkaisuihin, joilla opetusta voidaan tehostaa. Näitä ratkaisuja työssä ovat mm. ohjelmointikielen valinta, käytettävän kehitysympäristön löytäminen sekä kurssia tukevien opetusapuvälineiden etsiminen. Lisäksi kurssin läpivientiin liittyvien toimintojen, kuten harjoitusten ja mahdollisten viikkotehtävien valinta kuuluu osaksitätä työtä. Työ itsessään lähestyy aihetta tutkimalla Pythonin soveltuvuutta ohjelmoinnin alkeisopetukseen mm. vertailemalla sitä muihin olemassa oleviin yleisiin opetuskieliin, kuten C, C++ tai Java. Se tarkastelee kielen hyviä ja huonoja puolia, sekä tutkii, voidaanko Pythonia hyödyntää luontevasti pääasiallisena opetuskielenä. Lisäksi työ perehtyy siihen, mitä kaikkea kurssilla tulisi opettaa, sekä siihen, kuinka kurssin läpivienti olisi tehokkainta toteuttaa ja minkälaiset tekniset puitteet kurssin toteuttamista varten olisi järkevää valita.

A meta-analysis of acupuncture for chronic pain.

Results of 14 randomized controlled trials of acupuncture for chronic pain were pooled in a meta-analysis and analysed in three subgroups according to site of pain; and in two subgroups each according to type to trial, type of treatment, type of control, 'blindness' of participating agents, trial size, and type of journal in which results were published. While few individual trials had statistically significant results, pooled results of many subgroups attained statistical significance in favour of acupuncture. Various potential sources of bias, including problems with blindness, precluded a conclusive finding although most results apparently favoured acupuncture.