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Sample records for meta-analysis identifies metastatic

  1. Bevacizumab Combined with Chemotherapy Improves Survival for Patients with Metastatic Colorectal Cancer: Evidence from Meta Analysis

    PubMed Central

    Jankovic, Slobodan

    2016-01-01

    Background Colorectal cancer is one of the leading causes of cancer deaths in both sexes in the world. Improvement of existing therapy modalities and implementing new ones in order to improve survival of patients with colorectal cancer represents a great challenge for medicine. The aim of this paper was to assess the impact that adding bevacizumab to chemotherapy has on survival in patients with metastatic colorectal cancer, compared to the use of chemotherapy alone. Methods Hazard ratios (HRs) with their 95% confidence intervals (CI) were determined from the studies and pooled. Two-sided p values were reported and considered to indicate statistical significance if less than 0.05. Results A total of 12 studies that meet the inclusion criteria were identified in the literature search, 3 phase II studies and 9 phase III studies. Based on the random effects meta-analysis, a statistically significant improvement was identified for both overall survival (HR = 0.84; 95% CI: 0.74–0.94; p = 0.003) and progression free survival (HR = 0.64; 95% CI: 0.55–0.73; p<0.00001) in patients with metastatic colorectal cancer when bevacizumab was added to chemotherapy, compared to chemotherapy treatment alone. Conclusion The findings of this meta analysis confirm the benefit of adding bevacizumab to chemotherapy in terms of survival and progression free survival, but the magnitude of this effect is not consistent throughout the included studies. This suggests the need for further research of interaction of bevacizumab with chemotherapeutic agents as well as recognition of patients’ characteristics important for the treatment selection criteria. PMID:27579775

  2. Genomewide meta-analysis identifies novel multiple sclerosis susceptibility loci

    PubMed Central

    Patsopoulos, Nikolaos A.; de Bakker, Paul I.W.

    2011-01-01

    Objective To perform a one-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and explore functional consequences of new susceptibility loci. Methods We synthesized 7 MS GWAS. Each dataset was imputed using HapMap phase II and a per-SNP meta-analysis was performed across the 7 datasets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. Results We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified three novel susceptibility alleles: rs170934T at 3p24.1 (OR=1.17, P = 1.6 × 10−8) near EOMES, rs2150702G in the second intron of MLANA on chromosome 9p24.1 (OR = 1.16, P = 3.3 × 10−8), and rs6718520A in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR = 1.17, P = 3.4 × 10−8). The three new loci do not have a strong “cis” effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive P<1×10−6, some of which have evidence of association in other inflammatory diseases, i.e. IL12B, TAGAP, PLEK, and ZMIZ1. Interpretation We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights three novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS. PMID:22190364

  3. Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials

    PubMed Central

    Flaherty, Keith T; Hennig, Michael; Lee, Sandra J; Ascierto, Paolo A; Dummer, Reinhard; Eggermont, Alexander M M; Hauschild, Axel; Kefford, Richard; Kirkwood, John M; Long, Georgina V; Lorigan, Paul; Mackensen, Andreas; McArthur, Grant; O'Day, Steven; Patel, Poulam M; Robert, Caroline; Schadendorf, Dirk

    2015-01-01

    Summary Background Recent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable surrogate for overall survival through a meta-analysis of randomised trials. Methods We systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR). We correlated HRs for overall survival and PFS, weighted by sample size or by precision of the HR estimate, assuming fixed and random effects. We did sensitivity analyses according to presence of crossover, trial size, and dacarbazine dose. Findings After screening 1649 reports and meeting abstracts published before Sept 8, 2013, we identified 12 eligible randomised trials that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, we noted a strong correlation between the treatment effects for PFS and overall survival, which seemed independent of treatment type. Pearson correlation coefficients were 0.71 (95% CI 0.29–0.90) with a random-effects assumption, 0.85 (0.59–0.95) with a fixed-effects assumption, and 0.89 (0.68–0.97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0.96 (0.81–0.99), which decreased to 0.93 (0.74–0.98) when two additional trials with less than 50% crossover were included. Inclusion of mature follow-up data after at least 50% crossover (in vemurafenib and dabrafenib phase 3 trials) weakened the PFS to overall survival correlation (0.55, 0.03–0.84). Inclusion of trials with no or little crossover with the random-effects assumption yielded a conservative statement of the PFS to overall survival correlation of 0.85 (0.51–0.96). Interpretation PFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomised trials of

  4. Identifying Effective Psychological Treatments of Insomnia: A Meta-Analysis.

    ERIC Educational Resources Information Center

    Murtagh, Douglas R. R.; Greenwood, Kenneth M.

    1995-01-01

    Clarified efficacy of psychological treatments for insomnia through a meta-analysis of 66 outcome studies representing 139 treatment groups. Psychological treatments produced considerable enhancement of both sleep patterns and the subjective experience of sleep. Participants who were clinically referred and who did not regularly use sedatives…

  5. Robust Microarray Meta-Analysis Identifies Differentially Expressed Genes for Clinical Prediction

    PubMed Central

    Phan, John H.; Young, Andrew N.; Wang, May D.

    2012-01-01

    Combining multiple microarray datasets increases sample size and leads to improved reproducibility in identification of informative genes and subsequent clinical prediction. Although microarrays have increased the rate of genomic data collection, sample size is still a major issue when identifying informative genetic biomarkers. Because of this, feature selection methods often suffer from false discoveries, resulting in poorly performing predictive models. We develop a simple meta-analysis-based feature selection method that captures the knowledge in each individual dataset and combines the results using a simple rank average. In a comprehensive study that measures robustness in terms of clinical application (i.e., breast, renal, and pancreatic cancer), microarray platform heterogeneity, and classifier (i.e., logistic regression, diagonal LDA, and linear SVM), we compare the rank average meta-analysis method to five other meta-analysis methods. Results indicate that rank average meta-analysis consistently performs well compared to five other meta-analysis methods. PMID:23365541

  6. Identifying Evidence-Based Practices in Special Education through High Quality Meta-Analysis

    ERIC Educational Resources Information Center

    Friedt, Brian

    2012-01-01

    The purpose of this study was to determine if meta-analysis can be used to enhance efforts to identify evidence-based practices (EBPs). In this study, the quality of included studies acted as the moderating variable. I used the quality indicators for experimental and quasi-experimental research developed by Gersten, Fuchs, Coyne, Greenwood, and…

  7. Effectiveness and safety of monoclonal antibodies for metastatic colorectal cancer treatment: systematic review and meta-analysis

    PubMed Central

    Rosa, Bruno; de Jesus, Jose Paulo; de Mello, Eduardo L; Cesar, Daniel; Correia, Mauro M

    2015-01-01

    Background The effectiveness of chemotherapy (CT) for select cases of metastatic colorectal cancer (MCRC) has been well established in the literature, however, it provides limited benefits and in many cases constitutes a treatment with high toxicity. The use of specific molecular biological treatments with monoclonal antibodies (MA) has been shown to be relevant, particularly for its potential for increasing the response rate of the host to the tumour, as these have molecular targets present in the cancerous cells and their microenvironment thereby blocking their development. The combination of MA and CT can bring a significant increase in the rate of resectability of metastases, the progression-free survival (PFS), and the global survival (GS) in MCRC patients. Objective To assess the effectiveness and safety of MA in the treatment of MCRC. Methods A systematic review was carried out with a meta-analysis of randomised clinical trials comparing the use of cetuximab, bevacizumab, and panitumumab in the treatment of MCRC. Results Sixteen randomised clinical trials were selected. The quality of the evidence on the question was considered moderate and data from eight randomised clinical trials were included in this meta-analysis. The GS and PFS were greater in the groups which received the MA associated with CT, however, the differences were not statistically significant between the groups (mean of 17.7 months versus 17.1 months; mean difference of 1.09 (CI: 0.10–2.07); p = 0.84; and 7.4 versus 6.9 months. mean difference of 0.76 (CI: 0.08–1.44); p = 0.14 respectively). The meta-analysis was not done for any of the secondary outcomes. Conclusion The addition of MA to CT for patients with metastatic colorectal cancer does not prolong GS and PFS. PMID:26557880

  8. Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials.

    PubMed

    Hofheinz, R-D; Ronellenfitsch, U; Kubicka, S; Falcone, A; Burkholder, I; Hacker, U T

    2016-01-01

    Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression. Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55-0.75) and OS (HR 0.83; 95%-CI, 0.76-0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41-3.58). Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs. PMID:27656206

  9. Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

    PubMed Central

    Kubicka, S.; Falcone, A.; Burkholder, I.; Hacker, U. T.

    2016-01-01

    Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression. Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58). Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs. PMID:27656206

  10. Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

    PubMed Central

    Kubicka, S.; Falcone, A.; Burkholder, I.; Hacker, U. T.

    2016-01-01

    Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression. Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58). Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

  11. Comparative efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: a systematic review and meta-analysis

    PubMed Central

    Wang, Hai; Man, Libo; Li, Guizhong; Huang, Guanglin; Wang, Jianwei

    2016-01-01

    Objective This study was performed to evaluate the comparative efficacy and safety of axitinib and sorafenib in the therapy of metastatic renal cell carcinoma. Materials and methods Eligible studies were searched from PubMed, Embase, and Future Medicine databases. The pooled hazard ratios and relative risk ratios (RRs) were calculated by using Stata 12.0 software. Results A total of 1,011 patients qualified to participate in this Phase III study that included randomized controlled trials. Meta-analysis results showed that axitinib was more highly and significantly associated with a survival benefit in the independently assessed progression-free survival in comparison to sorafenib. The values of RR of the objective response rate and disease control rate were also significantly different. Results of the analysis of adverse events concerning hypertension and hypothyroidism demonstrated that the values of RR were significantly higher in the axitinib group and lower risks were established in the patients treated with axitinib. Conclusion Therefore, axitinib was a better treatment option for metastatic renal cell carcinoma treatment than sorafenib, especially after failure of prior systemic therapies. This analysis revealed that axitinib had higher risks of hypertension and hypothyroidism and lower risks of rash and palmar-plantar erythrodysesthesia. PMID:27354814

  12. Acquired Hypothyroidism as a Predictive Marker of Outcome in Patients With Metastatic Renal Cell Carcinoma Treated With Tyrosine Kinase Inhibitors: A Literature-Based Meta-Analysis.

    PubMed

    Nearchou, Andreas; Valachis, Antonis; Lind, Pehr; Akre, Olof; Sandström, Per

    2015-08-01

    Hypothyroidism in patients with metastatic renal cell carcinoma (mRCC) during treatment with the tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib is a well-established side effect. Furthermore, the potential role of hypothyroidism as predictive marker of outcome has been studied but with conflicting results. The aim of the present meta-analysis was to assess the predictive value of hypothyroidism for progression-free (PFS) and overall survival (OS) in patients with mRCC during TKI therapy. We searched PubMed and the electronic abstract databases of the major international congresses' proceedings to identify all eligible studies that reported a correlation between the development of hypothyroidism during TKI treatment and outcome in patients with mRCC. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and OS were obtained from these publications and pooled in a meta-analysis. Eleven studies with a total of 500 patients fulfilled the inclusion criteria. We found no statistical significant difference in PFS between patients who developed hypothyroidism during sunitinib therapy and unaffected patients (HR, 0.82; 95% CI, 0.59-1.13; P = .22; 6 studies; 250 patients). The HR for OS was 0.52 (95% CI, 0.31-0.87; P = .01) for patients who developed hypothyroidism during sunitinib therapy compared with patients who did not (4 studies; 147 patients). The development of hypothyroidism during TKI therapy is not clearly shown to be predictive of efficacy in patients with mRCC. The observed advantage in OS for the patients with acquired hypothyroidism should be interpreted with caution.

  13. Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci

    PubMed Central

    Asselbergs, Folkert W.; Guo, Yiran; van Iperen, Erik P.A.; Sivapalaratnam, Suthesh; Tragante, Vinicius; Lanktree, Matthew B.; Lange, Leslie A.; Almoguera, Berta; Appelman, Yolande E.; Barnard, John; Baumert, Jens; Beitelshees, Amber L.; Bhangale, Tushar R.; Chen, Yii-Der Ida; Gaunt, Tom R.; Gong, Yan; Hopewell, Jemma C.; Johnson, Toby; Kleber, Marcus E.; Langaee, Taimour Y.; Li, Mingyao; Li, Yun R.; Liu, Kiang; McDonough, Caitrin W.; Meijs, Matthijs F.L.; Middelberg, Rita P.S.; Musunuru, Kiran; Nelson, Christopher P.; O’Connell, Jeffery R.; Padmanabhan, Sandosh; Pankow, James S.; Pankratz, Nathan; Rafelt, Suzanne; Rajagopalan, Ramakrishnan; Romaine, Simon P.R.; Schork, Nicholas J.; Shaffer, Jonathan; Shen, Haiqing; Smith, Erin N.; Tischfield, Sam E.; van der Most, Peter J.; van Vliet-Ostaptchouk, Jana V.; Verweij, Niek; Volcik, Kelly A.; Zhang, Li; Bailey, Kent R.; Bailey, Kristian M.; Bauer, Florianne; Boer, Jolanda M.A.; Braund, Peter S.; Burt, Amber; Burton, Paul R.; Buxbaum, Sarah G.; Chen, Wei; Cooper-DeHoff, Rhonda M.; Cupples, L. Adrienne; deJong, Jonas S.; Delles, Christian; Duggan, David; Fornage, Myriam; Furlong, Clement E.; Glazer, Nicole; Gums, John G.; Hastie, Claire; Holmes, Michael V.; Illig, Thomas; Kirkland, Susan A.; Kivimaki, Mika; Klein, Ronald; Klein, Barbara E.; Kooperberg, Charles; Kottke-Marchant, Kandice; Kumari, Meena; LaCroix, Andrea Z.; Mallela, Laya; Murugesan, Gurunathan; Ordovas, Jose; Ouwehand, Willem H.; Post, Wendy S.; Saxena, Richa; Scharnagl, Hubert; Schreiner, Pamela J.; Shah, Tina; Shields, Denis C.; Shimbo, Daichi; Srinivasan, Sathanur R.; Stolk, Ronald P.; Swerdlow, Daniel I.; Taylor, Herman A.; Topol, Eric J.; Toskala, Elina; van Pelt, Joost L.; van Setten, Jessica; Yusuf, Salim; Whittaker, John C.; Zwinderman, A.H.; Anand, Sonia S.; Balmforth, Anthony J.; Berenson, Gerald S.; Bezzina, Connie R.; Boehm, Bernhard O.; Boerwinkle, Eric; Casas, Juan P.; Caulfield, Mark J.; Clarke, Robert; Connell, John M.; Cruickshanks, Karen J.; Davidson, Karina W.; Day, Ian N.M.; de Bakker, Paul I.W.; Doevendans, Pieter A.; Dominiczak, Anna F.; Hall, Alistair S.; Hartman, Catharina A.; Hengstenberg, Christian; Hillege, Hans L.; Hofker, Marten H.; Humphries, Steve E.; Jarvik, Gail P.; Johnson, Julie A.; Kaess, Bernhard M.; Kathiresan, Sekar; Koenig, Wolfgang; Lawlor, Debbie A.; März, Winfried; Melander, Olle; Mitchell, Braxton D.; Montgomery, Grant W.; Munroe, Patricia B.; Murray, Sarah S.; Newhouse, Stephen J.; Onland-Moret, N. Charlotte; Poulter, Neil; Psaty, Bruce; Redline, Susan; Rich, Stephen S.; Rotter, Jerome I.; Schunkert, Heribert; Sever, Peter; Shuldiner, Alan R.; Silverstein, Roy L.; Stanton, Alice; Thorand, Barbara; Trip, Mieke D.; Tsai, Michael Y.; van der Harst, Pim; van der Schoot, Ellen; van der Schouw, Yvonne T.; Verschuren, W.M. Monique; Watkins, Hugh; Wilde, Arthur A.M.; Wolffenbuttel, Bruce H.R.; Whitfield, John B.; Hovingh, G. Kees; Ballantyne, Christie M.; Wijmenga, Cisca; Reilly, Muredach P.; Martin, Nicholas G.; Wilson, James G.; Rader, Daniel J.; Samani, Nilesh J.; Reiner, Alex P.; Hegele, Robert A.; Kastelein, John J.P.; Hingorani, Aroon D.; Talmud, Philippa J.; Hakonarson, Hakon; Elbers, Clara C.; Keating, Brendan J.; Drenos, Fotios

    2012-01-01

    Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids. PMID:23063622

  14. A meta-analysis to identify animal and management factors influencing gestating sow efficiency.

    PubMed

    Douglas, S L; Szyszka, O; Stoddart, K; Edwards, S A; Kyriazakis, I

    2014-12-01

    A meta-analysis on the effects of management and animal-based factors on the reproductive efficiency of gestating sows can provide information on single-factor and interaction effects that may not have been detected in individual studies. This study analyzed the effects of such factors on the number of piglets born alive per litter (BA), piglet birth weight (BiW) and weaning weight (WW), and number of piglets born alive per kilogram of sow feed intake during gestation (BA/FI). A total of 51 papers and 7 data sources were identified for the meta-analysis, out of which 23 papers and 5 sets of production data were useable (a total of 121 treatments). The information gathered included the dependent variables as well as information regarding animal, management, and feed characteristics. While a number of factors were individually significant, the multivariate models identified significant effects only of 1) floor type (P=0.003), sow BW at the end of gestation (P=0.002), and housing (stalls vs. loose; P=0.004) on BA; as floor type and housing were confounded, they were included in 2 separate models. The BA was higher on solid (12.1) in comparison to partly slatted (11.4) and fully slatted floors (10.2); 2) sow gestation environment (P=0.017) and gestation feed allowance (P=0.046) on BiW, with BiW of pigs higher for sows kept outdoors rather than indoors (1.75 versus 1.49 kg); 3) parity number (P=0.003) and feed intake during gestation (P=0.017) on WW; in addition there was an interaction between parity number×feed ME and parity number×feed CP content of feed during gestation on WW, with the positive effects of feed ME and CP contents seen during early rather than later parities; and 4) floor type (P=0.019) and feed crude fiber (P=0.003) for BA/FI with a greater number for those kept on solid floors (5.11) versus partially and fully slatted floors (4.07 and 4.05). The meta-analysis confirmed the significant effect of several well-known factors on the efficiency of

  15. Predictors of Extubation Failure in Neurocritical Patients Identified by a Systematic Review and Meta-Analysis

    PubMed Central

    Huang, Kaibin; Lin, Zhenzhou; Qiao, Weiguang; Pan, Suyue

    2014-01-01

    Background Prediction of extubation failure, particularly in neurocritical patients, is unique and controversial. We conducted a systematic review and meta-analysis to identify the risk factors for extubation failure in these patients. Methods A literature search of databases (MEDLINE, EMBASE, the Cochrane Library, and Web of Science) was performed up to August of 2013 to identify trials that evaluated extubation failure predictors. Included trials were either prospective or retrospective cohort studies. Results Nine studies involving 928 participants were included. The systematic review and meta-analysis revealed that the following were predictive for extubation failure: pneumonia, atelectasis, mechanical ventilation of >24 h, a low Glasgow Coma Scale score (7–9T) (OR = 4.96, 95% CI = 1.61–15.26, P = 0.005), the inability to follow commands (OR = 2.07, 95% CI = 1.15–3.71, P = 0.02), especially the command to close the eyes, thick secretion, and no intact gag reflex. Meanwhile, the following were not predictive for extubation failure: sex, secretion volume, coughing upon suctioning, and the inability to follow one command among showing two fingers, wiggling the toes, or coughing on command. Additionally, some traditional weaning parameters were shown to poorly predict extubation failure in neurocritical patients. Conclusions Besides pneumonia, atelectasis, and the duration of mechanical ventilation, other factors that should be taken into consideration in the prediction of extubation failure when neurocritical patients are weaned from tracheal intubation include neurologic abilities (Glasgow Coma Scale score and following commands), the secretion texture, and the presence of a gag reflex. PMID:25486091

  16. Variants identified in a GWAS meta-analysis for blood lipids are associated with the lipid response to fenofibrate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A recent large-scale meta-analysis of genome-wide studies has identified 95 loci, 59 of them novel, as statistically significant predictors of blood lipid traits; we tested whether the same loci explain the observed heterogeneity in response to lipid-lowering therapy with fenofibrate. Using data fro...

  17. Combination of meta-analysis and graph clustering to identify prognostic markers of ESCC.

    PubMed

    Gao, Hongyun; Wang, Lishan; Cui, Shitao; Wang, Mingsong

    2012-04-01

    Esophageal squamous cell carcinoma (ESCC) is one of the most malignant gastrointestinal cancers and occurs at a high frequency rate in China and other Asian countries. Recently, several molecular markers were identified for predicting ESCC. Notwithstanding, additional prognostic markers, with a clear understanding of their underlying roles, are still required. Through bioinformatics, a graph-clustering method by DPClus was used to detect co-expressed modules. The aim was to identify a set of discriminating genes that could be used for predicting ESCC through graph-clustering and GO-term analysis. The results showed that CXCL12, CYP2C9, TGM3, MAL, S100A9, EMP-1 and SPRR3 were highly associated with ESCC development. In our study, all their predicted roles were in line with previous reports, whereby the assumption that a combination of meta-analysis, graph-clustering and GO-term analysis is effective for both identifying differentially expressed genes, and reflecting on their functions in ESCC.

  18. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

    PubMed

    Stahl, Eli A; Raychaudhuri, Soumya; Remmers, Elaine F; Xie, Gang; Eyre, Stephen; Thomson, Brian P; Li, Yonghong; Kurreeman, Fina A S; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I; Ardlie, Kristin G; Barton, Anne; Bowes, John; Brouwer, Elisabeth; Burtt, Noel P; Catanese, Joseph J; Coblyn, Jonathan; Coenen, Marieke J H; Costenbader, Karen H; Criswell, Lindsey A; Crusius, J Bart A; Cui, Jing; de Bakker, Paul I W; De Jager, Philip L; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J; Huizinga, Tom W J; Kastner, Daniel L; Ke, Xiayi; Lee, Annette T; Liu, Xiangdong; Martin, Paul; Morgan, Ann W; Padyukov, Leonid; Posthumus, Marcel D; Radstake, Timothy R D J; Reid, David M; Seielstad, Mark; Seldin, Michael F; Shadick, Nancy A; Steer, Sophia; Tak, Paul P; Thomson, Wendy; van der Helm-van Mil, Annette H M; van der Horst-Bruinsma, Irene E; van der Schoot, C Ellen; van Riel, Piet L C M; Weinblatt, Michael E; Wilson, Anthony G; Wolbink, Gert Jan; Wordsworth, B Paul; Wijmenga, Cisca; Karlson, Elizabeth W; Toes, Rene E M; de Vries, Niek; Begovich, Ann B; Worthington, Jane; Siminovitch, Katherine A; Gregersen, Peter K; Klareskog, Lars; Plenge, Robert M

    2010-06-01

    To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles. PMID:20453842

  19. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

    PubMed Central

    Stahl, Eli A.; Raychaudhuri, Soumya; Remmers, Elaine F.; Xie, Gang; Eyre, Stephen; Thomson, Brian P.; Li, Yonghong; Kurreeman, Fina A. S.; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I.; Ardlie, Kristin G.; Barton, Anne; Bowes, John; Brouwer, Elisabeth; Burtt, Noel P.; Catanese, Joseph J.; Coblyn, Jonathan; Coenen, Marieke JH; Costenbader, Karen H.; Criswell, Lindsey A.; Crusius, J. Bart A.; Cui, Jing; de Bakker, Paul I.W.; De Jager, Phillip L.; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J.; Huizinga, Tom W. J.; Kastner, Daniel L.; Ke, Xiayi; Lee, Annette T.; Liu, Xiangdong; Martin, Paul; Morgan, Ann W.; Padyukov, Leonid; Posthumus, Marcel D.; Radstake, Timothy RDJ; Reid, David M.; Seielstad, Mark; Seldin, Michael F.; Shadick, Nancy A.; Steer, Sophia; Tak, Paul P.; Thomson, Wendy; van der Helm-van Mil, Annette H. M.; van der Horst-Bruinsma, Irene E.; van der Schoot, C. Ellen; van Riel, Piet LCM; Weinblatt, Michael E.; Wilson, Anthony G.; Wolbink, Gert Jan; Wordsworth, Paul; Wijmenga, Cisca; Karlson, Elizabeth W.; Toes, Rene E. M.; de Vries, Niek; Begovich, Ann B.; Worthington, Jane; Siminovitch, Katherine A.; Gregersen, Peter K.; Klareskog, Lars; Plenge, Robert M.

    2014-01-01

    To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles. PMID:20453842

  20. Acute toxicity tests and meta-analysis identify gaps in tropical ecotoxicology for amphibians.

    PubMed

    Ghose, Sonia L; Donnelly, Maureen A; Kerby, Jacob; Whitfield, Steven M

    2014-09-01

    Amphibian populations are declining worldwide, particularly in tropical regions where amphibian diversity is highest. Pollutants, including agricultural pesticides, have been identified as a potential contributor to decline, yet toxicological studies of tropical amphibians are very rare. The present study assesses toxic effects on amphibians of 10 commonly used commercial pesticides in tropical agriculture using 2 approaches. First, the authors conducted 8-d toxicity assays with formulations of each pesticide using individually reared red-eyed tree frog (Agalychnis callidryas) tadpoles. Second, they conducted a review of available data for the lethal concentration to kill 50% of test animals from the US Environmental Protection Agency's ECOTOX database to allow comparison with their findings. Lethal concentration estimates from the assays ranged over several orders of magnitude. The nematicides terbufos and ethoprophos and the fungicide chlorothalonil were very highly toxic, with evident effects within an order of magnitude of environmental concentrations. Acute toxicity assays and meta-analysis show that nematicides and fungicides are generally more toxic than herbicides yet receive far less research attention than less toxic herbicides. Given that the tropics have a high diversity of amphibians, the findings emphasize the need for research into the effects of commonly used pesticides in tropical countries and should help guide future ecotoxicological research in tropical regions.

  1. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility

    PubMed Central

    Yin, Xianyong; Low, Hui Qi; Wang, Ling; Li, Yonghong; Ellinghaus, Eva; Han, Jiali; Estivill, Xavier; Sun, Liangdan; Zuo, Xianbo; Shen, Changbing; Zhu, Caihong; Zhang, Anping; Sanchez, Fabio; Padyukov, Leonid; Catanese, Joseph J.; Krueger, Gerald G.; Duffin, Kristina Callis; Mucha, Sören; Weichenthal, Michael; Weidinger, Stephan; Lieb, Wolfgang; Foo, Jia Nee; Li, Yi; Sim, Karseng; Liany, Herty; Irwan, Ishak; Teo, Yikying; Theng, Colin T. S.; Gupta, Rashmi; Bowcock, Anne; De Jager, Philip L.; Qureshi, Abrar A.; de Bakker, Paul I. W.; Seielstad, Mark; Liao, Wilson; Ståhle, Mona; Franke, Andre; Zhang, Xuejun; Liu, Jianjun

    2015-01-01

    Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations. PMID:25903422

  2. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.

    PubMed

    Yin, Xianyong; Low, Hui Qi; Wang, Ling; Li, Yonghong; Ellinghaus, Eva; Han, Jiali; Estivill, Xavier; Sun, Liangdan; Zuo, Xianbo; Shen, Changbing; Zhu, Caihong; Zhang, Anping; Sanchez, Fabio; Padyukov, Leonid; Catanese, Joseph J; Krueger, Gerald G; Duffin, Kristina Callis; Mucha, Sören; Weichenthal, Michael; Weidinger, Stephan; Lieb, Wolfgang; Foo, Jia Nee; Li, Yi; Sim, Karseng; Liany, Herty; Irwan, Ishak; Teo, Yikying; Theng, Colin T S; Gupta, Rashmi; Bowcock, Anne; De Jager, Philip L; Qureshi, Abrar A; de Bakker, Paul I W; Seielstad, Mark; Liao, Wilson; Ståhle, Mona; Franke, Andre; Zhang, Xuejun; Liu, Jianjun

    2015-04-23

    Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.

  3. Acute toxicity tests and meta-analysis identify gaps in tropical ecotoxicology for amphibians.

    PubMed

    Ghose, Sonia L; Donnelly, Maureen A; Kerby, Jacob; Whitfield, Steven M

    2014-09-01

    Amphibian populations are declining worldwide, particularly in tropical regions where amphibian diversity is highest. Pollutants, including agricultural pesticides, have been identified as a potential contributor to decline, yet toxicological studies of tropical amphibians are very rare. The present study assesses toxic effects on amphibians of 10 commonly used commercial pesticides in tropical agriculture using 2 approaches. First, the authors conducted 8-d toxicity assays with formulations of each pesticide using individually reared red-eyed tree frog (Agalychnis callidryas) tadpoles. Second, they conducted a review of available data for the lethal concentration to kill 50% of test animals from the US Environmental Protection Agency's ECOTOX database to allow comparison with their findings. Lethal concentration estimates from the assays ranged over several orders of magnitude. The nematicides terbufos and ethoprophos and the fungicide chlorothalonil were very highly toxic, with evident effects within an order of magnitude of environmental concentrations. Acute toxicity assays and meta-analysis show that nematicides and fungicides are generally more toxic than herbicides yet receive far less research attention than less toxic herbicides. Given that the tropics have a high diversity of amphibians, the findings emphasize the need for research into the effects of commonly used pesticides in tropical countries and should help guide future ecotoxicological research in tropical regions. PMID:24934557

  4. Decoding and Reading Comprehension: A Meta-Analysis to Identify Which Reader and Assessment Characteristics Influence the Strength of the Relationship in English

    ERIC Educational Resources Information Center

    García, J. Ricardo; Cain, Kate

    2014-01-01

    The twofold purpose of this meta-analysis was to determine the relative importance of decoding skills to reading comprehension in reading development and to identify which reader characteristics and reading assessment characteristics contribute to differences in the decoding and reading comprehension correlation. A meta-analysis of 110 studies…

  5. Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.

    PubMed

    Eicher, John D; Chami, Nathalie; Kacprowski, Tim; Nomura, Akihiro; Chen, Ming-Huei; Yanek, Lisa R; Tajuddin, Salman M; Schick, Ursula M; Slater, Andrew J; Pankratz, Nathan; Polfus, Linda; Schurmann, Claudia; Giri, Ayush; Brody, Jennifer A; Lange, Leslie A; Manichaikul, Ani; Hill, W David; Pazoki, Raha; Elliot, Paul; Evangelou, Evangelos; Tzoulaki, Ioanna; Gao, He; Vergnaud, Anne-Claire; Mathias, Rasika A; Becker, Diane M; Becker, Lewis C; Burt, Amber; Crosslin, David R; Lyytikäinen, Leo-Pekka; Nikus, Kjell; Hernesniemi, Jussi; Kähönen, Mika; Raitoharju, Emma; Mononen, Nina; Raitakari, Olli T; Lehtimäki, Terho; Cushman, Mary; Zakai, Neil A; Nickerson, Deborah A; Raffield, Laura M; Quarells, Rakale; Willer, Cristen J; Peloso, Gina M; Abecasis, Goncalo R; Liu, Dajiang J; Deloukas, Panos; Samani, Nilesh J; Schunkert, Heribert; Erdmann, Jeanette; Fornage, Myriam; Richard, Melissa; Tardif, Jean-Claude; Rioux, John D; Dube, Marie-Pierre; de Denus, Simon; Lu, Yingchang; Bottinger, Erwin P; Loos, Ruth J F; Smith, Albert Vernon; Harris, Tamara B; Launer, Lenore J; Gudnason, Vilmundur; Velez Edwards, Digna R; Torstenson, Eric S; Liu, Yongmei; Tracy, Russell P; Rotter, Jerome I; Rich, Stephen S; Highland, Heather M; Boerwinkle, Eric; Li, Jin; Lange, Ethan; Wilson, James G; Mihailov, Evelin; Mägi, Reedik; Hirschhorn, Joel; Metspalu, Andres; Esko, Tõnu; Vacchi-Suzzi, Caterina; Nalls, Mike A; Zonderman, Alan B; Evans, Michele K; Engström, Gunnar; Orho-Melander, Marju; Melander, Olle; O'Donoghue, Michelle L; Waterworth, Dawn M; Wallentin, Lars; White, Harvey D; Floyd, James S; Bartz, Traci M; Rice, Kenneth M; Psaty, Bruce M; Starr, J M; Liewald, David C M; Hayward, Caroline; Deary, Ian J; Greinacher, Andreas; Völker, Uwe; Thiele, Thomas; Völzke, Henry; van Rooij, Frank J A; Uitterlinden, André G; Franco, Oscar H; Dehghan, Abbas; Edwards, Todd L; Ganesh, Santhi K; Kathiresan, Sekar; Faraday, Nauder; Auer, Paul L; Reiner, Alex P; Lettre, Guillaume; Johnson, Andrew D

    2016-07-01

    Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

  6. Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.

    PubMed

    Eicher, John D; Chami, Nathalie; Kacprowski, Tim; Nomura, Akihiro; Chen, Ming-Huei; Yanek, Lisa R; Tajuddin, Salman M; Schick, Ursula M; Slater, Andrew J; Pankratz, Nathan; Polfus, Linda; Schurmann, Claudia; Giri, Ayush; Brody, Jennifer A; Lange, Leslie A; Manichaikul, Ani; Hill, W David; Pazoki, Raha; Elliot, Paul; Evangelou, Evangelos; Tzoulaki, Ioanna; Gao, He; Vergnaud, Anne-Claire; Mathias, Rasika A; Becker, Diane M; Becker, Lewis C; Burt, Amber; Crosslin, David R; Lyytikäinen, Leo-Pekka; Nikus, Kjell; Hernesniemi, Jussi; Kähönen, Mika; Raitoharju, Emma; Mononen, Nina; Raitakari, Olli T; Lehtimäki, Terho; Cushman, Mary; Zakai, Neil A; Nickerson, Deborah A; Raffield, Laura M; Quarells, Rakale; Willer, Cristen J; Peloso, Gina M; Abecasis, Goncalo R; Liu, Dajiang J; Deloukas, Panos; Samani, Nilesh J; Schunkert, Heribert; Erdmann, Jeanette; Fornage, Myriam; Richard, Melissa; Tardif, Jean-Claude; Rioux, John D; Dube, Marie-Pierre; de Denus, Simon; Lu, Yingchang; Bottinger, Erwin P; Loos, Ruth J F; Smith, Albert Vernon; Harris, Tamara B; Launer, Lenore J; Gudnason, Vilmundur; Velez Edwards, Digna R; Torstenson, Eric S; Liu, Yongmei; Tracy, Russell P; Rotter, Jerome I; Rich, Stephen S; Highland, Heather M; Boerwinkle, Eric; Li, Jin; Lange, Ethan; Wilson, James G; Mihailov, Evelin; Mägi, Reedik; Hirschhorn, Joel; Metspalu, Andres; Esko, Tõnu; Vacchi-Suzzi, Caterina; Nalls, Mike A; Zonderman, Alan B; Evans, Michele K; Engström, Gunnar; Orho-Melander, Marju; Melander, Olle; O'Donoghue, Michelle L; Waterworth, Dawn M; Wallentin, Lars; White, Harvey D; Floyd, James S; Bartz, Traci M; Rice, Kenneth M; Psaty, Bruce M; Starr, J M; Liewald, David C M; Hayward, Caroline; Deary, Ian J; Greinacher, Andreas; Völker, Uwe; Thiele, Thomas; Völzke, Henry; van Rooij, Frank J A; Uitterlinden, André G; Franco, Oscar H; Dehghan, Abbas; Edwards, Todd L; Ganesh, Santhi K; Kathiresan, Sekar; Faraday, Nauder; Auer, Paul L; Reiner, Alex P; Lettre, Guillaume; Johnson, Andrew D

    2016-07-01

    Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors. PMID:27346686

  7. Meta-Analysis of Placental Transcriptome Data Identifies a Novel Molecular Pathway Related to Preeclampsia

    PubMed Central

    van Uitert, Miranda; Moerland, Perry D.; Enquobahrie, Daniel A.; Laivuori, Hannele; van der Post, Joris A. M.; Ris-Stalpers, Carrie; Afink, Gijs B.

    2015-01-01

    Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings challenging. To generate a more robust preeclampsia gene expression signature, we performed a meta-analysis on the original data of 11 placenta RNA microarray experiments, representing 139 normotensive and 116 preeclamptic pregnancies. Microarray data were pre-processed and analyzed using standardized bioinformatics and statistical procedures and the effect sizes were combined using an inverse-variance random-effects model. Interactions between genes in the resulting gene expression signature were identified by pathway analysis (Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, Graphite) and protein-protein associations (STRING). This approach has resulted in a comprehensive list of differentially expressed genes that led to a 388-gene meta-signature of preeclamptic placenta. Pathway analysis highlights the involvement of the previously identified hypoxia/HIF1A pathway in the establishment of the preeclamptic gene expression profile, while analysis of protein interaction networks indicates CREBBP/EP300 as a novel element central to the preeclamptic placental transcriptome. In addition, there is an apparent high incidence of preeclampsia in women carrying a child with a mutation in CREBBP/EP300 (Rubinstein-Taybi Syndrome). The 388-gene preeclampsia meta-signature offers a vital starting point for further studies into the relevance of these genes (in particular CREBBP/EP300) and their concomitant pathways as biomarkers or functional molecules in preeclampsia. This will result in a better understanding of the molecular basis of this disease and opens up the opportunity to develop rational therapies targeting the placental dysfunction causal to preeclampsia. PMID:26171964

  8. Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier

    PubMed Central

    Bhasin, Manoj K.; Ndebele, Kenneth; Bucur, Octavian; Yee, Eric U.; Otu, Hasan H.; Plati, Jessica; Bullock, Andrea; Gu, Xuesong; Castan, Eduardo; Zhang, Peng; Najarian, Robert; Muraru, Maria S.

    2016-01-01

    Purpose Pancreatic ductal adenocarcinoma (PDAC) is largely incurable due to late diagnosis. Superior early detection biomarkers are critical to improving PDAC survival and risk stratification. Experimental Design Optimized meta-analysis of PDAC transcriptome datasets identified and validated key PDAC biomarkers. PDAC-specific expression of a 5-gene biomarker panel was measured by qRT-PCR in microdissected patient-derived FFPE tissues. Cell-based assays assessed impact of two of these biomarkers, TMPRSS4 and ECT2, on PDAC cells. Results A 5-gene PDAC classifier (TMPRSS4, AHNAK2, POSTN, ECT2, SERPINB5) achieved on average 95% sensitivity and 89% specificity in discriminating PDAC from non-tumor samples in four training sets and similar performance (sensitivity = 94%, specificity = 89.6%) in five independent validation datasets. This classifier accurately discriminated PDAC from chronic pancreatitis (AUC = 0.83), other cancers (AUC = 0.89), and non-tumor from PDAC precursors (AUC = 0.92) in three independent datasets. Importantly, the classifier distinguished PanIN from healthy pancreas in the PDX1-Cre;LSL-KrasG12D PDAC mouse model. Discriminatory expression of the PDAC classifier genes was confirmed in microdissected FFPE samples of PDAC and matched surrounding non-tumor pancreas or pancreatitis. Notably, knock-down of TMPRSS4 and ECT2 reduced PDAC soft agar growth and cell viability and TMPRSS4 knockdown also blocked PDAC migration and invasion. Conclusions This study identified and validated a highly accurate 5-gene PDAC classifier for discriminating PDAC and early precursor lesions from non-malignant tissue that may facilitate early diagnosis and risk stratification upon validation in prospective clinical trials. Cell-based experiments of two overexpressed proteins encoded by the panel, TMPRSS4 and ECT2, suggest a causal link to PDAC development and progression, confirming them as potential therapeutic targets. PMID:26993610

  9. Identifying homogenous subgroups for individual patient meta-analysis based on Rough Set Theory.

    PubMed

    Gil-Herrera, Eleazar; Tsalatsanis, Athanasios; Kumar, Ambuj; Mhaskar, Rahul; Miladinovic, Branko; Yalcin, Ali; Djulbegovic, Benjamin

    2014-01-01

    Failure to detect and manage heterogeneity between clinical trials included in meta-analysis may lead to misinterpretation of summary effect estimates. This may ultimately compromise the validity of the results of the meta-analysis. Typically, when heterogeneity between trials is detected, researchers use sensitivity or subgroup analysis to manage it. However, both methods fail to explain why heterogeneity existed in the first place. Here we propose a novel methodology that relies on Rough Set Theory (RST) to detect, explain, and manage the sources of heterogeneity applicable to meta-analysis performed on individual patient data (IPD). The method exploits the RST relations of discernibility and indiscernibility to create homogeneous groups of patients. We applied our methodology on a dataset of 1,111 patients enrolled in 9 randomized controlled trials studying the effect of two transplantation procedures in the management of hematologic malignancies. Our method was able to create three subgroups of patients with remarkably low statistical heterogeneity values (16.8%, 0% and 0% respectively). The proposed methodology has the potential to automatize and standardize the process of detecting and managing heterogeneity in IPD meta-analysis. Future work involves investigating the applications of the proposed methodology in analyzing treatment effects in patients belonging to different risk groups, which will ultimately assist in personalized healthcare decision making.

  10. Identifying Predictors of Social Functioning in College Students: A Meta-Analysis

    ERIC Educational Resources Information Center

    Beard, Jennifer Blair

    2011-01-01

    This meta-analysis draws studies from the literature on college student persistence, need theories, and positive psychology in investigating the strongest predictors of social functioning in college students in the United States and Canada. The predictor categories included background characteristics, measures of personality, mental health…

  11. Further Replication Studies of the EVE Consortium Meta-Analysis Identifies Two Asthma Risk Loci in European Americans

    PubMed Central

    Myers, Rachel A.; Himes, Blanca E.; Gignoux, Christopher R.; Yang, James J.; Gauderman, W. James; Rebordosa, Cristina; Xie, Jianming; Torgerson, Dara G.; Levin, Albert M.; Baurley, James; Graves, Penelope E.; Mathias, Rasika A.; Romieu, Isabelle; Roth, Lindsey A.; Conti, David; Avila, Lydia; Eng, Celeste; Vora, Hita; LeNoir, Michael A.; Soto-Quiros, Manuel; Liu, Jinghua; Celedon, Juan C.; Farber, Harold J.; Kumar, Rajesh; Avila, Pedro C.; Meade, Kelley; Serebrisky, Denise; Thyne, Shannon; Rodriguez-Cintron, William; Rodriguez-Santana, Jose R.; Borrell, Luisa N.; Lemanske, Robert F.; Bleecker, Eugene R.; Meyers, Deborah A.; London, Stephanie J.; Barnes, Kathleen C.; Raby, Benjamin A.; Martinez, Fernando D.; Gilliland, Frank D.; Williams, L. Keoki; Burchard, Esteban G.; Weiss, Scott T.; Nicolae, Dan L.; Ober, Carole

    2013-01-01

    Background Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk. Objectives We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis. Methods We selected 3186 SNPs for replication based on the p-values from the EVE Consortium meta-analysis. These SNPs were genotyped in ethnically diverse replication samples from nine different studies, totaling to 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study and the resulting test statistics were combined in a meta-analysis. Results Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined OR = 1.18; 95% CI 1.10 – 1.25) and rs9570077 (combined OR =1.20 95% CI 1.12–1.29) on chromosome 13q21. We could not replicate any additional associations in the African American or Latino individuals. Conclusions This extended replication study identified two additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latino individuals highlights the difficulty in replicating associations in admixed populations. PMID:23040885

  12. Genome-Wide Association Study to Identify Common Variants Associated with Brachial Circumference: A Meta-Analysis of 14 Cohorts

    PubMed Central

    Boraska, Vesna; Day-Williams, Aaron; Franklin, Christopher S.; Elliott, Katherine S.; Panoutsopoulou, Kalliope; Tachmazidou, Ioanna; Albrecht, Eva; Bandinelli, Stefania; Beilin, Lawrence J.; Bochud, Murielle; Cadby, Gemma; Ernst, Florian; Evans, David M.; Hayward, Caroline; Hicks, Andrew A.; Huffman, Jennifer; Huth, Cornelia; James, Alan L.; Klopp, Norman; Kolcic, Ivana; Kutalik, Zoltán; Lawlor, Debbie A.; Musk, Arthur W.; Pehlic, Marina; Pennell, Craig E.; Perry, John R. B.; Peters, Annette; Polasek, Ozren; Pourcain, Beate St; Ring, Susan M.; Salvi, Erika; Schipf, Sabine; Staessen, Jan A.; Teumer, Alexander; Timpson, Nicholas; Vitart, Veronique; Warrington, Nicole M.; Yaghootkar, Hanieh; Zemunik, Tatijana; Zgaga, Lina; An, Ping; Anttila, Verneri; Borecki, Ingrid B.; Holmen, Jostein; Ntalla, Ioanna; Palotie, Aarno; Pietiläinen, Kirsi H.; Wedenoja, Juho; Winsvold, Bendik S.; Dedoussis, George V.; Kaprio, Jaakko; Province, Michael A.; Zwart, John-Anker; Burnier, Michel; Campbell, Harry; Cusi, Daniele; Davey Smith, George; Frayling, Timothy M.; Gieger, Christian; Palmer, Lyle J.; Pramstaller, Peter P.; Rudan, Igor; Völzke, Henry; Wichmann, H. -Erich; Wright, Alan F.; Zeggini, Eleftheria

    2012-01-01

    Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC. PMID:22479309

  13. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

    PubMed Central

    Law, Matthew H.; Bishop, D. Timothy; Martin, Nicholas G.; Moses, Eric K.; Song, Fengju; Barrett, Jennifer H.; Kumar, Rajiv; Easton, Douglas F.; Pharoah, Paul D. P.; Swerdlow, Anthony J.; Kypreou, Katerina P.; Taylor, John C.; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A.; Andresen, Per A.; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M.; Dębniak, Tadeusz; Duffy, David L.; Elder, David E.; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M.; Goldstein, Alisa M.; Gruis, Nelleke A.; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A.; Chen, Wei V.; Landi, Maria Teresa; Lang, Julie; Lathrop, G. Mark; Lubiński, Jan; Mackie, Rona M.; Mann, Graham J.; Molven, Anders; Montgomery, Grant W.; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A.; Radford-Smith, Graham L.; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C.; Craig, Jamie E.; Schadendorf, Dirk; Simms, Lisa A.; Burdon, Kathryn P.; Nyholt, Dale R.; Pooley, Karen A.; Orr, Nick; Stratigos, Alexander J.; Cust, Anne E.; Ward, Sarah V.; Hayward, Nicholas K.; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M.; Bishop, Julia A. Newton; MacGregor, Stuart; Iles, Mark M.

    2015-01-01

    Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5×10–8), as did two previously-reported but un-replicated loci and all thirteen established loci. Novel SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes including one involved in telomere biology. PMID:26237428

  14. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

    PubMed

    Law, Matthew H; Bishop, D Timothy; Lee, Jeffrey E; Brossard, Myriam; Martin, Nicholas G; Moses, Eric K; Song, Fengju; Barrett, Jennifer H; Kumar, Rajiv; Easton, Douglas F; Pharoah, Paul D P; Swerdlow, Anthony J; Kypreou, Katerina P; Taylor, John C; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A; Andresen, Per A; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M; Dȩbniak, Tadeusz; Duffy, David L; Elder, David E; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M; Goldstein, Alisa M; Gruis, Nelleke A; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A; Chen, Wei V; Landi, Maria Teresa; Lang, Julie; Lathrop, G Mark; Lubiński, Jan; Mackie, Rona M; Mann, Graham J; Molven, Anders; Montgomery, Grant W; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A; Radford-Smith, Graham L; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C; Craig, Jamie E; Schadendorf, Dirk; Simms, Lisa A; Burdon, Kathryn P; Nyholt, Dale R; Pooley, Karen A; Orr, Nick; Stratigos, Alexander J; Cust, Anne E; Ward, Sarah V; Hayward, Nicholas K; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M; Bishop, Julia A Newton; Demenais, Florence; Amos, Christopher I; MacGregor, Stuart; Iles, Mark M

    2015-09-01

    Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology. PMID:26237428

  15. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis.

    PubMed

    Mao, Chen; Liao, Ru-Yan; Qiu, Li-Xin; Wang, Xi-Wen; Ding, Hong; Chen, Qing

    2011-04-01

    Epidemiologic studies have evaluated the association between BRAF mutations and resistance to the treatment of anti-EGFR monoclonal antibodies (MoAb) in patients with metastatic colorectal cancer (mCRC). However, the results are still inconclusive. To derive a more precise estimation of the relationship, we performed this meta-analysis. A total of 11 studies were included in the final meta-analysis. There were seven studies for unselected mCRC patients and four studies for patients with wild type KRAS mCRC. Among unselected mCRC patients, BRAF V600E mutation was detected in 48 of 546 primary tumors (8.8%). The objective response rate (ORR) of patients with mutant BRAF was 29.2% (14/48), whereas the ORR of patients with wild-type BRAF was 33.5% (158/472).The overall RR for ORR of mutant BRAF patients over wild-type BRAF patients was 0.86 (95% CI=0.57-1.30; P=0.48). For patients with KRAS wild-type mCRC, BRAF V600E mutation was detected in 40 of 376 primary tumors (10.6%). The ORR of patients with mutant BRAF was 0.0% (0/40), whereas the ORR of patients with wild-type BRAF was 36.3% (122/336). The pooled RR of mutant BRAF patients over wild-type BRAF patients was 0.14 (95% CI=0.04-0.53; P=0.004). In conclusion, this meta-analysis provides evidence that BRAF V600E mutation is associated with lack of response in wild-type KRAS mCRC treated with anti-EGFR MoAbs. BRAF mutation may be used as an additional biomarker for the selection of mCRC patients who might benefit from anti-EGFR MoAbs therapy.

  16. Bisphosphonates in the Treatment of Patients With Metastatic Breast, Lung, and Prostate Cancer: A Meta-Analysis.

    PubMed

    Liu, Jing; Huang, Wenhui; Zhou, Ruoyu; Jia, Shuting; Tang, Wenru; Luo, Ying; Zhang, Jihong

    2015-11-01

    The purpose of this meta-analysis was to investigate whether bisphosphonates are a key therapy for bone metastases in lung cancer, breast cancer, and prostate cancer by comparing all randomized controlled trials that appraised the effects of bisphosphonates on risk of skeletal-related events (SREs).PubMed, Embase, and Medline databases (up to December 2014) were used to search all related articles. Using the data from 19 available publications, the authors examined the efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer by meta-analysis.Bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.69-0.95, P = 0.008], breast cancer (OR = 0.62, 95% CI = 0.54-0.71, P = 0.000), and prostate cancer (OR = 0.62, 95% CI = 0.45-0.86, P = 0.004).This meta-analysis suggests that bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer.

  17. GWAS meta analysis identifies TSNARE1 as a novel Schizophrenia / Bipolar susceptibility locus

    PubMed Central

    Sleiman, Patrick; Wang, Dai; Glessner, Joseph; Hadley, Dexter; Gur, Raquel E.; Cohen, Nadine; Li, Qingqin; Hakonarson, Hakon; Sleiman, Patrick; Glessner, Joseph; Hadley, Dexter; Kao, Charlly; Wu, Zhi-liang; Kim, Cecilia; Thomas, Kelly; Hakonarson, Hakon; Wang, Dai; Favis, Reyna; Fu, Dong-Jing; Chung, Hedy; Savitz, Adam; Gopal, Srihari; Cohen, Nadine; Li, Qingqin

    2013-01-01

    We carried out a GWAS meta-analysis of combined mixed-ancestry schizophrenia, schizoaffective, and bipolar cohorts that resulted in the identification of six genome-wide significant loci, including one novel locus at chr8q24.3, encompassing TSNARE1 (P = 1.28 × 10−9). The analysis included a total of 13,394 cases and 34,676 controls. While the function of TSNARE1 remains unknown, bioinformatic predictions based on phylogenetic ancestry indicate it may have a vertebrate-specific function in intracellular protein transport and synaptic vesicle exocytosis. PMID:24166486

  18. Vascular endothelial growth factor receptor tyrosine kinase inhibitors versus bevacizumab in metastatic colorectal cancer: A systematic review and meta-analysis

    PubMed Central

    LIN, ZEXIN; YANG, YILIN; HUANG, YONGLIANG; LIANG, JUNJIE; LU, FANG; LAO, XUEJUN

    2015-01-01

    Bevacizumab has demonstrated a survival benefit in patients with metastatic colorectal cancer (mCRC) when combined with chemotherapy. Several randomized clinical trials comparing the efficacy and toxicity of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) against bevacizumab have been reported. The present meta-analysis was conducted to identify the potentially significant benefit of the combined treatment regimens in patients with mCRC. PubMed, Embase and Cochrane Library databases were searched for the randomized controlled trials published on or before September 2014, which compared the efficacy and toxicity of VEGFR TKIs with bevacizumab in combination with chemotherapy in patients with mCRC. The primary endpoints included progression-free survival (PFS), overall survival (OS) and overall response rate (ORR), and secondary endpoints were the toxicity profiles. Relative risks (RRs) with 95% confidence intervals (CIs) for response rate and adverse events (AEs) were calculated, as well as hazard ratios (HRs) for PFS and OS. The final analysis included 4 studies comprising a total of 1,929 intent-to-treat patients with mCRC, which compared VEGFR TKIs (cediranib and axitinib) plus chemotherapy with bevacizumab plus chemotherapy. Results demonstrated that VEGFR TKIs plus chemotherapy significantly resulted in a modest but significantly shorter PFS [hazard ratio (HR), 1.12; 95% CI, 1.00–1.25; P=0.05] compared with that of bevacizumab plus chemotherapy but not in OS (HR, 1.10; 95% CI, 0.88–1.17; P=0.87) and ORR (RR, 0.95; 95% CI, 0.85–1.05; P=0.30). VEGFR TKIs treatment showed a less favorable AE profile compared with bevacizumab, with higher rates of grade-III/IV diarrhea, fatigue, hypertension, neutropenia and thrombocytopenia, whereas a higher incidence of peripheral neuropathy associated with the bevacizumab group was observed. In conclusion, the addition of VEGFR TKIs to chemotherapy resulted in a modest but

  19. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

    PubMed

    Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I; Conti, David V; Schumacher, Fredrick; Han, Ying; Benlloch, Sara; Hazelett, Dennis J; Wang, Zhaoming; Saunders, Ed; Leongamornlert, Daniel; Lindstrom, Sara; Jugurnauth-Little, Sara; Dadaev, Tokhir; Tymrakiewicz, Malgorzata; Stram, Daniel O; Rand, Kristin; Wan, Peggy; Stram, Alex; Sheng, Xin; Pooler, Loreall C; Park, Karen; Xia, Lucy; Tyrer, Jonathan; Kolonel, Laurence N; Le Marchand, Loic; Hoover, Robert N; Machiela, Mitchell J; Yeager, Merideth; Burdette, Laurie; Chung, Charles C; Hutchinson, Amy; Yu, Kai; Goh, Chee; Ahmed, Mahbubl; Govindasami, Koveela; Guy, Michelle; Tammela, Teuvo L J; Auvinen, Anssi; Wahlfors, Tiina; Schleutker, Johanna; Visakorpi, Tapio; Leinonen, Katri A; Xu, Jianfeng; Aly, Markus; Donovan, Jenny; Travis, Ruth C; Key, Tim J; Siddiq, Afshan; Canzian, Federico; Khaw, Kay-Tee; Takahashi, Atsushi; Kubo, Michiaki; Pharoah, Paul; Pashayan, Nora; Weischer, Maren; Nordestgaard, Borge G; Nielsen, Sune F; Klarskov, Peter; Røder, Martin Andreas; Iversen, Peter; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Stanford, Janet L; Kolb, Suzanne; Holt, Sarah; Knudsen, Beatrice; Coll, Antonio Hurtado; Gapstur, Susan M; Diver, W Ryan; Stevens, Victoria L; Maier, Christiane; Luedeke, Manuel; Herkommer, Kathleen; Rinckleb, Antje E; Strom, Sara S; Pettaway, Curtis; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; Cannon-Albright, Lisa; Cybulski, Cezary; Wokołorczyk, Dominika; Kluźniak, Wojciech; Park, Jong; Sellers, Thomas; Lin, Hui-Yi; Isaacs, William B; Partin, Alan W; Brenner, Hermann; Dieffenbach, Aida Karina; Stegmaier, Christa; Chen, Constance; Giovannucci, Edward L; Ma, Jing; Stampfer, Meir; Penney, Kathryn L; Mucci, Lorelei; John, Esther M; Ingles, Sue A; Kittles, Rick A; Murphy, Adam B; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej M; Blot, William; Signorello, Lisa B; Zheng, Wei; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Nemesure, Barbara; Carpten, John; Leske, Cristina; Wu, Suh-Yuh; Hennis, Anselm; Kibel, Adam S; Rybicki, Benjamin A; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Zheng, S Lilly; Batra, Jyotsna; Clements, Judith; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Witte, John S; Casey, Graham; Gillanders, Elizabeth M; Seminara, Daniella; Riboli, Elio; Hamdy, Freddie C; Coetzee, Gerhard A; Li, Qiyuan; Freedman, Matthew L; Hunter, David J; Muir, Kenneth; Gronberg, Henrik; Neal, David E; Southey, Melissa; Giles, Graham G; Severi, Gianluca; Cook, Michael B; Nakagawa, Hidewaki; Wiklund, Fredrik; Kraft, Peter; Chanock, Stephen J; Henderson, Brian E; Easton, Douglas F; Eeles, Rosalind A; Haiman, Christopher A

    2014-10-01

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

  20. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

    PubMed

    Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I; Conti, David V; Schumacher, Fredrick; Han, Ying; Benlloch, Sara; Hazelett, Dennis J; Wang, Zhaoming; Saunders, Ed; Leongamornlert, Daniel; Lindstrom, Sara; Jugurnauth-Little, Sara; Dadaev, Tokhir; Tymrakiewicz, Malgorzata; Stram, Daniel O; Rand, Kristin; Wan, Peggy; Stram, Alex; Sheng, Xin; Pooler, Loreall C; Park, Karen; Xia, Lucy; Tyrer, Jonathan; Kolonel, Laurence N; Le Marchand, Loic; Hoover, Robert N; Machiela, Mitchell J; Yeager, Merideth; Burdette, Laurie; Chung, Charles C; Hutchinson, Amy; Yu, Kai; Goh, Chee; Ahmed, Mahbubl; Govindasami, Koveela; Guy, Michelle; Tammela, Teuvo L J; Auvinen, Anssi; Wahlfors, Tiina; Schleutker, Johanna; Visakorpi, Tapio; Leinonen, Katri A; Xu, Jianfeng; Aly, Markus; Donovan, Jenny; Travis, Ruth C; Key, Tim J; Siddiq, Afshan; Canzian, Federico; Khaw, Kay-Tee; Takahashi, Atsushi; Kubo, Michiaki; Pharoah, Paul; Pashayan, Nora; Weischer, Maren; Nordestgaard, Borge G; Nielsen, Sune F; Klarskov, Peter; Røder, Martin Andreas; Iversen, Peter; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Stanford, Janet L; Kolb, Suzanne; Holt, Sarah; Knudsen, Beatrice; Coll, Antonio Hurtado; Gapstur, Susan M; Diver, W Ryan; Stevens, Victoria L; Maier, Christiane; Luedeke, Manuel; Herkommer, Kathleen; Rinckleb, Antje E; Strom, Sara S; Pettaway, Curtis; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; Cannon-Albright, Lisa; Cybulski, Cezary; Wokołorczyk, Dominika; Kluźniak, Wojciech; Park, Jong; Sellers, Thomas; Lin, Hui-Yi; Isaacs, William B; Partin, Alan W; Brenner, Hermann; Dieffenbach, Aida Karina; Stegmaier, Christa; Chen, Constance; Giovannucci, Edward L; Ma, Jing; Stampfer, Meir; Penney, Kathryn L; Mucci, Lorelei; John, Esther M; Ingles, Sue A; Kittles, Rick A; Murphy, Adam B; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej M; Blot, William; Signorello, Lisa B; Zheng, Wei; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Nemesure, Barbara; Carpten, John; Leske, Cristina; Wu, Suh-Yuh; Hennis, Anselm; Kibel, Adam S; Rybicki, Benjamin A; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Zheng, S Lilly; Batra, Jyotsna; Clements, Judith; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Witte, John S; Casey, Graham; Gillanders, Elizabeth M; Seminara, Daniella; Riboli, Elio; Hamdy, Freddie C; Coetzee, Gerhard A; Li, Qiyuan; Freedman, Matthew L; Hunter, David J; Muir, Kenneth; Gronberg, Henrik; Neal, David E; Southey, Melissa; Giles, Graham G; Severi, Gianluca; Cook, Michael B; Nakagawa, Hidewaki; Wiklund, Fredrik; Kraft, Peter; Chanock, Stephen J; Henderson, Brian E; Easton, Douglas F; Eeles, Rosalind A; Haiman, Christopher A

    2014-10-01

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease. PMID:25217961

  1. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

    PubMed

    Cornelis, M C; Byrne, E M; Esko, T; Nalls, M A; Ganna, A; Paynter, N; Monda, K L; Amin, N; Fischer, K; Renstrom, F; Ngwa, J S; Huikari, V; Cavadino, A; Nolte, I M; Teumer, A; Yu, K; Marques-Vidal, P; Rawal, R; Manichaikul, A; Wojczynski, M K; Vink, J M; Zhao, J H; Burlutsky, G; Lahti, J; Mikkilä, V; Lemaitre, R N; Eriksson, J; Musani, S K; Tanaka, T; Geller, F; Luan, J; Hui, J; Mägi, R; Dimitriou, M; Garcia, M E; Ho, W-K; Wright, M J; Rose, L M; Magnusson, P K E; Pedersen, N L; Couper, D; Oostra, B A; Hofman, A; Ikram, M A; Tiemeier, H W; Uitterlinden, A G; van Rooij, F J A; Barroso, I; Johansson, I; Xue, L; Kaakinen, M; Milani, L; Power, C; Snieder, H; Stolk, R P; Baumeister, S E; Biffar, R; Gu, F; Bastardot, F; Kutalik, Z; Jacobs, D R; Forouhi, N G; Mihailov, E; Lind, L; Lindgren, C; Michaëlsson, K; Morris, A; Jensen, M; Khaw, K-T; Luben, R N; Wang, J J; Männistö, S; Perälä, M-M; Kähönen, M; Lehtimäki, T; Viikari, J; Mozaffarian, D; Mukamal, K; Psaty, B M; Döring, A; Heath, A C; Montgomery, G W; Dahmen, N; Carithers, T; Tucker, K L; Ferrucci, L; Boyd, H A; Melbye, M; Treur, J L; Mellström, D; Hottenga, J J; Prokopenko, I; Tönjes, A; Deloukas, P; Kanoni, S; Lorentzon, M; Houston, D K; Liu, Y; Danesh, J; Rasheed, A; Mason, M A; Zonderman, A B; Franke, L; Kristal, B S; Karjalainen, J; Reed, D R; Westra, H-J; Evans, M K; Saleheen, D; Harris, T B; Dedoussis, G; Curhan, G; Stumvoll, M; Beilby, J; Pasquale, L R; Feenstra, B; Bandinelli, S; Ordovas, J M; Chan, A T; Peters, U; Ohlsson, C; Gieger, C; Martin, N G; Waldenberger, M; Siscovick, D S; Raitakari, O; Eriksson, J G; Mitchell, P; Hunter, D J; Kraft, P; Rimm, E B; Boomsma, D I; Borecki, I B; Loos, R J F; Wareham, N J; Vollenweider, P; Caporaso, N; Grabe, H J; Neuhouser, M L; Wolffenbuttel, B H R; Hu, F B; Hyppönen, E; Järvelin, M-R; Cupples, L A; Franks, P W; Ridker, P M; van Duijn, C M; Heiss, G; Metspalu, A; North, K E; Ingelsson, E; Nettleton, J A; van Dam, R M; Chasman, D I

    2015-05-01

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee. PMID:25288136

  2. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

    PubMed

    Cornelis, M C; Byrne, E M; Esko, T; Nalls, M A; Ganna, A; Paynter, N; Monda, K L; Amin, N; Fischer, K; Renstrom, F; Ngwa, J S; Huikari, V; Cavadino, A; Nolte, I M; Teumer, A; Yu, K; Marques-Vidal, P; Rawal, R; Manichaikul, A; Wojczynski, M K; Vink, J M; Zhao, J H; Burlutsky, G; Lahti, J; Mikkilä, V; Lemaitre, R N; Eriksson, J; Musani, S K; Tanaka, T; Geller, F; Luan, J; Hui, J; Mägi, R; Dimitriou, M; Garcia, M E; Ho, W-K; Wright, M J; Rose, L M; Magnusson, P K E; Pedersen, N L; Couper, D; Oostra, B A; Hofman, A; Ikram, M A; Tiemeier, H W; Uitterlinden, A G; van Rooij, F J A; Barroso, I; Johansson, I; Xue, L; Kaakinen, M; Milani, L; Power, C; Snieder, H; Stolk, R P; Baumeister, S E; Biffar, R; Gu, F; Bastardot, F; Kutalik, Z; Jacobs, D R; Forouhi, N G; Mihailov, E; Lind, L; Lindgren, C; Michaëlsson, K; Morris, A; Jensen, M; Khaw, K-T; Luben, R N; Wang, J J; Männistö, S; Perälä, M-M; Kähönen, M; Lehtimäki, T; Viikari, J; Mozaffarian, D; Mukamal, K; Psaty, B M; Döring, A; Heath, A C; Montgomery, G W; Dahmen, N; Carithers, T; Tucker, K L; Ferrucci, L; Boyd, H A; Melbye, M; Treur, J L; Mellström, D; Hottenga, J J; Prokopenko, I; Tönjes, A; Deloukas, P; Kanoni, S; Lorentzon, M; Houston, D K; Liu, Y; Danesh, J; Rasheed, A; Mason, M A; Zonderman, A B; Franke, L; Kristal, B S; Karjalainen, J; Reed, D R; Westra, H-J; Evans, M K; Saleheen, D; Harris, T B; Dedoussis, G; Curhan, G; Stumvoll, M; Beilby, J; Pasquale, L R; Feenstra, B; Bandinelli, S; Ordovas, J M; Chan, A T; Peters, U; Ohlsson, C; Gieger, C; Martin, N G; Waldenberger, M; Siscovick, D S; Raitakari, O; Eriksson, J G; Mitchell, P; Hunter, D J; Kraft, P; Rimm, E B; Boomsma, D I; Borecki, I B; Loos, R J F; Wareham, N J; Vollenweider, P; Caporaso, N; Grabe, H J; Neuhouser, M L; Wolffenbuttel, B H R; Hu, F B; Hyppönen, E; Järvelin, M-R; Cupples, L A; Franks, P W; Ridker, P M; van Duijn, C M; Heiss, G; Metspalu, A; North, K E; Ingelsson, E; Nettleton, J A; van Dam, R M; Chasman, D I

    2015-05-01

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

  3. mTOR inhibitors, a new era for metastatic luminal HER2-negative breast cancer? A systematic review and a meta-analysis of randomized trials

    PubMed Central

    Rotundo, Maria Saveria; Galeano, Teresa; Tassone, Pierfrancesco; Tagliaferri, Pierosandro

    2016-01-01

    We evaluated if standard hormonal therapy (HT) could be improved by the addition of mammalian target of rapamycin inhibitors (mTOR-I) in metastatic luminal breast cancer. A meta-analysis on 4 phase II-III randomized clinical trials was performed. Pooled hazard ratio (HR) for progression free survival (PFS)/ time to progression (TTP) was 0.62 in favor of mTOR-I+HT arm (95% confidence interval [CI] 0.55-0.70; p<0.0001). There was significant heterogeneity for PFS/TTP (Cochran's Q 32, p<0.0001, I2 index 90.6%). Pooled HR for overall survival (OS) was 0.84 in favor of the combination arm (95% CI 0.71-0.99; p=0.04). Heterogeneity was not significant (Cochran's Q 4.47, p=0.1, I2 index 55.3%). Pooled risk ratio (RR) for objective response rate (ORR) was 0.88 in favor of experimental arm (95% CI 0.85-0.91; p<0.0001). Heterogeneity was not significant (Cochran's Q 2.11, p=0.3, I2 index 5.2%). Adverse events (AEs), in particular those of grade 3-4, mostly occurred in mTOR-I+HT arm. Combination therapy of HT plus mTOR-I improves the outcome of metastatic luminal breast cancer patients. Our results provide evidence of a class-effect of these targeting molecules. PMID:26895472

  4. Meta-analysis comparing maintenance strategies with continuous therapy and complete chemotherapy-free interval strategies in the treatment of metastatic colorectal cancer.

    PubMed

    Zhao, Lei; Wang, Jing; Li, Huihui; Che, Juanjuan; Cao, Bangwei

    2016-05-31

    There is as yet no consensus as to the best choice among the three treatment options (maintenance, complete chemotherapy-free intervals [CFIs], and continuous) for metastatic colorectal cancer (CRC). We performed a meta-analysis of six trials (N = 2, 454 patients) to compare the safety and efficacy of those three treatment strategies. Maintenance appeared to offer an advantage over CFI with respect to progression-free survival (PFS) (hazard ratio [HR]: 0.53, 95% confidence interval [CI], 0.40-0.69). PFS and overall survival (OS) were comparable between the maintenance and continuous strategies (HR: 1.18, 95% CI, 0.96-1.46; HR: 1.05, 95% CI, 0.98-1.27, respectively), as was OS between the maintenance and CFI strategies (HR: 0.84; 95% CI, 0.70-1.00). The incidence of grade 3/4 toxicity, including neutropenia, neuropathy, hand-foot syndrome and fatigue, was lower with maintenance than with continuous therapy. A maintenance regimen utilizing bevacizumab-based doublets appeared to confer a slight advantage over bevacizumab monotherapy with respect to PFS (P = 0.011). Maintenance appeared to reduce cumulative grade 3/4 toxicity as compared to the continuous strategy, while showing comparable efficacy. Bevacizumab-based doublets appeared to be of particular value in patients with metastatic CRC.

  5. Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.

    PubMed

    Okada, Yukinori; Sim, Xueling; Go, Min Jin; Wu, Jer-Yuarn; Gu, Dongfeng; Takeuchi, Fumihiko; Takahashi, Atsushi; Maeda, Shiro; Tsunoda, Tatsuhiko; Chen, Peng; Lim, Su-Chi; Wong, Tien-Yin; Liu, Jianjun; Young, Terri L; Aung, Tin; Seielstad, Mark; Teo, Yik-Ying; Kim, Young Jin; Lee, Jong-Young; Han, Bok-Ghee; Kang, Daehee; Chen, Chien-Hsiun; Tsai, Fuu-Jen; Chang, Li-Ching; Fann, S-J Cathy; Mei, Hao; Rao, Dabeeru C; Hixson, James E; Chen, Shufeng; Katsuya, Tomohiro; Isono, Masato; Ogihara, Toshio; Chambers, John C; Zhang, Weihua; Kooner, Jaspal S; Albrecht, Eva; Yamamoto, Kazuhiko; Kubo, Michiaki; Nakamura, Yusuke; Kamatani, Naoyuki; Kato, Norihiro; He, Jiang; Chen, Yuan-Tsong; Cho, Yoon Shin; Tai, E-Shyong; Tanaka, Toshihiro

    2012-08-01

    Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function. PMID:22797727

  6. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

    PubMed Central

    Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I.; Conti, David V.; Schumacher, Fredrick; Han, Ying; Benlloch, Sara; Hazelett, Dennis J.; Wang, Zhaoming; Saunders, Ed; Leongamornlert, Daniel; Lindstrom, Sara; Jugurnauth-Little, Sara; Dadaev, Tokhir; Tymrakiewicz, Malgorzata; Stram, Daniel O.; Rand, Kristin; Wan, Peggy; Stram, Alex; Sheng, Xin; Pooler, Loreall C.; Park, Karen; Xia, Lucy; Tyrer, Jonathan; Kolonel, Laurence N.; Le Marchand, Loic; Hoover, Robert N.; Machiela, Mitchell J.; Yeager, Merideth; Burdette, Laurie; Chung, Charles C.; Hutchinson, Amy; Yu, Kai; Goh, Chee; Ahmed, Mahbubl; Govindasami, Koveela; Guy, Michelle; Tammela, Teuvo L.J.; Auvinen, Anssi; Wahlfors, Tiina; Schleutker, Johanna; Visakorpi, Tapio; Leinonen, Katri A.; Xu, Jianfeng; Aly, Markus; Donovan, Jenny; Travis, Ruth C.; Key, Tim J.; Siddiq, Afshan; Canzian, Federico; Khaw, Kay-Tee; Takahashi, Atsushi; Kubo, Michiaki; Pharoah, Paul; Pashayan, Nora; Weischer, Maren; Nordestgaard, Borge G.; Nielsen, Sune F.; Klarskov, Peter; Røder, Martin Andreas; Iversen, Peter; Thibodeau, Stephen N.; McDonnell, Shannon K; Schaid, Daniel J; Stanford, Janet L.; Kolb, Suzanne; Holt, Sarah; Knudsen, Beatrice; Coll, Antonio Hurtado; Gapstur, Susan M.; Diver, W. Ryan; Stevens, Victoria L.; Maier, Christiane; Luedeke, Manuel; Herkommer, Kathleen; Rinckleb, Antje E.; Strom, Sara S.; Pettaway, Curtis; Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P.; Cannon-Albright, Lisa; Cybulski, Cezary; Wokołorczyk, Dominika; Kluźniak, Wojciech; Park, Jong; Sellers, Thomas; Lin, Hui-Yi; Isaacs, William B.; Partin, Alan W.; Brenner, Hermann; Dieffenbach, Aida Karina; Stegmaier, Christa; Chen, Constance; Giovannucci, Edward L.; Ma, Jing; Stampfer, Meir; Penney, Kathryn L.; Mucci, Lorelei; John, Esther M.; Ingles, Sue A.; Kittles, Rick A.; Murphy, Adam B.; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej M.; Blot, William; Signorello, Lisa B.; Zheng, Wei; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Nemesure, Barbara; Carpten, John; Leske, Cristina; Wu, Suh-Yuh; Hennis, Anselm; Kibel, Adam S.; Rybicki, Benjamin A.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A; Zheng, S. Lilly; Batra, Jyotsna; Clements, Judith; Spurdle, Amanda; Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Witte, John S.; Casey, Graham; Gillanders, Elizabeth M.; Seminara, Daniella; Riboli, Elio; Hamdy, Freddie C.; Coetzee, Gerhard A.; Li, Qiyuan; Freedman, Matthew L.; Hunter, David J.; Muir, Kenneth; Gronberg, Henrik; Neal, David E.; Southey, Melissa; Giles, Graham G.; Severi, Gianluca; Cook, Michael B.; Nakagawa, Hidewaki; Wiklund, Fredrik; Kraft, Peter; Chanock, Stephen J.; Henderson, Brian E.; Easton, Douglas F.; Eeles, Rosalind A.; Haiman, Christopher A.

    2014-01-01

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three novel susceptibility loci were revealed at P<5×10-8; 15 variants were identified among men of European ancestry, 7 from multiethnic analyses and one was associated with early-onset prostate cancer. These 23 variants, in combination with the known prostate cancer risk variants, explain 33% of the familial risk of the disease in European ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the utility of combining ancestrally diverse populations to discover risk loci for disease. PMID:25217961

  7. Systematic Review and Meta-Analysis on the Role of Chemotherapy in Advanced and Metastatic Neuroendocrine Tumor (NET)

    PubMed Central

    Wong, Matthew H.; Lee, Adrian; Li, Bob T.; Lumba, Sumit; Clarke, Stephen J.; Samra, Jaswinder; Pavlakis, Nick

    2016-01-01

    Background/Objectives In the era of somatostatin analogues and targeted therapies, the role of chemotherapy in NET remains largely undefined. This systematic review aimed to assess the effect of chemotherapy on response rates (RR), progression-free survival (PFS), overall survival (OS) and toxicity compared to other chemotherapies/systemic therapies or best supportive care in patients with advanced or metastatic NET. Methods Randomised controlled trials (RCTs) from 1946 to 2015 were identified from MEDLINE, EMBASE, other databases and conference proceedings. Review of abstracts, quality assessment and data abstraction were performed independently by two investigators. Meta-analyses were conducted using Mantel-Haenszel analysis with random-effects modelling. Results Six RCTs comparing standard streptozotocin plus 5-fluorouacil (STZ/5FU) chemotherapy to other chemotherapy regimens, and 2 comparing this to interferon (IFN) were included. Only 1 study was considered at low risk of bias. STZ/5-FU was no different to other chemotherapies in response rate [RR 0.96; 95% confidence interval (CI) 0.72–1.27], PFS (RR 0.95; CI 0.81–1.13), or OS (RR 1.03; CI 0.77–1.39). IFN may produce higher response than STZ/5FU (RR 0.20; CI 0.04–1.13), but event rates were small and survival was no different. Interferon was associated with higher overall haematological (RR 0.47; CI 0.27–0.82) and lower overall renal toxicity (RR 3.61; CI 1.24–10.51). Conclusion Strong evidence is lacking in the area of chemotherapy in neuroendocrine tumors. There is currently no evidence that one chemotherapeutic regimen is significantly better than the other, nor is interferon better than chemotherapy. There is an urgent need to design RCTs comparing modern chemotherapy to other agents in NET. PMID:27362760

  8. Diagnostic performance of diffusion-weighted MRI for detection of pelvic metastatic lymph nodes in patients with cervical cancer: a systematic review and meta-analysis.

    PubMed

    Shen, G; Zhou, H; Jia, Z; Deng, H

    2015-08-01

    In recent years, diffusion-weighted (DW) MRI has emerged as a new technique for detecting the pelvic lymph metastases in patients with cervical cancer. The aim of this meta-analysis was to assess the diagnostic value of DW imaging (DWI) for benign/malignant discrimination of pelvic lymph nodes (LNs). Studies about DWI for the detection of metastatic LNs were searched in the PubMed, EMBASE, Web of Science, EBSCO, the Cochrane Library and three Chinese databases. Based on the extracted data, we determined pooled sensitivities, specificities and diagnostic odds ratios (DORs) across studies, calculated positive and negative likelihood ratios (LRs) and constructed summary receiver operating characteristic curves with area under the curve (AUC) and Q* obtained. We also analysed the heterogeneity between studies based on subgroup analysis, threshold effect and publication bias. In total, 15 studies involving 1021 patients met the inclusion criteria. The pooled sensitivity, specificity and DOR of DWI were 0.86 [95% confidence interval (CI), 0.84-0.89], 0.84 (95% CI, 0.83-0.86) and 47.21 (95% CI, 25.67-86.81), respectively. LR syntheses yielded overall positive LR of 6.55 (95% CI, 4.77-9.01) and negative LR of 0.17 (95% CI, 0.12-0.23). The AUC and Q* index were 0.9384 and 0.8754, respectively. The heterogeneity was relatively high between studies; however, there was no evidence for threshold effect and publication bias. DWI is beneficial in the pelvic nodal assessment in patients with cervical cancer. Large-scale, high-quality trials with standard protocols are required to evaluate its clinical value for discrimination of metastatic from non-metastatic pelvic LNs in patients with cervical cancer. Advances in knowledge include providing evidence to assess the role of DWI in nodal staging of cervical cancer.

  9. Meta-analysis of age-related gene expression profiles identifies common signatures of aging

    PubMed Central

    de Magalhães, João Pedro; Curado, João; Church, George M.

    2009-01-01

    Motivation: Numerous microarray studies of aging have been conducted, yet given the noisy nature of gene expression changes with age, elucidating the transcriptional features of aging and how these relate to physiological, biochemical and pathological changes remains a critical problem. Results: We performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats and humans. Our results reveal several common signatures of aging, including 56 genes consistently overexpressed with age, the most significant of which was APOD, and 17 genes underexpressed with age. We characterized the biological processes associated with these signatures and found that age-related gene expression changes most notably involve an overexpression of inflammation and immune response genes and of genes associated with the lysosome. An underexpression of collagen genes and of genes associated with energy metabolism, particularly mitochondrial genes, as well as alterations in the expression of genes related to apoptosis, cell cycle and cellular senescence biomarkers, were also observed. By employing a new method that emphasizes sensitivity, our work further reveals previously unknown transcriptional changes with age in many genes, processes and functions. We suggest these molecular signatures reflect a combination of degenerative processes but also transcriptional responses to the process of aging. Overall, our results help to understand how transcriptional changes relate to the process of aging and could serve as targets for future studies. Availability: http://genomics.senescence.info/uarrays/signatures.html Contact: jp@senescence.info Supplementary information: Supplementary data are available at Bioinformatics online. PMID:19189975

  10. Meta-Analysis Identifies Gene-by-Environment Interactions as Demonstrated in a Study of 4,965 Mice

    PubMed Central

    Joo, Jong Wha J.; Shih, Diana; Davis, Richard C.; Lusis, Aldons J.; Eskin, Eleazar

    2014-01-01

    Identifying environmentally-specific genetic effects is a key challenge in understanding the structure of complex traits. Model organisms play a crucial role in the identification of such gene-by-environment interactions, as a result of the unique ability to observe genetically similar individuals across multiple distinct environments. Many model organism studies examine the same traits but under varying environmental conditions. For example, knock-out or diet-controlled studies are often used to examine cholesterol in mice. These studies, when examined in aggregate, provide an opportunity to identify genomic loci exhibiting environmentally-dependent effects. However, the straightforward application of traditional methodologies to aggregate separate studies suffers from several problems. First, environmental conditions are often variable and do not fit the standard univariate model for interactions. Additionally, applying a multivariate model results in increased degrees of freedom and low statistical power. In this paper, we jointly analyze multiple studies with varying environmental conditions using a meta-analytic approach based on a random effects model to identify loci involved in gene-by-environment interactions. Our approach is motivated by the observation that methods for discovering gene-by-environment interactions are closely related to random effects models for meta-analysis. We show that interactions can be interpreted as heterogeneity and can be detected without utilizing the traditional uni- or multi-variate approaches for discovery of gene-by-environment interactions. We apply our new method to combine 17 mouse studies containing in aggregate 4,965 distinct animals. We identify 26 significant loci involved in High-density lipoprotein (HDL) cholesterol, many of which are consistent with previous findings. Several of these loci show significant evidence of involvement in gene-by-environment interactions. An additional advantage of our meta-analysis

  11. Mitogenomic Meta-Analysis Identifies Two Phases of Migration in the History of Eastern Eurasian Sheep.

    PubMed

    Lv, Feng-Hua; Peng, Wei-Feng; Yang, Ji; Zhao, Yong-Xin; Li, Wen-Rong; Liu, Ming-Jun; Ma, Yue-Hui; Zhao, Qian-Jun; Yang, Guang-Li; Wang, Feng; Li, Jin-Quan; Liu, Yong-Gang; Shen, Zhi-Qiang; Zhao, Sheng-Guo; Hehua, Eer; Gorkhali, Neena A; Farhad Vahidi, S M; Muladno, Muhammad; Naqvi, Arifa N; Tabell, Jonna; Iso-Touru, Terhi; Bruford, Michael W; Kantanen, Juha; Han, Jian-Lin; Li, Meng-Hua

    2015-10-01

    Despite much attention, history of sheep (Ovis aries) evolution, including its dating, demographic trajectory and geographic spread, remains controversial. To address these questions, we generated 45 complete and 875 partial mitogenomic sequences, and performed a meta-analysis of these and published ovine mitochondrial DNA sequences (n = 3,229) across Eurasia. We inferred that O. orientalis and O. musimon share the most recent female ancestor with O. aries at approximately 0.790 Ma (95% CI: 0.637-0.934 Ma) during the Middle Pleistocene, substantially predating the domestication event (∼8-11 ka). By reconstructing historical variations in effective population size, we found evidence of a rapid population increase approximately 20-60 ka, immediately before the Last Glacial Maximum. Analyses of lineage expansions showed two sheep migratory waves at approximately 4.5-6.8 ka (lineages A and B: ∼6.4-6.8 ka; C: ∼4.5 ka) across eastern Eurasia, which could have been influenced by prehistoric West-East commercial trade and deliberate mating of domestic and wild sheep, respectively. A continent-scale examination of lineage diversity and approximate Bayesian computation analyses indicated that the Mongolian Plateau region was a secondary center of dispersal, acting as a "transportation hub" in eastern Eurasia: Sheep from the Middle Eastern domestication center were inferred to have migrated through the Caucasus and Central Asia, and arrived in North and Southwest China (lineages A, B, and C) and the Indian subcontinent (lineages B and C) through this region. Our results provide new insights into sheep domestication, particularly with respect to origins and migrations to and from eastern Eurasia.

  12. Mitogenomic Meta-Analysis Identifies Two Phases of Migration in the History of Eastern Eurasian Sheep

    PubMed Central

    Lv, Feng-Hua; Peng, Wei-Feng; Yang, Ji; Zhao, Yong-Xin; Li, Wen-Rong; Liu, Ming-Jun; Ma, Yue-Hui; Zhao, Qian-Jun; Yang, Guang-Li; Wang, Feng; Li, Jin-Quan; Liu, Yong-Gang; Shen, Zhi-Qiang; Zhao, Sheng-Guo; Hehua, EEr; Gorkhali, Neena A.; Farhad Vahidi, S. M.; Muladno, Muhammad; Naqvi, Arifa N.; Tabell, Jonna; Iso-Touru, Terhi; Bruford, Michael W.; Kantanen, Juha; Han, Jian-Lin; Li, Meng-Hua

    2015-01-01

    Despite much attention, history of sheep (Ovis aries) evolution, including its dating, demographic trajectory and geographic spread, remains controversial. To address these questions, we generated 45 complete and 875 partial mitogenomic sequences, and performed a meta-analysis of these and published ovine mitochondrial DNA sequences (n = 3,229) across Eurasia. We inferred that O. orientalis and O. musimon share the most recent female ancestor with O. aries at approximately 0.790 Ma (95% CI: 0.637–0.934 Ma) during the Middle Pleistocene, substantially predating the domestication event (∼8–11 ka). By reconstructing historical variations in effective population size, we found evidence of a rapid population increase approximately 20–60 ka, immediately before the Last Glacial Maximum. Analyses of lineage expansions showed two sheep migratory waves at approximately 4.5–6.8 ka (lineages A and B: ∼6.4–6.8 ka; C: ∼4.5 ka) across eastern Eurasia, which could have been influenced by prehistoric West–East commercial trade and deliberate mating of domestic and wild sheep, respectively. A continent-scale examination of lineage diversity and approximate Bayesian computation analyses indicated that the Mongolian Plateau region was a secondary center of dispersal, acting as a “transportation hub” in eastern Eurasia: Sheep from the Middle Eastern domestication center were inferred to have migrated through the Caucasus and Central Asia, and arrived in North and Southwest China (lineages A, B, and C) and the Indian subcontinent (lineages B and C) through this region. Our results provide new insights into sheep domestication, particularly with respect to origins and migrations to and from eastern Eurasia. PMID:26085518

  13. Mitogenomic Meta-Analysis Identifies Two Phases of Migration in the History of Eastern Eurasian Sheep.

    PubMed

    Lv, Feng-Hua; Peng, Wei-Feng; Yang, Ji; Zhao, Yong-Xin; Li, Wen-Rong; Liu, Ming-Jun; Ma, Yue-Hui; Zhao, Qian-Jun; Yang, Guang-Li; Wang, Feng; Li, Jin-Quan; Liu, Yong-Gang; Shen, Zhi-Qiang; Zhao, Sheng-Guo; Hehua, Eer; Gorkhali, Neena A; Farhad Vahidi, S M; Muladno, Muhammad; Naqvi, Arifa N; Tabell, Jonna; Iso-Touru, Terhi; Bruford, Michael W; Kantanen, Juha; Han, Jian-Lin; Li, Meng-Hua

    2015-10-01

    Despite much attention, history of sheep (Ovis aries) evolution, including its dating, demographic trajectory and geographic spread, remains controversial. To address these questions, we generated 45 complete and 875 partial mitogenomic sequences, and performed a meta-analysis of these and published ovine mitochondrial DNA sequences (n = 3,229) across Eurasia. We inferred that O. orientalis and O. musimon share the most recent female ancestor with O. aries at approximately 0.790 Ma (95% CI: 0.637-0.934 Ma) during the Middle Pleistocene, substantially predating the domestication event (∼8-11 ka). By reconstructing historical variations in effective population size, we found evidence of a rapid population increase approximately 20-60 ka, immediately before the Last Glacial Maximum. Analyses of lineage expansions showed two sheep migratory waves at approximately 4.5-6.8 ka (lineages A and B: ∼6.4-6.8 ka; C: ∼4.5 ka) across eastern Eurasia, which could have been influenced by prehistoric West-East commercial trade and deliberate mating of domestic and wild sheep, respectively. A continent-scale examination of lineage diversity and approximate Bayesian computation analyses indicated that the Mongolian Plateau region was a secondary center of dispersal, acting as a "transportation hub" in eastern Eurasia: Sheep from the Middle Eastern domestication center were inferred to have migrated through the Caucasus and Central Asia, and arrived in North and Southwest China (lineages A, B, and C) and the Indian subcontinent (lineages B and C) through this region. Our results provide new insights into sheep domestication, particularly with respect to origins and migrations to and from eastern Eurasia. PMID:26085518

  14. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process.

    PubMed

    Springelkamp, Henriët; Höhn, René; Mishra, Aniket; Hysi, Pirro G; Khor, Chiea-Chuen; Loomis, Stephanie J; Bailey, Jessica N Cooke; Gibson, Jane; Thorleifsson, Gudmar; Janssen, Sarah F; Luo, Xiaoyan; Ramdas, Wishal D; Vithana, Eranga; Nongpiur, Monisha E; Montgomery, Grant W; Xu, Liang; Mountain, Jenny E; Gharahkhani, Puya; Lu, Yi; Amin, Najaf; Karssen, Lennart C; Sim, Kar-Seng; van Leeuwen, Elisabeth M; Iglesias, Adriana I; Verhoeven, Virginie J M; Hauser, Michael A; Loon, Seng-Chee; Despriet, Dominiek D G; Nag, Abhishek; Venturini, Cristina; Sanfilippo, Paul G; Schillert, Arne; Kang, Jae H; Landers, John; Jonasson, Fridbert; Cree, Angela J; van Koolwijk, Leonieke M E; Rivadeneira, Fernando; Souzeau, Emmanuelle; Jonsson, Vesteinn; Menon, Geeta; Weinreb, Robert N; de Jong, Paulus T V M; Oostra, Ben A; Uitterlinden, André G; Hofman, Albert; Ennis, Sarah; Thorsteinsdottir, Unnur; Burdon, Kathryn P; Spector, Timothy D; Mirshahi, Alireza; Saw, Seang-Mei; Vingerling, Johannes R; Teo, Yik-Ying; Haines, Jonathan L; Wolfs, Roger C W; Lemij, Hans G; Tai, E-Shyong; Jansonius, Nomdo M; Jonas, Jost B; Cheng, Ching-Yu; Aung, Tin; Viswanathan, Ananth C; Klaver, Caroline C W; Craig, Jamie E; Macgregor, Stuart; Mackey, David A; Lotery, Andrew J; Stefansson, Kari; Bergen, Arthur A B; Young, Terri L; Wiggs, Janey L; Pfeiffer, Norbert; Wong, Tien-Yin; Pasquale, Louis R; Hewitt, Alex W; van Duijn, Cornelia M; Hammond, Christopher J

    2014-09-22

    Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

  15. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process.

    PubMed

    Springelkamp, Henriët; Höhn, René; Mishra, Aniket; Hysi, Pirro G; Khor, Chiea-Chuen; Loomis, Stephanie J; Bailey, Jessica N Cooke; Gibson, Jane; Thorleifsson, Gudmar; Janssen, Sarah F; Luo, Xiaoyan; Ramdas, Wishal D; Vithana, Eranga; Nongpiur, Monisha E; Montgomery, Grant W; Xu, Liang; Mountain, Jenny E; Gharahkhani, Puya; Lu, Yi; Amin, Najaf; Karssen, Lennart C; Sim, Kar-Seng; van Leeuwen, Elisabeth M; Iglesias, Adriana I; Verhoeven, Virginie J M; Hauser, Michael A; Loon, Seng-Chee; Despriet, Dominiek D G; Nag, Abhishek; Venturini, Cristina; Sanfilippo, Paul G; Schillert, Arne; Kang, Jae H; Landers, John; Jonasson, Fridbert; Cree, Angela J; van Koolwijk, Leonieke M E; Rivadeneira, Fernando; Souzeau, Emmanuelle; Jonsson, Vesteinn; Menon, Geeta; Weinreb, Robert N; de Jong, Paulus T V M; Oostra, Ben A; Uitterlinden, André G; Hofman, Albert; Ennis, Sarah; Thorsteinsdottir, Unnur; Burdon, Kathryn P; Spector, Timothy D; Mirshahi, Alireza; Saw, Seang-Mei; Vingerling, Johannes R; Teo, Yik-Ying; Haines, Jonathan L; Wolfs, Roger C W; Lemij, Hans G; Tai, E-Shyong; Jansonius, Nomdo M; Jonas, Jost B; Cheng, Ching-Yu; Aung, Tin; Viswanathan, Ananth C; Klaver, Caroline C W; Craig, Jamie E; Macgregor, Stuart; Mackey, David A; Lotery, Andrew J; Stefansson, Kari; Bergen, Arthur A B; Young, Terri L; Wiggs, Janey L; Pfeiffer, Norbert; Wong, Tien-Yin; Pasquale, Louis R; Hewitt, Alex W; van Duijn, Cornelia M; Hammond, Christopher J

    2014-01-01

    Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition. PMID:25241763

  16. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

    PubMed Central

    Springelkamp, Henriët.; Höhn, René; Mishra, Aniket; Hysi, Pirro G.; Khor, Chiea-Chuen; Loomis, Stephanie J.; Bailey, Jessica N. Cooke; Gibson, Jane; Thorleifsson, Gudmar; Janssen, Sarah F.; Luo, Xiaoyan; Ramdas, Wishal D.; Vithana, Eranga; Nongpiur, Monisha E.; Montgomery, Grant W.; Xu, Liang; Mountain, Jenny E.; Gharahkhani, Puya; Lu, Yi; Amin, Najaf; Karssen, Lennart C.; Sim, Kar-Seng; van Leeuwen, Elisabeth M.; Iglesias, Adriana I.; Verhoeven, Virginie J. M.; Hauser, Michael A.; Loon, Seng-Chee; Despriet, Dominiek D. G.; Nag, Abhishek; Venturini, Cristina; Sanfilippo, Paul G.; Schillert, Arne; Kang, Jae H.; Landers, John; Jonasson, Fridbert; Cree, Angela J.; van Koolwijk, Leonieke M. E.; Rivadeneira, Fernando; Souzeau, Emmanuelle; Jonsson, Vesteinn; Menon, Geeta; Mitchell, Paul; Wang, Jie Jin; Rochtchina, Elena; Attia, John; Scott, Rodney; Holliday, Elizabeth G.; Wong, Tien-Yin; Baird, Paul N.; Xie, Jing; Inouye, Michael; Viswanathan, Ananth; Sim, Xueling; Weinreb, Robert N.; de Jong, Paulus T. V. M.; Oostra, Ben A.; Uitterlinden, André G.; Hofman, Albert; Ennis, Sarah; Thorsteinsdottir, Unnur; Burdon, Kathryn P.; Allingham, R. Rand; Brilliant, Murray H.; Budenz, Donald L.; Cooke Bailey, Jessica N.; Christen, William G.; Fingert, John; Friedman, David S.; Gaasterland, Douglas; Gaasterland, Terry; Haines, Jonathan L.; Hauser, Michael A.; Kang, Jae Hee; Kraft, Peter; Lee, Richard K.; Lichter, Paul R.; Liu, Yutao; Loomis, Stephanie J.; Moroi, Sayoko E.; Pasquale, Louis R.; Pericak-Vance, Margaret A.; Realini, Anthony; Richards, Julia E.; Schuman, Joel S.; Scott, William K.; Singh, Kuldev; Sit, Arthur J.; Vollrath, Douglas; Weinreb, Robert N.; Wiggs, Janey L.; Wollstein, Gadi; Zack, Donald J.; Zhang, Kang; Donnelly (Chair), Peter; Barroso (Deputy Chair), Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew (Chair), Christopher G.; Blackwell, Jenefer M.; Brown, Matthew A.; Corvin, Aiden; Spencer, Chris C. A.; Spector, Timothy D.; Mirshahi, Alireza; Saw, Seang-Mei; Vingerling, Johannes R.; Teo, Yik-Ying; Haines, Jonathan L.; Wolfs, Roger C. W.; Lemij, Hans G.; Tai, E-Shyong; Jansonius, Nomdo M.; Jonas, Jost B.; Cheng, Ching-Yu; Aung, Tin; Viswanathan, Ananth C.; Klaver, Caroline C. W.; Craig, Jamie E.; Macgregor, Stuart; Mackey, David A.; Lotery, Andrew J.; Stefansson, Kari; Bergen, Arthur A. B.; Young, Terri L.; Wiggs, Janey L.; Pfeiffer, Norbert; Wong, Tien-Yin; Pasquale, Louis R.; Hewitt, Alex W.; van Duijn, Cornelia M.; Hammond, Christopher J.

    2014-01-01

    Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition. PMID:25241763

  17. Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.

    PubMed

    Woo, Daniel; Falcone, Guido J; Devan, William J; Brown, W Mark; Biffi, Alessandro; Howard, Timothy D; Anderson, Christopher D; Brouwers, H Bart; Valant, Valerie; Battey, Thomas W K; Radmanesh, Farid; Raffeld, Miriam R; Baedorf-Kassis, Sylvia; Deka, Ranjan; Woo, Jessica G; Martin, Lisa J; Haverbusch, Mary; Moomaw, Charles J; Sun, Guangyun; Broderick, Joseph P; Flaherty, Matthew L; Martini, Sharyl R; Kleindorfer, Dawn O; Kissela, Brett; Comeau, Mary E; Jagiella, Jeremiasz M; Schmidt, Helena; Freudenberger, Paul; Pichler, Alexander; Enzinger, Christian; Hansen, Björn M; Norrving, Bo; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; Elosua, Roberto; Cuadrado-Godia, Elisa; Soriano, Carolina; Roquer, Jaume; Kraft, Peter; Ayres, Alison M; Schwab, Kristin; McCauley, Jacob L; Pera, Joanna; Urbanik, Andrzej; Rost, Natalia S; Goldstein, Joshua N; Viswanathan, Anand; Stögerer, Eva-Maria; Tirschwell, David L; Selim, Magdy; Brown, Devin L; Silliman, Scott L; Worrall, Bradford B; Meschia, James F; Kidwell, Chelsea S; Montaner, Joan; Fernandez-Cadenas, Israel; Delgado, Pilar; Malik, Rainer; Dichgans, Martin; Greenberg, Steven M; Rothwell, Peter M; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Langefeld, Carl D; Rosand, Jonathan

    2014-04-01

    Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. PMID:24656865

  18. Meta-analysis of chemotherapy with irinotecan or oxaliplatin-involved regimen for untreated metastatic advanced colorectal cancer.

    PubMed

    Zhuang, Luhong; Bai, Jianling; Huang, Huaying; Tang, Cuiju; Yang, Jinsong; Zhou, Baoning; Gong, Yongling; Duanmu, Zhong; Chen, Jinfei

    2010-01-01

    A large number of randomized controlled trials involving chemotherapy in the management of advanced colorectal cancer were conducted. 5-FU/LV in combination with irinotecan (IRI) or oxaliplatin (OXA) was used. The aim of the meta-analysis was to compare and evaluate the effectiveness and safety of the two therapeutic approaches for patients with advanced colorectal cancer. A literature search, study selection and assessment, data collection, and analysis were undertaken by two reviewers according to the Cochrane Handbook for Systematic Reviews of Interventions. Randomized controlled trials (RCTs) or quasi-RCTs comparing IRI versus OXA, in combination with 5-FU/LV in the treatment of advanced colorectal cancer were performed. Seven studies involving 2,107 patients met the inclusion criteria. The OXA + 5-FU/LV regimen showed a significant increase in survival by lower hazard ratios (HR) [HR 1.28; 95% CI (1.13-1.45)] and was associated with lower toxicities. The OXA + 5-FU/LV regimen was superior or equal to the IRI + 5-FU/LV regimen in prolonging time to progression and median survival. The IRI + 5-FU/LV regimen resulted in higher hazard ratios in nausea vomiting/emesis and diarrhea [HR 1.99, 95% CI (1.19-3.31); HR 1.83, 95% CI (1.38-2.44)] and lower hazard ratios in paresthesia, sensory neuropathy, and thrombocytopenia [HR 0.09, 95% CI (0.03-0.23); HR 0.04 95% CI (0.01-0.13); HR 0.19 95% CI (0.05-0.64)] than the OXA + 5-FU/LV regimen. Compared with IRI, OXA is more appropriate for the treatment of advanced colorectal cancer when combined with 5-FU/LV. OXA + 5-FU/LV should be considered as the first-line standard of care for advanced CRC patients.

  19. A meta-analysis of combination therapy versus single-agent therapy in anthracycline- and taxane-pretreated metastatic breast cancer: results from nine randomized Phase III trials

    PubMed Central

    Xu, Liang; Wu, Xiaobo; Hu, Chun; Zhang, Zhiying; Zhang, Le; Liang, Shujing; Xu, Yingchun; Zhang, Fengchun

    2016-01-01

    Nowadays, the philosophy of treating metastatic breast cancer (MBC) is slowly evolving. Especially for the anthracycline- and taxane-pretreated MBC patients, no standard therapy exists in this setting. Whether to choose doublet agents or single agent as salvage treatment remains fiercely debated. Thus, we conducted a meta-analysis to resolve this problem. Databases including PubMed, EMBASE, and Cochrane library were searched for Phase III randomized clinical trials (published before August 2015) comparing the efficacy and adverse effects between the combination therapy and single-agent therapy in anthracycline- and taxane-pretreated MBC patients. The primary end point was the overall survival (OS), and the secondary end points were the progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 toxicities. The pooled hazard ratio (HR) and pooled risk ratio (RR) were used to evaluate the efficacy. Analyses were also performed to estimate the side effects and safety of both groups. In all, nine eligible randomized clinical trials were included in this meta-analysis. Improvements were proven in the doublet agents group on OS (HR 0.90, 95% confidence interval [CI] 0.84–0.96, P=0.002), PFS (HR 0.81, 95% CI 0.76–0.88, P<0.001), and ORR (RR 1.72, 95% CI 1.34–2.21, P<0.001). Notably, subgroup analysis failed to favor the targeted agent-based combination in terms of OS (HR 1.08, 95% CI 0.89–1.31, P=0.365), PFS (HR 1.09, 95% CI 0.88–1.35, P=0.433), and ORR (RR 1.60, 95% CI 0.69–3.71, P=0.278) compared with single agent. In addition, although more hematological and gastrointestinal toxicities were observed in the doublet agents group, they were acceptable and manageable. Taken together, when compared with single-agent therapy, doublet agents should be considered a treatment option because of the superior efficacy and the manageable safety profile for the prior anthracycline- and taxane-treated MBC patients. PMID:27445497

  20. Comparison of Short-Course Radiotherapy Versus Long-Course Radiotherapy for Treatment of Metastatic Spinal Cord Compression: A Systematic Review and Meta-Analysis.

    PubMed

    Qu, Song; Meng, Hui-Ling; Liang, Zhong-Guo; Zhu, Xiao-Dong; Li, Ling; Chen, Ling-Xiao; Zhou, Zhi-Rui

    2015-10-01

    In this study, we evaluate the efficacy of short-course radiotherapy (SCRT) versus long-course radiotherapy (LCRT) in the treatment of metastatic spinal cord compression (MSCC).PubMed, EMBASE, and Web of Science were searched up to April 2015. Relevant data were extracted based on inclusion and exclusion criteria. Methodological quality of randomized controlled trial (RCT) was evaluated using modified Jadad scale; non-RCT was evaluated using Newcastle-Ottawa Scale. Meta-analysis was performed using RevMan 5.3 software.Fourteen studies with 2239 patients were included. Results of meta-analysis showed that there were no significant differences between SCRT and long-course radiotherapy LCRT in 6-month overall survival rate (risk ratio [RR] = 0.97, 95% confidence interval [CI] 0.88, 1.07, P = 0.55), 1-year overall survival rate (RR = 0.94, 95% CI 0.85, 1.04, P = 0.22), motor function improvement (RR = 0.96, 95% CI 0.81, 1.13, P = 0.63), no change on motor function (RR = 0.98, 95% CI (0.88, 1.09), P = 0.74], and deterioration on motor function (RR = 0.96, 95% CI 0.71, 1.31, P = 0.78). Compared with SCRT, LCRT significantly increased 6-month local control rate (RR = 0.87, 95% CI 0.80, 0.95, P = 0.002), 1-year local control rate (RR = 0.83, 95% CI 0.71, 0.97, P = 0.02), and 2-year local control rate (RR = 0.83, 95% CI 0.79, 0.87, P < 0.00001).Both LCRT and SCRT provided similar survival rates and functional outcome, but LCRT showed better local control rates than SCRT. However, considering low cost and good patient's compliance, SCRT may be a better choice.

  1. A meta-analysis of combination therapy versus single-agent therapy in anthracycline- and taxane-pretreated metastatic breast cancer: results from nine randomized Phase III trials.

    PubMed

    Xu, Liang; Wu, Xiaobo; Hu, Chun; Zhang, Zhiying; Zhang, Le; Liang, Shujing; Xu, Yingchun; Zhang, Fengchun

    2016-01-01

    Nowadays, the philosophy of treating metastatic breast cancer (MBC) is slowly evolving. Especially for the anthracycline- and taxane-pretreated MBC patients, no standard therapy exists in this setting. Whether to choose doublet agents or single agent as salvage treatment remains fiercely debated. Thus, we conducted a meta-analysis to resolve this problem. Databases including PubMed, EMBASE, and Cochrane library were searched for Phase III randomized clinical trials (published before August 2015) comparing the efficacy and adverse effects between the combination therapy and single-agent therapy in anthracycline- and taxane-pretreated MBC patients. The primary end point was the overall survival (OS), and the secondary end points were the progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 toxicities. The pooled hazard ratio (HR) and pooled risk ratio (RR) were used to evaluate the efficacy. Analyses were also performed to estimate the side effects and safety of both groups. In all, nine eligible randomized clinical trials were included in this meta-analysis. Improvements were proven in the doublet agents group on OS (HR 0.90, 95% confidence interval [CI] 0.84-0.96, P=0.002), PFS (HR 0.81, 95% CI 0.76-0.88, P<0.001), and ORR (RR 1.72, 95% CI 1.34-2.21, P<0.001). Notably, subgroup analysis failed to favor the targeted agent-based combination in terms of OS (HR 1.08, 95% CI 0.89-1.31, P=0.365), PFS (HR 1.09, 95% CI 0.88-1.35, P=0.433), and ORR (RR 1.60, 95% CI 0.69-3.71, P=0.278) compared with single agent. In addition, although more hematological and gastrointestinal toxicities were observed in the doublet agents group, they were acceptable and manageable. Taken together, when compared with single-agent therapy, doublet agents should be considered a treatment option because of the superior efficacy and the manageable safety profile for the prior anthracycline- and taxane-treated MBC patients. PMID:27445497

  2. Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta-analysis of anti-CTLA-4 and anti-PD-1 agents trials.

    PubMed

    Yun, Seongseok; Vincelette, Nicole D; Green, Myke R; Wahner Hendrickson, Andrea E; Abraham, Ivo

    2016-07-01

    Anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) inhibitors have been shown to significantly improve survival in patients with metastatic cutaneous melanoma. However, there was some heterogeneity as well as some variation in the degree of benefit across studies. We reviewed randomized trials and performed a meta-analysis to determine the efficacy and safety of immune checkpoint inhibitors in comparison with conventional regimens. Eligible studies were limited to randomized controlled trials comparing anti-CTLA-4 or anti-PD-1 inhibitors to chemotherapy or vaccination treatment in adult patients with unresectable cutaneous metastatic melanoma. Progression-free survival (PFS) rate at 6 months was 28.5% versus 17.7% (RR: 0.84, 95% CI: 0.76-0.93), overall survival (OS) rate at 1 year was 51.2% versus 38.8% (RR: 0.72, 95% CI: 0.59-0.88), and overall response rate (ORR) at 6 months was 29.6% versus 17.7% (RR: 0.85, 95% CI: 0.76-0.95) favoring immune check point inhibitors over chemotherapies or vaccination. Immune check point inhibitors were associated with more frequent immune-related adverse events at 13.7% versus 2.4% of treated patients (RR: 6.74, 95% CI: 4.65-9.75). Subgroup analyses demonstrated significant PFS (RR: 0.92 vs. 0.74, P < 0.00001) and ORR (RR: 0.95 vs. 0.76, P = 0.0004) improvement with anti-PD-1 treatment compared to anti-CTLA-4 when each of them was compared to control treatments. Collectively, these results demonstrate that immune checkpoint inhibitors have superior outcomes compared to conventional chemotherapies or vaccination, and support the results of recent randomized trials that showed superior outcomes with anti-PD-1 agents over ipilimumab in unresectable metastatic cutaneous melanoma patients. PMID:27167347

  3. Neoadjuvant Bevacizumab plus Chemotherapy versus Chemotherapy Alone to Treat Non-Metastatic Breast Cancer: A Meta-Analysis of Randomised Controlled Trials

    PubMed Central

    Liu, Min-feng; Chen, Lu-jia; Hu, Xiao-lei; Ye, Chang-sheng

    2015-01-01

    Purpose Results from previous randomised controlled trials (RCTs) investigating whether the addition of bevacizumab to neoadjuvant chemotherapy (NAC) could statistically significantly increase the pathological complete response (pCR) and to identify which subgroup would benefit most from such regimens have produced conflicting results. This meta-analysis was designed to assess the efficacy and safety of bevacizumab plus chemotherapy compared with chemotherapy alone in the neoadjuvant setting. Methods A literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane library was performed to identify eligible studies. The primary endpoint of interest was pCR. The secondary endpoints were clinical complete rate (cCR), surgery rate, breast-conserving surgery (BCS) rate, and toxicity. The meta-analysis was performed using Review Manager software version 5.3. Results Nine RCTs matched the selection criteria, yielding a total of 4967 patients (bevacizumab plus chemotherapy: 50.1%, chemotherapy alone: 49.9%). The results of this meta-analysis demonstrated that the addition of bevacizumab to NAC significantly increased the pCR rate (odds ratio [OR] = 1.34 [1.18–1.54]; P < 0.0001) compared with chemotherapy alone. Subgroup analysis showed that the effect of bevacizumab was more pronounced in patients with HER2-negative cancer (OR = 1.34 [1.17–1.54]; P < 0.0001) compared with HER2-positive cancer (OR = 1.69 [0.90–3.20]; P = 0.11). Similarly, in patients with HER2-negative cancer, the effect of bevacizumab was also more pronounced in patients with HR-negative cancer (OR = 1.38 [1.09–1.74]; P = 0.007) compared with HR-positive cancer (OR = 1.36 [0.78–2.35]; P = 0.27). No significant differences were observed between the groups with respect to cCR, surgery rate, or BCS rate. Additionally bevacizumab was associated with a higher incidence of neutropenia, febrile neutropenia, and hand–foot syndrome. Conclusions Higher proportions of patients achieved pCR when

  4. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.

    PubMed

    Liu, Chunyu; Kraja, Aldi T; Smith, Jennifer A; Brody, Jennifer A; Franceschini, Nora; Bis, Joshua C; Rice, Kenneth; Morrison, Alanna C; Lu, Yingchang; Weiss, Stefan; Guo, Xiuqing; Palmas, Walter; Martin, Lisa W; Chen, Yii-Der Ida; Surendran, Praveen; Drenos, Fotios; Cook, James P; Auer, Paul L; Chu, Audrey Y; Giri, Ayush; Zhao, Wei; Jakobsdottir, Johanna; Lin, Li-An; Stafford, Jeanette M; Amin, Najaf; Mei, Hao; Yao, Jie; Voorman, Arend; Larson, Martin G; Grove, Megan L; Smith, Albert V; Hwang, Shih-Jen; Chen, Han; Huan, Tianxiao; Kosova, Gulum; Stitziel, Nathan O; Kathiresan, Sekar; Samani, Nilesh; Schunkert, Heribert; Deloukas, Panos; Li, Man; Fuchsberger, Christian; Pattaro, Cristian; Gorski, Mathias; Kooperberg, Charles; Papanicolaou, George J; Rossouw, Jacques E; Faul, Jessica D; Kardia, Sharon L R; Bouchard, Claude; Raffel, Leslie J; Uitterlinden, André G; Franco, Oscar H; Vasan, Ramachandran S; O'Donnell, Christopher J; Taylor, Kent D; Liu, Kiang; Bottinger, Erwin P; Gottesman, Omri; Daw, E Warwick; Giulianini, Franco; Ganesh, Santhi; Salfati, Elias; Harris, Tamara B; Launer, Lenore J; Dörr, Marcus; Felix, Stephan B; Rettig, Rainer; Völzke, Henry; Kim, Eric; Lee, Wen-Jane; Lee, I-Te; Sheu, Wayne H-H; Tsosie, Krystal S; Edwards, Digna R Velez; Liu, Yongmei; Correa, Adolfo; Weir, David R; Völker, Uwe; Ridker, Paul M; Boerwinkle, Eric; Gudnason, Vilmundur; Reiner, Alexander P; van Duijn, Cornelia M; Borecki, Ingrid B; Edwards, Todd L; Chakravarti, Aravinda; Rotter, Jerome I; Psaty, Bruce M; Loos, Ruth J F; Fornage, Myriam; Ehret, Georg B; Newton-Cheh, Christopher; Levy, Daniel; Chasman, Daniel I

    2016-10-01

    Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

  5. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

    PubMed Central

    Anderson, Carl A.; Boucher, Gabrielle; Lees, Charlie W.; Franke, Andre; D’Amato, Mauro; Taylor, Kent D.; Lee, James C.; Goyette, Philippe; Imielinski, Marcin; Latiano, Anna; Lagacé, Caroline; Scott, Regan; Amininejad, Leila; Bumpstead, Suzannah; Baidoo, Leonard; Baldassano, Robert N.; Barclay, Murray; Bayless, Theodore M.; Brand, Stephan; Büning, Carsten; Colombel, Jean-Frédéric; Denson, Lee A.; De Vos, Martine; Dubinsky, Marla; Edwards, Cathryn; Ellinghaus, David; Fehrmann, Rudolf S.N.; Floyd, James A.B.; Florin, Tim; Franchimont, Denis; Franke, Lude; Georges, Michel; Glas, Jürgen; Glazer, Nicole L.; Guthery, Stephen L.; Haritunians, Talin; Hayward, Nicholas K.; Hugot, Jean-Pierre; Jobin, Gilles; Laukens, Debby; Lawrance, Ian; Lémann, Marc; Levine, Arie; Libioulle, Cecile; Louis, Edouard; McGovern, Dermot P.; Milla, Monica; Montgomery, Grant W.; Morley, Katherine I.; Mowat, Craig; Ng, Aylwin; Newman, William; Ophoff, Roel A; Papi, Laura; Palmieri, Orazio; Peyrin-Biroulet, Laurent; Panés, Julián; Phillips, Anne; Prescott, Natalie J.; Proctor, Deborah D.; Roberts, Rebecca; Russell, Richard; Rutgeerts, Paul; Sanderson, Jeremy; Sans, Miquel; Schumm, Philip; Seibold, Frank; Sharma, Yashoda; Simms, Lisa; Seielstad, Mark; Steinhart, A. Hillary; Targan, Stephan R.; van den Berg, Leonard H.; Vatn, Morten; Verspaget, Hein; Walters, Thomas; Wijmenga, Cisca; Wilson, David C.; Westra, Harm-Jan; Xavier, Ramnik J.; Zhao, Zhen Z.; Ponsioen, Cyriel Y.; Andersen, Vibeke; Torkvist, Leif; Gazouli, Maria; Anagnou, Nicholas P.; Karlsen, Tom H.; Kupcinskas, Limas; Sventoraityte, Jurgita; Mansfield, John C.; Kugathasan, Subra; Silverberg, Mark S.; Halfvarson, Jonas; Rotter, Jerome I.; Mathew, Christopher G.; Griffiths, Anne M.; Gearry, Richard; Ahmad, Tariq; Brant, Steven R.; Chamaillard, Mathias; Satsangi, Jack; Cho, Judy H.; Schreiber, Stefan; Daly, Mark J.; Barrett, Jeffrey C.; Parkes, Miles; Annese, Vito; Hakonarson, Hakon; Radford-Smith, Graham; Duerr, Richard H.; Vermeire, Séverine; Weersma, Rinse K.; Rioux, John D.

    2011-01-01

    Genome-wide association studies (GWAS) and candidate gene studies in ulcerative colitis (UC) have identified 18 susceptibility loci. We conducted a meta-analysis of 6 UC GWAS, comprising 6,687 cases and 19,718 controls, and followed-up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P<5×10-8), increasing the number of UC associated loci to 47. After annotating associated regions using GRAIL, eQTL data and correlations with non-synonymous SNPs, we identified many candidate genes providing potentially important insights into disease pathogenesis, including IL1R2, IL8RA/B, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease (IBD) risk loci is now 99, including a minimum of 28 shared association signals between Crohn’s disease (CD) and UC. PMID:21297633

  6. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

    PubMed Central

    Elks, Cathy E.; Perry, John R.B.; Sulem, Patrick; Chasman, Daniel I.; Franceschini, Nora; He, Chunyan; Lunetta, Kathryn L.; Visser, Jenny A.; Byrne, Enda M.; Cousminer, Diana L.; Gudbjartsson, Daniel F.; Esko, Tõnu; Feenstra, Bjarke; Hottenga, Jouke-Jan; Koller, Daniel L.; Kutalik, Zoltán; Lin, Peng; Mangino, Massimo; Marongiu, Mara; McArdle, Patrick F.; Smith, Albert V.; Stolk, Lisette; van Wingerden, Sophie W.; Zhao, Jing Hua; Albrecht, Eva; Corre, Tanguy; Ingelsson, Erik; Hayward, Caroline; Magnusson, Patrik K.E.; Smith, Erin N.; Ulivi, Shelia; Warrington, Nicole M.; Zgaga, Lina; Alavere, Helen; Amin, Najaf; Aspelund, Thor; Bandinelli, Stefania; Barroso, Ines; Berenson, Gerald S.; Bergmann, Sven; Blackburn, Hannah; Boerwinkle, Eric; Buring, Julie E.; Busonero, Fabio; Campbell, Harry; Chanock, Stephen J.; Chen, Wei; Cornelis, Marilyn C.; Couper, David; Coviello, Andrea D.; d’Adamo, Pio; de Faire, Ulf; de Geus, Eco J.C.; Deloukas, Panos; Döring, Angela; Smith, George Davey; Easton, Douglas F.; Eiriksdottir, Gudny; Emilsson, Valur; Eriksson, Johan; Ferrucci, Luigi; Folsom, Aaron R.; Foroud, Tatiana; Garcia, Melissa; Gasparini, Paolo; Geller, Frank; Gieger, Christian; Gudnason, Vilmundur; Hall, Per; Hankinson, Susan E.; Ferreli, Liana; Heath, Andrew C.; Hernandez, Dena G.; Hofman, Albert; Hu, Frank B.; Illig, Thomas; Järvelin, Marjo-Riitta; Johnson, Andrew D.; Karasik, David; Khaw, Kay-Tee; Kiel, Douglas P.; Kilpeläinen, Tuomas O.; Kolcic, Ivana; Kraft, Peter; Launer, Lenore J.; Laven, Joop S.E.; Li, Shengxu; Liu, Jianjun; Levy, Daniel; Martin, Nicholas G.; McArdle, Wendy L.; Melbye, Mads; Mooser, Vincent; Murray, Jeffrey C.; Murray, Sarah S.; Nalls, Michael A.; Navarro, Pau; Nelis, Mari; Ness, Andrew R.; Northstone, Kate; Oostra, Ben A.; Peacock, Munro; Palmer, Lyle J.; Palotie, Aarno; Paré, Guillaume; Parker, Alex N.; Pedersen, Nancy L.; Peltonen, Leena; Pennell, Craig E.; Pharoah, Paul; Polasek, Ozren; Plump, Andrew S.; Pouta, Anneli; Porcu, Eleonora; Rafnar, Thorunn; Rice, John P.; Ring, Susan M.; Rivadeneira, Fernando; Rudan, Igor; Sala, Cinzia; Salomaa, Veikko; Sanna, Serena; Schlessinger, David; Schork, Nicholas J.; Scuteri, Angelo; Segrè, Ayellet V.; Shuldiner, Alan R.; Soranzo, Nicole; Sovio, Ulla; Srinivasan, Sathanur R.; Strachan, David P.; Tammesoo, Mar-Liis; Tikkanen, Emmi; Toniolo, Daniela; Tsui, Kim; Tryggvadottir, Laufey; Tyrer, Jonathon; Uda, Manuela; van Dam, Rob M.; van Meurs, Joyve B.J.; Vollenweider, Peter; Waeber, Gerard; Wareham, Nicholas J.; Waterworth, Dawn M.; Weedon, Michael N.; Wichmann, H. Erich; Willemsen, Gonneke; Wilson, James F.; Wright, Alan F.; Young, Lauren; Zhai, Guangju; Zhuang, Wei Vivian; Bierut, Laura J.; Boomsma, Dorret I.; Boyd, Heather A.; Crisponi, Laura; Demerath, Ellen W.; van Duijn, Cornelia M.; Econs, Michael J.; Harris, Tamara B.; Hunter, David J.; Loos, Ruth J.F.; Metspalu, Andres; Montgomery, Grant W.; Ridker, Paul M.; Spector, Tim D.; Streeten, Elizabeth A.; Stefansson, Kari; Thorsteinsdottir, Unnur; Uitterlinden, André G.; Widen, Elisabeth; Murabito, Joanne M.; Ong, Ken K.; Murray, Anna

    2011-01-01

    To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P=5.4×10−60) and 9q31.2 (P=2.2×10−33), we identified 30 novel menarche loci (all P<5×10−8) and found suggestive evidence for a further 10 loci (P<1.9×10−6). New loci included four previously associated with BMI (in/near FTO, SEC16B, TRA2B and TMEM18), three in/near other genes implicated in energy homeostasis (BSX, CRTC1, and MCHR2), and three in/near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and MAGENTA pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing. PMID:21102462

  7. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.

    PubMed

    Liu, Chunyu; Kraja, Aldi T; Smith, Jennifer A; Brody, Jennifer A; Franceschini, Nora; Bis, Joshua C; Rice, Kenneth; Morrison, Alanna C; Lu, Yingchang; Weiss, Stefan; Guo, Xiuqing; Palmas, Walter; Martin, Lisa W; Chen, Yii-Der Ida; Surendran, Praveen; Drenos, Fotios; Cook, James P; Auer, Paul L; Chu, Audrey Y; Giri, Ayush; Zhao, Wei; Jakobsdottir, Johanna; Lin, Li-An; Stafford, Jeanette M; Amin, Najaf; Mei, Hao; Yao, Jie; Voorman, Arend; Larson, Martin G; Grove, Megan L; Smith, Albert V; Hwang, Shih-Jen; Chen, Han; Huan, Tianxiao; Kosova, Gulum; Stitziel, Nathan O; Kathiresan, Sekar; Samani, Nilesh; Schunkert, Heribert; Deloukas, Panos; Li, Man; Fuchsberger, Christian; Pattaro, Cristian; Gorski, Mathias; Kooperberg, Charles; Papanicolaou, George J; Rossouw, Jacques E; Faul, Jessica D; Kardia, Sharon L R; Bouchard, Claude; Raffel, Leslie J; Uitterlinden, André G; Franco, Oscar H; Vasan, Ramachandran S; O'Donnell, Christopher J; Taylor, Kent D; Liu, Kiang; Bottinger, Erwin P; Gottesman, Omri; Daw, E Warwick; Giulianini, Franco; Ganesh, Santhi; Salfati, Elias; Harris, Tamara B; Launer, Lenore J; Dörr, Marcus; Felix, Stephan B; Rettig, Rainer; Völzke, Henry; Kim, Eric; Lee, Wen-Jane; Lee, I-Te; Sheu, Wayne H-H; Tsosie, Krystal S; Edwards, Digna R Velez; Liu, Yongmei; Correa, Adolfo; Weir, David R; Völker, Uwe; Ridker, Paul M; Boerwinkle, Eric; Gudnason, Vilmundur; Reiner, Alexander P; van Duijn, Cornelia M; Borecki, Ingrid B; Edwards, Todd L; Chakravarti, Aravinda; Rotter, Jerome I; Psaty, Bruce M; Loos, Ruth J F; Fornage, Myriam; Ehret, Georg B; Newton-Cheh, Christopher; Levy, Daniel; Chasman, Daniel I

    2016-10-01

    Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk. PMID:27618448

  8. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.

    PubMed

    Nalls, Mike A; Pankratz, Nathan; Lill, Christina M; Do, Chuong B; Hernandez, Dena G; Saad, Mohamad; DeStefano, Anita L; Kara, Eleanna; Bras, Jose; Sharma, Manu; Schulte, Claudia; Keller, Margaux F; Arepalli, Sampath; Letson, Christopher; Edsall, Connor; Stefansson, Hreinn; Liu, Xinmin; Pliner, Hannah; Lee, Joseph H; Cheng, Rong; Ikram, M Arfan; Ioannidis, John P A; Hadjigeorgiou, Georgios M; Bis, Joshua C; Martinez, Maria; Perlmutter, Joel S; Goate, Alison; Marder, Karen; Fiske, Brian; Sutherland, Margaret; Xiromerisiou, Georgia; Myers, Richard H; Clark, Lorraine N; Stefansson, Kari; Hardy, John A; Heutink, Peter; Chen, Honglei; Wood, Nicholas W; Houlden, Henry; Payami, Haydeh; Brice, Alexis; Scott, William K; Gasser, Thomas; Bertram, Lars; Eriksson, Nicholas; Foroud, Tatiana; Singleton, Andrew B

    2014-09-01

    We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

  9. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.

    PubMed

    Nalls, Mike A; Pankratz, Nathan; Lill, Christina M; Do, Chuong B; Hernandez, Dena G; Saad, Mohamad; DeStefano, Anita L; Kara, Eleanna; Bras, Jose; Sharma, Manu; Schulte, Claudia; Keller, Margaux F; Arepalli, Sampath; Letson, Christopher; Edsall, Connor; Stefansson, Hreinn; Liu, Xinmin; Pliner, Hannah; Lee, Joseph H; Cheng, Rong; Ikram, M Arfan; Ioannidis, John P A; Hadjigeorgiou, Georgios M; Bis, Joshua C; Martinez, Maria; Perlmutter, Joel S; Goate, Alison; Marder, Karen; Fiske, Brian; Sutherland, Margaret; Xiromerisiou, Georgia; Myers, Richard H; Clark, Lorraine N; Stefansson, Kari; Hardy, John A; Heutink, Peter; Chen, Honglei; Wood, Nicholas W; Houlden, Henry; Payami, Haydeh; Brice, Alexis; Scott, William K; Gasser, Thomas; Bertram, Lars; Eriksson, Nicholas; Foroud, Tatiana; Singleton, Andrew B

    2014-09-01

    We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation. PMID:25064009

  10. Meta-analysis of Genome-wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage

    PubMed Central

    Woo, Daniel; Falcone, Guido J.; Devan, William J.; Brown, W. Mark; Biffi, Alessandro; Howard, Timothy D.; Anderson, Christopher D.; Brouwers, H. Bart; Valant, Valerie; Battey, Thomas W.K.; Radmanesh, Farid; Raffeld, Miriam R.; Baedorf-Kassis, Sylvia; Deka, Ranjan; Woo, Jessica G.; Martin, Lisa J.; Haverbusch, Mary; Moomaw, Charles J.; Sun, Guangyun; Broderick, Joseph P.; Flaherty, Matthew L.; Martini, Sharyl R.; Kleindorfer, Dawn O.; Kissela, Brett; Comeau, Mary E.; Jagiella, Jeremiasz M.; Schmidt, Helena; Freudenberger, Paul; Pichler, Alexander; Enzinger, Christian; Hansen, Björn M.; Norrving, Bo; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; Elosua, Roberto; Cuadrado-Godia, Elisa; Soriano, Carolina; Roquer, Jaume; Kraft, Peter; Ayres, Alison M.; Schwab, Kristin; McCauley, Jacob L.; Pera, Joanna; Urbanik, Andrzej; Rost, Natalia S.; Goldstein, Joshua N.; Viswanathan, Anand; Stögerer, Eva-Maria; Tirschwell, David L.; Selim, Magdy; Brown, Devin L.; Silliman, Scott L.; Worrall, Bradford B.; Meschia, James F.; Kidwell, Chelsea S.; Montaner, Joan; Fernandez-Cadenas, Israel; Delgado, Pilar; Malik, Rainer; Dichgans, Martin; Greenberg, Steven M.; Rothwell, Peter M.; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Langefeld, Carl D.; Rosand, Jonathan

    2014-01-01

    Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10−6 was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10−8); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10−8). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10−4; meta-analysis p = 2.2 × 10−10) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10−5). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly. PMID:24656865

  11. Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.

    PubMed

    Corvol, Harriet; Blackman, Scott M; Boëlle, Pierre-Yves; Gallins, Paul J; Pace, Rhonda G; Stonebraker, Jaclyn R; Accurso, Frank J; Clement, Annick; Collaco, Joseph M; Dang, Hong; Dang, Anthony T; Franca, Arianna; Gong, Jiafen; Guillot, Loic; Keenan, Katherine; Li, Weili; Lin, Fan; Patrone, Michael V; Raraigh, Karen S; Sun, Lei; Zhou, Yi-Hui; O'Neal, Wanda K; Sontag, Marci K; Levy, Hara; Durie, Peter R; Rommens, Johanna M; Drumm, Mitchell L; Wright, Fred A; Strug, Lisa J; Cutting, Garry R; Knowles, Michael R

    2015-09-29

    The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10(-11)), chr5p15.3 (SLC9A3; P=6.8 × 10(-12)), chr6p21.3 (HLA Class II; P=1.2 × 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.

  12. A Meta-Analysis Identifies New Loci Associated with Body Mass index in Individuals of African Ancestry

    PubMed Central

    Monda, Keri L.; Chen, Gary K.; Taylor, Kira C.; Palmer, Cameron; Edwards, Todd L.; Lange, Leslie A.; Ng, Maggie C.Y.; Adeyemo, Adebowale A.; Allison, Matthew A.; Bielak, Lawrence F.; Chen, Guanji; Graff, Mariaelisa; Irvin, Marguerite R.; Rhie, Suhn K.; Li, Guo; Liu, Yongmei; Liu, Youfang; Lu, Yingchang; Nalls, Michael A.; Sun, Yan V.; Wojczynski, Mary K.; Yanek, Lisa R.; Aldrich, Melinda C.; Ademola, Adeyinka; Amos, Christopher I.; Bandera, Elisa V.; Bock, Cathryn H.; Britton, Angela; Broeckel, Ulrich; Cai, Quiyin; Caporaso, Neil E.; Carlson, Chris; Carpten, John; Casey, Graham; Chen, Wei-Min; Chen, Fang; Chen, Yii-Der I.; Chiang, Charleston W.K.; Coetzee, Gerhard A.; Demerath, Ellen; Deming-Halverson, Sandra L.; Driver, Ryan W.; Dubbert, Patricia; Feitosa, Mary F.; Freedman, Barry I.; Gillanders, Elizabeth M.; Gottesman, Omri; Guo, Xiuqing; Haritunians, Talin; Harris, Tamara; Harris, Curtis C.; Hennis, Anselm JM; Hernandez, Dena G.; McNeill, Lorna H.; Howard, Timothy D.; Howard, Barbara V.; Howard, Virginia J.; Johnson, Karen C.; Kang, Sun J.; Keating, Brendan J.; Kolb, Suzanne; Kuller, Lewis H.; Kutlar, Abdullah; Langefeld, Carl D.; Lettre, Guillaume; Lohman, Kurt; Lotay, Vaneet; Lyon, Helen; Manson, JoAnn E.; Maixner, William; Meng, Yan A.; Monroe, Kristine R.; Morhason-Bello, Imran; Murphy, Adam B.; Mychaleckyj, Josyf C.; Nadukuru, Rajiv; Nathanson, Katherine L.; Nayak, Uma; N’Diaye, Amidou; Nemesure, Barbara; Wu, Suh-Yuh; Leske, M. Cristina; Neslund-Dudas, Christine; Neuhouser, Marian; Nyante, Sarah; Ochs-Balcom, Heather; Ogunniyi, Adesola; Ogundiran, Temidayo O.; Ojengbede, Oladosu; Olopade, Olufunmilayo I.; Palmer, Julie R.; Ruiz-Narvaez, Edward A.; Palmer, Nicholette D.; Press, Michael F.; Rampersaud, Evandine; Rasmussen-Torvik, Laura J.; Rodriguez-Gil, Jorge L.; Salako, Babatunde; Schadt, Eric E.; Schwartz, Ann G.; Shriner, Daniel A.; Siscovick, David; Smith, Shad B.; Wassertheil-Smoller, Sylvia; Speliotes, Elizabeth K.; Spitz, Margaret R.; Sucheston, Lara; Taylor, Herman; Tayo, Bamidele O.; Tucker, Margaret A.; Van Den Berg, David J.; Velez Edwards, Digna R.; Wang, Zhaoming; Wiencke, John K.; Winkler, Thomas W.; Witte, John S.; Wrensch, Margaret; Wu, Xifeng; Yang, James J.; Levin, Albert M.; Young, Taylor R.; Zakai, Neil A.; Cushman, Mary; Zanetti, Krista A.; Zhao, Jing Hua; Zhao, Wei; Zheng, Yonglan; Zhou, Jie; Ziegler, Regina G.; Zmuda, Joseph M.; Fernandes, Jyotika K.; Gilkeson, Gary S.; Kamen, Diane L.; Hunt, Kelly J.; Spruill, Ida J.; Ambrosone, Christine B.; Ambs, Stefan; Arnett, Donna K.; Atwood, Larry; Becker, Diane M.; Berndt, Sonja I.; Bernstein, Leslie; Blot, William J.; Borecki, Ingrid B.; Bottinger, Erwin P.; Bowden, Donald W.; Burke, Gregory; Chanock, Stephen J.; Cooper, Richard S.; Ding, Jingzhong; Duggan, David; Evans, Michele K.; Fox, Caroline; Garvey, W. Timothy; Bradfield, Jonathan P.; Hakonarson, Hakon; Grant, Struan F.A.; Hsing, Ann; Chu, Lisa; Hu, Jennifer J.; Huo, Dezheng; Ingles, Sue A.; John, Esther M.; Jordan, Joanne M.; Kabagambe, Edmond K.; Kardia, Sharon L.R.; Kittles, Rick A.; Goodman, Phyllis J.; Klein, Eric A.; Kolonel, Laurence N.; Le Marchand, Loic; Liu, Simin; McKnight, Barbara; Millikan, Robert C.; Mosley, Thomas H.; Padhukasahasram, Badri; Williams, L. Keoki; Patel, Sanjay R.; Peters, Ulrike; Pettaway, Curtis A.; Peyser, Patricia A.; Psaty, Bruce M.; Redline, Susan; Rotimi, Charles N.; Rybicki, Benjamin A.; Sale, Michèle M.; Schreiner, Pamela J.; Signorello, Lisa B.; Singleton, Andrew B.; Stanford, Janet L.; Strom, Sara S.; Thun, Michael J.; Vitolins, Mara; Zheng, Wei; Moore, Jason H.; Williams, Scott M.; Zhu, Xiaofeng; Zonderman, Alan B.; Kooperberg, Charles; Papanicolaou, George; Henderson, Brian E.; Reiner, Alex P.; Hirschhorn, Joel N.; Loos, Ruth JF; North, Kari E.; Haiman, Christopher A.

    2013-01-01

    Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations. PMID:23583978

  13. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.

    PubMed

    Cho, Yoon Shin; Chen, Chien-Hsiun; Hu, Cheng; Long, Jirong; Ong, Rick Twee Hee; Sim, Xueling; Takeuchi, Fumihiko; Wu, Ying; Go, Min Jin; Yamauchi, Toshimasa; Chang, Yi-Cheng; Kwak, Soo Heon; Ma, Ronald C W; Yamamoto, Ken; Adair, Linda S; Aung, Tin; Cai, Qiuyin; Chang, Li-Ching; Chen, Yuan-Tsong; Gao, Yutang; Hu, Frank B; Kim, Hyung-Lae; Kim, Sangsoo; Kim, Young Jin; Lee, Jeannette Jen-Mai; Lee, Nanette R; Li, Yun; Liu, Jian Jun; Lu, Wei; Nakamura, Jiro; Nakashima, Eitaro; Ng, Daniel Peng-Keat; Tay, Wan Ting; Tsai, Fuu-Jen; Wong, Tien Yin; Yokota, Mitsuhiro; Zheng, Wei; Zhang, Rong; Wang, Congrong; So, Wing Yee; Ohnaka, Keizo; Ikegami, Hiroshi; Hara, Kazuo; Cho, Young Min; Cho, Nam H; Chang, Tien-Jyun; Bao, Yuqian; Hedman, Åsa K; Morris, Andrew P; McCarthy, Mark I; Takayanagi, Ryoichi; Park, Kyong Soo; Jia, Weiping; Chuang, Lee-Ming; Chan, Juliana C N; Maeda, Shiro; Kadowaki, Takashi; Lee, Jong-Young; Wu, Jer-Yuarn; Teo, Yik Ying; Tai, E Shyong; Shu, Xiao Ou; Mohlke, Karen L; Kato, Norihiro; Han, Bok-Ghee; Seielstad, Mark

    2012-01-01

    We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D. PMID:22158537

  14. Genome-Wide Meta-Analysis of Cotinine Levels in Cigarette Smokers Identifies Locus at 4q13.2

    PubMed Central

    Ware, Jennifer J.; Chen, Xiangning; Vink, Jacqueline; Loukola, Anu; Minica, Camelia; Pool, Rene; Milaneschi, Yuri; Mangino, Massimo; Menni, Cristina; Chen, Jingchun; Peterson, Roseann E.; Auro, Kirsi; Lyytikäinen, Leo-Pekka; Wedenoja, Juho; Stiby, Alexander I.; Hemani, Gibran; Willemsen, Gonneke; Hottenga, Jouke Jan; Korhonen, Tellervo; Heliövaara, Markku; Perola, Markus; Rose, Richard J.; Paternoster, Lavinia; Timpson, Nic; Wassenaar, Catherine A.; Zhu, Andy Z. X.; Davey Smith, George; T. Raitakari, Olli; Lehtimäki, Terho; Kähönen, Mika; Koskinen, Seppo; Spector, Timothy; Penninx, Brenda W. J. H.; Salomaa, Veikko; Boomsma, Dorret I.; Tyndale, Rachel F.; Kaprio, Jaakko; Munafò, Marcus R.

    2016-01-01

    Genome-wide association studies (GWAS) of complex behavioural phenotypes such as cigarette smoking typically employ self-report phenotypes. However, precise biomarker phenotypes may afford greater statistical power and identify novel variants. Here we report the results of a GWAS meta-analysis of levels of cotinine, the primary metabolite of nicotine, in 4,548 daily smokers of European ancestry. We identified a locus close to UGT2B10 at 4q13.2 (minimum p = 5.89 × 10−10 for rs114612145), which was consequently replicated. This variant is in high linkage disequilibrium with a known functional variant in the UGT2B10 gene which is associated with reduced nicotine and cotinine glucuronidation activity, but intriguingly is not associated with nicotine intake. Additionally, we observed association between multiple variants within the 15q25.1 region and cotinine levels, all located within the CHRNA5-A3-B4 gene cluster or adjacent genes, consistent with previous much larger GWAS using self-report measures of smoking quantity. These results clearly illustrate the increase in power afforded by using precise biomarker measures in GWAS. Perhaps more importantly however, they also highlight that biomarkers do not always mark the phenotype of interest. The use of metabolite data as a proxy for environmental exposures should be carefully considered in the context of individual differences in metabolic pathways. PMID:26833182

  15. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

    PubMed Central

    Springelkamp, Henriët; Mishra, Aniket; Hysi, Pirro G.; Gharahkhani, Puya; Höhn, René; Khor, Chiea-Chuen; Cooke Bailey, Jessica N.; Luo, Xiaoyan; Ramdas, Wishal D.; Vithana, Eranga; Koh, Victor; Yazar, Seyhan; Xu, Liang; Forward, Hannah; Kearns, Lisa S.; Amin, Najaf; Iglesias, Adriana I.; Sim, Kar-Seng; van Leeuwen, Elisabeth M.; Demirkan, Ayse; van der Lee, Sven; Loon, Seng-Chee; Rivadeneira, Fernando; Nag, Abhishek; Sanfilippo, Paul G.; Schillert, Arne; de Jong, Paulus T. V. M.; Oostra, Ben A.; Uitterlinden, André G.; Hofman, Albert; Zhou, Tiger; Burdon, Kathryn P.; Spector, Timothy D.; Lackner, Karl J.; Saw, Seang-Mei; Vingerling, Johannes R.; Teo, Yik-Ying; Pasquale, Louis R.; Wolfs, Roger C. W.; Lemij, Hans G.; Tai, E-Shyong; Jonas, Jost B.; Cheng, Ching-Yu; Aung, Tin; Jansonius, Nomdo M.; Klaver, Caroline C. W.; Craig, Jamie E.; Young, Terri L.; Haines, Jonathan L.; MacGregor, Stuart; Mackey, David A.; Pfeiffer, Norbert; Wong, Tien-Yin; Wiggs, Janey L.; Hewitt, Alex W.; van Duijn, Cornelia M.; Hammond, Christopher J.

    2015-01-01

    Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma. PMID:25631615

  16. A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.

    PubMed

    Monda, Keri L; Chen, Gary K; Taylor, Kira C; Palmer, Cameron; Edwards, Todd L; Lange, Leslie A; Ng, Maggie C Y; Adeyemo, Adebowale A; Allison, Matthew A; Bielak, Lawrence F; Chen, Guanjie; Graff, Mariaelisa; Irvin, Marguerite R; Rhie, Suhn K; Li, Guo; Liu, Yongmei; Liu, Youfang; Lu, Yingchang; Nalls, Michael A; Sun, Yan V; Wojczynski, Mary K; Yanek, Lisa R; Aldrich, Melinda C; Ademola, Adeyinka; Amos, Christopher I; Bandera, Elisa V; Bock, Cathryn H; Britton, Angela; Broeckel, Ulrich; Cai, Quiyin; Caporaso, Neil E; Carlson, Chris S; Carpten, John; Casey, Graham; Chen, Wei-Min; Chen, Fang; Chen, Yii-Der I; Chiang, Charleston W K; Coetzee, Gerhard A; Demerath, Ellen; Deming-Halverson, Sandra L; Driver, Ryan W; Dubbert, Patricia; Feitosa, Mary F; Feng, Ye; Freedman, Barry I; Gillanders, Elizabeth M; Gottesman, Omri; Guo, Xiuqing; Haritunians, Talin; Harris, Tamara; Harris, Curtis C; Hennis, Anselm J M; Hernandez, Dena G; McNeill, Lorna H; Howard, Timothy D; Howard, Barbara V; Howard, Virginia J; Johnson, Karen C; Kang, Sun J; Keating, Brendan J; Kolb, Suzanne; Kuller, Lewis H; Kutlar, Abdullah; Langefeld, Carl D; Lettre, Guillaume; Lohman, Kurt; Lotay, Vaneet; Lyon, Helen; Manson, Joann E; Maixner, William; Meng, Yan A; Monroe, Kristine R; Morhason-Bello, Imran; Murphy, Adam B; Mychaleckyj, Josyf C; Nadukuru, Rajiv; Nathanson, Katherine L; Nayak, Uma; N'diaye, Amidou; Nemesure, Barbara; Wu, Suh-Yuh; Leske, M Cristina; Neslund-Dudas, Christine; Neuhouser, Marian; Nyante, Sarah; Ochs-Balcom, Heather; Ogunniyi, Adesola; Ogundiran, Temidayo O; Ojengbede, Oladosu; Olopade, Olufunmilayo I; Palmer, Julie R; Ruiz-Narvaez, Edward A; Palmer, Nicholette D; Press, Michael F; Rampersaud, Evandine; Rasmussen-Torvik, Laura J; Rodriguez-Gil, Jorge L; Salako, Babatunde; Schadt, Eric E; Schwartz, Ann G; Shriner, Daniel A; Siscovick, David; Smith, Shad B; Wassertheil-Smoller, Sylvia; Speliotes, Elizabeth K; Spitz, Margaret R; Sucheston, Lara; Taylor, Herman; Tayo, Bamidele O; Tucker, Margaret A; Van Den Berg, David J; Edwards, Digna R Velez; Wang, Zhaoming; Wiencke, John K; Winkler, Thomas W; Witte, John S; Wrensch, Margaret; Wu, Xifeng; Yang, James J; Levin, Albert M; Young, Taylor R; Zakai, Neil A; Cushman, Mary; Zanetti, Krista A; Zhao, Jing Hua; Zhao, Wei; Zheng, Yonglan; Zhou, Jie; Ziegler, Regina G; Zmuda, Joseph M; Fernandes, Jyotika K; Gilkeson, Gary S; Kamen, Diane L; Hunt, Kelly J; Spruill, Ida J; Ambrosone, Christine B; Ambs, Stefan; Arnett, Donna K; Atwood, Larry; Becker, Diane M; Berndt, Sonja I; Bernstein, Leslie; Blot, William J; Borecki, Ingrid B; Bottinger, Erwin P; Bowden, Donald W; Burke, Gregory; Chanock, Stephen J; Cooper, Richard S; Ding, Jingzhong; Duggan, David; Evans, Michele K; Fox, Caroline; Garvey, W Timothy; Bradfield, Jonathan P; Hakonarson, Hakon; Grant, Struan F A; Hsing, Ann; Chu, Lisa; Hu, Jennifer J; Huo, Dezheng; Ingles, Sue A; John, Esther M; Jordan, Joanne M; Kabagambe, Edmond K; Kardia, Sharon L R; Kittles, Rick A; Goodman, Phyllis J; Klein, Eric A; Kolonel, Laurence N; Le Marchand, Loic; Liu, Simin; McKnight, Barbara; Millikan, Robert C; Mosley, Thomas H; Padhukasahasram, Badri; Williams, L Keoki; Patel, Sanjay R; Peters, Ulrike; Pettaway, Curtis A; Peyser, Patricia A; Psaty, Bruce M; Redline, Susan; Rotimi, Charles N; Rybicki, Benjamin A; Sale, Michèle M; Schreiner, Pamela J; Signorello, Lisa B; Singleton, Andrew B; Stanford, Janet L; Strom, Sara S; Thun, Michael J; Vitolins, Mara; Zheng, Wei; Moore, Jason H; Williams, Scott M; Ketkar, Shamika; Zhu, Xiaofeng; Zonderman, Alan B; Kooperberg, Charles; Papanicolaou, George J; Henderson, Brian E; Reiner, Alex P; Hirschhorn, Joel N; Loos, Ruth J F; North, Kari E; Haiman, Christopher A

    2013-06-01

    Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

  17. Prognostic Value of EMT-inducing Transcription Factors (EMT-TFs) in Metastatic Breast Cancer: A Systematic Review and Meta-analysis.

    PubMed

    Imani, Saber; Hosseinifard, Hossein; Cheng, Jingliang; Wei, Chunli; Fu, Junjiang

    2016-06-23

    The epithelial-to-mesenchymal transition (EMT) is a vital control point in metastatic breast cancer (MBC). TWIST1, SNAIL1, SLUG, and ZEB1, as key EMT-inducing transcription factors (EMT-TFs), are involved in MBC through different signaling cascades. This updated meta-analysis was conducted to assess the correlation between the expression of EMT-TFs and prognostic value in MBC patients. A total of 3,218 MBC patients from fourteen eligible studies were evaluated. The pooled hazard ratios (HR) for EMT-TFs suggested that high EMT-TF expression was significantly associated with poor prognosis in MBC patients (HRs = 1.72; 95% confidence intervals (CIs) = 1.53-1.93; P = 0.001). In addition, the overexpression of SLUG was the most impactful on the risk of MBC compared with TWIST1 and SNAIL1, which sponsored fixed models. Strikingly, the increased risk of MBC was less associated with ZEB1 expression. However, the EMT-TF expression levels significantly increased the risk of MBC in the Asian population (HR = 2.11, 95% CI = 1.70-2.62) without any publication bias (t = 1.70, P = 0.11). These findings suggest that the overexpression of potentially TWIST1, SNAIL1 and especially SLUG play a key role in the aggregation of MBC treatment as well as in the improvement of follow-up plans in Asian MBC patients.

  18. Prognostic Value of EMT-inducing Transcription Factors (EMT-TFs) in Metastatic Breast Cancer: A Systematic Review and Meta-analysis

    PubMed Central

    Imani, Saber; Hosseinifard, Hossein; Cheng, Jingliang; Wei, Chunli; Fu, Junjiang

    2016-01-01

    The epithelial-to-mesenchymal transition (EMT) is a vital control point in metastatic breast cancer (MBC). TWIST1, SNAIL1, SLUG, and ZEB1, as key EMT-inducing transcription factors (EMT-TFs), are involved in MBC through different signaling cascades. This updated meta-analysis was conducted to assess the correlation between the expression of EMT-TFs and prognostic value in MBC patients. A total of 3,218 MBC patients from fourteen eligible studies were evaluated. The pooled hazard ratios (HR) for EMT-TFs suggested that high EMT-TF expression was significantly associated with poor prognosis in MBC patients (HRs = 1.72; 95% confidence intervals (CIs) = 1.53–1.93; P = 0.001). In addition, the overexpression of SLUG was the most impactful on the risk of MBC compared with TWIST1 and SNAIL1, which sponsored fixed models. Strikingly, the increased risk of MBC was less associated with ZEB1 expression. However, the EMT-TF expression levels significantly increased the risk of MBC in the Asian population (HR = 2.11, 95% CI = 1.70–2.62) without any publication bias (t = 1.70, P = 0.11). These findings suggest that the overexpression of potentially TWIST1, SNAIL1 and especially SLUG play a key role in the aggregation of MBC treatment as well as in the improvement of follow-up plans in Asian MBC patients. PMID:27335258

  19. A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer.

    PubMed

    Al-Tassan, Nada A; Whiffin, Nicola; Hosking, Fay J; Palles, Claire; Farrington, Susan M; Dobbins, Sara E; Harris, Rebecca; Gorman, Maggie; Tenesa, Albert; Meyer, Brian F; Wakil, Salma M; Kinnersley, Ben; Campbell, Harry; Martin, Lynn; Smith, Christopher G; Idziaszczyk, Shelley; Barclay, Ella; Maughan, Timothy S; Kaplan, Richard; Kerr, Rachel; Kerr, David; Buchanan, Daniel D; Buchannan, Daniel D; Win, Aung Ko; Hopper, John; Jenkins, Mark; Lindor, Noralane M; Newcomb, Polly A; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Dunlop, Malcolm G; Tomlinson, Ian P; Cheadle, Jeremy P; Houlston, Richard S

    2015-01-01

    Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants. PMID:25990418

  20. A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer

    PubMed Central

    Al-Tassan, Nada A.; Whiffin, Nicola; Hosking, Fay J.; Palles, Claire; Farrington, Susan M.; Dobbins, Sara E.; Harris, Rebecca; Gorman, Maggie; Tenesa, Albert; Meyer, Brian F.; Wakil, Salma M.; Kinnersley, Ben; Campbell, Harry; Martin, Lynn; Smith, Christopher G.; Idziaszczyk, Shelley; Barclay, Ella; Maughan, Timothy S.; Kaplan, Richard; Kerr, Rachel; Kerr, David; Buchannan, Daniel D.; Ko Win, Aung; Hopper, John; Jenkins, Mark; Lindor, Noralane M.; Newcomb, Polly A.; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Dunlop, Malcolm G.; Tomlinson, Ian P.; Cheadle, Jeremy P.; Houlston, Richard S.

    2015-01-01

    Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10−8, odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10−8; OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10-8; OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants. PMID:25990418

  1. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.

    PubMed

    Gormley, Padhraig; Anttila, Verneri; Winsvold, Bendik S; Palta, Priit; Esko, Tonu; Pers, Tune H; Farh, Kai-How; Cuenca-Leon, Ester; Muona, Mikko; Furlotte, Nicholas A; Kurth, Tobias; Ingason, Andres; McMahon, George; Ligthart, Lannie; Terwindt, Gisela M; Kallela, Mikko; Freilinger, Tobias M; Ran, Caroline; Gordon, Scott G; Stam, Anine H; Steinberg, Stacy; Borck, Guntram; Koiranen, Markku; Quaye, Lydia; Adams, Hieab H H; Lehtimäki, Terho; Sarin, Antti-Pekka; Wedenoja, Juho; Hinds, David A; Buring, Julie E; Schürks, Markus; Ridker, Paul M; Hrafnsdottir, Maria Gudlaug; Stefansson, Hreinn; Ring, Susan M; Hottenga, Jouke-Jan; Penninx, Brenda W J H; Färkkilä, Markus; Artto, Ville; Kaunisto, Mari; Vepsäläinen, Salli; Malik, Rainer; Heath, Andrew C; Madden, Pamela A F; Martin, Nicholas G; Montgomery, Grant W; Kurki, Mitja I; Kals, Mart; Mägi, Reedik; Pärn, Kalle; Hämäläinen, Eija; Huang, Hailiang; Byrnes, Andrea E; Franke, Lude; Huang, Jie; Stergiakouli, Evie; Lee, Phil H; Sandor, Cynthia; Webber, Caleb; Cader, Zameel; Muller-Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Eriksson, Johan G; Salomaa, Veikko; Heikkilä, Kauko; Loehrer, Elizabeth; Uitterlinden, Andre G; Hofman, Albert; van Duijn, Cornelia M; Cherkas, Lynn; Pedersen, Linda M; Stubhaug, Audun; Nielsen, Christopher S; Männikkö, Minna; Mihailov, Evelin; Milani, Lili; Göbel, Hartmut; Esserlind, Ann-Louise; Christensen, Anne Francke; Hansen, Thomas Folkmann; Werge, Thomas; Kaprio, Jaakko; Aromaa, Arpo J; Raitakari, Olli; Ikram, M Arfan; Spector, Tim; Järvelin, Marjo-Riitta; Metspalu, Andres; Kubisch, Christian; Strachan, David P; Ferrari, Michel D; Belin, Andrea C; Dichgans, Martin; Wessman, Maija; van den Maagdenberg, Arn M J M; Zwart, John-Anker; Boomsma, Dorret I; Smith, George Davey; Stefansson, Kari; Eriksson, Nicholas; Daly, Mark J; Neale, Benjamin M; Olesen, Jes; Chasman, Daniel I; Nyholt, Dale R; Palotie, Aarno

    2016-08-01

    Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies. PMID:27322543

  2. META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IDENTIFIES THREE NEW RISK LOCI FOR ATOPIC DERMATITIS

    PubMed Central

    Paternoster, Lavinia; Standl, Marie; Chen, Chih-Mei; Ramasamy, Adaikalavan; Bønnelykke, Klaus; Duijts, Liesbeth; Ferreira, Manuel A; Alves, Alexessander Couto; Thyssen, Jacob P; Albrecht, Eva; Baurecht, Hansjörg; Feenstra, Bjarke; Sleiman, Patrick MA; Hysi, Pirro; Warrington, Nicole M; Curjuric, Ivan; Myhre, Ronny; Curtin, John A; Groen-Blokhuis, Maria M; Kerkhof, Marjan; Sääf, Annika; Franke, Andre; Ellinghaus, David; Fölster-Holst, Regina; Dermitzakis, Emmanouil; Montgomery, Stephen B; Prokisch, Holger; Heim, Katharina; Hartikainen, Anna-Liisa; Pouta, Anneli; Pekkanen, Juha; Blakemore, Alexandra IF; Buxton, Jessica L; Kaakinen, Marika; Duffy, David L; Madden, Pamela A; Heath, Andrew C; Montgomery, Grant W; Thompson, Philip J; Matheson, Melanie C; Le Souëf, Peter; Pourcain, Beate St; Smith, George Davey; Henderson, John; Kemp, John P; Timpson, Nicholas J; Deloukas, Panos; Ring, Susan M; Wichmann, H-Erich; Müller-Nurasyid, Martina; Novak, Natalija; Klopp, Norman; Rodríguez, Elke; McArdle, Wendy; Linneberg, Allan; Menné, Torkil; Nohr, Ellen A; Hofman, Albert; Uitterlinden, André G; van Duijn, Cornélia M; Rivadeneira, Fernando; de Jongste, Johan C; van der Valk, Ralf JP; Wjst, Matthias; Jogi, Rain; Geller, Frank; Boyd, Heather A; Murray, Jeffrey C; Kim, Cecilia; Mentch, Frank; March, Michael; Mangino, Massimo; Spector, Tim D; Bataille, Veronique; Pennell, Craig E; Holt, Patrick G; Sly, Peter; Tiesler, Carla MT; Thiering, Elisabeth; Illig, Thomas; Imboden, Medea; Nystad, Wenche; Simpson, Angela; Hottenga, Jouke-Jan; Postma, Dirkje; Koppelman, Gerard H; Smit, Henriette A; Söderhäll, Cilla; Chawes, Bo; Kreiner-Møller, Eskil; Bisgaard, Hans; Melén, Erik; Boomsma, Dorret I; Custovic, Adnan; Jacobsson, Bo; Probst-Hensch, Nicole M; Palmer, Lyle J; Glass, Daniel; Hakonarson, Hakon; Melbye, Mads; Jarvis, Deborah L; Jaddoe, Vincent WV; Gieger, Christian; Strachan, David P; Martin, Nicholas G; Jarvelin, Marjo-Riitta; Heinrich, Joachim; Evans, David M; Weidinger, Stephan

    2011-01-01

    Atopic dermatitis (AD) is a common chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing AD are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 cases and 20,565 controls from 16 population-based cohorts and followed up the ten most strongly associated novel markers in a further 5,419 cases and 19,833 controls from 14 studies. Three SNPs met genome-wide significance in the discovery and replication cohorts combined: rs479844 upstream of OVOL1 (OR=0.88, p=1.1×10−13) and rs2164983 near ACTL9 (OR=1.16, p=7.1×10−9), genes which have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster on 5q31.1 (OR=1.11, p=3.8×10−8). We also replicated the FLG locus and two recently identified association signals at 11q13.5 (rs7927894, p=0.008) and 20q13.3 (rs6010620, p=0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in AD pathogenesis. PMID:22197932

  3. Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

    PubMed Central

    Fan, Qiao; Verhoeven, Virginie J. M.; Wojciechowski, Robert; Barathi, Veluchamy A.; Hysi, Pirro G.; Guggenheim, Jeremy A.; Höhn, René; Vitart, Veronique; Khawaja, Anthony P.; Yamashiro, Kenji; Hosseini, S Mohsen; Lehtimäki, Terho; Lu, Yi; Haller, Toomas; Xie, Jing; Delcourt, Cécile; Pirastu, Mario; Wedenoja, Juho; Gharahkhani, Puya; Venturini, Cristina; Miyake, Masahiro; Hewitt, Alex W.; Guo, Xiaobo; Mazur, Johanna; Huffman, Jenifer E.; Williams, Katie M.; Polasek, Ozren; Campbell, Harry; Rudan, Igor; Vatavuk, Zoran; Wilson, James F.; Joshi, Peter K.; McMahon, George; St Pourcain, Beate; Evans, David M.; Simpson, Claire L.; Schwantes-An, Tae-Hwi; Igo, Robert P.; Mirshahi, Alireza; Cougnard-Gregoire, Audrey; Bellenguez, Céline; Blettner, Maria; Raitakari, Olli; Kähönen, Mika; Seppala, Ilkka; Zeller, Tanja; Meitinger, Thomas; Ried, Janina S.; Gieger, Christian; Portas, Laura; van Leeuwen, Elisabeth M.; Amin, Najaf; Uitterlinden, André G.; Rivadeneira, Fernando; Hofman, Albert; Vingerling, Johannes R.; Wang, Ya Xing; Wang, Xu; Tai-Hui Boh, Eileen; Ikram, M. Kamran; Sabanayagam, Charumathi; Gupta, Preeti; Tan, Vincent; Zhou, Lei; Ho, Candice E. H.; Lim, Wan'e; Beuerman, Roger W.; Siantar, Rosalynn; Tai, E-Shyong; Vithana, Eranga; Mihailov, Evelin; Khor, Chiea-Chuen; Hayward, Caroline; Luben, Robert N.; Foster, Paul J.; Klein, Barbara E. K.; Klein, Ronald; Wong, Hoi-Suen; Mitchell, Paul; Metspalu, Andres; Aung, Tin; Young, Terri L.; He, Mingguang; Pärssinen, Olavi; van Duijn, Cornelia M.; Jin Wang, Jie; Williams, Cathy; Jonas, Jost B.; Teo, Yik-Ying; Mackey, David A.; Oexle, Konrad; Yoshimura, Nagahisa; Paterson, Andrew D.; Pfeiffer, Norbert; Wong, Tien-Yin; Baird, Paul N.; Stambolian, Dwight; Wilson, Joan E. Bailey; Cheng, Ching-Yu; Hammond, Christopher J.; Klaver, Caroline C. W.; Saw, Seang-Mei; Rahi, Jugnoo S.; Korobelnik, Jean-François; Kemp, John P.; Timpson, Nicholas J.; Smith, George Davey; Craig, Jamie E.; Burdon, Kathryn P.; Fogarty, Rhys D.; Iyengar, Sudha K.; Chew, Emily; Janmahasatian, Sarayut; Martin, Nicholas G.; MacGregor, Stuart; Xu, Liang; Schache, Maria; Nangia, Vinay; Panda-Jonas, Songhomitra; Wright, Alan F.; Fondran, Jeremy R.; Lass, Jonathan H.; Feng, Sheng; Zhao, Jing Hua; Khaw, Kay-Tee; Wareham, Nick J.; Rantanen, Taina; Kaprio, Jaakko; Pang, Chi Pui; Chen, Li Jia; Tam, Pancy O.; Jhanji, Vishal; Young, Alvin L.; Döring, Angela; Raffel, Leslie J.; Cotch, Mary-Frances; Li, Xiaohui; Yip, Shea Ping; Yap, Maurice K.H.; Biino, Ginevra; Vaccargiu, Simona; Fossarello, Maurizio; Fleck, Brian; Yazar, Seyhan; Tideman, Jan Willem L.; Tedja, Milly; Deangelis, Margaret M.; Morrison, Margaux; Farrer, Lindsay; Zhou, Xiangtian; Chen, Wei; Mizuki, Nobuhisa; Meguro, Akira; Mäkelä, Kari Matti

    2016-01-01

    Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia. PMID:27020472

  4. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

    PubMed

    Fan, Qiao; Verhoeven, Virginie J M; Wojciechowski, Robert; Barathi, Veluchamy A; Hysi, Pirro G; Guggenheim, Jeremy A; Höhn, René; Vitart, Veronique; Khawaja, Anthony P; Yamashiro, Kenji; Hosseini, S Mohsen; Lehtimäki, Terho; Lu, Yi; Haller, Toomas; Xie, Jing; Delcourt, Cécile; Pirastu, Mario; Wedenoja, Juho; Gharahkhani, Puya; Venturini, Cristina; Miyake, Masahiro; Hewitt, Alex W; Guo, Xiaobo; Mazur, Johanna; Huffman, Jenifer E; Williams, Katie M; Polasek, Ozren; Campbell, Harry; Rudan, Igor; Vatavuk, Zoran; Wilson, James F; Joshi, Peter K; McMahon, George; St Pourcain, Beate; Evans, David M; Simpson, Claire L; Schwantes-An, Tae-Hwi; Igo, Robert P; Mirshahi, Alireza; Cougnard-Gregoire, Audrey; Bellenguez, Céline; Blettner, Maria; Raitakari, Olli; Kähönen, Mika; Seppala, Ilkka; Zeller, Tanja; Meitinger, Thomas; Ried, Janina S; Gieger, Christian; Portas, Laura; van Leeuwen, Elisabeth M; Amin, Najaf; Uitterlinden, André G; Rivadeneira, Fernando; Hofman, Albert; Vingerling, Johannes R; Wang, Ya Xing; Wang, Xu; Tai-Hui Boh, Eileen; Ikram, M Kamran; Sabanayagam, Charumathi; Gupta, Preeti; Tan, Vincent; Zhou, Lei; Ho, Candice E H; Lim, Wan'e; Beuerman, Roger W; Siantar, Rosalynn; Tai, E-Shyong; Vithana, Eranga; Mihailov, Evelin; Khor, Chiea-Chuen; Hayward, Caroline; Luben, Robert N; Foster, Paul J; Klein, Barbara E K; Klein, Ronald; Wong, Hoi-Suen; Mitchell, Paul; Metspalu, Andres; Aung, Tin; Young, Terri L; He, Mingguang; Pärssinen, Olavi; van Duijn, Cornelia M; Jin Wang, Jie; Williams, Cathy; Jonas, Jost B; Teo, Yik-Ying; Mackey, David A; Oexle, Konrad; Yoshimura, Nagahisa; Paterson, Andrew D; Pfeiffer, Norbert; Wong, Tien-Yin; Baird, Paul N; Stambolian, Dwight; Wilson, Joan E Bailey; Cheng, Ching-Yu; Hammond, Christopher J; Klaver, Caroline C W; Saw, Seang-Mei; Rahi, Jugnoo S; Korobelnik, Jean-François; Kemp, John P; Timpson, Nicholas J; Smith, George Davey; Craig, Jamie E; Burdon, Kathryn P; Fogarty, Rhys D; Iyengar, Sudha K; Chew, Emily; Janmahasatian, Sarayut; Martin, Nicholas G; MacGregor, Stuart; Xu, Liang; Schache, Maria; Nangia, Vinay; Panda-Jonas, Songhomitra; Wright, Alan F; Fondran, Jeremy R; Lass, Jonathan H; Feng, Sheng; Zhao, Jing Hua; Khaw, Kay-Tee; Wareham, Nick J; Rantanen, Taina; Kaprio, Jaakko; Pang, Chi Pui; Chen, Li Jia; Tam, Pancy O; Jhanji, Vishal; Young, Alvin L; Döring, Angela; Raffel, Leslie J; Cotch, Mary-Frances; Li, Xiaohui; Yip, Shea Ping; Yap, Maurice K H; Biino, Ginevra; Vaccargiu, Simona; Fossarello, Maurizio; Fleck, Brian; Yazar, Seyhan; Tideman, Jan Willem L; Tedja, Milly; Deangelis, Margaret M; Morrison, Margaux; Farrer, Lindsay; Zhou, Xiangtian; Chen, Wei; Mizuki, Nobuhisa; Meguro, Akira; Mäkelä, Kari Matti

    2016-03-29

    Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

  5. Meta-analysis identifies six new susceptibility loci for atrial fibrillation

    PubMed Central

    Ellinor, Patrick T; Lunetta, Kathryn L; Albert, Christine M; Glazer, Nicole L; Ritchie, Marylyn D; Smith, Albert V; Arking, Dan E; Müller-Nurasyid, Martina; Krijthe, Bouwe P; Lubitz, Steven A; Bis, Joshua C; Chung, Mina K; Dörr, Marcus; Ozaki, Kouichi; Roberts, Jason D; Smith, J Gustav; Pfeufer, Arne; Sinner, Moritz F; Lohman, Kurt; Ding, Jingzhong; Smith, Nicholas L; Smith, Jonathan D; Rienstra, Michiel; Rice, Kenneth M; Van Wagoner, David R; Magnani, Jared W; Wakili, Reza; Clauss, Sebastian; Rotter, Jerome I; Steinbeck, Gerhard; Launer, Lenore J; Davies, Robert W; Borkovich, Matthew; Harris, Tamara B; Lin, Honghuang; Völker, Uwe; Völzke, Henry; Milan, David J; Hofman, Albert; Boerwinkle, Eric; Chen, Lin Y; Soliman, Elsayed Z; Voight, Benjamin F; Li, Guo; Chakravarti, Aravinda; Kubo, Michiaki; Tedrow, Usha B; Rose, Lynda M; Ridker, Paul M; Conen, David; Tsunoda, Tatsuhiko; Furukawa, Tetsushi; Sotoodehnia, Nona; Xu, Siyan; Kamatani, Naoyuki; Levy, Daniel; Nakamura, Yusuke; Parvez, Babar; Mahida, Saagar; Furie, Karen L; Rosand, Jonathan; Muhammad, Raafia; Psaty, Bruce M; Meitinger, Thomas; Perz, Siegfried; Wichmann, H-Erich; Witteman, Jacqueline C M; Kao, W H Linda; Kathiresan, Sekar; Roden, Dan M; Uitterlinden, Andre G; Rivadeneira, Fernando; McKnight, Barbara; Sjögren, Marketa; Newman, Anne B; Liu, Yongmei; Gollob, Michael H; Melander, Olle; Tanaka, Toshihiro; Ch Stricker, Bruno H; Felix, Stephan B; Alonso, Alvaro; Darbar, Dawood; Barnard, John; Chasman, Daniel I; Heckbert, Susan R; Benjamin, Emelia J; Gudnason, Vilmundur; Kääb, Stefan

    2012-01-01

    Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death1. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 1 0,030 subjects without atrial fibrillation (P < 5 × 10−8). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules. PMID:22544366

  6. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.

    PubMed

    de Vries, Paul S; Chasman, Daniel I; Sabater-Lleal, Maria; Chen, Ming-Huei; Huffman, Jennifer E; Steri, Maristella; Tang, Weihong; Teumer, Alexander; Marioni, Riccardo E; Grossmann, Vera; Hottenga, Jouke J; Trompet, Stella; Müller-Nurasyid, Martina; Zhao, Jing Hua; Brody, Jennifer A; Kleber, Marcus E; Guo, Xiuqing; Wang, Jie Jin; Auer, Paul L; Attia, John R; Yanek, Lisa R; Ahluwalia, Tarunveer S; Lahti, Jari; Venturini, Cristina; Tanaka, Toshiko; Bielak, Lawrence F; Joshi, Peter K; Rocanin-Arjo, Ares; Kolcic, Ivana; Navarro, Pau; Rose, Lynda M; Oldmeadow, Christopher; Riess, Helene; Mazur, Johanna; Basu, Saonli; Goel, Anuj; Yang, Qiong; Ghanbari, Mohsen; Willemsen, Gonneke; Rumley, Ann; Fiorillo, Edoardo; de Craen, Anton J M; Grotevendt, Anne; Scott, Robert; Taylor, Kent D; Delgado, Graciela E; Yao, Jie; Kifley, Annette; Kooperberg, Charles; Qayyum, Rehan; Lopez, Lorna M; Berentzen, Tina L; Räikkönen, Katri; Mangino, Massimo; Bandinelli, Stefania; Peyser, Patricia A; Wild, Sarah; Trégouët, David-Alexandre; Wright, Alan F; Marten, Jonathan; Zemunik, Tatijana; Morrison, Alanna C; Sennblad, Bengt; Tofler, Geoffrey; de Maat, Moniek P M; de Geus, Eco J C; Lowe, Gordon D; Zoledziewska, Magdalena; Sattar, Naveed; Binder, Harald; Völker, Uwe; Waldenberger, Melanie; Khaw, Kay-Tee; Mcknight, Barbara; Huang, Jie; Jenny, Nancy S; Holliday, Elizabeth G; Qi, Lihong; Mcevoy, Mark G; Becker, Diane M; Starr, John M; Sarin, Antti-Pekka; Hysi, Pirro G; Hernandez, Dena G; Jhun, Min A; Campbell, Harry; Hamsten, Anders; Rivadeneira, Fernando; Mcardle, Wendy L; Slagboom, P Eline; Zeller, Tanja; Koenig, Wolfgang; Psaty, Bruce M; Haritunians, Talin; Liu, Jingmin; Palotie, Aarno; Uitterlinden, André G; Stott, David J; Hofman, Albert; Franco, Oscar H; Polasek, Ozren; Rudan, Igor; Morange, Pierre-Emmanuel; Wilson, James F; Kardia, Sharon L R; Ferrucci, Luigi; Spector, Tim D; Eriksson, Johan G; Hansen, Torben; Deary, Ian J; Becker, Lewis C; Scott, Rodney J; Mitchell, Paul; März, Winfried; Wareham, Nick J; Peters, Annette; Greinacher, Andreas; Wild, Philipp S; Jukema, J Wouter; Boomsma, Dorret I; Hayward, Caroline; Cucca, Francesco; Tracy, Russell; Watkins, Hugh; Reiner, Alex P; Folsom, Aaron R; Ridker, Paul M; O'Donnell, Christopher J; Smith, Nicholas L; Strachan, David P; Dehghan, Abbas

    2016-01-15

    Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

  7. Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.

    PubMed

    Kerns, Sarah L; Dorling, Leila; Fachal, Laura; Bentzen, Søren; Pharoah, Paul D P; Barnes, Daniel R; Gómez-Caamaño, Antonio; Carballo, Ana M; Dearnaley, David P; Peleteiro, Paula; Gulliford, Sarah L; Hall, Emma; Michailidou, Kyriaki; Carracedo, Ángel; Sia, Michael; Stock, Richard; Stone, Nelson N; Sydes, Matthew R; Tyrer, Jonathan P; Ahmed, Shahana; Parliament, Matthew; Ostrer, Harry; Rosenstein, Barry S; Vega, Ana; Burnet, Neil G; Dunning, Alison M; Barnett, Gillian C; West, Catharine M L

    2016-08-01

    Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16×10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value=3.21×10(-8)). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling. PMID:27515689

  8. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.

    PubMed

    Pharoah, Paul D P; Tsai, Ya-Yu; Ramus, Susan J; Phelan, Catherine M; Goode, Ellen L; Lawrenson, Kate; Buckley, Melissa; Fridley, Brooke L; Tyrer, Jonathan P; Shen, Howard; Weber, Rachel; Karevan, Rod; Larson, Melissa C; Song, Honglin; Tessier, Daniel C; Bacot, François; Vincent, Daniel; Cunningham, Julie M; Dennis, Joe; Dicks, Ed; Aben, Katja K; Anton-Culver, Hoda; Antonenkova, Natalia; Armasu, Sebastian M; Baglietto, Laura; Bandera, Elisa V; Beckmann, Matthias W; Birrer, Michael J; Bloom, Greg; Bogdanova, Natalia; Brenton, James D; Brinton, Louise A; Brooks-Wilson, Angela; Brown, Robert; Butzow, Ralf; Campbell, Ian; Carney, Michael E; Carvalho, Renato S; Chang-Claude, Jenny; Chen, Y Anne; Chen, Zhihua; Chow, Wong-Ho; Cicek, Mine S; Coetzee, Gerhard; Cook, Linda S; Cramer, Daniel W; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Despierre, Evelyn; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Edwards, Robert; Ekici, Arif B; Fasching, Peter A; Fenstermacher, David; Flanagan, James; Gao, Yu-Tang; Garcia-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Giles, Graham; Gjyshi, Anxhela; Gore, Martin; Gronwald, Jacek; Guo, Qi; Halle, Mari K; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hillemanns, Peter; Hoatlin, Maureen; Høgdall, Estrid; Høgdall, Claus K; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Kalli, Kimberly R; Karlan, Beth Y; Kelemen, Linda E; Kiemeney, Lambertus A; Kjaer, Susanne Krüger; Konecny, Gottfried E; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Nathan; Lee, Janet; Leminen, Arto; Lim, Boon Kiong; Lissowska, Jolanta; Lubiński, Jan; Lundvall, Lene; Lurie, Galina; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Nakanishi, Toru; Narod, Steven A; Ness, Roberta B; Nevanlinna, Heli; Nickels, Stefan; Noushmehr, Houtan; Odunsi, Kunle; Olson, Sara; Orlow, Irene; Paul, James; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jenny; Pike, Malcolm C; Poole, Elizabeth M; Qu, Xiaotao; Risch, Harvey A; Rodriguez-Rodriguez, Lorna; Rossing, Mary Anne; Rudolph, Anja; Runnebaum, Ingo; Rzepecka, Iwona K; Salvesen, Helga B; Schwaab, Ira; Severi, Gianluca; Shen, Hui; Shridhar, Vijayalakshmi; Shu, Xiao-Ou; Sieh, Weiva; Southey, Melissa C; Spellman, Paul; Tajima, Kazuo; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tworoger, Shelley S; van Altena, Anne M; van den Berg, David; Vergote, Ignace; Vierkant, Robert A; Vitonis, Allison F; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wik, Elisabeth; Winterhoff, Boris; Woo, Yin Ling; Wu, Anna H; Yang, Hannah P; Zheng, Wei; Ziogas, Argyrios; Zulkifli, Famida; Goodman, Marc T; Hall, Per; Easton, Douglas F; Pearce, Celeste L; Berchuck, Andrew; Chenevix-Trench, Georgia; Iversen, Edwin; Monteiro, Alvaro N A; Gayther, Simon A; Schildkraut, Joellen M; Sellers, Thomas A

    2013-04-01

    Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer. PMID:23535730

  9. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

    PubMed Central

    Pharoah, Paul D. P.; Tsai, Ya-Yu; Ramus, Susan J.; Phelan, Catherine M.; Goode, Ellen L.; Lawrenson, Kate; Price, Melissa; Fridley, Brooke L.; Tyrer, Jonathan P.; Shen, Howard; Weber, Rachel; Karevan, Rod; Larson, Melissa C.; Song, Honglin; Tessier, Daniel C.; Bacot, François; Vincent, Daniel; Cunningham, Julie M.; Dennis, Joe; Dicks, Ed; Aben, Katja K.; Anton-Culver, Hoda; Antonenkova, Natalia; Armasu, Sebastian M.; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Birrer, Michael J.; Bloom, Greg; Bogdanova, Natalia; Brenton, James D.; Brinton, Louise A.; Brooks-Wilson, Angela; Brown, Robert; Butzow, Ralf; Campbell, Ian; Carney, Michael E; Carvalho, Renato S.; Chang-Claude, Jenny; Chen, Y. Anne; Chen, Zhihua; Chow, Wong-Ho; Cicek, Mine S.; Coetzee, Gerhard; Cook, Linda S.; Cramer, Daniel W.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Despierre, Evelyn; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Edwards, Robert; Ekici, Arif B.; Fasching, Peter A.; Fenstermacher, David; Flanagan, James; Gao, Yu-Tang; Garcia-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Giles, Graham; Gjyshi, Anxhela; Gore, Martin; Gronwald, Jacek; Guo, Qi; Halle, Mari K; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hillemanns, Peter; Hoatlin, Maureen; Høgdall, Estrid; Høgdall, Claus K.; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Kalli, Kimberly R.; Karlan, Beth Y.; Kelemen, Linda E.; Kiemeney, Lambertus A.; Kjaer, Susanne Krüger; Konecny, Gottfried E.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Nathan; Lee, Janet; Leminen, Arto; Lim, Boon Kiong; Lissowska, Jolanta; Lubiński, Jan; Lundvall, Lene; Lurie, Galina; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Nakanishi, Toru; Narod, Steven A.; Ness, Roberta B.; Nevanlinna, Heli; Nickels, Stefan; Noushmehr, Houtan; Odunsi, Kunle; Olson, Sara; Orlow, Irene; Paul, James; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jenny; Pike, Malcolm C; Poole, Elizabeth M; Qu, Xiaotao; Risch, Harvey A.; Rodriguez-Rodriguez, Lorna; Rossing, Mary Anne; Rudolph, Anja; Runnebaum, Ingo; Rzepecka, Iwona K; Salvesen, Helga B.; Schwaab, Ira; Severi, Gianluca; Shen, Hui; Shridhar, Vijayalakshmi; Shu, Xiao-Ou; Sieh, Weiva; Southey, Melissa C.; Spellman, Paul; Tajima, Kazuo; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Timorek, Agnieszka; Tworoger, Shelley S.; van Altena, Anne M.; Berg, David Van Den; Vergote, Ignace; Vierkant, Robert A.; Vitonis, Allison F.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wik, Elisabeth; Winterhoff, Boris; Woo, Yin Ling; Wu, Anna H; Yang, Hannah P.; Zheng, Wei; Ziogas, Argyrios; Zulkifli, Famida; Goodman, Marc T.; Hall, Per; Easton, Douglas F; Pearce, Celeste L; Berchuck, Andrew; Chenevix-Trench, Georgia; Iversen, Edwin; Monteiro, Alvaro N.A.; Gayther, Simon A.; Schildkraut, Joellen M.; Sellers, Thomas A.

    2013-01-01

    Genome wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC) with another two loci being close to genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the United Kingdom. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. Follow-up genotyping was carried out in 18,174 cases and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 previously near genome-wide significance and identified three novel loci associated with risk; two loci associated with all EOC subtypes, at 8q21 (rs11782652, P=5.5×10-9) and 10p12 (rs1243180; P=1.8×10-8), and another locus specific to the serous subtype at 17q12 (rs757210; P=8.1×10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility that implicates CHMP4C in the pathogenesis of ovarian cancer. PMID:23535730

  10. Acute Tc-99m DMSA scan for identifying dilating vesicoureteral reflux in children: a meta-analysis.

    PubMed

    Mantadakis, Elpis; Vouloumanou, Evridiki K; Georgantzi, Georgia G; Tsalkidis, Aggelos; Chatzimichael, Athanassios; Falagas, Matthew E

    2011-07-01

    Controversy exists regarding the type and/or sequence of imaging studies needed during the first febrile urinary tract infection (UTI) in young children. Several investigators have claimed that because acute-phase Tc-99m dimercaptosuccinic acid (DMSA) renal-scan results are abnormal in the presence of dilating vesicoureteral reflux, a normal DMSA-scan result makes voiding cystourethrography (VCUG) unnecessary in the primary examination of infants with UTI. To evaluate the accuracy of acute-phase DMSA scanning in identifying dilating (grades III through V) vesicoureteral reflux documented by VCUG in children with a first febrile UTI, we performed a meta-analysis of the accuracy of diagnostic tests as reported from relevant studies identified through the PubMed and Scopus databases. Patient-based and renal unit-based analyses were performed. Overall, 13 cohort studies were identified. Nine studies involved patients younger than 2 years, 3 involved children aged 16 years or younger, and 1 involved exclusively neonates. Girls constituted 22% to 85% of the involved children. Pooled (95% confidence intervals) sensitivity and specificity rates of DMSA scanning were 79% and 53%, respectively, for the patient-based analysis (8 studies) and 60% and 65% for the renal unit-based analysis (5 studies). The respective areas under the hierarchical summary receiver operating curves were 0.71 and 0.67. Marked statistical heterogeneity was observed in both analyses, as indicated by I(2) test values of 91% and 87%, respectively. Acute-phase DMSA renal scanning cannot be recommended as replacement for VCUG in the evaluation of young children with a first febrile UTI.

  11. Meta-analysis of genome-wide association data identifies novel susceptibility loci for obesity

    PubMed Central

    Pei, Yu-Fang; Zhang, Lei; Liu, Yongjun; Li, Jian; Shen, Hui; Liu, Yao-Zhong; Tian, Qing; He, Hao; Wu, Shuyan; Ran, Shu; Han, Yingying; Hai, Rong; Lin, Yong; Zhu, Jingying; Zhu, Xue-Zhen; Papasian, Christopher J.; Deng, Hong-Wen

    2014-01-01

    Obesity is a major public health problem with strong genetic determination. Multiple genetic variants have been implicated for obesity by conducting genome-wide association (GWA) studies, primarily focused on body mass index (BMI). Fat body mass (FBM) is phenotypically more homogeneous than BMI and is more appropriate for obesity research; however, relatively few studies have been conducted on FBM. Aiming to identify variants associated with obesity, we carried out meta-analyses of seven GWA studies for BMI-related traits including FBM, and followed these analyses by de novo replication. The discovery cohorts consisted of 21 969 individuals from diverse ethnic populations and a total of over 4 million genotyped or imputed SNPs. The de novo replication cohorts consisted of 6663 subjects from two independent samples. To complement individual SNP-based association analyses, we also carried out gene-based GWA analyses in which all variations within a gene were considered jointly. Individual SNP-based association analyses identified a novel locus 1q21 [rs2230061, CTSS (Cathepsin S)] that was associated with FBM after the adjustment of lean body mass (LBM) (P = 3.57 × 10−8) at the genome-wide significance level. Gene-based association analyses identified a novel gene NLK (nemo-like kinase) in 17q11 that was significantly associated with FBM adjusted by LBM. In addition, we confirmed three previously reported obesity susceptibility loci: 16q12 [rs62033400, P = 1.97 × 10−14, FTO (fat mass and obesity associated)], 18q22 [rs6567160, P = 8.09 × 10−19, MC4R (melanocortin 4 receptor)] and 2p25 [rs939583, P = 1.07 × 10−7, TMEM18 (transmembrane protein 18)]. We also found that rs6567160 may exert pleiotropic effects to both FBM and LBM. Our results provide additional insights into the molecular genetic basis of obesity and may provide future targets for effective prevention and therapeutic intervention. PMID:24064335

  12. Meta-analysis identifies seven susceptibility loci involved in the atopic march.

    PubMed

    Marenholz, Ingo; Esparza-Gordillo, Jorge; Rüschendorf, Franz; Bauerfeind, Anja; Strachan, David P; Spycher, Ben D; Baurecht, Hansjörg; Margaritte-Jeannin, Patricia; Sääf, Annika; Kerkhof, Marjan; Ege, Markus; Baltic, Svetlana; Matheson, Melanie C; Li, Jin; Michel, Sven; Ang, Wei Q; McArdle, Wendy; Arnold, Andreas; Homuth, Georg; Demenais, Florence; Bouzigon, Emmanuelle; Söderhäll, Cilla; Pershagen, Göran; de Jongste, Johan C; Postma, Dirkje S; Braun-Fahrländer, Charlotte; Horak, Elisabeth; Ogorodova, Ludmila M; Puzyrev, Valery P; Bragina, Elena Yu; Hudson, Thomas J; Morin, Charles; Duffy, David L; Marks, Guy B; Robertson, Colin F; Montgomery, Grant W; Musk, Bill; Thompson, Philip J; Martin, Nicholas G; James, Alan; Sleiman, Patrick; Toskala, Elina; Rodriguez, Elke; Fölster-Holst, Regina; Franke, Andre; Lieb, Wolfgang; Gieger, Christian; Heinzmann, Andrea; Rietschel, Ernst; Keil, Thomas; Cichon, Sven; Nöthen, Markus M; Pennell, Craig E; Sly, Peter D; Schmidt, Carsten O; Matanovic, Anja; Schneider, Valentin; Heinig, Matthias; Hübner, Norbert; Holt, Patrick G; Lau, Susanne; Kabesch, Michael; Weidinger, Stefan; Hakonarson, Hakon; Ferreira, Manuel A R; Laprise, Catherine; Freidin, Maxim B; Genuneit, Jon; Koppelman, Gerard H; Melén, Erik; Dizier, Marie-Hélène; Henderson, A John; Lee, Young Ae

    2015-01-01

    Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema. PMID:26542096

  13. Meta-analysis identifies seven susceptibility loci involved in the atopic march

    PubMed Central

    Marenholz, Ingo; Esparza-Gordillo, Jorge; Rüschendorf, Franz; Bauerfeind, Anja; Strachan, David P.; Spycher, Ben D.; Baurecht, Hansjörg; Margaritte-Jeannin, Patricia; Sääf, Annika; Kerkhof, Marjan; Ege, Markus; Baltic, Svetlana; Matheson, Melanie C.; Li, Jin; Michel, Sven; Ang, Wei Q.; McArdle, Wendy; Arnold, Andreas; Homuth, Georg; Demenais, Florence; Bouzigon, Emmanuelle; Söderhäll, Cilla; Pershagen, Göran; de Jongste, Johan C.; Postma, Dirkje S.; Braun-Fahrländer, Charlotte; Horak, Elisabeth; Ogorodova, Ludmila M.; Puzyrev, Valery P.; Bragina, Elena Yu; Hudson, Thomas J.; Morin, Charles; Duffy, David L.; Marks, Guy B.; Robertson, Colin F.; Montgomery, Grant W.; Musk, Bill; Thompson, Philip J.; Martin, Nicholas G.; James, Alan; Sleiman, Patrick; Toskala, Elina; Rodriguez, Elke; Fölster-Holst, Regina; Franke, Andre; Lieb, Wolfgang; Gieger, Christian; Heinzmann, Andrea; Rietschel, Ernst; Keil, Thomas; Cichon, Sven; Nöthen, Markus M.; Pennell, Craig E.; Sly, Peter D.; Schmidt, Carsten O.; Matanovic, Anja; Schneider, Valentin; Heinig, Matthias; Hübner, Norbert; Holt, Patrick G.; Lau, Susanne; Kabesch, Michael; Weidinger, Stefan; Hakonarson, Hakon; Ferreira, Manuel A. R.; Laprise, Catherine; Freidin, Maxim B.; Genuneit, Jon; Koppelman, Gerard H.; Melén, Erik; Dizier, Marie- Hélène; Henderson, A John; Lee, Young Ae

    2015-01-01

    Eczema often precedes the development of asthma in a disease course called the ‘atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema. PMID:26542096

  14. Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials.

    PubMed

    Lv, Zhong-Chuan; Ning, Jin-Yao; Chen, Hong-Bing

    2014-12-01

    Cetuxiamb, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the efficacy of combined therapies of cetuximab and different chemotherapy regimens remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and toxicity of adding cetuximab to oxaliplatin-based or irinotecan-based chemotherapeutic regimens for the treatment of patients with mCRC with wild-type/mutated KRAS tumors. Randomized controlled trials (RCTs), published in Pubmed and Embase were systematically reviewed to assess the survival benefits and toxicity profile mCRC patients treated with cetuximab plus chemotherapy. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicities. Results were expressed as the hazard ratio (HR) with 95 % confidence intervals (CI). Pooled estimates were generated by using a fixed-effects model or a randomized-effects model, depending on the heterogeneity among studies. A total of 12 trials involving 6,297 patients met the inclusion criteria and were included in this meta-analysis. All patients were administered oxaliplatin-based or irinotecan-based chemotherapy with or without cetuximab. Pooled results showed that the addition of cetuximab did not significantly improve the OS (HR = 0.99, 95 % CI = 0.89-1.09; Z = 0.28, P = 0.78) or PFS (HR = 0.94, 95 % CI = 0.81-1.10; Z = 0.76, P = 0.49), but did improve ORR (RR = 1.34, 95 % CI = 1.08-1.65; Z = 2.72, P = 0.00), when compared with chemotherapy alone. Subgroup analysis showed the highest PFS benefit in patients with wild-type KRAS tumors (HR = 0.80, 95 % CI = 0.65-0.99; Z = 2.1, P = 0.04) or wild-type KRAS/BRAF tumors (HR = 0.64, 95 % CI = 0.52-0.79; Z = 4.15, P = 0.00). When combined with cetuximab, irinotecan

  15. Genome-wide Association Study and Meta-Analysis Identify ISL1 as Genome-wide Significant Susceptibility Gene for Bladder Exstrophy

    PubMed Central

    Draaken, Markus; Knapp, Michael; Pennimpede, Tracie; Schmidt, Johanna M.; Ebert, Anne-Karolin; Rösch, Wolfgang; Stein, Raimund; Utsch, Boris; Hirsch, Karin; Boemers, Thomas M.; Mangold, Elisabeth; Heilmann, Stefanie; Ludwig, Kerstin U.; Jenetzky, Ekkehart; Zwink, Nadine; Moebus, Susanne; Herrmann, Bernhard G.; Mattheisen, Manuel; Nöthen, Markus M.

    2015-01-01

    The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10−12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region. PMID:25763902

  16. Genome-wide association study and meta-analysis identify ISL1 as genome-wide significant susceptibility gene for bladder exstrophy.

    PubMed

    Draaken, Markus; Knapp, Michael; Pennimpede, Tracie; Schmidt, Johanna M; Ebert, Anne-Karolin; Rösch, Wolfgang; Stein, Raimund; Utsch, Boris; Hirsch, Karin; Boemers, Thomas M; Mangold, Elisabeth; Heilmann, Stefanie; Ludwig, Kerstin U; Jenetzky, Ekkehart; Zwink, Nadine; Moebus, Susanne; Herrmann, Bernhard G; Mattheisen, Manuel; Nöthen, Markus M; Ludwig, Michael; Reutter, Heiko

    2015-03-01

    The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10-12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region.

  17. A Powerful Procedure for Pathway-Based Meta-analysis Using Summary Statistics Identifies 43 Pathways Associated with Type II Diabetes in European Populations

    PubMed Central

    Zhang, Han; Wheeler, William; Hyland, Paula L.; Yang, Yifan; Shi, Jianxin; Chatterjee, Nilanjan; Yu, Kai

    2016-01-01

    Meta-analysis of multiple genome-wide association studies (GWAS) has become an effective approach for detecting single nucleotide polymorphism (SNP) associations with complex traits. However, it is difficult to integrate the readily accessible SNP-level summary statistics from a meta-analysis into more powerful multi-marker testing procedures, which generally require individual-level genetic data. We developed a general procedure called Summary based Adaptive Rank Truncated Product (sARTP) for conducting gene and pathway meta-analysis that uses only SNP-level summary statistics in combination with genotype correlation estimated from a panel of individual-level genetic data. We demonstrated the validity and power advantage of sARTP through empirical and simulated data. We conducted a comprehensive pathway-based meta-analysis with sARTP on type 2 diabetes (T2D) by integrating SNP-level summary statistics from two large studies consisting of 19,809 T2D cases and 111,181 controls with European ancestry. Among 4,713 candidate pathways from which genes in neighborhoods of 170 GWAS established T2D loci were excluded, we detected 43 T2D globally significant pathways (with Bonferroni corrected p-values < 0.05), which included the insulin signaling pathway and T2D pathway defined by KEGG, as well as the pathways defined according to specific gene expression patterns on pancreatic adenocarcinoma, hepatocellular carcinoma, and bladder carcinoma. Using summary data from 8 eastern Asian T2D GWAS with 6,952 cases and 11,865 controls, we showed 7 out of the 43 pathways identified in European populations remained to be significant in eastern Asians at the false discovery rate of 0.1. We created an R package and a web-based tool for sARTP with the capability to analyze pathways with thousands of genes and tens of thousands of SNPs. PMID:27362418

  18. A Powerful Procedure for Pathway-Based Meta-analysis Using Summary Statistics Identifies 43 Pathways Associated with Type II Diabetes in European Populations.

    PubMed

    Zhang, Han; Wheeler, William; Hyland, Paula L; Yang, Yifan; Shi, Jianxin; Chatterjee, Nilanjan; Yu, Kai

    2016-06-01

    Meta-analysis of multiple genome-wide association studies (GWAS) has become an effective approach for detecting single nucleotide polymorphism (SNP) associations with complex traits. However, it is difficult to integrate the readily accessible SNP-level summary statistics from a meta-analysis into more powerful multi-marker testing procedures, which generally require individual-level genetic data. We developed a general procedure called Summary based Adaptive Rank Truncated Product (sARTP) for conducting gene and pathway meta-analysis that uses only SNP-level summary statistics in combination with genotype correlation estimated from a panel of individual-level genetic data. We demonstrated the validity and power advantage of sARTP through empirical and simulated data. We conducted a comprehensive pathway-based meta-analysis with sARTP on type 2 diabetes (T2D) by integrating SNP-level summary statistics from two large studies consisting of 19,809 T2D cases and 111,181 controls with European ancestry. Among 4,713 candidate pathways from which genes in neighborhoods of 170 GWAS established T2D loci were excluded, we detected 43 T2D globally significant pathways (with Bonferroni corrected p-values < 0.05), which included the insulin signaling pathway and T2D pathway defined by KEGG, as well as the pathways defined according to specific gene expression patterns on pancreatic adenocarcinoma, hepatocellular carcinoma, and bladder carcinoma. Using summary data from 8 eastern Asian T2D GWAS with 6,952 cases and 11,865 controls, we showed 7 out of the 43 pathways identified in European populations remained to be significant in eastern Asians at the false discovery rate of 0.1. We created an R package and a web-based tool for sARTP with the capability to analyze pathways with thousands of genes and tens of thousands of SNPs.

  19. Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies

    PubMed Central

    Song, Ci; Nutile, Teresa; Vernon Smith, Albert; Concas, Maria Pina; Traglia, Michela; Barbieri, Caterina; Ndiaye, Ndeye Coumba; Stathopoulou, Maria G.; Lagou, Vasiliki; Maestrale, Giovanni Battista; Sala, Cinzia; Debette, Stephanie; Kovacs, Peter; Lind, Lars; Lamont, John; Fitzgerald, Peter; Tönjes, Anke; Gudnason, Vilmundur; Toniolo, Daniela; Pirastu, Mario; Bellenguez, Celine; Vasan, Ramachandran S.; Ingelsson, Erik; Leutenegger, Anne-Louise; Johnson, Andrew D.; DeStefano, Anita L.; Visvikis-Siest, Sophie; Seshadri, Sudha; Ciullo, Marina

    2016-01-01

    Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79x10-13), rs74506613 (JMJD1C, P = 1.17x10-19), rs4782371 (ZFPM1, P = 1.59x10-9) and rs2639990 (ZADH2, P = 1.72x10-8), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52x10-18; rs7043199, VLDLR-AS1, P = 5.12x10-14) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39x10-1467; rs1740073, C6orf223, P = 2.34x10-17; rs6993770, ZFPM2, P = 2.44x10-60; rs2375981, KCNV2, P = 1.48x10-100). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the

  20. Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies.

    PubMed

    Choi, Seung Hoan; Ruggiero, Daniela; Sorice, Rossella; Song, Ci; Nutile, Teresa; Vernon Smith, Albert; Concas, Maria Pina; Traglia, Michela; Barbieri, Caterina; Ndiaye, Ndeye Coumba; Stathopoulou, Maria G; Lagou, Vasiliki; Maestrale, Giovanni Battista; Sala, Cinzia; Debette, Stephanie; Kovacs, Peter; Lind, Lars; Lamont, John; Fitzgerald, Peter; Tönjes, Anke; Gudnason, Vilmundur; Toniolo, Daniela; Pirastu, Mario; Bellenguez, Celine; Vasan, Ramachandran S; Ingelsson, Erik; Leutenegger, Anne-Louise; Johnson, Andrew D; DeStefano, Anita L; Visvikis-Siest, Sophie; Seshadri, Sudha; Ciullo, Marina

    2016-02-01

    Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and

  1. Trans-Ethnic Meta-Analysis Identifies Common and Rare Variants Associated with Hepatocyte Growth Factor Levels in the Multi-Ethnic Study of Atherosclerosis (MESA)

    PubMed Central

    Larson, Nicholas B.; Berardi, Cecilia; Decker, Paul A.; Wassel, Christina L.; Kirsch, Phillip S.; Pankow, James S.; Sale, Michele M.; de Andrade, Mariza; Sicotte, Hugues; Tang, Weihong; Hanson, Naomi Q.; Tsai, Michael Y.; Taylor, Kent D.; Bielinski, Suzette J.

    2015-01-01

    Summary Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, motility, mitogenesis, and morphogenesis in a variety of cells, and increased serum levels of HGF have been linked to a number of clinical and subclinical cardiovascular disease phenotypes. However, little is currently known regarding what genetic factors influence HGF levels, despite evidence of substantial genetic contributions to HGF variation. Based upon ethnicity-stratified single-variant association analysis and trans-ethnic meta-analysis of 6201 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we discovered five statistically significant common and low-frequency variants: HGF missense polymorphism rs5745687 (p.E299K) as well as four variants (rs16844364, rs4690098, rs114303452, rs3748034) within or in proximity to HGFAC. We also identified two significant ethnicity-specific gene-level associations (A1BG in African Americans; FASN in Chinese Americans) based upon low-frequency/rare variants, while meta-analysis of gene-level results identified a significant association for HGFAC. However, identified single-variant associations explained modest proportions of the total trait variation and were not significantly associated with coronary artery calcium or coronary heart disease. Our findings indicate genetic factors influencing circulating HGF levels may be complex and ethnically diverse. PMID:25998175

  2. Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects, and tissue-specific enrichment of eQTLs

    PubMed Central

    Below, Jennifer E.; Parra, Esteban J.; Gamazon, Eric R.; Torres, Jason; Krithika, S.; Candille, Sophie; Lu, Yingchang; Manichakul, Ani; Peralta-Romero, Jesus; Duan, Qing; Li, Yun; Morris, Andrew P.; Gottesman, Omri; Bottinger, Erwin; Wang, Xin-Qun; Taylor, Kent D.; Ida Chen, Y.-D.; Rotter, Jerome I.; Rich, Stephen S.; Loos, Ruth J. F.; Tang, Hua; Cox, Nancy J.; Cruz, Miguel; Hanis, Craig L.; Valladares-Salgado, Adan

    2016-01-01

    We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals, and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol, and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci. PMID:26780889

  3. Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects, and tissue-specific enrichment of eQTLs.

    PubMed

    Below, Jennifer E; Parra, Esteban J; Gamazon, Eric R; Torres, Jason; Krithika, S; Candille, Sophie; Lu, Yingchang; Manichakul, Ani; Peralta-Romero, Jesus; Duan, Qing; Li, Yun; Morris, Andrew P; Gottesman, Omri; Bottinger, Erwin; Wang, Xin-Qun; Taylor, Kent D; Ida Chen, Y-D; Rotter, Jerome I; Rich, Stephen S; Loos, Ruth J F; Tang, Hua; Cox, Nancy J; Cruz, Miguel; Hanis, Craig L; Valladares-Salgado, Adan

    2016-01-01

    We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals, and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol, and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci. PMID:26780889

  4. Meta-Analysis at Middle Age: A Personal History

    ERIC Educational Resources Information Center

    Glass, Gene V.

    2015-01-01

    The 40-year history of meta-analysis is traced from the vantage point of one of its originators. Research syntheses leading to the first examples of meta-analysis are identified. Early meta-analyses of the literature on psychotherapy outcomes and school class size are recounted. The influence on the development of meta-analysis of several…

  5. Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus.

    PubMed

    Zhang, Yan; Zhang, Jing; Yang, Jing; Wang, Yongfei; Zhang, Lu; Zuo, Xianbo; Sun, Liangdan; Pan, Hai-Feng; Hirankarn, Nattiya; Wang, Tingyou; Chen, Ruoyan; Ying, Dingge; Zeng, Shuai; Shen, Jiangshan Jane; Lee, Tsz Leung; Lau, Chak Sing; Chan, Tak Mao; Leung, Alexander Moon Ho; Mok, Chi Chiu; Wong, Sik Nin; Lee, Ka Wing; Ho, Marco Hok Kung; Lee, Pamela Pui Wah; Chung, Brian Hon-Yin; Chong, Chun Yin; Wong, Raymond Woon Sing; Mok, Mo Yin; Wong, Wilfred Hing Sang; Tong, Kwok Lung; Tse, Niko Kei Chiu; Li, Xiang-Pei; Avihingsanon, Yingyos; Rianthavorn, Pornpimol; Deekajorndej, Thavatchai; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk; Ying, Shirley King Yee; Fung, Samuel Ka Shun; Lai, Wai Ming; Wong, Chun-Ming; Ng, Irene Oi Lin; Garcia-Barcelo, Maria-Merce; Cherny, Stacey S; Tam, Paul Kwong-Hang; Sham, Pak Chung; Yang, Sen; Ye, Dong Qing; Cui, Yong; Zhang, Xue-Jun; Lau, Yu Lung; Yang, Wanling

    2015-01-01

    Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease. PMID:25149475

  6. Correlation between progression-free survival and overall survival in metastatic breast cancer patients receiving anthracyclines, taxanes, or targeted therapies: a trial-level meta-analysis

    PubMed Central

    Adunlin, George; Cyrus, John W. W.; Dranitsaris, George

    2016-01-01

    Over the past decade, several new drugs have received regulatory approval for metastatic breast cancer (MBC). However, some of these approvals were based on improvement in progression-free survival (PFS), without a concomitant increase in overall survival (OS). This has led some to question the utility of using PFS as a measure for drug approval. To address the uncertainty of using PFS as a surrogate for OS in MBC, a systematic literature review followed by a trial-level correlative analysis was conducted in patients receiving anthracyclines, taxanes, or targeted therapies. Electronic databases were searched to identify randomized trials published between January 1990 and August 2015. Data extraction included hazard ratios for PFS (HRPFS) and OS (HROS) between comparative arms as well as trial-level parameters. Weighted multivariate regression analysis was then used to test the strength of the association between HRPFS and HROS. 72 trials providing 84 comparative arms met the inclusion criteria. HRPFS was a significant predictor of HROS (model coefficient = 0.18, p = 0.04). However, only 31 % (i.e., model R2) of the variability between the PFS–OS association was accounted for. When trials were limited to ≥2nd-line setting, the strength of the association improved (model coefficient = 0.40, p < 0.001) and the model R2 increased to 55 %. However, the HRPFS–HROS association was no longer significant when only 1st-line trials were considered (p = 0.90). HRPFS is a predictor for HROS in MBC randomized trials. However, the effect was driven by trials in the ≥2nd-line setting. Therefore, PFS can be a suitable surrogate for OS in trials evaluating new treatments in the 2nd setting and beyond. The use of PFS alone as a primary trial endpoint in the 1st-line setting is not recommended. PMID:26596731

  7. Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies

    PubMed Central

    Matsuba, Ren; Imamura, Minako; Tanaka, Yasushi; Iwata, Minoru; Hirose, Hiroshi; Kaku, Kohei; Maegawa, Hiroshi; Watada, Hirotaka; Tobe, Kazuyuki; Kashiwagi, Atsunori; Kawamori, Ryuzo; Maeda, Shiro

    2016-01-01

    Aim We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014. Methods We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. Results Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019–1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026–1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. Conclusions Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population. PMID:27115357

  8. Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

    PubMed

    Wen, Wanqing; Zheng, Wei; Okada, Yukinori; Takeuchi, Fumihiko; Tabara, Yasuharu; Hwang, Joo-Yeon; Dorajoo, Rajkumar; Li, Huaixing; Tsai, Fuu-Jen; Yang, Xiaobo; He, Jiang; Wu, Ying; He, Meian; Zhang, Yi; Liang, Jun; Guo, Xiuqing; Sheu, Wayne Huey-Herng; Delahanty, Ryan; Guo, Xingyi; Kubo, Michiaki; Yamamoto, Ken; Ohkubo, Takayoshi; Go, Min Jin; Liu, Jian Jun; Gan, Wei; Chen, Ching-Chu; Gao, Yong; Li, Shengxu; Lee, Nanette R; Wu, Chen; Zhou, Xueya; Song, Huaidong; Yao, Jie; Lee, I-Te; Long, Jirong; Tsunoda, Tatsuhiko; Akiyama, Koichi; Takashima, Naoyuki; Cho, Yoon Shin; Ong, Rick Th; Lu, Ling; Chen, Chien-Hsiun; Tan, Aihua; Rice, Treva K; Adair, Linda S; Gui, Lixuan; Allison, Matthew; Lee, Wen-Jane; Cai, Qiuyin; Isomura, Minoru; Umemura, Satoshi; Kim, Young Jin; Seielstad, Mark; Hixson, James; Xiang, Yong-Bing; Isono, Masato; Kim, Bong-Jo; Sim, Xueling; Lu, Wei; Nabika, Toru; Lee, Juyoung; Lim, Wei-Yen; Gao, Yu-Tang; Takayanagi, Ryoichi; Kang, Dae-Hee; Wong, Tien Yin; Hsiung, Chao Agnes; Wu, I-Chien; Juang, Jyh-Ming Jimmy; Shi, Jiajun; Choi, Bo Youl; Aung, Tin; Hu, Frank; Kim, Mi Kyung; Lim, Wei Yen; Wang, Tzung-Dao; Shin, Min-Ho; Lee, Jeannette; Ji, Bu-Tian; Lee, Young-Hoon; Young, Terri L; Shin, Dong Hoon; Chun, Byung-Yeol; Cho, Myeong-Chan; Han, Bok-Ghee; Hwu, Chii-Min; Assimes, Themistocles L; Absher, Devin; Yan, Xiaofei; Kim, Eric; Kuo, Jane Z; Kwon, Soonil; Taylor, Kent D; Chen, Yii-Der I; Rotter, Jerome I; Qi, Lu; Zhu, Dingliang; Wu, Tangchun; Mohlke, Karen L; Gu, Dongfeng; Mo, Zengnan; Wu, Jer-Yuarn; Lin, Xu; Miki, Tetsuro; Tai, E Shyong; Lee, Jong-Young; Kato, Norihiro; Shu, Xiao-Ou; Tanaka, Toshihiro

    2014-10-15

    Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity. PMID:24861553

  9. Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

    PubMed Central

    Wen, Wanqing; Zheng, Wei; Okada, Yukinori; Takeuchi, Fumihiko; Tabara, Yasuharu; Hwang, Joo-Yeon; Dorajoo, Rajkumar; Li, Huaixing; Tsai, Fuu-Jen; Yang, Xiaobo; He, Jiang; Wu, Ying; He, Meian; Zhang, Yi; Liang, Jun; Guo, Xiuqing; Sheu, Wayne Huey-Herng; Delahanty, Ryan; Guo, Xingyi; Kubo, Michiaki; Yamamoto, Ken; Ohkubo, Takayoshi; Go, Min Jin; Liu, Jian Jun; Gan, Wei; Chen, Ching-Chu; Gao, Yong; Li, Shengxu; Lee, Nanette R.; Wu, Chen; Zhou, Xueya; Song, Huaidong; Yao, Jie; Lee, I-Te; Long, Jirong; Tsunoda, Tatsuhiko; Akiyama, Koichi; Takashima, Naoyuki; Cho, Yoon Shin; Ong, Rick TH; Lu, Ling; Chen, Chien-Hsiun; Tan, Aihua; Rice, Treva K; Adair, Linda S.; Gui, Lixuan; Allison, Matthew; Lee, Wen-Jane; Cai, Qiuyin; Isomura, Minoru; Umemura, Satoshi; Kim, Young Jin; Seielstad, Mark; Hixson, James; Xiang, Yong-Bing; Isono, Masato; Kim, Bong-Jo; Sim, Xueling; Lu, Wei; Nabika, Toru; Lee, Juyoung; Lim, Wei-Yen; Gao, Yu-Tang; Takayanagi, Ryoichi; Kang, Dae-Hee; Wong, Tien Yin; Hsiung, Chao Agnes; Wu, I-Chien; Juang, Jyh-Ming Jimmy; Shi, Jiajun; Choi, Bo Youl; Aung, Tin; Hu, Frank; Kim, Mi Kyung; Lim, Wei Yen; Wang, Tzung-Dao; Shin, Min-Ho; Lee, Jeannette; Ji, Bu-Tian; Lee, Young-Hoon; Young, Terri L.; Shin, Dong Hoon; Chun, Byung-Yeol; Cho, Myeong-Chan; Han, Bok-Ghee; Hwu, Chii-Min; Assimes, Themistocles L.; Absher, Devin; Yan, Xiaofei; Kim, Eric; Kuo, Jane Z.; Kwon, Soonil; Taylor, Kent D.; Chen, Yii-Der I.; Rotter, Jerome I.; Qi, Lu; Zhu, Dingliang; Wu, Tangchun; Mohlke, Karen L.; Gu, Dongfeng; Mo, Zengnan; Wu, Jer-Yuarn; Lin, Xu; Miki, Tetsuro; Tai, E. Shyong; Lee, Jong-Young; Kato, Norihiro; Shu, Xiao-Ou; Tanaka, Toshihiro

    2014-01-01

    Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488–47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10−13), ALDH2/MYL2 (rs671, P = 3.40 × 10−11; rs12229654, P = 4.56 × 10−9), ITIH4 (rs2535633, P = 1.77 × 10−10) and NT5C2 (rs11191580, P = 3.83 × 10−8) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10−8) and an additional 14 at P < 1.0 × 10−3 with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity. PMID:24861553

  10. Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

    PubMed

    Wen, Wanqing; Zheng, Wei; Okada, Yukinori; Takeuchi, Fumihiko; Tabara, Yasuharu; Hwang, Joo-Yeon; Dorajoo, Rajkumar; Li, Huaixing; Tsai, Fuu-Jen; Yang, Xiaobo; He, Jiang; Wu, Ying; He, Meian; Zhang, Yi; Liang, Jun; Guo, Xiuqing; Sheu, Wayne Huey-Herng; Delahanty, Ryan; Guo, Xingyi; Kubo, Michiaki; Yamamoto, Ken; Ohkubo, Takayoshi; Go, Min Jin; Liu, Jian Jun; Gan, Wei; Chen, Ching-Chu; Gao, Yong; Li, Shengxu; Lee, Nanette R; Wu, Chen; Zhou, Xueya; Song, Huaidong; Yao, Jie; Lee, I-Te; Long, Jirong; Tsunoda, Tatsuhiko; Akiyama, Koichi; Takashima, Naoyuki; Cho, Yoon Shin; Ong, Rick Th; Lu, Ling; Chen, Chien-Hsiun; Tan, Aihua; Rice, Treva K; Adair, Linda S; Gui, Lixuan; Allison, Matthew; Lee, Wen-Jane; Cai, Qiuyin; Isomura, Minoru; Umemura, Satoshi; Kim, Young Jin; Seielstad, Mark; Hixson, James; Xiang, Yong-Bing; Isono, Masato; Kim, Bong-Jo; Sim, Xueling; Lu, Wei; Nabika, Toru; Lee, Juyoung; Lim, Wei-Yen; Gao, Yu-Tang; Takayanagi, Ryoichi; Kang, Dae-Hee; Wong, Tien Yin; Hsiung, Chao Agnes; Wu, I-Chien; Juang, Jyh-Ming Jimmy; Shi, Jiajun; Choi, Bo Youl; Aung, Tin; Hu, Frank; Kim, Mi Kyung; Lim, Wei Yen; Wang, Tzung-Dao; Shin, Min-Ho; Lee, Jeannette; Ji, Bu-Tian; Lee, Young-Hoon; Young, Terri L; Shin, Dong Hoon; Chun, Byung-Yeol; Cho, Myeong-Chan; Han, Bok-Ghee; Hwu, Chii-Min; Assimes, Themistocles L; Absher, Devin; Yan, Xiaofei; Kim, Eric; Kuo, Jane Z; Kwon, Soonil; Taylor, Kent D; Chen, Yii-Der I; Rotter, Jerome I; Qi, Lu; Zhu, Dingliang; Wu, Tangchun; Mohlke, Karen L; Gu, Dongfeng; Mo, Zengnan; Wu, Jer-Yuarn; Lin, Xu; Miki, Tetsuro; Tai, E Shyong; Lee, Jong-Young; Kato, Norihiro; Shu, Xiao-Ou; Tanaka, Toshihiro

    2014-10-15

    Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.

  11. Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

    PubMed Central

    Murabito, Joanne M.; White, Charles C.; Kavousi, Maryam; Sun, Yan V.; Feitosa, Mary F.; Nambi, Vijay; Lamina, Claudia; Schillert, Arne; Coassin, Stefan; Bis, Joshua C.; Broer, Linda; Crawford, Dana C.; Franceschini, Nora; Frikke-Schmidt, Ruth; Haun, Margot; Holewijn, Suzanne; Huffman, Jennifer E.; Hwang, Shih-Jen; Kiechl, Stefan; Kollerits, Barbara; Montasser, May E.; Nolte, Ilja M.; Rudock, Megan E.; Senft, Andrea; Teumer, Alexander; van der Harst, Pim; Vitart, Veronique; Waite, Lindsay L.; Wood, Andrew R.; Wassel, Christina L.; Absher, Devin M.; Allison, Matthew A.; Amin, Najaf; Arnold, Alice; Asselbergs, Folkert W.; Aulchenko, Yurii; Bandinelli, Stefania; Barbalic, Maja; Boban, Mladen; Brown-Gentry, Kristin; Couper, David J.; Criqui, Michael H.; Dehghan, Abbas; Heijer, Martin den; Dieplinger, Benjamin; Ding, Jingzhong; Dörr, Marcus; Espinola-Klein, Christine; Felix, Stephan B.; Ferrucci, Luigi; Folsom, Aaron R.; Fraedrich, Gustav; Gibson, Quince; Goodloe, Robert; Gunjaca, Grgo; Haltmayer, Meinhard; Heiss, Gerardo; Hofman, Albert; Kieback, Arne; Kiemeney, Lambertus A.; Kolcic, Ivana; Kullo, Iftikhar J.; Kritchevsky, Stephen B.; Lackner, Karl J.; Li, Xiaohui; Lieb, Wolfgang; Lohman, Kurt; Meisinger, Christa; Melzer, David; Mohler, Emile R; Mudnic, Ivana; Mueller, Thomas; Navis, Gerjan; Oberhollenzer, Friedrich; Olin, Jeffrey W.; O’Connell, Jeff; O’Donnell, Christopher J.; Palmas, Walter; Penninx, Brenda W.; Petersmann, Astrid; Polasek, Ozren; Psaty, Bruce M.; Rantner, Barbara; Rice, Ken; Rivadeneira, Fernando; Rotter, Jerome I.; Seldenrijk, Adrie; Stadler, Marietta; Summerer, Monika; Tanaka, Toshiko; Tybjaerg-Hansen, Anne; Uitterlinden, Andre G.; van Gilst, Wiek H.; Vermeulen, Sita H.; Wild, Sarah H.; Wild, Philipp S.; Willeit, Johann; Zeller, Tanja; Zemunik, Tatijana; Zgaga, Lina; Assimes, Themistocles L.; Blankenberg, Stefan; Boerwinkle, Eric; Campbell, Harry; Cooke, John P.; de Graaf, Jacqueline; Herrington, David; Kardia, Sharon L. R.; Mitchell, Braxton D.; Murray, Anna; Münzel, Thomas; Newman, Anne; Oostra, Ben A.; Rudan, Igor; Shuldiner, Alan R.; Snieder, Harold; van Duijn, Cornelia M.; Völker, Uwe; Wright, Alan F.; Wichmann, H.-Erich; Wilson, James F.; Witteman, Jacqueline C.M.; Liu, Yongmei; Hayward, Caroline; Borecki, Ingrid B.; Ziegler, Andreas; North, Kari E.; Cupples, L. Adrienne; Kronenberg, Florian

    2012-01-01

    Background Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. Methods and Results Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026). Conclusions GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI. PMID:22199011

  12. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

    PubMed Central

    Zeggini, Eleftheria; Scott, Laura J.; Saxena, Richa; Voight, Benjamin F.; Marchini, Jonathan L; Hu, Tainle; de Bakker, Paul IW; Abecasis, Gonçalo R; Almgren, Peter; Andersen, Gitte; Ardlie, Kristin; Boström, Kristina Bengtsson; Bergman, Richard N; Bonnycastle, Lori L; Borch-Johnsen, Knut; Burtt, Noël P; Chen, Hong; Chines, Peter S; Daly, Mark J; Deodhar, Parimal; Ding, Charles; Doney, Alex S F; Duren, William L; Elliott, Katherine S; Erdos, Michael R; Frayling, Timothy M; Freathy, Rachel M; Gianniny, Lauren; Grallert, Harald; Grarup, Niels; Groves, Christopher J; Guiducci, Candace; Hansen, Torben; Herder, Christian; Hitman, Graham A; Hughes, Thomas E; Isomaa, Bo; Jackson, Anne U; Jørgensen, Torben; Kong, Augustine; Kubalanza, Kari; Kuruvilla, Finny G; Kuusisto, Johanna; Langenberg, Claudia; Lango, Hana; Lauritzen, Torsten; Li, Yun; Lindgren, Cecilia M; Lyssenko, Valeriya; Marvelle, Amanda F; Meisinger, Christa; Midthjell, Kristian; Mohlke, Karen L; Morken, Mario A; Morris, Andrew D; Narisu, Narisu; Nilsson, Peter; Owen, Katharine R; Palmer, Colin NA; Payne, Felicity; Perry, John RB; Pettersen, Elin; Platou, Carl; Prokopenko, Inga; Qi, Lu; Qin, Li; Rayner, Nigel W; Rees, Matthew; Roix, Jeffrey J; Sandbæk, Anelli; Shields, Beverley; Sjögren, Marketa; Steinthorsdottir, Valgerdur; Stringham, Heather M; Swift, Amy J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Timpson, Nicholas J; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Walker, Mark; Watanabe, Richard M; Weedon, Michael N; Willer, Cristen J; Illig, Thomas; Hveem, Kristian; Hu, Frank B; Laakso, Markku; Stefansson, Kari; Pedersen, Oluf; Wareham, Nicholas J; Barroso, Inês; Hattersley, Andrew T; Collins, Francis S; Groop, Leif; McCarthy, Mark I; Boehnke, Michael; Altshuler, David

    2009-01-01

    Genome-wide association (GWA) studies have identified multiple new genomic loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)1-11. Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to discover loci at which common alleles have modest effects, we performed meta-analysis of three T2D GWA scans encompassing 10,128 individuals of European-descent and ~2.2 million SNPs (directly genotyped and imputed). Replication testing was performed in an independent sample with an effective sample size of up to 53,975. At least six new loci with robust evidence for association were detected, including the JAZF1 (p=5.0×10−14), CDC123/CAMK1D (p=1.2×10−10), TSPAN8/LGR5 (p=1.1×10−9), THADA (p=1.1×10−9), ADAMTS9 (p=1.2×10−8), and NOTCH2 (p=4.1×10−8) gene regions. The large number of loci with relatively small effects indicates the value of large discovery and follow-up samples in identifying additional clues about the inherited basis of T2D. PMID:18372903

  13. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women.

    PubMed

    Wang, Zhaoming; Seow, Wei Jie; Shiraishi, Kouya; Hsiung, Chao A; Matsuo, Keitaro; Liu, Jie; Chen, Kexin; Yamji, Taiki; Yang, Yang; Chang, I-Shou; Wu, Chen; Hong, Yun-Chul; Burdett, Laurie; Wyatt, Kathleen; Chung, Charles C; Li, Shengchao A; Yeager, Meredith; Hutchinson, Amy; Hu, Wei; Caporaso, Neil; Landi, Maria T; Chatterjee, Nilanjan; Song, Minsun; Fraumeni, Joseph F; Kohno, Takashi; Yokota, Jun; Kunitoh, Hideo; Ashikawa, Kyota; Momozawa, Yukihide; Daigo, Yataro; Mitsudomi, Tetsuya; Yatabe, Yasushi; Hida, Toyoaki; Hu, Zhibin; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Song, Bao; Wang, Zhehai; Cheng, Sensen; Yin, Zhihua; Li, Xuelian; Ren, Yangwu; Guan, Peng; Chang, Jiang; Tan, Wen; Chen, Chien-Jen; Chang, Gee-Chen; Tsai, Ying-Huang; Su, Wu-Chou; Chen, Kuan-Yu; Huang, Ming-Shyan; Chen, Yuh-Min; Zheng, Hong; Li, Haixin; Cui, Ping; Guo, Huan; Xu, Ping; Liu, Li; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro; Zhu, Junjie; Jiang, Gening; Fei, Ke; Park, Jae Yong; Kim, Yeul Hong; Sung, Jae Sook; Park, Kyong Hwa; Kim, Young Tae; Jung, Yoo Jin; Kang, Chang Hyun; Park, In Kyu; Kim, Hee Nam; Jeon, Hyo-Sung; Choi, Jin Eun; Choi, Yi Young; Kim, Jin Hee; Oh, In-Jae; Kim, Young-Chul; Sung, Sook Whan; Kim, Jun Suk; Yoon, Ho-Il; Kweon, Sun-Seog; Shin, Min-Ho; Seow, Adeline; Chen, Ying; Lim, Wei-Yen; Liu, Jianjun; Wong, Maria Pik; Lee, Victor Ho Fun; Bassig, Bryan A; Tucker, Margaret; Berndt, Sonja I; Chow, Wong-Ho; Ji, Bu-Tian; Wang, Junwen; Xu, Jun; Sihoe, Alan Dart Loon; Ho, James C M; Chan, John K C; Wang, Jiu-Cun; Lu, Daru; Zhao, Xueying; Zhao, Zhenhong; Wu, Junjie; Chen, Hongyan; Jin, Li; Wei, Fusheng; Wu, Guoping; An, She-Juan; Zhang, Xu-Chao; Su, Jian; Wu, Yi-Long; Gao, Yu-Tang; Xiang, Yong-Bing; He, Xingzhou; Li, Jihua; Zheng, Wei; Shu, Xiao-Ou; Cai, Qiuyin; Klein, Robert; Pao, William; Lawrence, Charles; Hosgood, H Dean; Hsiao, Chin-Fu; Chien, Li-Hsin; Chen, Ying-Hsiang; Chen, Chung-Hsing; Wang, Wen-Chang; Chen, Chih-Yi; Wang, Chih-Liang; Yu, Chong-Jen; Chen, Hui-Ling; Su, Yu-Chun; Tsai, Fang-Yu; Chen, Yi-Song; Li, Yao-Jen; Yang, Tsung-Ying; Lin, Chien-Chung; Yang, Pan-Chyr; Wu, Tangchun; Lin, Dongxin; Zhou, Baosen; Yu, Jinming; Shen, Hongbing; Kubo, Michiaki; Chanock, Stephen J; Rothman, Nathaniel; Lan, Qing

    2016-02-01

    Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings.

  14. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women.

    PubMed

    Wang, Zhaoming; Seow, Wei Jie; Shiraishi, Kouya; Hsiung, Chao A; Matsuo, Keitaro; Liu, Jie; Chen, Kexin; Yamji, Taiki; Yang, Yang; Chang, I-Shou; Wu, Chen; Hong, Yun-Chul; Burdett, Laurie; Wyatt, Kathleen; Chung, Charles C; Li, Shengchao A; Yeager, Meredith; Hutchinson, Amy; Hu, Wei; Caporaso, Neil; Landi, Maria T; Chatterjee, Nilanjan; Song, Minsun; Fraumeni, Joseph F; Kohno, Takashi; Yokota, Jun; Kunitoh, Hideo; Ashikawa, Kyota; Momozawa, Yukihide; Daigo, Yataro; Mitsudomi, Tetsuya; Yatabe, Yasushi; Hida, Toyoaki; Hu, Zhibin; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Song, Bao; Wang, Zhehai; Cheng, Sensen; Yin, Zhihua; Li, Xuelian; Ren, Yangwu; Guan, Peng; Chang, Jiang; Tan, Wen; Chen, Chien-Jen; Chang, Gee-Chen; Tsai, Ying-Huang; Su, Wu-Chou; Chen, Kuan-Yu; Huang, Ming-Shyan; Chen, Yuh-Min; Zheng, Hong; Li, Haixin; Cui, Ping; Guo, Huan; Xu, Ping; Liu, Li; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro; Zhu, Junjie; Jiang, Gening; Fei, Ke; Park, Jae Yong; Kim, Yeul Hong; Sung, Jae Sook; Park, Kyong Hwa; Kim, Young Tae; Jung, Yoo Jin; Kang, Chang Hyun; Park, In Kyu; Kim, Hee Nam; Jeon, Hyo-Sung; Choi, Jin Eun; Choi, Yi Young; Kim, Jin Hee; Oh, In-Jae; Kim, Young-Chul; Sung, Sook Whan; Kim, Jun Suk; Yoon, Ho-Il; Kweon, Sun-Seog; Shin, Min-Ho; Seow, Adeline; Chen, Ying; Lim, Wei-Yen; Liu, Jianjun; Wong, Maria Pik; Lee, Victor Ho Fun; Bassig, Bryan A; Tucker, Margaret; Berndt, Sonja I; Chow, Wong-Ho; Ji, Bu-Tian; Wang, Junwen; Xu, Jun; Sihoe, Alan Dart Loon; Ho, James C M; Chan, John K C; Wang, Jiu-Cun; Lu, Daru; Zhao, Xueying; Zhao, Zhenhong; Wu, Junjie; Chen, Hongyan; Jin, Li; Wei, Fusheng; Wu, Guoping; An, She-Juan; Zhang, Xu-Chao; Su, Jian; Wu, Yi-Long; Gao, Yu-Tang; Xiang, Yong-Bing; He, Xingzhou; Li, Jihua; Zheng, Wei; Shu, Xiao-Ou; Cai, Qiuyin; Klein, Robert; Pao, William; Lawrence, Charles; Hosgood, H Dean; Hsiao, Chin-Fu; Chien, Li-Hsin; Chen, Ying-Hsiang; Chen, Chung-Hsing; Wang, Wen-Chang; Chen, Chih-Yi; Wang, Chih-Liang; Yu, Chong-Jen; Chen, Hui-Ling; Su, Yu-Chun; Tsai, Fang-Yu; Chen, Yi-Song; Li, Yao-Jen; Yang, Tsung-Ying; Lin, Chien-Chung; Yang, Pan-Chyr; Wu, Tangchun; Lin, Dongxin; Zhou, Baosen; Yu, Jinming; Shen, Hongbing; Kubo, Michiaki; Chanock, Stephen J; Rothman, Nathaniel; Lan, Qing

    2016-02-01

    Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings. PMID:26732429

  15. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

    PubMed Central

    Heid, Iris M; Jackson, Anne U; Randall, Joshua C; Winkler, Thomas W; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M Carola; Speliotes, Elizabeth K; Mägi, Reedik; Workalemahu, Tsegaselassie; White, Charles C; Bouatia-Naji, Nabila; Harris, Tamara B; Berndt, Sonja I; Ingelsson, Erik; Willer, Cristen J; Weedon, Michael N; Luan, Jian’An; Vedantam, Sailaja; Esko, Tõnu; Kilpeläinen, Tuomas O; Kutalik, Zoltán; Li, Shengxu; Monda, Keri L; Dixon, Anna L; Holmes, Christopher C; Kaplan, Lee M; Liang, Liming; Min, Josine L; Moffatt, Miriam F; Molony, Cliona; Nicholson, George; Schadt, Eric E; Zondervan, Krina T; Feitosa, Mary F; Ferreira, Teresa; Allen, Hana Lango; Weyant, Robert J; Wheeler, Eleanor; Wood, Andrew R; Estrada, Karol; Goddard, Michael E; Lettre, Guillaume; Mangino, Massimo; Nyholt, Dale R; Purcell, Shaun; Smith, Albert Vernon; Visscher, Peter M; Yang, Jian; McCarroll, Steven A; Nemesh, James; Voight, Benjamin F; Absher, Devin; Amin, Najaf; Aspelund, Thor; Coin, Lachlan; Glazer, Nicole L; Hayward, Caroline; Heard-costa, Nancy L; Hottenga, Jouke-Jan; Johansson, Åsa; Johnson, Toby; Kaakinen, Marika; Kapur, Karen; Ketkar, Shamika; Knowles, Joshua W; Kraft, Peter; Kraja, Aldi T; Lamina, Claudia; Leitzmann, Michael F; McKnight, Barbara; Morris, Andrew P; Ong, Ken K; Perry, John R B; Peters, Marjolein J; Polasek, Ozren; Prokopenko, Inga; Rayner, Nigel W; Ripatti, Samuli; Rivadeneira, Fernando; Robertson, Neil R; Sanna, Serena; Sovio, Ulla; Surakka, Ida; Teumer, Alexander; van Wingerden, Sophie; Vitart, Veronique; Zhao, Jing Hua; Cavalcanti-Proença, Christine; Chines, Peter S; Fisher, Eva; Kulzer, Jennifer R; Lecoeur, Cecile; Narisu, Narisu; Sandholt, Camilla; Scott, Laura J; Silander, Kaisa; Stark, Klaus; Tammesoo, Mari-Liis; Teslovich, Tanya M; Timpson, Nicholas John; Watanabe, Richard M; Welch, Ryan; Chasman, Daniel I; Cooper, Matthew N; Jansson, John-Olov; Kettunen, Johannes; Lawrence, Robert W; Pellikka, Niina; Perola, Markus; Vandenput, Liesbeth; Alavere, Helene; Almgren, Peter; Atwood, Larry D; Bennett, Amanda J; Biffar, Reiner; Bonnycastle, Lori L; Bornstein, Stefan R; Buchanan, Thomas A; Campbell, Harry; Day, Ian N M; Dei, Mariano; Dörr, Marcus; Elliott, Paul; Erdos, Michael R; Eriksson, Johan G; Freimer, Nelson B; Fu, Mao; Gaget, Stefan; Geus, Eco J C; Gjesing, Anette P; Grallert, Harald; Gräßler, Jürgen; Groves, Christopher J; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Havulinna, Aki S; Herzig, Karl-Heinz; Hicks, Andrew A; Hui, Jennie; Igl, Wilmar; Jousilahti, Pekka; Jula, Antti; Kajantie, Eero; Kinnunen, Leena; Kolcic, Ivana; Koskinen, Seppo; Kovacs, Peter; Kroemer, Heyo K; Krzelj, Vjekoslav; Kuusisto, Johanna; Kvaloy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lathrop, G Mark; Lokki, Marja-Liisa; Luben, Robert N; Ludwig, Barbara; McArdle, Wendy L; McCarthy, Anne; Morken, Mario A; Nelis, Mari; Neville, Matt J; Paré, Guillaume; Parker, Alex N; Peden, John F; Pichler, Irene; Pietiläinen, Kirsi H; Platou, Carl G P; Pouta, Anneli; Ridderstråle, Martin; Samani, Nilesh J; Saramies, Jouko; Sinisalo, Juha; Smit, Jan H; Strawbridge, Rona J; Stringham, Heather M; Swift, Amy J; Teder-Laving, Maris; Thomson, Brian; Usala, Gianluca; van Meurs, Joyce B J; van Ommen, Gert-Jan; Vatin, Vincent; Volpato, Claudia B; Wallaschofski, Henri; Walters, G Bragi; Widen, Elisabeth; Wild, Sarah H; Willemsen, Gonneke; Witte, Daniel R; Zgaga, Lina; Zitting, Paavo; Beilby, John P; James, Alan L; Kähönen, Mika; Lehtimäki, Terho; Nieminen, Markku S; Ohlsson, Claes; Palmer, Lyle J; Raitakari, Olli; Ridker, Paul M; Stumvoll, Michael; Tönjes, Anke; Viikari, Jorma; Balkau, Beverley; Ben-Shlomo, Yoav; Bergman, Richard N; Boeing, Heiner; Smith, George Davey; Ebrahim, Shah; Froguel, Philippe; Hansen, Torben; Hengstenberg, Christian; Hveem, Kristian; Isomaa, Bo; Jørgensen, Torben; Karpe, Fredrik; Khaw, Kay-Tee; Laakso, Markku; Lawlor, Debbie A; Marre, Michel; Meitinger, Thomas; Metspalu, Andres; Midthjell, Kristian; Pedersen, Oluf; Salomaa, Veikko; Schwarz, Peter E H; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Valle, Timo T; Wareham, Nicholas J; Arnold, Alice M; Beckmann, Jacques S; Bergmann, Sven; Boerwinkle, Eric; Boomsma, Dorret I; Caulfield, Mark J; Collins, Francis S; Eiriksdottir, Gudny; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Hattersley, Andrew T; Hofman, Albert; Hu, Frank B; Illig, Thomas; Iribarren, Carlos; Jarvelin, Marjo-Riitta; Kao, W H Linda; Kaprio, Jaakko; Launer, Lenore J; Munroe, Patricia B; Oostra, Ben; Penninx, Brenda W; Pramstaller, Peter P; Psaty, Bruce M; Quertermous, Thomas; Rissanen, Aila; Rudan, Igor; Shuldiner, Alan R; Soranzo, Nicole; Spector, Timothy D; Syvanen, Ann-Christine; Uda, Manuela; Uitterlinden, André; Völzke, Henry; Vollenweider, Peter; Wilson, James F; Witteman, Jacqueline C; Wright, Alan F; Abecasis, Gonçalo R; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Groop, Leif C; Haritunians, Talin; Hunter, David J; Kaplan, Robert C; North, Kari E; O’connell, Jeffrey R; Peltonen, Leena; Schlessinger, David; Strachan, David P; Hirschhorn, Joel N; Assimes, Themistocles L; Wichmann, H-Erich; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Stefansson, Kari; Cupples, L Adrienne; Loos, Ruth J F; Barroso, Inês; McCarthy, Mark I; Fox, Caroline S; Mohlke, Karen L; Lindgren, Cecilia M

    2011-01-01

    Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions. PMID:20935629

  16. Integrative transcriptomic meta-analysis of Parkinson’s disease and depression identifies NAMPT as a potential blood biomarker for de novo Parkinson’s disease

    PubMed Central

    Santiago, Jose A.; Littlefield, Alyssa M.; Potashkin, Judith A.

    2016-01-01

    Emerging research indicates that depression could be one of the earliest prodromal symptoms or risk factors associated with the pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder worldwide, but the mechanisms underlying the association between both diseases remains unknown. Understanding the molecular networks linking these diseases could facilitate the discovery of novel diagnostic and therapeutics. Transcriptomic meta-analysis and network analysis of blood microarrays from untreated patients with PD and depression identified genes enriched in pathways related to the immune system, metabolism of lipids, glucose, fatty acids, nicotinamide, lysosome, insulin signaling and type 1 diabetes. Nicotinamide phosphoribosyltransferase (NAMPT), an adipokine that plays a role in lipid and glucose metabolism, was identified as the most significant dysregulated gene. Relative abundance of NAMPT was upregulated in blood of 99 early stage and drug-naïve PD patients compared to 101 healthy controls (HC) nested in the cross-sectional Parkinson’s Progression Markers Initiative (PPMI). Thus, here we demonstrate that shared molecular networks between PD and depression provide an additional source of biologically relevant biomarkers. Evaluation of NAMPT in a larger prospective longitudinal study including samples from other neurodegenerative diseases, and patients at risk of PD is warranted. PMID:27680512

  17. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.

    PubMed

    Heid, Iris M; Jackson, Anne U; Randall, Joshua C; Winkler, Thomas W; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M Carola; Speliotes, Elizabeth K; Mägi, Reedik; Workalemahu, Tsegaselassie; White, Charles C; Bouatia-Naji, Nabila; Harris, Tamara B; Berndt, Sonja I; Ingelsson, Erik; Willer, Cristen J; Weedon, Michael N; Luan, Jian'an; Vedantam, Sailaja; Esko, Tõnu; Kilpeläinen, Tuomas O; Kutalik, Zoltán; Li, Shengxu; Monda, Keri L; Dixon, Anna L; Holmes, Christopher C; Kaplan, Lee M; Liang, Liming; Min, Josine L; Moffatt, Miriam F; Molony, Cliona; Nicholson, George; Schadt, Eric E; Zondervan, Krina T; Feitosa, Mary F; Ferreira, Teresa; Lango Allen, Hana; Weyant, Robert J; Wheeler, Eleanor; Wood, Andrew R; Estrada, Karol; Goddard, Michael E; Lettre, Guillaume; Mangino, Massimo; Nyholt, Dale R; Purcell, Shaun; Smith, Albert Vernon; Visscher, Peter M; Yang, Jian; McCarroll, Steven A; Nemesh, James; Voight, Benjamin F; Absher, Devin; Amin, Najaf; Aspelund, Thor; Coin, Lachlan; Glazer, Nicole L; Hayward, Caroline; Heard-Costa, Nancy L; Hottenga, Jouke-Jan; Johansson, Asa; Johnson, Toby; Kaakinen, Marika; Kapur, Karen; Ketkar, Shamika; Knowles, Joshua W; Kraft, Peter; Kraja, Aldi T; Lamina, Claudia; Leitzmann, Michael F; McKnight, Barbara; Morris, Andrew P; Ong, Ken K; Perry, John R B; Peters, Marjolein J; Polasek, Ozren; Prokopenko, Inga; Rayner, Nigel W; Ripatti, Samuli; Rivadeneira, Fernando; Robertson, Neil R; Sanna, Serena; Sovio, Ulla; Surakka, Ida; Teumer, Alexander; van Wingerden, Sophie; Vitart, Veronique; Zhao, Jing Hua; Cavalcanti-Proença, Christine; Chines, Peter S; Fisher, Eva; Kulzer, Jennifer R; Lecoeur, Cecile; Narisu, Narisu; Sandholt, Camilla; Scott, Laura J; Silander, Kaisa; Stark, Klaus; Tammesoo, Mari-Liis; Teslovich, Tanya M; Timpson, Nicholas John; Watanabe, Richard M; Welch, Ryan; Chasman, Daniel I; Cooper, Matthew N; Jansson, John-Olov; Kettunen, Johannes; Lawrence, Robert W; Pellikka, Niina; Perola, Markus; Vandenput, Liesbeth; Alavere, Helene; Almgren, Peter; Atwood, Larry D; Bennett, Amanda J; Biffar, Reiner; Bonnycastle, Lori L; Bornstein, Stefan R; Buchanan, Thomas A; Campbell, Harry; Day, Ian N M; Dei, Mariano; Dörr, Marcus; Elliott, Paul; Erdos, Michael R; Eriksson, Johan G; Freimer, Nelson B; Fu, Mao; Gaget, Stefan; Geus, Eco J C; Gjesing, Anette P; Grallert, Harald; Grässler, Jürgen; Groves, Christopher J; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Havulinna, Aki S; Herzig, Karl-Heinz; Hicks, Andrew A; Hui, Jennie; Igl, Wilmar; Jousilahti, Pekka; Jula, Antti; Kajantie, Eero; Kinnunen, Leena; Kolcic, Ivana; Koskinen, Seppo; Kovacs, Peter; Kroemer, Heyo K; Krzelj, Vjekoslav; Kuusisto, Johanna; Kvaloy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lathrop, G Mark; Lokki, Marja-Liisa; Luben, Robert N; Ludwig, Barbara; McArdle, Wendy L; McCarthy, Anne; Morken, Mario A; Nelis, Mari; Neville, Matt J; Paré, Guillaume; Parker, Alex N; Peden, John F; Pichler, Irene; Pietiläinen, Kirsi H; Platou, Carl G P; Pouta, Anneli; Ridderstråle, Martin; Samani, Nilesh J; Saramies, Jouko; Sinisalo, Juha; Smit, Jan H; Strawbridge, Rona J; Stringham, Heather M; Swift, Amy J; Teder-Laving, Maris; Thomson, Brian; Usala, Gianluca; van Meurs, Joyce B J; van Ommen, Gert-Jan; Vatin, Vincent; Volpato, Claudia B; Wallaschofski, Henri; Walters, G Bragi; Widen, Elisabeth; Wild, Sarah H; Willemsen, Gonneke; Witte, Daniel R; Zgaga, Lina; Zitting, Paavo; Beilby, John P; James, Alan L; Kähönen, Mika; Lehtimäki, Terho; Nieminen, Markku S; Ohlsson, Claes; Palmer, Lyle J; Raitakari, Olli; Ridker, Paul M; Stumvoll, Michael; Tönjes, Anke; Viikari, Jorma; Balkau, Beverley; Ben-Shlomo, Yoav; Bergman, Richard N; Boeing, Heiner; Smith, George Davey; Ebrahim, Shah; Froguel, Philippe; Hansen, Torben; Hengstenberg, Christian; Hveem, Kristian; Isomaa, Bo; Jørgensen, Torben; Karpe, Fredrik; Khaw, Kay-Tee; Laakso, Markku; Lawlor, Debbie A; Marre, Michel; Meitinger, Thomas; Metspalu, Andres; Midthjell, Kristian; Pedersen, Oluf; Salomaa, Veikko; Schwarz, Peter E H; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Valle, Timo T; Wareham, Nicholas J; Arnold, Alice M; Beckmann, Jacques S; Bergmann, Sven; Boerwinkle, Eric; Boomsma, Dorret I; Caulfield, Mark J; Collins, Francis S; Eiriksdottir, Gudny; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Hattersley, Andrew T; Hofman, Albert; Hu, Frank B; Illig, Thomas; Iribarren, Carlos; Jarvelin, Marjo-Riitta; Kao, W H Linda; Kaprio, Jaakko; Launer, Lenore J; Munroe, Patricia B; Oostra, Ben; Penninx, Brenda W; Pramstaller, Peter P; Psaty, Bruce M; Quertermous, Thomas; Rissanen, Aila; Rudan, Igor; Shuldiner, Alan R; Soranzo, Nicole; Spector, Timothy D; Syvanen, Ann-Christine; Uda, Manuela; Uitterlinden, André; Völzke, Henry; Vollenweider, Peter; Wilson, James F; Witteman, Jacqueline C; Wright, Alan F; Abecasis, Gonçalo R; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Groop, Leif C; Haritunians, Talin; Hunter, David J; Kaplan, Robert C; North, Kari E; O'Connell, Jeffrey R; Peltonen, Leena; Schlessinger, David; Strachan, David P; Hirschhorn, Joel N; Assimes, Themistocles L; Wichmann, H-Erich; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Stefansson, Kari; Cupples, L Adrienne; Loos, Ruth J F; Barroso, Inês; McCarthy, Mark I; Fox, Caroline S; Mohlke, Karen L; Lindgren, Cecilia M

    2010-11-01

    Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

  18. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

    PubMed Central

    Amin Al Olama, Ali; Kote-Jarai, Zsofia; Schumacher, Fredrick R.; Wiklund, Fredrik; Berndt, Sonja I.; Benlloch, Sara; Giles, Graham G.; Severi, Gianluca; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Hunter, David J.; Henderson, Brian E.; Thun, Michael J.; Gaziano, Michael; Giovannucci, Edward L.; Siddiq, Afshan; Travis, Ruth C.; Cox, David G.; Canzian, Federico; Riboli, Elio; Key, Timothy J.; Andriole, Gerald; Albanes, Demetrius; Hayes, Richard B.; Schleutker, Johanna; Auvinen, Anssi; Tammela, Teuvo L.J.; Weischer, Maren; Stanford, Janet L.; Ostrander, Elaine A.; Cybulski, Cezary; Lubinski, Jan; Thibodeau, Stephen N.; Schaid, Daniel J.; Sorensen, Karina D.; Batra, Jyotsna; Clements, Judith A.; Chambers, Suzanne; Aitken, Joanne; Gardiner, Robert A.; Maier, Christiane; Vogel, Walther; Dörk, Thilo; Brenner, Hermann; Habuchi, Tomonori; Ingles, Sue; John, Esther M.; Dickinson, Joanne L.; Cannon-Albright, Lisa; Teixeira, Manuel R.; Kaneva, Radka; Zhang, Hong-Wei; Lu, Yong-Jie; Park, Jong Y.; Cooney, Kathleen A.; Muir, Kenneth R.; Leongamornlert, Daniel A.; Saunders, Edward; Tymrakiewicz, Malgorzata; Mahmud, Nadiya; Guy, Michelle; Govindasami, Koveela; O'Brien, Lynne T.; Wilkinson, Rosemary A.; Hall, Amanda L.; Sawyer, Emma J.; Dadaev, Tokhir; Morrison, Jonathan; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas; Woodhouse, Christopher J.; Thompson, Alan; Dudderidge, Tim; Ogden, Chris; Cooper, Colin S.; Lophatonanon, Artitaya; Southey, Melissa C.; Hopper, John L.; English, Dallas; Virtamo, Jarmo; Le Marchand, Loic; Campa, Daniele; Kaaks, Rudolf; Lindstrom, Sara; Diver, W. Ryan; Gapstur, Susan; Yeager, Meredith; Cox, Angela; Stern, Mariana C.; Corral, Roman; Aly, Markus; Isaacs, William; Adolfsson, Jan; Xu, Jianfeng; Zheng, S. Lilly; Wahlfors, Tiina; Taari, Kimmo; Kujala, Paula; Klarskov, Peter; Nordestgaard, Børge G.; Røder, M. Andreas; Frikke-Schmidt, Ruth; Bojesen, Stig E.; FitzGerald, Liesel M.; Kolb, Suzanne; Kwon, Erika M.; Karyadi, Danielle M.; Orntoft, Torben Falck; Borre, Michael; Rinckleb, Antje; Luedeke, Manuel; Herkommer, Kathleen; Meyer, Andreas; Serth, Jürgen; Marthick, James R.; Patterson, Briony; Wokolorczyk, Dominika; Spurdle, Amanda; Lose, Felicity; McDonnell, Shannon K.; Joshi, Amit D.; Shahabi, Ahva; Pinto, Pedro; Santos, Joana; Ray, Ana; Sellers, Thomas A.; Lin, Hui-Yi; Stephenson, Robert A.; Teerlink, Craig; Muller, Heiko; Rothenbacher, Dietrich; Tsuchiya, Norihiko; Narita, Shintaro; Cao, Guang-Wen; Slavov, Chavdar; Mitev, Vanio; Chanock, Stephen; Gronberg, Henrik; Haiman, Christopher A.; Kraft, Peter; Easton, Douglas F.; Eeles, Rosalind A.

    2013-01-01

    Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03–1.21), P = 1.4 × 10−8]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis. PMID:23065704

  19. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

    PubMed Central

    Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi-Hsiang; Duncan, Emma L; Ntzani, Evangelia E; Oei, Ling; Albagha, Omar M E; Amin, Najaf; Kemp, John P; Koller, Daniel L; Li, Guo; Liu, Ching-Ti; Minster, Ryan L; Moayyeri, Alireza; Vandenput, Liesbeth; Willner, Dana; Xiao, Su-Mei; Yerges-Armstrong, Laura M; Zheng, Hou-Feng; Alonso, Nerea; Eriksson, Joel; Kammerer, Candace M; Kaptoge, Stephen K; Leo, Paul J; Thorleifsson, Gudmar; Wilson, Scott G; Wilson, James F; Aalto, Ville; Alen, Markku; Aragaki, Aaron K; Aspelund, Thor; Center, Jacqueline R; Dailiana, Zoe; Duggan, David J; Garcia, Melissa; Garcia-Giralt, Natàlia; Giroux, Sylvie; Hallmans, Göran; Hocking, Lynne J; Husted, Lise Bjerre; Jameson, Karen A; Khusainova, Rita; Kim, Ghi Su; Kooperberg, Charles; Koromila, Theodora; Kruk, Marcin; Laaksonen, Marika; Lacroix, Andrea Z; Lee, Seung Hun; Leung, Ping C; Lewis, Joshua R; Masi, Laura; Mencej-Bedrac, Simona; Nguyen, Tuan V; Nogues, Xavier; Patel, Millan S; Prezelj, Janez; Rose, Lynda M; Scollen, Serena; Siggeirsdottir, Kristin; Smith, Albert V; Svensson, Olle; Trompet, Stella; Trummer, Olivia; van Schoor, Natasja M; Woo, Jean; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Buckley, Brendan M; Cheng, Sulin; Christiansen, Claus; Cooper, Cyrus; Dedoussis, George; Ford, Ian; Frost, Morten; Goltzman, David; González-Macías, Jesús; Kähönen, Mika; Karlsson, Magnus; Khusnutdinova, Elza; Koh, Jung-Min; Kollia, Panagoula; Langdahl, Bente Lomholt; Leslie, William D; Lips, Paul; Ljunggren, Östen; Lorenc, Roman S; Marc, Janja; Mellström, Dan; Obermayer-Pietsch, Barbara; Olmos, José M; Pettersson-Kymmer, Ulrika; Reid, David M; Riancho, José A; Ridker, Paul M; Rousseau, François; Slagboom, P Eline; Tang, Nelson LS; Urreizti, Roser; Van Hul, Wim; Viikari, Jorma; Zarrabeitia, María T; Aulchenko, Yurii S; Castano-Betancourt, Martha; Grundberg, Elin; Herrera, Lizbeth; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Kwan, Tony; Li, Rui; Luben, Robert; Medina-Gómez, Carolina; Palsson, Stefan Th; Reppe, Sjur; Rotter, Jerome I; Sigurdsson, Gunnar; van Meurs, Joyce B J; Verlaan, Dominique; Williams, Frances MK; Wood, Andrew R; Zhou, Yanhua; Gautvik, Kaare M; Pastinen, Tomi; Raychaudhuri, Soumya; Cauley, Jane A; Chasman, Daniel I; Clark, Graeme R; Cummings, Steven R; Danoy, Patrick; Dennison, Elaine M; Eastell, Richard; Eisman, John A; Gudnason, Vilmundur; Hofman, Albert; Jackson, Rebecca D; Jones, Graeme; Jukema, J Wouter; Khaw, Kay-Tee; Lehtimäki, Terho; Liu, Yongmei; Lorentzon, Mattias; McCloskey, Eugene; Mitchell, Braxton D; Nandakumar, Kannabiran; Nicholson, Geoffrey C; Oostra, Ben A; Peacock, Munro; Pols, Huibert A P; Prince, Richard L; Raitakari, Olli; Reid, Ian R; Robbins, John; Sambrook, Philip N; Sham, Pak Chung; Shuldiner, Alan R; Tylavsky, Frances A; van Duijn, Cornelia M; Wareham, Nick J; Cupples, L Adrienne; Econs, Michael J; Evans, David M; Harris, Tamara B; Kung, Annie Wai Chee; Psaty, Bruce M; Reeve, Jonathan; Spector, Timothy D; Streeten, Elizabeth A; Zillikens, M Carola; Thorsteinsdottir, Unnur; Ohlsson, Claes; Karasik, David; Richards, J Brent; Brown, Matthew A; Stefansson, Kari; Uitterlinden, André G; Ralston, Stuart H; Ioannidis, John P A; Kiel, Douglas P; Rivadeneira, Fernando

    2012-01-01

    Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. PMID:22504420

  20. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus.

    PubMed

    Morris, David L; Sheng, Yujun; Zhang, Yan; Wang, Yong-Fei; Zhu, Zhengwei; Tombleson, Philip; Chen, Lingyan; Cunninghame Graham, Deborah S; Bentham, James; Roberts, Amy L; Chen, Ruoyan; Zuo, Xianbo; Wang, Tingyou; Wen, Leilei; Yang, Chao; Liu, Lu; Yang, Lulu; Li, Feng; Huang, Yuanbo; Yin, Xianyong; Yang, Sen; Rönnblom, Lars; Fürnrohr, Barbara G; Voll, Reinhard E; Schett, Georg; Costedoat-Chalumeau, Nathalie; Gaffney, Patrick M; Lau, Yu Lung; Zhang, Xuejun; Yang, Wanling; Cui, Yong; Vyse, Timothy J

    2016-08-01

    Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis. PMID:27399966

  1. Comprehensive Meta-analysis of Ontology Annotated 16S rRNA Profiles Identifies Beta Diversity Clusters of Environmental Bacterial Communities

    PubMed Central

    Henschel, Andreas; Anwar, Muhammad Zohaib; Manohar, Vimitha

    2015-01-01

    Comprehensive mapping of environmental microbiomes in terms of their compositional features remains a great challenge in understanding the microbial biosphere of the Earth. It bears promise to identify the driving forces behind the observed community patterns and whether community assembly happens deterministically. Advances in Next Generation Sequencing allow large community profiling studies, exceeding sequencing data output of conventional methods in scale by orders of magnitude. However, appropriate collection systems are still in a nascent state. We here present a database of 20,427 diverse environmental 16S rRNA profiles from 2,426 independent studies, which forms the foundation of our meta-analysis. We conducted a sample size adaptive all-against-all beta diversity comparison while also respecting phylogenetic relationships of Operational Taxonomic Units(OTUs). After conventional hierarchical clustering we systematically test for enrichment of Environmental Ontology terms and their abstractions in all possible clusters. This post-hoc algorithm provides a novel formalism that quantifies to what extend compositional and semantic similarity of microbial community samples coincide. We automatically visualize significantly enriched subclusters on a comprehensive dendrogram of microbial communities. As a result we obtain the hitherto most differentiated and comprehensive view on global patterns of microbial community diversity. We observe strong clusterability of microbial communities in ecosystems such as human/mammal-associated, geothermal, fresh water, plant-associated, soils and rhizosphere microbiomes, whereas hypersaline and anthropogenic samples are less homogeneous. Moreover, saline samples appear less cohesive in terms of compositional properties than previously reported. PMID:26458130

  2. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus

    PubMed Central

    Wang, Yong-Fei; Zhu, Zhengwei; Tombleson, Philip; Chen, Lingyan; Cunninghame Graham, Deborah S; Bentham, James; Roberts, Amy L; Chen, Ruoyan; Zuo, Xianbo; Wang, Tingyou; Wen, Leilei; Yang, Chao; Liu, Lu; Yang, Lulu; Li, Feng; Huang, Yuanbo; Yin, Xianyong; Yang, Sen; Rönnblom, Lars; Fürnrohr, Barbara G; Voll, Reinhard E; Schett, Georg; Costedoat-Chalumeau, Nathalie; Gaffney, Patrick M; Lau, Yu Lung; Zhang, Xuejun; Yang, Wanling; Cui, Yong

    2016-01-01

    Systemic lupus erythematosus (SLE; OMIM 1 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis. PMID:27399966

  3. Meta-Analysis of Arabidopsis KANADI1 Direct Target Genes Identifies a Basic Growth-Promoting Module Acting Upstream of Hormonal Signaling Pathways1[OPEN

    PubMed Central

    Xie, Yakun; Straub, Daniel; Eguen, Tenai; Brandt, Ronny; Stahl, Mark; Martínez-García, Jaime F.; Wenkel, Stephan

    2015-01-01

    An intricate network of antagonistically acting transcription factors mediates the formation of a flat leaf lamina of Arabidopsis (Arabidopsis thaliana) plants. In this context, members of the class III homeodomain leucine zipper (HD-ZIPIII) transcription factor family specify the adaxial domain (future upper side) of the leaf, while antagonistically acting KANADI transcription factors determine the abaxial domain (future lower side). Here, we used a messenger RNA sequencing approach to identify genes regulated by KANADI1 (KAN1) and subsequently performed a meta-analysis combining our data sets with published genome-wide data sets. Our analysis revealed that KAN1 acts upstream of several genes encoding auxin biosynthetic enzymes. When exposed to shade, we found three YUCCA genes, YUC2, YUC5, and YUC8, to be transcriptionally up-regulated, which correlates with an increase in the levels of free auxin. When ectopically expressed, KAN1 is able to transcriptionally repress these three YUC genes and thereby block shade-induced auxin biosynthesis. Consequently, KAN1 is able to strongly suppress shade-avoidance responses. Taken together, we hypothesize that HD-ZIPIII/KAN form the basis of a basic growth-promoting module. Hypocotyl extension in the shade and outgrowth of new leaves both involve auxin synthesis and signaling, which are under the direct control of HD-ZIPIII/KAN. PMID:26246448

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

    PubMed

    Berndt, Sonja I; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F; Justice, Anne E; Monda, Keri L; Croteau-Chonka, Damien C; Day, Felix R; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U; Luan, Jian'an; Randall, Joshua C; Vedantam, Sailaja; Willer, Cristen J; Winkler, Thomas W; Wood, Andrew R; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L; Neale, Benjamin M; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E; Jarick, Ivonne; Johansson, Åsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E; König, Inke R; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S; Nolte, Ilja M; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J; Preuss, Michael; Rose, Lynda M; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J; Surakka, Ida; Teumer, Alexander; Trip, Mieke D; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V; Vandenput, Liesbeth; Waite, Lindsay L; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W; Atalay, Mustafa; Attwood, Antony P; Balmforth, Anthony J; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I; Chines, Peter S; Collins, Francis S; Connell, John M; Cookson, William O; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M; Farrall, Martin; Ferrario, Marco M; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L; Heath, Andrew C; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B; Hunt, Sarah E; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimäki, Mika; Koenig, Wolfgang; Kraja, Aldi T; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H; Lakka, Timo A; Langenberg, Claudia; Launer, Lenore J; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A; Magnusson, Patrik K; Manunta, Paolo; Marek, Diana; März, Winfried; Mateo Leach, Irene; McKnight, Barbara; Medland, Sarah E; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W; Mooser, Vincent; Mühleisen, Thomas W; Munroe, Patricia B; Musk, Arthur W; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A; Ong, Ken K; Oostra, Ben A; Palmer, Colin N A; Palotie, Aarno; Peden, John F; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E; Sambrook, Jennifer G; Sanders, Alan R; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stančáková, Alena; Stark, Klaus; Stephens, Jonathan C; Stirrups, Kathleen; Stolk, Ronald P; Stumvoll, Michael; Swift, Amy J; Theodoraki, Eirini V; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M; van Meurs, Joyce B J; Vermeulen, Sita H; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H; Willemsen, Gonneke; Winkelmann, Bernhard R; Witteman, Jacqueline C M; Wolffenbuttel, Bruce H R; Wong, Andrew; Wright, Alan F; Zillikens, M Carola; Amouyel, Philippe; Boehm, Bernhard O; Boerwinkle, Eric; Boomsma, Dorret I; Caulfield, Mark J; Chanock, Stephen J; Cupples, L Adrienne; Cusi, Daniele; Dedoussis, George V; Erdmann, Jeanette; Eriksson, Johan G; Franks, Paul W; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B; Hengstenberg, Christian; Hicks, Andrew A; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Levinson, Douglas F; Martin, Nicholas G; Metspalu, Andres; Morris, Andrew D; Nieminen, Markku S; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J; Ouwehand, Willem H; Palmer, Lyle J; Penninx, Brenda; Power, Chris; Province, Michael A; Psaty, Bruce M; Qi, Lu; Rauramaa, Rainer; Ridker, Paul M; Ripatti, Samuli; Salomaa, Veikko; Samani, Nilesh J; Snieder, Harold; Sørensen, Thorkild I A; Spector, Timothy D; Stefansson, Kari; Tönjes, Anke; Tuomilehto, Jaakko; Uitterlinden, André G; Uusitupa, Matti; van der Harst, Pim; Vollenweider, Peter; Wallaschofski, Henri; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Wilson, James F; Abecasis, Goncalo R; Assimes, Themistocles L; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Fox, Caroline S; Frayling, Timothy; Groop, Leif C; Haritunian, Talin; Heid, Iris M; Hunter, David; Kaplan, Robert C; Karpe, Fredrik; Moffatt, Miriam F; Mohlke, Karen L; O'Connell, Jeffrey R; Pawitan, Yudi; Schadt, Eric E; Schlessinger, David; Steinthorsdottir, Valgerdur; Strachan, David P; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Visscher, Peter M; Di Blasio, Anna Maria; Hirschhorn, Joel N; Lindgren, Cecilia M; Morris, Andrew P; Meyre, David; Scherag, André; McCarthy, Mark I; Speliotes, Elizabeth K; North, Kari E; Loos, Ruth J F; Ingelsson, Erik

    2013-05-01

    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.

  5. Meta-analysis of genome-wide association studies identifies genetic risk factors for stroke in African-Americans

    PubMed Central

    Carty, Cara L.; Keene, Keith L.; Cheng, Yu-Ching; Meschia, James F.; Chen, Wei-Min; Nalls, Mike; Bis, Joshua C.; Kittner, Steven J.; Rich, Stephen S.; Tajuddin, Salman; Zonderman, Alan B.; Evans, Michele K.; Langefeld, Carl D.; Gottesman, Rebecca; Mosley, Thomas H.; Shahar, Eyal; Woo, Daniel; Yaffe, Kristine; Liu, YongMei; Sale, Michèle M.; Dichgans, Martin; Malik, Rainer; Longstreth, WT; Mitchell, Braxton D.; Psaty, Bruce M.; Kooperberg, Charles; Reiner, Alexander; Worrall, Bradford B.; Fornage, Myriam

    2015-01-01

    Background and Purpose The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African-Americans despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population genome-wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Methods Using METAL, we conducted meta-analyses of GWAS in 14,746 African-Americans (1,365 ischemic and 1,592 total stroke cases) from COMPASS, and tested SNPs with P<10−6 for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. Results The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613, P=3.9×10−8) in African-Americans. Nominal associations (P<10−6) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/ mRNA pre-splicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS. Conclusions We identified a novel SNP associated with total stroke in African-Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African-Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations. PMID:26089329

  6. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

    PubMed Central

    Cordell, Heather J.; Han, Younghun; Mells, George F.; Li, Yafang; Hirschfield, Gideon M.; Greene, Casey S.; Xie, Gang; Juran, Brian D.; Zhu, Dakai; Qian, David C.; Floyd, James A. B.; Morley, Katherine I.; Prati, Daniele; Lleo, Ana; Cusi, Daniele; Schlicht, Erik M; Lammert, Craig; Atkinson, Elizabeth J; Chan, Landon L; de Andrade, Mariza; Balschun, Tobias; Mason, Andrew L; Myers, Robert P; Zhang, Jinyi; Milkiewicz, Piotr; Qu, Jia; Odin, Joseph A; Luketic, Velimir A; Bacon, Bruce R; Bodenheimer Jr, Henry C; Liakina, Valentina; Vincent, Catherine; Levy, Cynthia; Gregersen, Peter K; Almasio, Piero L; Alvaro, Domenico; Andreone, Pietro; Andriulli, Angelo; Barlassina, Cristina; Battezzati, Pier Maria; Benedetti, Antonio; Bernuzzi, Francesca; Bianchi, Ilaria; Bragazzi, Maria Consiglia; Brunetto, Maurizia; Bruno, Savino; Casella, Giovanni; Coco, Barbara; Colli, Agostino; Colombo, Massimo; Colombo, Silvia; Cursaro, Carmela; Crocè, Lory Saveria; Crosignani, Andrea; Donato, Maria Francesca; Elia, Gianfranco; Fabris, Luca; Ferrari, Carlo; Floreani, Annarosa; Foglieni, Barbara; Fontana, Rosanna; Galli, Andrea; Lazzari, Roberta; Macaluso, Fabio; Malinverno, Federica; Marra, Fabio; Marzioni, Marco; Mattalia, Alberto; Montanari, Renzo; Morini, Lorenzo; Morisco, Filomena; Hani S, Mousa; Muratori, Luigi; Muratori, Paolo; Niro, Grazia A; Palmieri, Vincenzo O; Picciotto, Antonio; Podda, Mauro; Portincasa, Piero; Ronca, Vincenzo; Rosina, Floriano; Rossi, Sonia; Sogno, Ilaria; Spinzi, Giancarlo; Spreafico, Marta; Strazzabosco, Mario; Tarallo, Sonia; Tarocchi, Mirko; Tiribelli, Claudio; Toniutto, Pierluigi; Vinci, Maria; Zuin, Massimo; Ch'ng, Chin Lye; Rahman, Mesbah; Yapp, Tom; Sturgess, Richard; Healey, Christopher; Czajkowski, Marek; Gunasekera, Anton; Gyawali, Pranab; Premchand, Purushothaman; Kapur, Kapil; Marley, Richard; Foster, Graham; Watson, Alan; Dias, Aruna; Subhani, Javaid; Harvey, Rory; McCorry, Roger; Ramanaden, David; Gasem, Jaber; Evans, Richard; Mathialahan, Thiriloganathan; Shorrock, Christopher; Lipscomb, George; Southern, Paul; Tibble, Jeremy; Gorard, David; Palegwala, Altaf; Jones, Susan; Carbone, Marco; Dawwas, Mohamed; Alexander, Graeme; Dolwani, Sunil; Prince, Martin; Foxton, Matthew; Elphick, David; Mitchison, Harriet; Gooding, Ian; Karmo, Mazn; Saksena, Sushma; Mendall, Mike; Patel, Minesh; Ede, Roland; Austin, Andrew; Sayer, Joanna; Hankey, Lorraine; Hovell, Christopher; Fisher, Neil; Carter, Martyn; Koss, Konrad; Piotrowicz, Andrzej; Grimley, Charles; Neal, David; Lim, Guan; Levi, Sass; Ala, Aftab; Broad, Andrea; Saeed, Athar; Wood, Gordon; Brown, Jonathan; Wilkinson, Mark; Gordon, Harriet; Ramage, John; Ridpath, Jo; Ngatchu, Theodore; Grover, Bob; Shaukat, Syed; Shidrawi, Ray; Abouda, George; Ali, Faiz; Rees, Ian; Salam, Imroz; Narain, Mark; Brown, Ashley; Taylor-Robinson, Simon; Williams, Simon; Grellier, Leonie; Banim, Paul; Das, Debashis; Chilton, Andrew; Heneghan, Michael; Curtis, Howard; Gess, Markus; Drake, Ian; Aldersley, Mark; Davies, Mervyn; Jones, Rebecca; McNair, Alastair; Srirajaskanthan, Raj; Pitcher, Maxton; Sen, Sambit; Bird, George; Barnardo, Adrian; Kitchen, Paul; Yoong, Kevin; Chirag, Oza; Sivaramakrishnan, Nurani; MacFaul, George; Jones, David; Shah, Amir; Evans, Chris; Saha, Subrata; Pollock, Katharine; Bramley, Peter; Mukhopadhya, Ashis; Fraser, Andrew; Mills, Peter; Shallcross, Christopher; Campbell, Stewart; Bathgate, Andrew; Shepherd, Alan; Dillon, John; Rushbrook, Simon; Przemioslo, Robert; Macdonald, Christopher; Metcalf, Jane; Shmueli, Udi; Davis, Andrew; Naqvi, Asifabbas; Lee, Tom; Ryder, Stephen D; Collier, Jane; Klass, Howard; Ninkovic, Mary; Cramp, Matthew; Sharer, Nicholas; Aspinall, Richard; Goggin, Patrick; Ghosh, Deb; Douds, Andrew; Hoeroldt, Barbara; Booth, Jonathan; Williams, Earl; Hussaini, Hyder; Stableforth, William; Ayres, Reuben; Thorburn, Douglas; Marshall, Eileen; Burroughs, Andrew; Mann, Steven; Lombard, Martin; Richardson, Paul; Patanwala, Imran; Maltby, Julia; Brookes, Matthew; Mathew, Ray; Vyas, Samir; Singhal, Saket; Gleeson, Dermot; Misra, Sharat; Butterworth, Jeff; George, Keith; Harding, Tim; Douglass, Andrew; Panter, Simon; Shearman, Jeremy; Bray, Gary; Butcher, Graham; Forton, Daniel; Mclindon, John; Cowan, Matthew; Whatley, Gregory; Mandal, Aditya; Gupta, Hemant; Sanghi, Pradeep; Jain, Sanjiv; Pereira, Steve; Prasad, Geeta; Watts, Gill; Wright, Mark; Neuberger, James; Gordon, Fiona; Unitt, Esther; Grant, Allister; Delahooke, Toby; Higham, Andrew; Brind, Alison; Cox, Mark; Ramakrishnan, Subramaniam; King, Alistair; Collins, Carole; Whalley, Simon; Li, Andy; Fraser, Jocelyn; Bell, Andrew; Wong, Voi Shim; Singhal, Amit; Gee, Ian; Ang, Yeng; Ransford, Rupert; Gotto, James; Millson, Charles; Bowles, Jane; Thomas, Caradog; Harrison, Melanie; Galaska, Roman; Kendall, Jennie; Whiteman, Jessica; Lawlor, Caroline; Gray, Catherine; Elliott, Keith; Mulvaney-Jones, Caroline; Hobson, Lucie; Van Duyvenvoorde, Greta; Loftus, Alison; Seward, Katie; Penn, Ruth; Maiden, Jane; Damant, Rose; Hails, Janeane; Cloudsdale, Rebecca; Silvestre, Valeria; Glenn, Sue; Dungca, Eleanor; Wheatley, Natalie; Doyle, Helen; Kent, Melanie; Hamilton, Caroline; Braim, Delyth; Wooldridge, Helen; Abrahams, Rachel; Paton, Alison; Lancaster, Nicola; Gibbins, Andrew; Hogben, Karen; Desousa, Phillipa; Muscariu, Florin; Musselwhite, Janine; McKay, Alexandra; Tan, LaiTing; Foale, Carole; Brighton, Jacqueline; Flahive, Kerry; Nambela, Estelle; Townshend, Paula; Ford, Chris; Holder, Sophie; Palmer, Caroline; Featherstone, James; Nasseri, Mariam; Sadeghian, Joy; Williams, Bronwen; Thomas, Carol; Rolls, Sally-Ann; Hynes, Abigail; Duggan, Claire; Jones, Sarah; Crossey, Mary; Stansfield, Glynis; MacNicol, Carolyn; Wilkins, Joy; Wilhelmsen, Elva; Raymode, Parizade; Lee, Hye-Jeong; Durant, Emma; Bishop, Rebecca; Ncube, Noma; Tripoli, Sherill; Casey, Rebecca; Cowley, Caroline; Miller, Richard; Houghton, Kathryn; Ducker, Samantha; Wright, Fiona; Bird, Bridget; Baxter, Gwen; Keggans, Janie; Hughes, Maggie; Grieve, Emma; Young, Karin; Williams, D; Ocker, Kate; Hines, Frances; Martin, Kirsty; Innes, Caron; Valliani, Talal; Fairlamb, Helen; Thornthwaite, Sarah; Eastick, Anne; Tanqueray, Elizabeth; Morrison, Jennifer; Holbrook, Becky; Browning, Julie; Walker, Kirsten; Congreave, Susan; Verheyden, Juliette; Slininger, Susan; Stafford, Lizzie; O'Donnell, Denise; Ainsworth, Mark; Lord, Susan; Kent, Linda; March, Linda; Dickson, Christine; Simpson, Diane; Longhurst, Beverley; Hayes, Maria; Shpuza, Ervin; White, Nikki; Besley, Sarah; Pearson, Sallyanne; Wright, Alice; Jones, Linda; Gunter, Emma; Dewhurst, Hannah; Fouracres, Anna; Farrington, Liz; Graves, Lyn; Marriott, Suzie; Leoni, Marina; Tyrer, David; Martin, Kate; Dali-kemmery, Lola; Lambourne, Victoria; Green, Marie; Sirdefield, Dawn; Amor, Kelly; Colley, Julie; Shinder, Bal; Jones, Jayne; Mills, Marisa; Carnahan, Mandy; Taylor, Natalie; Boulton, Kerenza; Tregonning, Julie; Brown, Carly; Clifford, Gayle; Archer, Emily; Hamilton, Maria; Curtis, Janette; Shewan, Tracey; Walsh, Sue; Warner, Karen; Netherton, Kimberley; Mupudzi, Mcdonald; Gunson, Bridget; Gitahi, Jane; Gocher, Denise; Batham, Sally; Pateman, Hilary; Desmennu, Senayon; Conder, Jill; Clement, Darren; Gallagher, Susan; Orpe, Jacky; Chan, PuiChing; Currie, Lynn; O'Donohoe, Lynn; Oblak, Metod; Morgan, Lisa; Quinn, Marie; Amey, Isobel; Baird, Yolanda; Cotterill, Donna; Cumlat, Lourdes; Winter, Louise; Greer, Sandra; Spurdle, Katie; Allison, Joanna; Dyer, Simon; Sweeting, Helen; Kordula, Jean; Gershwin, M. Eric; Anderson, Carl A.; Lazaridis, Konstantinos N.; Invernizzi, Pietro; Seldin, Michael F.; Sandford, Richard N.; Amos, Christopher I.; Siminovitch, Katherine A.

    2015-01-01

    Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine–cytokine pathways, for which relevant therapies exist. PMID:26394269

  7. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

    PubMed

    Cordell, Heather J; Han, Younghun; Mells, George F; Li, Yafang; Hirschfield, Gideon M; Greene, Casey S; Xie, Gang; Juran, Brian D; Zhu, Dakai; Qian, David C; Floyd, James A B; Morley, Katherine I; Prati, Daniele; Lleo, Ana; Cusi, Daniele; Gershwin, M Eric; Anderson, Carl A; Lazaridis, Konstantinos N; Invernizzi, Pietro; Seldin, Michael F; Sandford, Richard N; Amos, Christopher I; Siminovitch, Katherine A

    2015-01-01

    Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist. PMID:26394269

  8. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

    PubMed

    Cordell, Heather J; Han, Younghun; Mells, George F; Li, Yafang; Hirschfield, Gideon M; Greene, Casey S; Xie, Gang; Juran, Brian D; Zhu, Dakai; Qian, David C; Floyd, James A B; Morley, Katherine I; Prati, Daniele; Lleo, Ana; Cusi, Daniele; Gershwin, M Eric; Anderson, Carl A; Lazaridis, Konstantinos N; Invernizzi, Pietro; Seldin, Michael F; Sandford, Richard N; Amos, Christopher I; Siminovitch, Katherine A

    2015-01-01

    Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

  9. Efficacy and Safety of Bevacizumab Combined with Chemotherapy for Managing Metastatic Breast Cancer: A Meta-Analysis of Randomized Controlled Trials.

    PubMed

    Li, Qin; Yan, Han; Zhao, Pengfei; Yang, Yifan; Cao, Bangwei

    2015-01-01

    Although the FDA revoked metastatic breast cancer (MBC) from bevacizumab (BEV) indication in 2011, BEV combined with paclitaxel has been written in the breast cancer NCCN guidelines. This systematic assessment was performed to evaluate the efficacy and safety of BEV + chemotherapy (CHE) for managing MBC. PubMed and EMBASE were searched for original articles written in English and published before July, 2015. Progression-free survival was significantly improved in the CHE + BEV arms compared to the CHE arms in overall group and in human epidermal growth factor receptor 2-negative group (HR 0.75, 95% CI: 0.68-0.84, P < 0.001; HR 0.75, 95% CI: 0.69-0.82, P < 0.001). There were no significant improvement in overall survival in the CHE + BEV arms compared to the CHE arms. Significantly more grade 3 febrile neutropenia, hypertension, proteinuria, and cardiac events were observed in the CHE + BEV arm, which are controllable and reversible. Severe bleeding occurred more in the BEV + taxane arms and in patients with brain metastases. Therefore, CHE + BEV significantly increases progression-free survival in patients with MBC, it should be considered as a treatment option for these patients under the premise of reasonable selection of target population and combined CHE drugs. PMID:26503902

  10. Efficacy and Safety of Bevacizumab Combined with Chemotherapy for Managing Metastatic Breast Cancer: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Li, Qin; Yan, Han; Zhao, Pengfei; Yang, Yifan; Cao, Bangwei

    2015-01-01

    Although the FDA revoked metastatic breast cancer (MBC) from bevacizumab (BEV) indication in 2011, BEV combined with paclitaxel has been written in the breast cancer NCCN guidelines. This systematic assessment was performed to evaluate the efficacy and safety of BEV + chemotherapy (CHE) for managing MBC. PubMed and EMBASE were searched for original articles written in English and published before July, 2015. Progression-free survival was significantly improved in the CHE + BEV arms compared to the CHE arms in overall group and in human epidermal growth factor receptor 2-negative group (HR 0.75, 95% CI: 0.68–0.84, P < 0.001; HR 0.75, 95% CI: 0.69–0.82, P < 0.001). There were no significant improvement in overall survival in the CHE + BEV arms compared to the CHE arms. Significantly more grade 3 febrile neutropenia, hypertension, proteinuria, and cardiac events were observed in the CHE + BEV arm, which are controllable and reversible. Severe bleeding occurred more in the BEV + taxane arms and in patients with brain metastases. Therefore, CHE + BEV significantly increases progression-free survival in patients with MBC, it should be considered as a treatment option for these patients under the premise of reasonable selection of target population and combined CHE drugs. PMID:26503902

  11. Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder.

    PubMed

    Chen, D T; Jiang, X; Akula, N; Shugart, Y Y; Wendland, J R; Steele, C J M; Kassem, L; Park, J-H; Chatterjee, N; Jamain, S; Cheng, A; Leboyer, M; Muglia, P; Schulze, T G; Cichon, S; Nöthen, M M; Rietschel, M; McMahon, F J; Farmer, A; McGuffin, P; Craig, I; Lewis, C; Hosang, G; Cohen-Woods, S; Vincent, J B; Kennedy, J L; Strauss, J

    2013-02-01

    Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750,000 high-quality genetic markers on a combined sample of ∼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.

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

    PubMed Central

    Berndt, Sonja I.; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F.; Justice, Anne E.; Monda, Keri L.; Croteau-Chonka, Damien C.; Day, Felix R.; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U.; Luan, Jian’an; Randall, Joshua C.; Vedantam, Sailaja; Willer, Cristen J.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L.; Neale, Benjamin M.; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L.; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jarick, Ivonne; Johansson, Åsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E.; König, Inke R.; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L.; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S.; Nolte, Ilja M.; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J.; Preuss, Michael; Rose, Lynda M.; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J.; Surakka, Ida; Teumer, Alexander; Trip, Mieke D.; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V.; Vandenput, Liesbeth; Waite, Lindsay L.; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W.; Atalay, Mustafa; Attwood, Antony P.; Balmforth, Anthony J.; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L.; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Connell, John M.; Cookson, William; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M.; Farrall, Martin; Ferrario, Marco M.; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V.; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S.; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L.; Heath, Andrew C.; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B.; Hunt, Sarah E.; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B.; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimaki, Mika; Koenig, Wolfgang; Kraja, Aldi T.; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H.; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A.; Magnusson, Patrik K.; Manunta, Paolo; Marek, Diana; März, Winfried; Mateo Leach, Irene; McKnight, Barbara; Medland, Sarah E.; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W.; Mooser, Vincent; Mühleisen, Thomas W.; Munroe, Patricia B.; Musk, Arthur W.; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A.; Ong, Ken K.; Oostra, Ben A.; Palmer, Colin N.A.; Palotie, Aarno; Peden, John F.; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E.; Sambrook, Jennifer G.; Sanders, Alan R.; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stančáková, Alena; Stark, Klaus; Stephens, Jonathan C.; Stirrups, Kathleen; Stolk, Ronald P.; Stumvoll, Michael; Swift, Amy J.; Theodoraki, Eirini V.; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M.; van Meurs, Joyce B.J.; Vermeulen, Sita H.; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Winkelmann, Bernhard R.; Witteman, Jacqueline C.M.; Wolffenbuttel, Bruce H.R.; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Amouyel, Philippe; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Cupples, L. Adrienne; Cusi, Daniele; Dedoussis, George V.; Erdmann, Jeanette; Eriksson, Johan G.; Franks, Paul W.; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hengstenberg, Christian; Hicks, Andrew A.; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz

    2014-01-01

    Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups. PMID:23563607

  13. Network-based SNP meta-analysis identifies joint and disjoint genetic features across common human diseases

    PubMed Central

    2012-01-01

    Background Genome-wide association studies (GWAS) have provided a large set of genetic loci influencing the risk for many common diseases. Association studies typically analyze one specific trait in single populations in an isolated fashion without taking into account the potential phenotypic and genetic correlation between traits. However, GWA data can be efficiently used to identify overlapping loci with analogous or contrasting effects on different diseases. Results Here, we describe a new approach to systematically prioritize and interpret available GWA data. We focus on the analysis of joint and disjoint genetic determinants across diseases. Using network analysis, we show that variant-based approaches are superior to locus-based analyses. In addition, we provide a prioritization of disease loci based on network properties and discuss the roles of hub loci across several diseases. We demonstrate that, in general, agonistic associations appear to reflect current disease classifications, and present the potential use of effect sizes in refining and revising these agonistic signals. We further identify potential branching points in disease etiologies based on antagonistic variants and describe plausible small-scale models of the underlying molecular switches. Conclusions The observation that a surprisingly high fraction (>15%) of the SNPs considered in our study are associated both agonistically and antagonistically with related as well as unrelated disorders indicates that the molecular mechanisms influencing causes and progress of human diseases are in part interrelated. Genetic overlaps between two diseases also suggest the importance of the affected entities in the specific pathogenic pathways and should be investigated further. PMID:22988944

  14. A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci.

    PubMed

    Hinds, David A; McMahon, George; Kiefer, Amy K; Do, Chuong B; Eriksson, Nicholas; Evans, David M; St Pourcain, Beate; Ring, Susan M; Mountain, Joanna L; Francke, Uta; Davey-Smith, George; Timpson, Nicholas J; Tung, Joyce Y

    2013-08-01

    Allergic disease is very common and carries substantial public-health burdens. We conducted a meta-analysis of genome-wide associations with self-reported cat, dust-mite and pollen allergies in 53,862 individuals. We used generalized estimating equations to model shared and allergy-specific genetic effects. We identified 16 shared susceptibility loci with association P<5×10(-8), including 8 loci previously associated with asthma, as well as 4p14 near TLR1, TLR6 and TLR10 (rs2101521, P=5.3×10(-21)); 6p21.33 near HLA-C and MICA (rs9266772, P=3.2×10(-12)); 5p13.1 near PTGER4 (rs7720838, P=8.2×10(-11)); 2q33.1 in PLCL1 (rs10497813, P=6.1×10(-10)), 3q28 in LPP (rs9860547, P=1.2×10(-9)); 20q13.2 in NFATC2 (rs6021270, P=6.9×10(-9)), 4q27 in ADAD1 (rs17388568, P=3.9×10(-8)); and 14q21.1 near FOXA1 and TTC6 (rs1998359, P=4.8×10(-8)). We identified one locus with substantial evidence of differences in effects across allergies at 6p21.32 in the class II human leukocyte antigen (HLA) region (rs17533090, P=1.7×10(-12)), which was strongly associated with cat allergy. Our study sheds new light on the shared etiology of immune and autoimmune disease. PMID:23817569

  15. Systematic large-scale meta-analysis identifies a panel of two mRNAs as blood biomarkers for colorectal cancer detection.

    PubMed

    Rodia, Maria Teresa; Ugolini, Giampaolo; Mattei, Gabriella; Montroni, Isacco; Zattoni, Davide; Ghignone, Federico; Veronese, Giacomo; Marisi, Giorgia; Lauriola, Mattia; Strippoli, Pierluigi; Solmi, Rossella

    2016-05-24

    Colorectal cancer (CRC) is the third most common cancer in the world. A significant survival rate is achieved if it is detected at an early stage. A whole blood screening test, without any attempt to isolate blood fractions, could be an important tool to improve early detection of colorectal cancer. We searched for candidate markers with a novel approach based on the Transcriptome Mapper (TRAM), aimed at identifying specific RNAs with the highest differential expression ratio between colorectal cancer tissue and normal blood samples. This tool permits a large-scale systematic meta-analysis of all available data obtained by microarray experiments. The targeting of RNA took into consideration that tumour phenotypic variation is associated with changes in the mRNA levels of genes regulating or affecting this variation.A real time quantitative reverse transcription polymerase chain reaction (qRT- PCR) was applied to the validation of candidate markers in the blood of 67 patients and 67 healthy controls. The expression of genes: TSPAN8, LGALS4, COL1A2 and CEACAM6 resulted as being statistically different.In particular ROC curves attested for TSPAN8 an AUC of 0.751 with a sensitivity of 83.6% and a specificity of 58.2% at a cut off of 10.85, while the panel of the two best genes showed an AUC of 0.861 and a sensitivity of 92.5% with a specificity of 67.2%.Our preliminary study on a total of 134 subjects showed promising results for a blood screening test to be validated in a larger cohort with the staging stratification and in patients with other gastrointestinal diseases. PMID:26993598

  16. Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions.

    PubMed

    Amin, Najaf; Hottenga, Jouke-Jan; Hansell, Narelle K; Janssens, A Cecile J W; de Moor, Marleen H M; Madden, Pamela A F; Zorkoltseva, Irina V; Penninx, Brenda W; Terracciano, Antonio; Uda, Manuela; Tanaka, Toshiko; Esko, Tonu; Realo, Anu; Ferrucci, Luigi; Luciano, Michelle; Davies, Gail; Metspalu, Andres; Abecasis, Goncalo R; Deary, Ian J; Raikkonen, Katri; Bierut, Laura J; Costa, Paul T; Saviouk, Viatcheslav; Zhu, Gu; Kirichenko, Anatoly V; Isaacs, Aaron; Aulchenko, Yurii S; Willemsen, Gonneke; Heath, Andrew C; Pergadia, Michele L; Medland, Sarah E; Axenovich, Tatiana I; de Geus, Eco; Montgomery, Grant W; Wright, Margaret J; Oostra, Ben A; Martin, Nicholas G; Boomsma, Dorret I; van Duijn, Cornelia M

    2013-08-01

    Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10(-06), KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene. PMID:23211697

  17. A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2.

    PubMed

    Wu, Ying; Gao, He; Li, Huaixing; Tabara, Yasuharu; Nakatochi, Masahiro; Chiu, Yen-Feng; Park, Eun Jung; Wen, Wanqing; Adair, Linda S; Borja, Judith B; Cai, Qiuyin; Chang, Yi-Cheng; Chen, Peng; Croteau-Chonka, Damien C; Fogarty, Marie P; Gan, Wei; He, Chih-Tsueng; Hsiung, Chao A; Hwu, Chii-Min; Ichihara, Sahoko; Igase, Michiya; Jo, Jaeseong; Kato, Norihiro; Kawamoto, Ryuichi; Kuzawa, Christophor W; Lee, Jeannette J M; Liu, Jianjun; Lu, Ling; McDade, Thomas W; Osawa, Haruhiko; Sheu, Wayne H-H; Teo, Yvonne; Vadlamudi, Swarooparani; Van Dam, Rob M; Wang, Yiqin; Xiang, Yong-Bing; Yamamoto, Ken; Ye, Xingwang; Young, Terri L; Zheng, Wei; Zhu, Jingwen; Shu, Xiao-Ou; Shin, Chol; Jee, Sun Ha; Chuang, Lee-Ming; Miki, Tetsuro; Yokota, Mitsuhiro; Lin, Xu; Mohlke, Karen L; Tai, E Shyong

    2014-02-15

    Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10(-4)), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10(-4)) and body mass index (BMI)-adjusted waist-hip ratio (P = 9.8 × 10(-3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.

  18. A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2

    PubMed Central

    Wu, Ying; Gao, He; Li, Huaixing; Tabara, Yasuharu; Nakatochi, Masahiro; Chiu, Yen-Feng; Park, Eun Jung; Wen, Wanqing; Adair, Linda S.; Borja, Judith B.; Cai, Qiuyin; Chang, Yi-Cheng; Chen, Peng; Croteau-Chonka, Damien C.; Fogarty, Marie P.; Gan, Wei; He, Chih-Tsueng; Hsiung, Chao A.; Hwu, Chii-Min; Ichihara, Sahoko; Igase, Michiya; Jo, Jaeseong; Kato, Norihiro; Kawamoto, Ryuichi; Kuzawa, Christophor W.; Lee, Jeannette J.M.; Liu, Jianjun; Lu, Ling; Mcdade, Thomas W.; Osawa, Haruhiko; Sheu, Wayne H-H.; Teo, Yvonne; Vadlamudi, Swarooparani; Van Dam, Rob M.; Wang, Yiqin; Xiang, Yong-Bing; Yamamoto, Ken; Ye, Xingwang; Young, Terri L.; Zheng, Wei; Zhu, Jingwen; Shu, Xiao-Ou; Shin, Chol; Jee, Sun Ha; Chuang, Lee-Ming; Miki, Tetsuro; Yokota, Mitsuhiro; Lin, Xu; Mohlke, Karen L; Tai, E Shyong

    2014-01-01

    Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10−14) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10−7). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10−165), ADIPOQ (P = 1.8 × 10−22), PEPD (P = 3.6 × 10−12), CMIP (P = 2.1 × 10−10), ZNF664 (P = 2.3 × 10−7) and GPR109A (P = 7.4 × 10−6). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10−7). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10−4), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10−4) and body mass index (BMI)-adjusted waist–hip ratio (P = 9.8 × 10−3). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms. PMID:24105470

  19. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

    PubMed Central

    Siddiq, Afshan; Couch, Fergus J.; Chen, Gary K.; Lindström, Sara; Eccles, Diana; Millikan, Robert C.; Michailidou, Kyriaki; Stram, Daniel O.; Beckmann, Lars; Rhie, Suhn Kyong; Ambrosone, Christine B.; Aittomäki, Kristiina; Amiano, Pilar; Apicella, Carmel; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Berg, Christine D.; Bernstein, Leslie; Blomqvist, Carl; Brauch, Hiltrud; Brinton, Louise; Bui, Quang M.; Buring, Julie E.; Buys, Saundra S.; Campa, Daniele; Carpenter, Jane E.; Chasman, Daniel I.; Chang-Claude, Jenny; Chen, Constance; Clavel-Chapelon, Françoise; Cox, Angela; Cross, Simon S.; Czene, Kamila; Deming, Sandra L.; Diasio, Robert B.; Diver, W. Ryan; Dunning, Alison M.; Durcan, Lorraine; Ekici, Arif B.; Fasching, Peter A.; Feigelson, Heather Spencer; Fejerman, Laura; Figueroa, Jonine D.; Fletcher, Olivia; Flesch-Janys, Dieter; Gaudet, Mia M.; Gerty, Susan M.; Rodriguez-Gil, Jorge L.; Giles, Graham G.; van Gils, Carla H.; Godwin, Andrew K.; Graham, Nikki; Greco, Dario; Hall, Per; Hankinson, Susan E.; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Hoover, Robert N.; Hopper, John L.; Hu, Jennifer J.; Huntsman, Scott; Ingles, Sue A.; Irwanto, Astrid; Isaacs, Claudine; Jacobs, Kevin B.; John, Esther M.; Justenhoven, Christina; Kaaks, Rudolf; Kolonel, Laurence N.; Coetzee, Gerhard A.; Lathrop, Mark; Le Marchand, Loic; Lee, Adam M.; Lee, I-Min; Lesnick, Timothy; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Martin, Nicholas G.; McLean, Catriona A.; Meijers-Heijboer, Hanne; Meindl, Alfons; Miron, Penelope; Monroe, Kristine R.; Montgomery, Grant W.; Müller-Myhsok, Bertram; Nickels, Stefan; Nyante, Sarah J.; Olswold, Curtis; Overvad, Kim; Palli, Domenico; Park, Daniel J.; Palmer, Julie R.; Pathak, Harsh; Peto, Julian; Pharoah, Paul; Rahman, Nazneen; Rivadeneira, Fernando; Schmidt, Daniel F.; Schmutzler, Rita K.; Slager, Susan; Southey, Melissa C.; Stevens, Kristen N.; Sinn, Hans-Peter; Press, Michael F.; Ross, Eric; Riboli, Elio; Ridker, Paul M.; Schumacher, Fredrick R.; Severi, Gianluca; dos Santos Silva, Isabel; Stone, Jennifer; Sund, Malin; Tapper, William J.; Thun, Michael J.; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Waisfisz, Quinten; Wang, Xianshu; Wang, Zhaoming; Weaver, JoEllen; Schulz-Wendtland, Rüdiger; Wilkens, Lynne R.; Van Den Berg, David; Zheng, Wei; Ziegler, Regina G.; Ziv, Elad; Nevanlinna, Heli; Easton, Douglas F.; Hunter, David J.; Henderson, Brian E.; Chanock, Stephen J.; Garcia-Closas, Montserrat; Kraft, Peter; Haiman, Christopher A.; Vachon, Celine M.

    2012-01-01

    Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5 in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10−8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10–6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10−9), and with both ER-positive (OR = 1.09; P = 1.5 × 10−5) and ER-negative (OR = 1.16, P = 2.5 × 10−7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci. PMID:22976474

  20. Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT) and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Botrel, Tobias Engel Ayer; Clark, Otávio; Lima Pompeo, Antônio Carlos; Horta Bretas, Francisco Flávio; Sadi, Marcus Vinicius; Ferreira, Ubirajara; Borges dos Reis, Rodolfo

    2016-01-01

    Objective Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC). Methods Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI). Results The final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001), and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001), also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group

  1. Pro: Meta-analysis: the case for.

    PubMed

    Mudge, David W; Webster, Angela C; Johnson, David W

    2016-06-01

    With ever-accumulating medical evidence for treatment benefits and harms, it is vital that clinicians are able to access and use up-to-date, best evidence in specific clinical scenarios involving individual patients-the primary goal of evidence-based medicine. In this article, we propose that meta-analysis, when properly conducted and reported in the context of a rigorous systematic review, is an indispensable tool for synthesis and interpretation of clinical evidence for the purpose of informing clinical decision-making by clinicians, patients and health care policy makers. Meta-analysis provides many benefits, including enhanced precision and statistical power, greater transparency, identification of bias, exploration of heterogeneity of effects, enhanced generalizability, efficient integration of clinical knowledge, identification of evidence gaps, better informed future trial design and avoidance of unnecessary research duplication and potential patient harm. The overall standard, clinical value and reach of meta-analysis has been further enhanced by the development of standards for registration, conduct and reporting, as well as advanced meta-analytic techniques, such as network meta-analysis. Of course, meta-analysis can at times be limited by poor quality studies, trial heterogeneity, publication bias and non-rigorous review and analysis, although through appraisal these issues are often able to be identified and explored, such that valuable clinical information can still be obtained. Consequently, meta-analysis is now the most highly cited form of research and is considered by many leading organizations to represent the highest level of clinical evidence. However, to maximize their considerable value, it is essential that all clinicians have the skills to critically appraise, carefully interpret and judiciously apply meta-analyses in their practice.

  2. [Meta-analysis in medicine].

    PubMed

    Hendl, J

    2002-04-26

    Systematic reviews are widely used in medicine as a method of decision making based on evidences. The systematic review is a method of locating and evaluation of a synthesising evidence. Meta-analysis refers to quantitative synthesis of the results of clinical trials or other primary studies. Simple introductory account about meta-analysis is given. We describe two examples of meta-analysis application and strengths and weaknesses of this research method. PMID:12038071

  3. Efficacy and safety of anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy for metastatic colorectal cancer in first-line and second-line therapies: a meta-analysis

    PubMed Central

    Wang, Hongchi; Ma, Bin; Gao, Peng; Song, Yongxi; Xu, Qingzhou; Hu, Yaoyuan; Zhang, Cong; Wang, Zhenning

    2016-01-01

    Aim This study aimed to compare anti-epidermal growth factor receptor (anti-EGFR) therapy and anti-vascular endothelial growth factor therapy as first-line and second-line therapies in patients with KRAS exon 2 codon 12/13 wild-type (KRAS-WT) metastatic colorectal cancer (mCRC). Methods Major databases were systematically searched. The hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (95% CIs) were used to estimate the effect measures. Review Manager software version 5.3 was used for statistical analysis. Results Seven trials including ten articles were eligible in the meta-analysis. The patients treated with anti-EGFR as first-line therapy showed a longer overall survival (OS) for KRAS-WT and all RAS wild-type (RAS-WT) mCRC (HR =0.81, 95% CI: 0.72–0.92, P<0.01, n=5; HR =0.78, 95% CI: 0.66–0.93, P<0.01, n=3, respectively). The objective response rate (ORR) was better with the anti-EGFR therapy for KRAS-WT and all RAS-WT mCRC (OR =1.32, 95% CI: 1.11–1.56, P<0.01, n=5; OR =1.55, 95% CI: 1.21–2.00, P<0.01, n=3, respectively). There was no difference in progression-free survival (PFS) for KRAS-WT mCRC and all RAS-WT mCRC between the two groups (HR =1.00; 95% CI: 0.92–1.09, P=0.99, n=4; HR =0.92, 95% CI: 0.71–1.19, P=0.52, n=3, respectively). In addition, two trials provided data on the second-line therapy; there was no significant difference in OS and PFS for the second-line therapy, but a significant improvement in ORR was found in the anti-EGFR group (OR =1.91, 95% CI: 1.16–3.16, P=0.01, n=2). No difference in the conversion therapy (OR =1.34; 95% CI: 0.91–1.99; P=0.14, n=4) was observed between the two therapies. Conclusion Our results indicate that anti-EGFR therapy is superior to anti-vascular endothelial growth factor therapy for OS and ORR as a first-line therapy for KRAS-WT mCRC. In the second-line therapy, there was no significant difference in the survival outcomes on the basis of OS and PFS between the two groups. However, ORR

  4. Efficacy and safety of anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy for metastatic colorectal cancer in first-line and second-line therapies: a meta-analysis

    PubMed Central

    Wang, Hongchi; Ma, Bin; Gao, Peng; Song, Yongxi; Xu, Qingzhou; Hu, Yaoyuan; Zhang, Cong; Wang, Zhenning

    2016-01-01

    Aim This study aimed to compare anti-epidermal growth factor receptor (anti-EGFR) therapy and anti-vascular endothelial growth factor therapy as first-line and second-line therapies in patients with KRAS exon 2 codon 12/13 wild-type (KRAS-WT) metastatic colorectal cancer (mCRC). Methods Major databases were systematically searched. The hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (95% CIs) were used to estimate the effect measures. Review Manager software version 5.3 was used for statistical analysis. Results Seven trials including ten articles were eligible in the meta-analysis. The patients treated with anti-EGFR as first-line therapy showed a longer overall survival (OS) for KRAS-WT and all RAS wild-type (RAS-WT) mCRC (HR =0.81, 95% CI: 0.72–0.92, P<0.01, n=5; HR =0.78, 95% CI: 0.66–0.93, P<0.01, n=3, respectively). The objective response rate (ORR) was better with the anti-EGFR therapy for KRAS-WT and all RAS-WT mCRC (OR =1.32, 95% CI: 1.11–1.56, P<0.01, n=5; OR =1.55, 95% CI: 1.21–2.00, P<0.01, n=3, respectively). There was no difference in progression-free survival (PFS) for KRAS-WT mCRC and all RAS-WT mCRC between the two groups (HR =1.00; 95% CI: 0.92–1.09, P=0.99, n=4; HR =0.92, 95% CI: 0.71–1.19, P=0.52, n=3, respectively). In addition, two trials provided data on the second-line therapy; there was no significant difference in OS and PFS for the second-line therapy, but a significant improvement in ORR was found in the anti-EGFR group (OR =1.91, 95% CI: 1.16–3.16, P=0.01, n=2). No difference in the conversion therapy (OR =1.34; 95% CI: 0.91–1.99; P=0.14, n=4) was observed between the two therapies. Conclusion Our results indicate that anti-EGFR therapy is superior to anti-vascular endothelial growth factor therapy for OS and ORR as a first-line therapy for KRAS-WT mCRC. In the second-line therapy, there was no significant difference in the survival outcomes on the basis of OS and PFS between the two groups. However, ORR

  5. Effectiveness of Reirradiation for Painful Bone Metastases: A Systematic Review and Meta-Analysis

    SciTech Connect

    Huisman, Merel; Bosch, Maurice A.A.J. van den; Wijlemans, Joost W.; Vulpen, Marco van; Linden, Yvette M. van der; Verkooijen, Helena M.

    2012-09-01

    Purpose: Reirradiation of painful bone metastases in nonresponders or patients with recurrent pain after initial response is performed in up to 42% of patients initially treated with radiotherapy. Literature on the effect of reirradiation for pain control in those patients is scarce. In this systematic review and meta-analysis, we quantify the effectiveness of reirradiation for achieving pain control in patients with painful bone metastases. Methods and Materials: A free text search was performed to identify eligible studies using the MEDLINE, EMBASE, and the Cochrane Collaboration library electronic databases. After study selection and quality assessment, a pooled estimate was calculated for overall pain response for reirradiation of metastatic bone pain. Results: Our literature search identified 707 titles, of which 10 articles were selected for systematic review and seven entered the meta-analysis. Overall study quality was mediocre. Of the 2,694 patients initially treated for metastatic bone pain, 527 (20%) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58% of patients (pooled overall response rate 0.58, 95% confidence interval = 0.49-0.67). There was a substantial between-study heterogeneity (I{sup 2} = 63.3%, p = 0.01) because of clinical and methodological differences between studies. Conclusions: Reirradiation of painful bone metastases is effective in terms of pain relief for a small majority of patients; approximately 40% of patients do not benefit from reirradiation. Although the validity of results is limited, this meta-analysis provides a comprehensive overview and the most quantitative estimate of reirradiation effectiveness to date.

  6. Meta-analysis of transcriptome data identified TGTCNN motif variants associated with the response to plant hormone auxin in Arabidopsis thaliana L.

    PubMed

    Zemlyanskaya, Elena V; Wiebe, Daniil S; Omelyanchuk, Nadezhda A; Levitsky, Victor G; Mironova, Victoria V

    2016-04-01

    Auxin is the major regulator of plant growth and development. It regulates gene expression via a family of transcription factors (ARFs) that bind to auxin responsive elements (AuxREs) in the gene promoters. The canonical AuxREs found in regulatory regions of many auxin responsive genes contain the TGTCTC core motif, whereas ARF binding site is a degenerate TGTCNN with TGTCGG strongly preferred. Thereby two questions arise: which TGTCNN variants are functional AuxRE cores and whether different TGTCNN variants have distinct functional roles? In this study, we performed meta-analysis of microarray data to reveal TGTCNN variants essential for auxin response and to characterize their functional features. Our results indicate that four TGTCNN motifs (TGTCTC, TGTCCC, TGTCGG, and TGTCTG) are associated with auxin up-regulation and two (TGTCGG, TGTCAT) with auxin down-regulation, but to a lesser extent. The genes having some of these motifs in their regulatory regions showed time-specific auxin response. Functional annotation of auxin up- and down-regulated genes also revealed GO terms specific for the auxin-regulated genes with certain TGTCNN variants in their promoters. Our results provide an idea that various TGTCNN motifs may play distinct roles in the auxin regulation of gene expression. PMID:27122321

  7. Meta-Analysis of Genome-Wide Association Studies and Network Analysis-Based Integration with Gene Expression Data Identify New Suggestive Loci and Unravel a Wnt-Centric Network Associated with Dupuytren’s Disease

    PubMed Central

    Becker, Kerstin; Siegert, Sabine; Toliat, Mohammad Reza; Du, Juanjiangmeng; Casper, Ramona; Dolmans, Guido H.; Werker, Paul M.; Tinschert, Sigrid; Franke, Andre; Gieger, Christian; Strauch, Konstantin; Nothnagel, Michael; Nürnberg, Peter; Hennies, Hans Christian

    2016-01-01

    Dupuytren´s disease, a fibromatosis of the connective tissue in the palm, is a common complex disease with a strong genetic component. Up to date nine genetic loci have been found to be associated with the disease. Six of these loci contain genes that code for Wnt signalling proteins. In spite of this striking first insight into the genetic factors in Dupuytren´s disease, much of the inherited risk in Dupuytren´s disease still needs to be discovered. The already identified loci jointly explain ~1% of the heritability in this disease. To further elucidate the genetic basis of Dupuytren´s disease, we performed a genome-wide meta-analysis combining three genome-wide association study (GWAS) data sets, comprising 1,580 cases and 4,480 controls. We corroborated all nine previously identified loci, six of these with genome-wide significance (p-value < 5x10-8). In addition, we identified 14 new suggestive loci (p-value < 10−5). Intriguingly, several of these new loci contain genes associated with Wnt signalling and therefore represent excellent candidates for replication. Next, we compared whole-transcriptome data between patient- and control-derived tissue samples and found the Wnt/β-catenin pathway to be the top deregulated pathway in patient samples. We then conducted network and pathway analyses in order to identify protein networks that are enriched for genes highlighted in the GWAS meta-analysis and expression data sets. We found further evidence that the Wnt signalling pathways in conjunction with other pathways may play a critical role in Dupuytren´s disease. PMID:27467239

  8. A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease

    PubMed Central

    Sabater-Lleal, Maria; Huang, Jie; Chasman, Daniel; Naitza, Silvia; Dehghan, Abbas; Johnson, Andrew D; Teumer, Alexander; Reiner, Alex P; Folkersen, Lasse; Basu, Saonli; Rudnicka, Alicja R; Trompet, Stella; Mälarstig, Anders; Baumert, Jens; Bis, Joshua C.; Guo, Xiuqing; Hottenga, Jouke J; Shin, So-Youn; Lopez, Lorna M; Lahti, Jari; Tanaka, Toshiko; Yanek, Lisa R; Oudot-Mellakh, Tiphaine; Wilson, James F; Navarro, Pau; Huffman, Jennifer E; Zemunik, Tatijana; Redline, Susan; Mehra, Reena; Pulanic, Drazen; Rudan, Igor; Wright, Alan F; Kolcic, Ivana; Polasek, Ozren; Wild, Sarah H; Campbell, Harry; Curb, J David; Wallace, Robert; Liu, Simin; Eaton, Charles B.; Becker, Diane M.; Becker, Lewis C.; Bandinelli, Stefania; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Fornage, Myriam; Green, David; Gross, Myron; Davies, Gail; Harris, Sarah E; Liewald, David C; Starr, John M; Williams, Frances M.K.; Grant, P.J.; Spector, Timothy D.; Strawbridge, Rona J; Silveira, Angela; Sennblad, Bengt; Rivadeneira, Fernando; Uitterlinden, Andre G; Franco, Oscar H; Hofman, Albert; van Dongen, Jenny; Willemsen, G; Boomsma, Dorret I; Yao, Jie; Jenny, Nancy Swords; Haritunians, Talin; McKnight, Barbara; Lumley, Thomas; Taylor, Kent D; Rotter, Jerome I; Psaty, Bruce M; Peters, Annette; Gieger, Christian; Illig, Thomas; Grotevendt, Anne; Homuth, Georg; Völzke, Henry; Kocher, Thomas; Goel, Anuj; Franzosi, Maria Grazia; Seedorf, Udo; Clarke, Robert; Steri, Maristella; Tarasov, Kirill V; Sanna, Serena; Schlessinger, David; Stott, David J; Sattar, Naveed; Buckley, Brendan M; Rumley, Ann; Lowe, Gordon D; McArdle, Wendy L; Chen, Ming-Huei; Tofler, Geoffrey H; Song, Jaejoon; Boerwinkle, Eric; Folsom, Aaron R.; Rose, Lynda M.; Franco-Cereceda, Anders; Teichert, Martina; Ikram, M Arfan; Mosley, Thomas H; Bevan, Steve; Dichgans, Martin; Rothwell, Peter M.; Sudlow, Cathie L M; Hopewell, Jemma C.; Chambers, John C.; Saleheen, Danish; Kooner, Jaspal S.; Danesh, John; Nelson, Christopher P; Erdmann, Jeanette; Reilly, Muredach P.; Kathiresan, Sekar; Schunkert, Heribert; Morange, Pierre-Emmanuel; Ferrucci, Luigi; Eriksson, Johan G; Jacobs, David; Deary, Ian J; Soranzo, Nicole; Witteman, Jacqueline CM; de Geus, Eco JC; Tracy, Russell P.; Hayward, Caroline; Koenig, Wolfgang; Cucca, Francesco; Jukema, J Wouter; Eriksson, Per; Seshadri, Sudha; Markus, Hugh S.; Watkins, Hugh; Samani, Nilesh J; Wallaschofski, Henri; Smith, Nicholas L.; Tregouet, David; Ridker, Paul M.; Tang, Weihong; Strachan, David P.; Hamsten, Anders; O’Donnell, Christopher J.

    2013-01-01

    Background Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation. Methods and Results We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE. Conclusion We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE. PMID:23969696

  9. Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals

    PubMed Central

    Below, J. E.; Gamazon, E. R.; Morrison, J. V.; Konkashbaev, A.; Pluzhnikov, A.; McKeigue, P. M.; Parra, E. J.; Elbein, S. C.; Hallman, D. M.; Nicolae, D. L.; Bell, G. I.; Cruz, M.

    2013-01-01

    Aims/hypothesis We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA. Method Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico. Result The top signals (unadjusted p value <1×10−5) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (PER3, PARD3B, EPHA4, TOMM7, PTPRD, HNT [also known as RREB1], LOC729993 and IL34) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene PER3, a system recently implicated in diabetes. We also report a second signal (minimum p value 1.52× 10−6) within PTPRD, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions HNF1A and KCNQ1. Annotation of top association signals in both studies revealed a marked excess of trans-acting eQTL in both adipose and muscle tissues. Conclusions/Interpretation In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues. PMID:21647700

  10. Exome Sequencing of Cell-Free DNA from Metastatic Cancer Patients Identifies Clinically Actionable Mutations Distinct from Primary Disease.

    PubMed

    Butler, Timothy M; Johnson-Camacho, Katherine; Peto, Myron; Wang, Nicholas J; Macey, Tara A; Korkola, James E; Koppie, Theresa M; Corless, Christopher L; Gray, Joe W; Spellman, Paul T

    2015-01-01

    The identification of the molecular drivers of cancer by sequencing is the backbone of precision medicine and the basis of personalized therapy; however, biopsies of primary tumors provide only a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. A liquid biopsy, in the form of cell-free DNA (cfDNA) sequencing, has the potential to capture the inter- and intra-tumoral heterogeneity present in metastatic disease, and, through serial blood draws, track the evolution of the tumor genome. In order to determine the clinical utility of cfDNA sequencing we performed whole-exome sequencing on cfDNA and tumor DNA from two patients with metastatic disease; only minor modifications to our sequencing and analysis pipelines were required for sequencing and mutation calling of cfDNA. The first patient had metastatic sarcoma and 47 of 48 mutations present in the primary tumor were also found in the cell-free DNA. The second patient had metastatic breast cancer and sequencing identified an ESR1 mutation in the cfDNA and metastatic site, but not in the primary tumor. This likely explains tumor progression on Anastrozole. Significant heterogeneity between the primary and metastatic tumors, with cfDNA reflecting the metastases, suggested separation from the primary lesion early in tumor evolution. This is best illustrated by an activating PIK3CA mutation (H1047R) which was clonal in the primary tumor, but completely absent from either the metastasis or cfDNA. Here we show that cfDNA sequencing supplies clinically actionable information with minimal risks compared to metastatic biopsies. This study demonstrates the utility of whole-exome sequencing of cell-free DNA from patients with metastatic disease. cfDNA sequencing identified an ESR1 mutation, potentially explaining a patient's resistance to aromatase inhibition, and gave insight into how metastatic lesions differ from the primary tumor.

  11. Standard melanoma-associated markers do not identify the MM127 metastatic melanoma cell line

    PubMed Central

    Haridas, Parvathi; McGovern, Jacqui A.; Kashyap, Abhishek S.; McElwain, D. L. Sean; Simpson, Matthew J.

    2016-01-01

    Reliable identification of different melanoma cell lines is important for many aspects of melanoma research. Common markers used to identify melanoma cell lines include: S100; HMB-45; and Melan-A. We explore the expression of these three markers in four different melanoma cell lines: WM35; WM793; SK-MEL-28; and MM127. The expression of these markers is examined at both the mRNA and protein level. Our results show that the metastatic cell line, MM127, cannot be detected using any of the commonly used melanoma-associated markers. This implies that it would be very difficult to identify this particular cell line in a heterogeneous sample, and as a result this cell line should be used with care. PMID:27087056

  12. β-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis.

    PubMed

    Childers, W Kurtis; Hollenbeak, Christopher S; Cheriyath, Pramil

    2015-12-01

    The normal physiologic stress mechanism, mediated by the sympathetic nervous system, causes a release of the neurotransmitters epinephrine and norepinephrine. Preclinical data have demonstrated an effect on tumor progression and metastasis via the sympathetic nervous system mediated primarily through the β-adrenergic receptor (β-AR) pathway. In vitro data have shown an increase in tumor growth, migration, tumor angiogenesis, and metastatic spread in breast cancer through activation of the β-AR. Retrospective cohort studies on the clinical outcomes of β-blockers in breast cancer outcomes showed no clear consensus. The purpose of this study was to perform a systematic review and meta-analysis of the effect of β-blockers on breast cancer outcomes. A systematic review was performed using the Cochrane library and PubMed. Publications between the dates of January 2010 and December 2013 were identified. Available hazard ratios (HRs) were extracted for breast cancer recurrence, breast cancer death, and all-cause mortality and pooled using a random effects meta-analysis. A total of 7 studies contained results for at least 1 of the outcomes of breast cancer recurrence, breast cancer death, or all-cause mortality in breast cancer patients receiving β-blockers. In the 5 studies that contained results for breast cancer recurrence, there was no statistically significant risk reduction (HR, 0.67; 95% confidence interval [CI], 0.39-1.13). Breast cancer death results were contained in 4 studies, which also suggested a significant reduction in risk (HR, 0.50; 95% CI, 0.32-0.80). Among the 4 studies that reported all-cause mortality, there was no significant effect of β-blockers on risk (HR, 1.02; 95% CI, 0.75-1.37). Results of this systematic review and meta-analysis suggest that the use of β-blockers significantly reduced risk of breast cancer death among women with breast cancer. PMID:26516037

  13. Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis

    PubMed Central

    Xie, Jiangan; Codd, Christopher; Mo, Kevin; He, Yongqun

    2016-01-01

    M. bovis strain Bacillus Calmette–Guérin (BCG) has been the only licensed live attenuated vaccine against tuberculosis (TB) for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs) have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE)-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis), skin (e.g., skin ulceration and cyanosis), and respiratory system (e.g., cough and pneumonia); in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria). With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG-associated death

  14. Rethinking Meta-Analysis: Applications for Air Pollution Data and Beyond

    PubMed Central

    Goodman, Julie E; Petito Boyce, Catherine; Sax, Sonja N; Beyer, Leslie A; Prueitt, Robyn L

    2015-01-01

    Meta-analyses offer a rigorous and transparent systematic framework for synthesizing data that can be used for a wide range of research areas, study designs, and data types. Both the outcome of meta-analyses and the meta-analysis process itself can yield useful insights for answering scientific questions and making policy decisions. Development of the National Ambient Air Quality Standards illustrates many potential applications of meta-analysis. These applications demonstrate the strengths and limitations of meta-analysis, issues that arise in various data realms, how meta-analysis design choices can influence interpretation of results, and how meta-analysis can be used to address bias and heterogeneity. Reviewing available data from a meta-analysis perspective can provide a useful framework and impetus for identifying and refining strategies for future research. Moreover, increased pervasiveness of a meta-analysis mindset—focusing on how the pieces of the research puzzle fit together—would benefit scientific research and data syntheses regardless of whether or not a quantitative meta-analysis is undertaken. While an individual meta-analysis can only synthesize studies addressing the same research question, the results of separate meta-analyses can be combined to address a question encompassing multiple data types. This observation applies to any scientific or policy area where information from a variety of disciplines must be considered to address a broader research question. PMID:25969128

  15. Meta-analysis of clinical data using human meiotic genes identifies a novel cohort of highly restricted cancer-specific marker genes

    PubMed Central

    Feichtinger, Julia; Almutairi, Mikhlid; Almatrafi, Ahmed; Alsiwiehri, Naif; Griffiths, Keith; Stuart, Nicholas; Wakeman, Jane A.; Larcombe, Lee; McFarlane, Ramsay J.

    2012-01-01

    Identifying cancer-specific biomarkers represents an ongoing challenge to the development of novel cancer diagnostic, prognostic and therapeutic strategies. Cancer/testis (CT) genes are an important gene family with expression tightly restricted to the testis in normal individuals but which can also be activated in cancers. Here we develop a pipeline to identify new CT genes. We analysed and validated expression profiles of human meiotic genes in normal and cancerous tissue followed by meta-analyses of clinical data sets from a range of tumour types resulting in the identification of a large cohort of highly specific cancer biomarker genes, including the recombination hot spot activator PRDM9 and the meiotic cohesin genes SMC1beta and RAD21L. These genes not only provide excellent cancer biomarkers for diagnostics and prognostics, but may serve as oncogenes and have excellent drug targeting potential. PMID:22918178

  16. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

    PubMed Central

    Fogh, Isabella; Ratti, Antonia; Gellera, Cinzia; Lin, Kuang; Tiloca, Cinzia; Moskvina, Valentina; Corrado, Lucia; Sorarù, Gianni; Cereda, Cristina; Corti, Stefania; Gentilini, Davide; Calini, Daniela; Castellotti, Barbara; Mazzini, Letizia; Querin, Giorgia; Gagliardi, Stella; Del Bo, Roberto; Conforti, Francesca L.; Siciliano, Gabriele; Inghilleri, Maurizio; Saccà, Francesco; Bongioanni, Paolo; Penco, Silvana; Corbo, Massimo; Sorbi, Sandro; Filosto, Massimiliano; Ferlini, Alessandra; Di Blasio, Anna M.; Signorini, Stefano; Shatunov, Aleksey; Jones, Ashley; Shaw, Pamela J.; Morrison, Karen E.; Farmer, Anne E.; Van Damme, Philip; Robberecht, Wim; Chiò, Adriano; Traynor, Bryan J.; Sendtner, Michael; Melki, Judith; Meininger, Vincent; Hardiman, Orla; Andersen, Peter M.; Leigh, Nigel P.; Glass, Jonathan D.; Overste, Daniel; Diekstra, Frank P.; Veldink, Jan H.; van Es, Michael A.; Shaw, Christopher E.; Weale, Michael E.; Lewis, Cathryn M.; Williams, Julie; Brown, Robert H.; Landers, John E.; Ticozzi, Nicola; Ceroni, Mauro; Pegoraro, Elena; Comi, Giacomo P.; D'Alfonso, Sandra; van den Berg, Leonard H.; Taroni, Franco; Al-Chalabi, Ammar; Powell, John; Silani, Vincenzo; Brescia Morra, Vincenzo; Filla, Alessandro; Massimo, Filosto; Marsili, Angela; Viviana, Pensato; Puorro, Giorgia; La Bella, Vincenzo; Logroscino, Giancarlo; Monsurrò, Maria Rosaria; Quattrone, Aldo; Simone, Isabella Laura; Ahmeti, Kreshnik B.; Ajroud-Driss, Senda; Armstrong, Jennifer; Birve, Anne; Blauw, Hylke M.; Bruijn, Lucie; Chen, Wenjie; Comeau, Mary C.; Cronin, Simon; Soraya, Gkazi Athina; Grab, Josh D.; Groen, Ewout J.; Haines, Jonathan L.; Heller, Scott; Huang, Jie; Hung, Wu-Yen; Jaworski, James M.; Khan, Humaira; Langefeld, Carl D.; Marion, Miranda C.; McLaughlin, Russell L.; Miller, Jack W.; Mora, Gabriele; Pericak-Vance, Margaret A.; Rampersaud, Evadnie; Siddique, Nailah; Siddique, Teepu; Smith, Bradley N.; Sufit, Robert; Topp, Simon; Vance, Caroline; van Vught, Paul; Yang, Yi; Zheng, J.G.

    2014-01-01

    Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10−8; OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10−9; OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10−9; OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci. PMID:24256812

  17. Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration.

    PubMed

    Lanktree, Matthew B; Elbers, Clara C; Li, Yun; Zhang, Guosheng; Duan, Qing; Karczewski, Konrad J; Guo, Yiran; Tragante, Vinicius; North, Kari E; Cushman, Mary; Asselbergs, Folkert W; Wilson, James G; Lange, Leslie A; Drenos, Fotios; Reiner, Alex P; Barnes, Michael R; Keating, Brendan J

    2015-09-01

    Meta-analyses of European populations has successfully identified genetic variants in over 150 loci associated with lipid levels, but results from additional ethnicities remain limited. Previously, we reported two novel lipid loci identified in a sample of 7,657 African Americans using a gene-centric array including 50,000 SNPs in 2,100 candidate genes. Initial discovery and follow-up of signals with P < 10(-5) in additional African American samples confirmed CD36 and ICAM1. Using an additional 8,244 African American female samples from the Women's Health Initiative SNP Health Association Resource genome-wide association study dataset, we further examined the previous meta-analyses results by attempting to replicate 20 additional putative lipid signals with P < 10(-4). Replication confirmed rs868213, located in a splice donor region of exocyst complex component 3-like 1 (EXOC3L1) as a novel signal for HDL (additive allelic effect β = 0.02; P = 1.4 × 10(-8); meta-analyses of discovery and replication). EXOC3L1 is strongly expressed in vascular endothelium and forms part of the exocyst complex, a key facilitator of the trafficking of lipid receptors. Increasing sample sizes for genetic studies in nonEuropean populations will continue to improve our understanding of lipid metabolism. PMID:26199122

  18. Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration.

    PubMed

    Lanktree, Matthew B; Elbers, Clara C; Li, Yun; Zhang, Guosheng; Duan, Qing; Karczewski, Konrad J; Guo, Yiran; Tragante, Vinicius; North, Kari E; Cushman, Mary; Asselbergs, Folkert W; Wilson, James G; Lange, Leslie A; Drenos, Fotios; Reiner, Alex P; Barnes, Michael R; Keating, Brendan J

    2015-09-01

    Meta-analyses of European populations has successfully identified genetic variants in over 150 loci associated with lipid levels, but results from additional ethnicities remain limited. Previously, we reported two novel lipid loci identified in a sample of 7,657 African Americans using a gene-centric array including 50,000 SNPs in 2,100 candidate genes. Initial discovery and follow-up of signals with P < 10(-5) in additional African American samples confirmed CD36 and ICAM1. Using an additional 8,244 African American female samples from the Women's Health Initiative SNP Health Association Resource genome-wide association study dataset, we further examined the previous meta-analyses results by attempting to replicate 20 additional putative lipid signals with P < 10(-4). Replication confirmed rs868213, located in a splice donor region of exocyst complex component 3-like 1 (EXOC3L1) as a novel signal for HDL (additive allelic effect β = 0.02; P = 1.4 × 10(-8); meta-analyses of discovery and replication). EXOC3L1 is strongly expressed in vascular endothelium and forms part of the exocyst complex, a key facilitator of the trafficking of lipid receptors. Increasing sample sizes for genetic studies in nonEuropean populations will continue to improve our understanding of lipid metabolism.

  19. A Conserved BDNF, Glutamate- and GABA-Enriched Gene Module Related to Human Depression Identified by Coexpression Meta-Analysis and DNA Variant Genome-Wide Association Studies

    PubMed Central

    Chang, Lun-Ching; Jamain, Stephane; Lin, Chien-Wei; Rujescu, Dan; Tseng, George C.; Sibille, Etienne

    2014-01-01

    Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases. In support of the superior discriminative power of this novel approach, we observed no significant enrichment for GWAS-related genes in coexpression modules extracted from single studies or in meta-modules using gene expression data from non-psychiatric control subjects. Genes in the identified module encode proteins implicated in neuronal signaling and structure, including glutamate metabotropic receptors (GRM1, GRM7), GABA receptors (GABRA2, GABRA4), and neurotrophic and development-related proteins [BDNF, reelin (RELN), Ephrin receptors (EPHA3, EPHA5)]. These results are consistent with the current understanding of molecular mechanisms of MDD and provide a set of putative interacting molecular partners, potentially reflecting components of a functional module across cells and biological pathways that are synchronously recruited in MDD, other brain disorders and MDD-related illnesses. Collectively, this study demonstrates the importance of integrating transcriptome data, gene coexpression modules

  20. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.

    PubMed

    Teumer, Alexander; Qi, Qibin; Nethander, Maria; Aschard, Hugues; Bandinelli, Stefania; Beekman, Marian; Berndt, Sonja I; Bidlingmaier, Martin; Broer, Linda; Cappola, Anne; Ceda, Gian Paolo; Chanock, Stephen; Chen, Ming-Huei; Chen, Tai C; Chen, Yii-Der Ida; Chung, Jonathan; Del Greco Miglianico, Fabiola; Eriksson, Joel; Ferrucci, Luigi; Friedrich, Nele; Gnewuch, Carsten; Goodarzi, Mark O; Grarup, Niels; Guo, Tingwei; Hammer, Elke; Hayes, Richard B; Hicks, Andrew A; Hofman, Albert; Houwing-Duistermaat, Jeanine J; Hu, Frank; Hunter, David J; Husemoen, Lise L; Isaacs, Aaron; Jacobs, Kevin B; Janssen, Joop A M J L; Jansson, John-Olov; Jehmlich, Nico; Johnson, Simon; Juul, Anders; Karlsson, Magnus; Kilpelainen, Tuomas O; Kovacs, Peter; Kraft, Peter; Li, Chao; Linneberg, Allan; Liu, Yongmei; Loos, Ruth J F; Lorentzon, Mattias; Lu, Yingchang; Maggio, Marcello; Magi, Reedik; Meigs, James; Mellström, Dan; Nauck, Matthias; Newman, Anne B; Pollak, Michael N; Pramstaller, Peter P; Prokopenko, Inga; Psaty, Bruce M; Reincke, Martin; Rimm, Eric B; Rotter, Jerome I; Saint Pierre, Aude; Schurmann, Claudia; Seshadri, Sudha; Sjögren, Klara; Slagboom, P Eline; Strickler, Howard D; Stumvoll, Michael; Suh, Yousin; Sun, Qi; Zhang, Cuilin; Svensson, Johan; Tanaka, Toshiko; Tare, Archana; Tönjes, Anke; Uh, Hae-Won; van Duijn, Cornelia M; van Heemst, Diana; Vandenput, Liesbeth; Vasan, Ramachandran S; Völker, Uwe; Willems, Sara M; Ohlsson, Claes; Wallaschofski, Henri; Kaplan, Robert C

    2016-10-01

    The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci. PMID:27329260

  1. Alcohol Involvement and the Five-Factor Model of Personality: A Meta-Analysis

    ERIC Educational Resources Information Center

    Malouff, John M.; Thorsteinsson, Einar B.; Rooke, Sally E.; Schutte, Nicola S.

    2007-01-01

    The purpose of this meta-analysis was to quantify the relationship between the Five-Factor Model of personality and alcohol involvement and to identify moderators of the relationship. The meta-analysis included 20 studies, 119 effect sizes, and 7,886 participants. Possible moderators examined included: five-factor rating type (self vs. other);…

  2. Can We Identify the Active Ingredients of Behaviour Change Interventions for Coronary Heart Disease Patients? A Systematic Review and Meta-Analysis

    PubMed Central

    Goodwin, Laura; Ostuzzi, Giovanni; Khan, Nadia; Hotopf, Matthew H.; Moss-Morris, Rona

    2016-01-01

    Background The main behaviour change intervention available for coronary heart disease (CHD) patients is cardiac rehabilitation. There is little recognition of what the active ingredients of behavioural interventions for CHD might be. Using a behaviour change technique (BCT) framework to code existing interventions may help to identify this. The objectives of this systematic review are to determine the effectiveness of CHD behaviour change interventions and how this may be explained by BCT content and structure. Methods and Findings A systematic search of Medline, EMBASE and PsycInfo electronic databases was conducted over a twelve year period (2003–2015) to identify studies which reported on behaviour change interventions for CHD patients. The content of the behaviour change interventions was coded using the Coventry Aberdeen and London—Refined (CALO-RE) taxonomy. Meta-regression analyses examined the BCT content as a predictor of mortality. Twenty two papers met the criteria for this review, reporting data on 16,766 participants. The most commonly included BCTs were providing information, and goal setting. There was a small but significant effect of the interventions on smoking (risk ratio (RR) = 0.89, 95% CI 0.81–0.97). The interventions did not reduce the risk of CHD events (RR = 0.86, 95% CI 0.68, 1.09), but significantly reduced the risk of mortality (RR = 0.82, 95% CI 0.69, 0.97). Sensitivity analyses did not find that any of the BCT variables predicted mortality and the number of BCTs included in an intervention was not associated with mortality (β = -0.02, 95% CI -0.06–0.03). Conclusions Behaviour change interventions for CHD patients appear to have a positive impact on a number of outcomes. Using an existing BCT taxonomy to code the interventions helped us to understand which were the most commonly used techniques, providing information and goal setting, but not the active components of these complex interventions. PMID:27105435

  3. Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits.

    PubMed

    2016-08-01

    Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury. PMID:27399967

  4. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

    PubMed Central

    Cheng, Timothy HT; Thompson, Deborah; Painter, Jodie; O’Mara, Tracy; Gorman, Maggie; Martin, Lynn; Palles, Claire; Jones, Angela; Buchanan, Daniel D.; Ko Win, Aung; Hopper, John; Jenkins, Mark; Lindor, Noralane M.; Newcomb, Polly A.; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Giles, Graham G; Pharoah, Paul; Peto, Julian; Cox, Angela; Swerdlow, Anthony; Couch, Fergus; Cunningham, Julie M; Goode, Ellen L; Winham, Stacey J; Lambrechts, Diether; Fasching, Peter; Burwinkel, Barbara; Brenner, Hermann; Brauch, Hiltrud; Chang-Claude, Jenny; Salvesen, Helga B.; Kristensen, Vessela; Darabi, Hatef; Li, Jingmei; Liu, Tao; Lindblom, Annika; Hall, Per; de Polanco, Magdalena Echeverry; Sans, Monica; Carracedo, Angel; Castellvi-Bel, Sergi; Rojas-Martinez, Augusto; Aguiar Jnr, Samuel; Teixeira, Manuel R.; Dunning, Alison M; Dennis, Joe; Otton, Geoffrey; Proietto, Tony; Holliday, Elizabeth; Attia, John; Ashton, Katie; Scott, Rodney J; McEvoy, Mark; Dowdy, Sean C; Fridley, Brooke L; Werner, Henrica MJ; Trovik, Jone; Njolstad, Tormund S; Tham, Emma; Mints, Miriam; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Amant, Frederic; Schrauwen, Stefanie; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif; Czene, Kamila; Meindl, Alfons; Bolla, Manjeet K; Michailidou, Kyriaki; Tyrer, Jonathan P; Wang, Qin; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Annibali, Daniela; Depreeuw, Jeroen; Al-Tassan, Nada A.; Harris, Rebecca; Meyer, Brian F.; Whiffin, Nicola; Hosking, Fay J; Kinnersley, Ben; Farrington, Susan M.; Timofeeva, Maria; Tenesa, Albert; Campbell, Harry; Haile, Robert W.; Hodgson, Shirley; Carvajal-Carmona, Luis; Cheadle, Jeremy P.; Easton, Douglas; Dunlop, Malcolm; Houlston, Richard; Spurdle, Amanda; Tomlinson, Ian

    2015-01-01

    High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10−9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10−8), with the alleles showing opposite effects on the risks of the two cancers. PMID:26621817

  5. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.

    PubMed

    Cheng, Timothy H T; Thompson, Deborah; Painter, Jodie; O'Mara, Tracy; Gorman, Maggie; Martin, Lynn; Palles, Claire; Jones, Angela; Buchanan, Daniel D; Ko Win, Aung; Hopper, John; Jenkins, Mark; Lindor, Noralane M; Newcomb, Polly A; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Giles, Graham G; Pharoah, Paul; Peto, Julian; Cox, Angela; Swerdlow, Anthony; Couch, Fergus; Cunningham, Julie M; Goode, Ellen L; Winham, Stacey J; Lambrechts, Diether; Fasching, Peter; Burwinkel, Barbara; Brenner, Hermann; Brauch, Hiltrud; Chang-Claude, Jenny; Salvesen, Helga B; Kristensen, Vessela; Darabi, Hatef; Li, Jingmei; Liu, Tao; Lindblom, Annika; Hall, Per; de Polanco, Magdalena Echeverry; Sans, Monica; Carracedo, Angel; Castellvi-Bel, Sergi; Rojas-Martinez, Augusto; Aguiar Jnr, Samuel; Teixeira, Manuel R; Dunning, Alison M; Dennis, Joe; Otton, Geoffrey; Proietto, Tony; Holliday, Elizabeth; Attia, John; Ashton, Katie; Scott, Rodney J; McEvoy, Mark; Dowdy, Sean C; Fridley, Brooke L; Werner, Henrica M J; Trovik, Jone; Njolstad, Tormund S; Tham, Emma; Mints, Miriam; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Amant, Frederic; Schrauwen, Stefanie; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif; Czene, Kamila; Meindl, Alfons; Bolla, Manjeet K; Michailidou, Kyriaki; Tyrer, Jonathan P; Wang, Qin; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Annibali, Daniela; Depreeuw, Jeroen; Al-Tassan, Nada A; Harris, Rebecca; Meyer, Brian F; Whiffin, Nicola; Hosking, Fay J; Kinnersley, Ben; Farrington, Susan M; Timofeeva, Maria; Tenesa, Albert; Campbell, Harry; Haile, Robert W; Hodgson, Shirley; Carvajal-Carmona, Luis; Cheadle, Jeremy P; Easton, Douglas; Dunlop, Malcolm; Houlston, Richard; Spurdle, Amanda; Tomlinson, Ian

    2015-01-01

    High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers. PMID:26621817

  6. A Meta-Analysis of Extensive Reading Research

    ERIC Educational Resources Information Center

    Nakanishi, Takayuki

    2015-01-01

    The purposes of this study were to investigate the overall effectiveness of extensive reading, whether learners' age impacts learning, and whether the length of time second language learners engage in extensive reading influences test scores. The author conducted a meta-analysis to answer research questions and to identify future research…

  7. The Psychological Effects of Meditation: A Meta-Analysis

    ERIC Educational Resources Information Center

    Sedlmeier, Peter; Eberth, Juliane; Schwarz, Marcus; Zimmermann, Doreen; Haarig, Frederik; Jaeger, Sonia; Kunze, Sonja

    2012-01-01

    In this meta-analysis, we give a comprehensive overview of the effects of meditation on psychological variables that can be extracted from empirical studies, concentrating on the effects of meditation on nonclinical groups of adult meditators. Mostly because of methodological problems, almost 3/4 of an initially identified 595 studies had to be…

  8. Formalizing the definition of meta-analysis in Molecular Ecology.

    PubMed

    ArchMiller, Althea A; Bauer, Eric F; Koch, Rebecca E; Wijayawardena, Bhagya K; Anil, Ammu; Kottwitz, Jack J; Munsterman, Amelia S; Wilson, Alan E

    2015-08-01

    Meta-analysis, the statistical synthesis of pertinent literature to develop evidence-based conclusions, is relatively new to the field of molecular ecology, with the first meta-analysis published in the journal Molecular Ecology in 2003 (Slate & Phua 2003). The goal of this article is to formalize the definition of meta-analysis for the authors, editors, reviewers and readers of Molecular Ecology by completing a review of the meta-analyses previously published in this journal. We also provide a brief overview of the many components required for meta-analysis with a more specific discussion of the issues related to the field of molecular ecology, including the use and statistical considerations of Wright's FST and its related analogues as effect sizes in meta-analysis. We performed a literature review to identify articles published as 'meta-analyses' in Molecular Ecology, which were then evaluated by at least two reviewers. We specifically targeted Molecular Ecology publications because as a flagship journal in this field, meta-analyses published in Molecular Ecology have the potential to set the standard for meta-analyses in other journals. We found that while many of these reviewed articles were strong meta-analyses, others failed to follow standard meta-analytical techniques. One of these unsatisfactory meta-analyses was in fact a secondary analysis. Other studies attempted meta-analyses but lacked the fundamental statistics that are considered necessary for an effective and powerful meta-analysis. By drawing attention to the inconsistency of studies labelled as meta-analyses, we emphasize the importance of understanding the components of traditional meta-analyses to fully embrace the strengths of quantitative data synthesis in the field of molecular ecology.

  9. How to do a meta-analysis.

    PubMed

    Field, Andy P; Gillett, Raphael

    2010-11-01

    Meta-analysis is a statistical tool for estimating the mean and variance of underlying population effects from a collection of empirical studies addressing ostensibly the same research question. Meta-analysis has become an increasing popular and valuable tool in psychological research, and major review articles typically employ these methods. This article describes the process of conducting meta-analysis: selecting articles, developing inclusion criteria, calculating effect sizes, conducting the actual analysis (including information on how to do the analysis on popular computer packages such as IBM SPSS and R) and estimating the effects of publication bias. Guidance is also given on how to write up a meta-analysis.

  10. Meta-analysis and its problems.

    PubMed Central

    Eysenck, H. J.

    1994-01-01

    Including all relevant material--good, bad, and indifferent--in meta-analysis admits the subjective judgments that meta-analysis was designed to avoid. Several problems arise in meta-analysis: regressions are often non-linear; effects are often multivariate rather than univariate; coverage can be restricted; bad studies may be included; the data summarised may not be homogeneous; grouping different causal factors may lead to meaningless estimates of effects; and the theory-directed approach may obscure discrepancies. Meta-analysis may not be the one best method for studying the diversity of fields for which it has been used. Images p790-a PMID:7950571

  11. Survival benefit and safety of the combinations of FOLFOXIRI ± bevacizumab versus the combinations of FOLFIRI ± bevacizumab as first-line treatment for unresectable metastatic colorectal cancer: a meta-analysis

    PubMed Central

    Xu, Wei; Kuang, Meng; Gong, Yang; Cao, Chunxiang; Chen, Jinfei; Tang, Cuiju

    2016-01-01

    Background The survival of patients with metastatic colorectal cancer (mCRC) could be improved with exposure to three active drugs, irinotecan, fluorouracil/leucovorin, and oxaliplatin, irrespective of their sequence. However, only 50%–80% of patients can be exposed to all the three drugs in a sequential strategy with two-drug combinations. We carried out this systematic assessment to compare the survival benefit and safety of FOLFOXIRI (irinotecan, fluorouracil/leucovorin, and oxaliplatin) ± bevacizumab (with or without bevacizumab) versus FOLFIRI (irinotecan and fluorouracil/leucovorin) ± bevacizumab (with or without bevacizumab) as first-line treatment for unresectable mCRC. Methods PubMed and EMBASE were searched for original articles written in English and published before December 2015. A total of 1,035 patients from three randomized controlled trials were included. Results Our results demonstrated that overall survival (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.73–0.97), progression-free survival (HR, 0.69; 95% CI, 0.59–0.81), and overall response rate (odds ratio, 1.96; 95% CI, 1.28–2.98) were significantly improved in the FOLFOXIRI ± bevacizumab arm compared to the FOLFIRI ± bevacizumab arm. Significantly higher incidences of neutropenia, anemia, diarrhea, stomatitis, and neuropathy were observed in the FOLFOXIRI ± bevacizumab arm. Conclusion Current evidence shows that the combination of FOLFOXIRI ± bevacizumab significantly improves the overall survival, progression-free survival, and overall response rate of patients with mCRC, with an increased but manageable toxicity, compared with the combinations of FOLFIRI ± bevacizumab. The combination of FOLFOXIRI ± bevacizumab should be considered as a treatment option for these patients under the premise of reasonable selection of target population. PMID:27536147

  12. Effect of BRAF V600E mutation on tumor response of anti-EGFR monoclonal antibodies for first-line metastatic colorectal cancer treatment: a meta-analysis of randomized studies.

    PubMed

    Cui, Dandan; Cao, Dan; Yang, Yu; Qiu, Meng; Huang, Ying; Yi, Cheng

    2014-03-01

    Anti-EGFR monoclonal antibodies (anti-EGFR MoAbs) in metastatic colorectal cancer (mCRC) treatment are still not effective in all patients. This study aimed to evaluate the relationship between BRAF V600E mutation and the tumor response of anti-EGFR MoAbs for first-line treatment in mCRC patients. We searched the MEDLINE and EMBASE databases, using the key words that included colorectal cancer, cetuximab, panitumumab, and BRAF mutation and retrieved 445 articles. Among them four were included in the systematic review. Relative risks (RRs) with 95% confidence intervals (CI) for response rate were calculated. BRAF mutation carriers had worse ORR than non-carriers in mCRC patients with KRAS wild-type in first-line treatment whether adding anti-EGFR MoAb to chemotherapy or not (RR = 0.43, [95% CI 0.16-0.75]; RR = 0.38, [95% CI 0.20-0.73]). But in the unselected patients whose KRAS mutation were unknown, BRAF mutation carriers had similar ORR whether adding cetuximab to chemotherapy or not (RR = 0.45, [95% CI 0.18-1.09]; RR = 0.57, [95% CI 0.15-2.23]). In BRAF mutation carriers adding anti-EGFR MoAb to chemotherapy was similar to chemotherapy alone whether in patients with wild-type KRAS or unselected patients (RR = 1.61, [95% CI 0.57-4.47]; RR = 0.71, [95% CI 0.18-2.77]). But in the BRAF mutation non-carriers, adding anti-EGFR MoAb produced a clear benefit in response rate than chemotherapy alone and this advantage was restricted to KRAS wild-type patients (RR = 1.48, [95% CI 1.28-1.71]). BRAF mutation decreases tumor response in first-line treatment whether cetuximab was given or not in patients with KRAS wild-type, and anti-EGFR MoAb produces a clear benefit in response rate in patients with BRAF and KRAS wild-type.

  13. Meta-analysis: an update.

    PubMed

    Sacks, H S; Reitman, D; Pagano, D; Kupelnick, B

    1996-01-01

    A fairly new type of research, termed meta-analysis, attempts to analyze and combine the results of previous reports. In 1992 we updated our 1987 survey of 86 meta-analyses of randomized control trial reports in the english language literature with an additional 78. We evaluated the quality of these meta-analyses using a scoring method that lists 23 items in six major areas: study design, combinability, control of bias, statistical analysis, sensitivity analysis, and application of results. Of the 23 individual items, the mean number satisfactorily addressed was 7.63 +/- 2.84 (mean +/- S.D.) for 40 papers published from 1955 through 1982, 6.80 +/- 3.86 for 66 papers published from 1983 through 1986, and 11.91 +/- 4.79 for 58 papers published from 1987 through 1990 (F = 31.3, p < .001). We noted that methodology has definitely improved since our first survey of meta-analyses, but an urgent need still exists for a better search of the literature, quality evaluation of trials, and a synthesis of the results. Recently, meta-analysis has expanded to cover non-randomized studies, including evaluation of diagnostic tests and pooling of epidemiologic studies. There is growing concern for standards, and several methodologic issues remain unresolved.

  14. A novel random effect model for GWAS meta-analysis and its application to trans-ethnic meta-analysis.

    PubMed

    Shi, Jingchunzi; Lee, Seunggeun

    2016-09-01

    Meta-analysis of trans-ethnic genome-wide association studies (GWAS) has proven to be a practical and profitable approach for identifying loci that contribute to the risk of complex diseases. However, the expected genetic effect heterogeneity cannot easily be accommodated through existing fixed-effects and random-effects methods. In response, we propose a novel random effect model for trans-ethnic meta-analysis with flexible modeling of the expected genetic effect heterogeneity across diverse populations. Specifically, we adopt a modified random effect model from the kernel regression framework, in which genetic effect coefficients are random variables whose correlation structure reflects the genetic distances across ancestry groups. In addition, we use the adaptive variance component test to achieve robust power regardless of the degree of genetic effect heterogeneity. Simulation studies show that our proposed method has well-calibrated type I error rates at very stringent significance levels and can improve power over the traditional meta-analysis methods. We reanalyzed the published type 2 diabetes GWAS meta-analysis (Consortium et al., 2014) and successfully identified one additional SNP that clearly exhibits genetic effect heterogeneity across different ancestry groups. Furthermore, our proposed method provides scalable computing time for genome-wide datasets, in which an analysis of one million SNPs would require less than 3 hours.

  15. Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke.

    PubMed

    Williams, Stephen R; Yang, Qiong; Chen, Fang; Liu, Xuan; Keene, Keith L; Jacques, Paul; Chen, Wei-Min; Weinstein, Galit; Hsu, Fang-Chi; Beiser, Alexa; Wang, Liewei; Bookman, Ebony; Doheny, Kimberly F; Wolf, Philip A; Zilka, Michelle; Selhub, Jacob; Nelson, Sarah; Gogarten, Stephanie M; Worrall, Bradford B; Seshadri, Sudha; Sale, Michèle M

    2014-03-01

    Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60 × 10(-63)], CBS [p = 3.15 × 10(-26)], CPS1 [p = 9.10 × 10(-13)], ALDH1L1 [p = 7.3 × 10(-13)] and PSPH [p = 1.17 × 10(-16)]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.

  16. Statistical Power in Meta-Analysis

    ERIC Educational Resources Information Center

    Liu, Jin

    2015-01-01

    Statistical power is important in a meta-analysis study, although few studies have examined the performance of simulated power in meta-analysis. The purpose of this study is to inform researchers about statistical power estimation on two sample mean difference test under different situations: (1) the discrepancy between the analytical power and…

  17. Uses and Misuses of Meta-Analysis.

    ERIC Educational Resources Information Center

    Kulik, James A.

    Meta-analysis does not solve all the problems encountered in qualitative research reviews, but it holds out some hope for increasing the reliability and dependability of a reviewer's conclusions. Several developments in meta-analysis are cause for optimism. First, different meta-analysts are doing work in the same areas, leading to increased…

  18. Trial Sequential Methods for Meta-Analysis

    ERIC Educational Resources Information Center

    Kulinskaya, Elena; Wood, John

    2014-01-01

    Statistical methods for sequential meta-analysis have applications also for the design of new trials. Existing methods are based on group sequential methods developed for single trials and start with the calculation of a required information size. This works satisfactorily within the framework of fixed effects meta-analysis, but conceptual…

  19. A Teacher's Guide to Meta-Analysis

    ERIC Educational Resources Information Center

    Banda, Devender R.; Therrien, William J.

    2008-01-01

    Technical terms such as "meta-analysis," research synthesis," and "effect size" may sound alien to practitioners in the field of education. Due to limited knowledge on meta-analysis among educators, the results of meta-analyses seldom translate from research to classroom practice--even though meta-analyses may provide valuable information on how…

  20. Hierarchical Dependence in Meta-Analysis

    ERIC Educational Resources Information Center

    Stevens, John R.; Taylor, Alan M.

    2009-01-01

    Meta-analysis is a frequent tool among education and behavioral researchers to combine results from multiple experiments to arrive at a clear understanding of some effect of interest. One of the traditional assumptions in a meta-analysis is the independence of the effect sizes from the studies under consideration. This article presents a…

  1. Human papillomavirus and breast cancer in Iran: a meta- analysis

    PubMed Central

    Haghshenas, Mohammad Reza; Mousavi, Tahoora; Moosazadeh, Mahmood; Afshari, Mahdi

    2016-01-01

    Objective(s): This study aims to investigate the relationship between human papillomavirus (HPV) and breast cancer using meta- analysis. Materials and Methods: Relevant studies were identified reviewing the national and international databases. We also increased the search sensitivity by investigating the references as well as interview with research centers and experts. Finally, quality assessment and implementation of inclusion/exclusion criteria determined the eligible articles for meta-analysis. Based on the heterogeneity observed among the results of the primary studies, random effects model was used to estimate the pooled prevalence of HPV infection and also pooled odds ratio between HPV and developing breast cancer using Stata SE V. 11 software. Results: This meta- analysis included 11 primary studies investigating the HPV infection prevalence among 1539 Iranian women. Pooled prevalence (95% confidence interval) of HPV infection among Iranian women with breast cancer was estimated as of 23.6% (6.7- 40.5), while, the odds ratio (95% confidence interval) between HPV infection and developing breast cancer was estimated as of 5.7% (0.7- 46.8). Conclusion: This meta- analysis showed a high prevalence of HPV infection among women with breast cancer. We also found that the odds of developing breast cancer among women with breast cancer was more than that of women without breast cancer. PMID:27114791

  2. S100 and annexin proteins identify cell membrane damage as the Achilles heel of metastatic cancer cells

    PubMed Central

    Jaiswal, Jyoti K; Nylandsted, Jesper

    2015-01-01

    Mechanical activity of cells and the stress imposed on them by extracellular environment is a constant source of injury to the plasma membrane (PM). In invasive tumor cells, increased motility together with the harsh environment of the tumor stroma further increases the risk of PM injury. The impact of these stresses on tumor cell plasma membrane and mechanism by which tumor cells repair the PM damage are poorly understood. Ca2+ entry through the injured PM initiates repair of the PM. Depending on the cell type, different organelles and proteins respond to this Ca2+ entry and facilitate repair of the damaged plasma membrane. We recently identified that proteins expressed in various metastatic cancers including Ca2+-binding EF hand protein S100A11 and its binding partner annexin A2 are used by tumor cells for plasma membrane repair (PMR). Here we will discuss the involvement of S100, annexin proteins and their regulation of actin cytoskeleton, leading to PMR. Additionally, we will show that another S100 member – S100A4 accumulates at the injured PM. These findings reveal a new role for the S100 and annexin protein up regulation in metastatic cancers and identify these proteins and PMR as targets for treating metastatic cancers. PMID:25565331

  3. Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets

    PubMed Central

    Ramaker, Ryne C.; Cooper, Sara J.; Chen, Dongquan; Sudarshan, Sunil; Wei, Shi; Guru, Arjun S.; Zhao, Amy; Cooper, Tiffiny; Della Manna, Deborah L.; Naik, Gurudatta; Myers, Richard M.; Sonpavde, Guru

    2016-01-01

    Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation. PMID:27574806

  4. Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets.

    PubMed

    Ghatalia, Pooja; Yang, Eddy S; Lasseigne, Brittany N; Ramaker, Ryne C; Cooper, Sara J; Chen, Dongquan; Sudarshan, Sunil; Wei, Shi; Guru, Arjun S; Zhao, Amy; Cooper, Tiffiny; Della Manna, Deborah L; Naik, Gurudatta; Myers, Richard M; Sonpavde, Guru

    2016-01-01

    Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation. PMID:27574806

  5. A novel genome-wide in vivo screen for metastatic suppressors in human colon cancer identifies the positive WNT-TCF pathway modulators TMED3 and SOX12

    PubMed Central

    Duquet, Arnaud; Melotti, Alice; Mishra, Sonakshi; Malerba, Monica; Seth, Chandan; Conod, Arwen; Ruiz i Altaba, Ariel

    2014-01-01

    The progression of tumors to the metastatic state involves the loss of metastatic suppressor functions. Finding these, however, is difficult as in vitro assays do not fully predict metastatic behavior, and the majority of studies have used cloned cell lines, which do not reflect primary tumor heterogeneity. Here, we have designed a novel genome-wide screen to identify metastatic suppressors using primary human tumor cells in mice, which allows saturation screens. Using this unbiased approach, we have tested the hypothesis that endogenous colon cancer metastatic suppressors affect WNT-TCF signaling. Our screen has identified two novel metastatic suppressors: TMED3 and SOX12, the knockdown of which increases metastatic growth after direct seeding. Moreover, both modify the type of self-renewing spheroids, but only knockdown of TMED3 also induces spheroid cell spreading and lung metastases from a subcutaneous xenograft. Importantly, whereas TMED3 and SOX12 belong to different families involved in protein secretion and transcriptional regulation, both promote endogenous WNT-TCF activity. Treatments for advanced or metastatic colon cancer may thus not benefit from WNT blockers, and these may promote a worse outcome. PMID:24920608

  6. Effects of Teacher Professional Development on Gains in Student Achievement: How Meta Analysis Provides Scientific Evidence Useful to Education Leaders

    ERIC Educational Resources Information Center

    Blank, Rolf K.; de las Alas, Nina

    2010-01-01

    This meta analysis study focused on identifying and analyzing research studies that measured effects of teacher professional development with a content focus on math or science. This meta analysis was carried out to address two primary questions: (1) What are the effects of content-focused professional development for math and science teachers on…

  7. A comparative meta-analysis of QTL between intraspecific Gossypium hirsutum interspecific populations and Gossypium hirsutum x Gossypium barbadense populations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent Meta-analysis of quantitative trait loci (QTL) in tetraploid cotton (Gossypium spp.) has identified regions of the genome with high concentrations of various trait QTL called clusters, and specific trait QTL called hotspots. The Meta-analysis included all population types of Gossypium mixing ...

  8. Drivers of Wetland Conversion: a Global Meta-Analysis

    PubMed Central

    van Asselen, Sanneke; Verburg, Peter H.; Vermaat, Jan E.; Janse, Jan H.

    2013-01-01

    Meta-analysis of case studies has become an important tool for synthesizing case study findings in land change. Meta-analyses of deforestation, urbanization, desertification and change in shifting cultivation systems have been published. This present study adds to this literature, with an analysis of the proximate causes and underlying forces of wetland conversion at a global scale using two complementary approaches of systematic review. Firstly, a meta-analysis of 105 case-study papers describing wetland conversion was performed, showing that different combinations of multiple-factor proximate causes, and underlying forces, drive wetland conversion. Agricultural development has been the main proximate cause of wetland conversion, and economic growth and population density are the most frequently identified underlying forces. Secondly, to add a more quantitative component to the study, a logistic meta-regression analysis was performed to estimate the likelihood of wetland conversion worldwide, using globally-consistent biophysical and socioeconomic location factor maps. Significant factors explaining wetland conversion, in order of importance, are market influence, total wetland area (lower conversion probability), mean annual temperature and cropland or built-up area. The regression analyses results support the outcomes of the meta-analysis of the processes of conversion mentioned in the individual case studies. In other meta-analyses of land change, similar factors (e.g., agricultural development, population growth, market/economic factors) are also identified as important causes of various types of land change (e.g., deforestation, desertification). Meta-analysis helps to identify commonalities across the various local case studies and identify which variables may lead to individual cases to behave differently. The meta-regression provides maps indicating the likelihood of wetland conversion worldwide based on the location factors that have determined historic

  9. Air Pollution and Quality of Sperm: A Meta-Analysis

    PubMed Central

    Fathi Najafi, Tahereh; Latifnejad Roudsari, Robab; Namvar, Farideh; Ghavami Ghanbarabadi, Vahid; Hadizadeh Talasaz, Zahra; Esmaeli, Mahin

    2015-01-01

    Context: Air pollution is common in all countries and affects reproductive functions in men and women. It particularly impacts sperm parameters in men. This meta-analysis aimed to examine the impact of air pollution on the quality of sperm. Evidence Acquisition: The scientific databases of Medline, PubMed, Scopus, Google scholar, Cochrane Library, and Elsevier were searched to identify relevant articles published between 1978 to 2013. In the first step, 76 articles were selected. These studies were ecological correlation, cohort, retrospective, cross-sectional, and case control ones that were found through electronic and hand search of references about air pollution and male infertility. The outcome measurement was the change in sperm parameters. A total of 11 articles were ultimately included in a meta-analysis to examine the impact of air pollution on sperm parameters. The authors applied meta-analysis sheets from Cochrane library, then data extraction, including mean and standard deviation of sperm parameters were calculated and finally their confidence interval (CI) were compared to CI of standard parameters. Results: The CI for pooled means were as follows: 2.68 ± 0.32 for ejaculation volume (mL), 62.1 ± 15.88 for sperm concentration (million per milliliter), 39.4 ± 5.52 for sperm motility (%), 23.91 ± 13.43 for sperm morphology (%) and 49.53 ± 11.08 for sperm count. Conclusions: The results of this meta-analysis showed that air pollution reduces sperm motility, but has no impact on the other sperm parameters of spermogram. PMID:26023349

  10. Meta-analysis of results from quantitative trait loci mapping studies on pig chromosome 4.

    PubMed

    Silva, K M; Bastiaansen, J W M; Knol, E F; Merks, J W M; Lopes, P S; Guimarães, S E F; van Arendonk, J A M

    2011-06-01

    Meta-analysis of results from multiple studies could lead to more precise quantitative trait loci (QTL) position estimates compared to the individual experiments. As the raw data from many different studies are not readily available, the use of results from published articles may be helpful. In this study, we performed a meta-analysis of QTL on chromosome 4 in pig, using data from 25 separate experiments. First, a meta-analysis was performed for individual traits: average daily gain and backfat thickness. Second, a meta-analysis was performed for the QTL of three traits affecting loin yield: loin eye area, carcass length and loin meat weight. Third, 78 QTL were selected from 20 traits that could be assigned to one of three broad categories: carcass, fatness or growth traits. For each analysis, the number of identified meta-QTL was smaller than the number of initial QTL. The reduction in the number of QTL ranged from 71% to 86% compared to the total number before the meta-analysis. In addition, the meta-analysis reduced the QTL confidence intervals by as much as 85% compared to individual QTL estimates. The reduction in the confidence interval was greater when a large number of independent QTL was included in the meta-analysis. Meta-QTL related to growth and fatness were found in the same region as the FAT1 region. Results indicate that the meta-analysis is an efficient strategy to estimate the number and refine the positions of QTL when QTL estimates are available from multiple populations and experiments. This strategy can be used to better target further studies such as the selection of candidate genes related to trait variation.

  11. Obesity and periodontitis: systematic review and meta-analysis.

    PubMed

    Moura-Grec, Patrícia Garcia de; Marsicano, Juliane Avansini; Carvalho, Cristiane Alves Paz de; Sales-Peres, Silvia Helena de Carvalho

    2014-06-01

    The scope of this study was to conduct a systematic review of the studies on the association between obesity and periodontitis. The methods applied included a literature search strategy and selection of studies using inclusion and exclusion in accordance with the criteria for characteristics of the studies and meta-analysis. The research was conducted in the PubMed, Embase and Lilacs databases through 2010. Selected papers were on studies on humans investigating whether or not obesity is a risk factor for periodontitis. Of the 822 studies identified, 31 studies met the inclusion criteria and were included in this meta-analysis. The risk of periodontitis was associated with obesity (or had a tendency for this) in 25 studies, though it was not associated in 6 studies. The meta-analysis showed a significant association with obesity and periodontitis (OR = 1.30 [95% Confidence Interval (CI), 1.25 - 1.35]) and with mean Body Mass Index (BMI) and periodontal disease (mean difference = 2.75). Obesity was associated with periodontitis, however the risk factors that aggravate these diseases should be better clarified to elucidate the direction of this association. Working with paired samples and avoiding confusion factors may contribute to homogeneity between the studies. PMID:24897477

  12. Radiosurgery of Glomus Jugulare Tumors: A Meta-Analysis

    SciTech Connect

    Guss, Zachary D.; Batra, Sachin; Limb, Charles J.; Li, Gordon; Sughrue, Michael E.; Redmond, Kristin; Rigamonti, Daniele; Parsa, Andrew T.; Chang, Steven; Kleinberg, Lawrence; Lim, Michael

    2011-11-15

    Purpose: During the past two decades, radiosurgery has arisen as a promising approach to the management of glomus jugulare. In the present study, we report on a systematic review and meta-analysis of the available published data on the radiosurgical management of glomus jugulare tumors. Methods and Materials: To identify eligible studies, systematic searches of all glomus jugulare tumors treated with radiosurgery were conducted in major scientific publication databases. The data search yielded 19 studies, which were included in the meta-analysis. The data from 335 glomus jugulare patients were extracted. The fixed effects pooled proportions were calculated from the data when Cochrane's statistic was statistically insignificant and the inconsistency among studies was <25%. Bias was assessed using the Egger funnel plot test. Results: Across all studies, 97% of patients achieved tumor control, and 95% of patients achieved clinical control. Eight studies reported a mean or median follow-up time of >36 months. In these studies, 95% of patients achieved clinical control and 96% achieved tumor control. The gamma knife, linear accelerator, and CyberKnife technologies all exhibited high rates of tumor and clinical control. Conclusions: The present study reports the results of a meta-analysis for the radiosurgical management of glomus jugulare. Because of its high effectiveness, we suggest considering radiosurgery for the primary management of glomus jugulare tumors.

  13. [Meta-analysis and its synonyms].

    PubMed

    Meissner, Anne

    2008-02-01

    The purpose of meta-interpretive literature reviews is to combine the individual findings of different studies into a single, coherent analysis (here: meta-studies). The positions on how to handle that differ enormously. This is reflected in the variety of terms and definitions for synonym circumstances, e.g. "meta-analysis", "systematic review", "narrative review", "meta-syntheses". Also ambiguous is why in some cases the systematic is highlighted due to prefix the term "systematic", in others not. This article is part of a master thesis at the Institute of Nursing Science (University Witten/Herdecke, Germany). The aim of this article is to constitute the different opinions and put the terms in order. Illustrative examples of the synonymously used terms will therefore be identified and embedded in the underlying philosophies. It is assumed that the different positions result from the underlying philosophies. Further on there is evidence that "narrative" often wrongly is interpreted as the opposite to "systematic". The article concludes with options of how to put the terms in order. PMID:18478684

  14. Meta-analysis for Discovering Rare-Variant Associations: Statistical Methods and Software Programs

    PubMed Central

    Tang, Zheng-Zheng; Lin, Dan-Yu

    2015-01-01

    There is heightened interest in using next-generation sequencing technologies to identify rare variants that influence complex human diseases and traits. Meta-analysis is essential to this endeavor because large sample sizes are required for detecting associations with rare variants. In this article, we provide a comprehensive overview of statistical methods for meta-analysis of sequencing studies for discovering rare-variant associations. Specifically, we discuss the calculation of relevant summary statistics from participating studies, the construction of gene-level association tests, the choice of transformation for quantitative traits, the use of fixed-effects versus random-effects models, and the removal of shadow association signals through conditional analysis. We also show that meta-analysis based on properly calculated summary statistics is as powerful as joint analysis of individual-participant data. In addition, we demonstrate the performance of different meta-analysis methods by using both simulated and empirical data. We then compare four major software packages for meta-analysis of rare-variant associations—MASS, RAREMETAL, MetaSKAT, and seqMeta—in terms of the underlying statistical methodology, analysis pipeline, and software interface. Finally, we present PreMeta, a software interface that integrates the four meta-analysis packages and allows a consortium to combine otherwise incompatible summary statistics. PMID:26094574

  15. Meta-analysis for Discovering Rare-Variant Associations: Statistical Methods and Software Programs.

    PubMed

    Tang, Zheng-Zheng; Lin, Dan-Yu

    2015-07-01

    There is heightened interest in using next-generation sequencing technologies to identify rare variants that influence complex human diseases and traits. Meta-analysis is essential to this endeavor because large sample sizes are required for detecting associations with rare variants. In this article, we provide a comprehensive overview of statistical methods for meta-analysis of sequencing studies for discovering rare-variant associations. Specifically, we discuss the calculation of relevant summary statistics from participating studies, the construction of gene-level association tests, the choice of transformation for quantitative traits, the use of fixed-effects versus random-effects models, and the removal of shadow association signals through conditional analysis. We also show that meta-analysis based on properly calculated summary statistics is as powerful as joint analysis of individual-participant data. In addition, we demonstrate the performance of different meta-analysis methods by using both simulated and empirical data. We then compare four major software packages for meta-analysis of rare-variant associations-MASS, RAREMETAL, MetaSKAT, and seqMeta-in terms of the underlying statistical methodology, analysis pipeline, and software interface. Finally, we present PreMeta, a software interface that integrates the four meta-analysis packages and allows a consortium to combine otherwise incompatible summary statistics.

  16. Functional Annotation of Metastasis-associated MicroRNAs of Melanoma: A Meta-analysis of Expression Profiles

    PubMed Central

    Li, Jing-Yi; Zheng, Li-Li; Wang, Ting-Ting; Hu, Min

    2016-01-01

    Background: Melanoma is a type of cancer that develops from the pigment-containing cells. Until now, its pathological mechanisms remain largely unknown. The aim of this study was to identify metastasis-related microRNA (miRNAs) and gain an understanding of the biological functions in the metastasis of melanoma. Methods: We searched the PubMed and Gene Expression Omnibus database to collect miRNA expression profiling datasets about melanoma, with key words of “melanoma”, “miRNA”, “microarray”, and “gene expression profiling”. Only the original experimental works published before June 2016 for analyzing the metastasis of melanoma were retained, other nonhuman studies, reviews, and meta-analyses were removed. We performed a meta-analysis to explore the differentially expressed miRNA between metastatic and nonmetastatic samples. Moreover, we predicted target genes of the miRNAs to study their biological roles for these miRNAs. Results: We identified a total of 63 significantly differentially expressed miRNAs by meta-analysis of the melanoma expression profiling data. The regulatory network constructed by using these miRNAs and the predicted targets identified several key genes involved in the metastasis of melanoma. Functional annotation of these genes indicated that they are mainly enriched in some biological pathways such as mitogen-activated protein kinase signaling pathway, cell junction, and focal adhesion. Conclusions: By collecting the miRNA expression datasets from different platforms, multiple biological markers were identified for the metastasis of melanoma. This study provided novel insights into the molecular mechanisms underlying this disease, thereby aiding the diagnosis and treatment of the disease. PMID:27748342

  17. Multivariate meta-analysis: potential and promise.

    PubMed

    Jackson, Dan; Riley, Richard; White, Ian R

    2011-09-10

    The multivariate random effects model is a generalization of the standard univariate model. Multivariate meta-analysis is becoming more commonly used and the techniques and related computer software, although continually under development, are now in place. In order to raise awareness of the multivariate methods, and discuss their advantages and disadvantages, we organized a one day 'Multivariate meta-analysis' event at the Royal Statistical Society. In addition to disseminating the most recent developments, we also received an abundance of comments, concerns, insights, critiques and encouragement. This article provides a balanced account of the day's discourse. By giving others the opportunity to respond to our assessment, we hope to ensure that the various view points and opinions are aired before multivariate meta-analysis simply becomes another widely used de facto method without any proper consideration of it by the medical statistics community. We describe the areas of application that multivariate meta-analysis has found, the methods available, the difficulties typically encountered and the arguments for and against the multivariate methods, using four representative but contrasting examples. We conclude that the multivariate methods can be useful, and in particular can provide estimates with better statistical properties, but also that these benefits come at the price of making more assumptions which do not result in better inference in every case. Although there is evidence that multivariate meta-analysis has considerable potential, it must be even more carefully applied than its univariate counterpart in practice.

  18. Meta-analysis in Stata using gllamm.

    PubMed

    Bagos, Pantelis G

    2015-12-01

    There are several user-written programs for performing meta-analysis in Stata (Stata Statistical Software: College Station, TX: Stata Corp LP). These include metan, metareg, mvmeta, and glst. However, there are several cases for which these programs do not suffice. For instance, there is no software for performing univariate meta-analysis with correlated estimates, for multilevel or hierarchical meta-analysis, or for meta-analysis of longitudinal data. In this work, we show with practical applications that many disparate models, including but not limited to the ones mentioned earlier, can be fitted using gllamm. The software is very versatile and can handle a wide variety of models with applications in a wide range of disciplines. The method presented here takes advantage of these modeling capabilities and makes use of appropriate transformations, based on the Cholesky decomposition of the inverse of the covariance matrix, known as generalized least squares, in order to handle correlated data. The models described earlier can be thought of as special instances of a general linear mixed-model formulation, but to the author's knowledge, a general exposition in order to incorporate all the available models for meta-analysis as special cases and the instructions to fit them in Stata has not been presented so far. Source code is available at http:www.compgen.org/tools/gllamm.

  19. Degarelix for the treatment of advanced prostate cancer compared with GnRh-Agonists: a systematic review and meta-analysis

    PubMed Central

    Hosseini, Seyed Alireza; Rajabi, Fatemeh; Akbari Sari, Ali; Ayati, Mohsen; Heidari, Saeed; Ghamary, Fawzieh

    2016-01-01

    Background: Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer. We performed a systematic review to compare safety, efficacy and effectiveness of degarelix, a new gonadotropin-releasing hormone (GnRH) antagonist (blocker), versus gonadotropin-releasing hormone (GnRH) agonists. Methods: MEDLINE, Web of Science and the Cochrane library were searched to identify all of the published Randomized Controlled Trials (RCTs) that used degarelix versus gonadotropin-releasing hormone agonists with or without anti-androgen therapy for the treatment of prostate cancer. We performed meta-analysis of extracted data on safety and efficacy of the target medication. Results: Six studies were included. They involved a total of 2296 patients which were used in the meta-analysis. Follow-up times after treatment were between 12 weeks and 12 months. Three of six RCTs compared degarelix with goserelin and the others compared it with leuprolide. Meta-analysis on safety outcomes revealed that the only statistically significant difference between the degarelix treated group and GnRH agonists treated group was complication in the injection site which was higher in degarelix-treated group (OR= 46.34, 95% CI: 15.79 to 136, p<0.001). Although general mortality rate was lower in degarelix-treated group (OR= 2.06, 95% CI: 1.08 to 3.93, p=0.03); mortality due to the drug side effects was not different. Meta-analysis of efficacy data also showed that International Prostate Symptom Score (IPSS) reduction at week 12, (MD=-1.85, 95% CI: -2.97 to - 0.72, p=0.001) and Testosterone reduction between day 1-28, (OR=11.58, 95% CI: 5.77 to 23.22, p<0.001) was statistically higher in degarelix-treated group. Testosterone reduction after day 28 and prostate volume reduction did not have significant difference. Conclusion: Our meta-analysis indicates that, compared with GnRH agonists, degarelix has significantly more effects on lower urinary tract

  20. Interpreting and evaluating meta-analysis.

    PubMed

    Hall, J A; Rosenthal, R

    1995-12-01

    This article offers some guidelines for interpreting and evaluating meta-analytic reviews of research. The fundamental goals of meta-analysis are to combine results across studies to yield an overall estimate of effect and to compare effects between studies in order to understand moderating factors. Suggestions are made for what readers should look for in a meta-analysis, and a discussion is provided of several issues that are not often explicitly addressed: choice of unit of analysis, fixed versus random effects, the meaning of heterogeneity, determination of when contrasts are appropriate, and the choice of measure of central tendency. We recommend that readers adopt a skeptical attitude about the results of meta-analysis, particularly when only complex analyses are reported. PMID:10153164

  1. Circulating microRNA Profiling Identifies a Subset of Metastatic Prostate Cancer Patients with Evidence of Cancer-Associated Hypoxia

    PubMed Central

    Kroh, Evan M.; Dowell, Alexander E.; Chéry, Lisly; Siddiqui, Javed; Nelson, Peter S.; Vessella, Robert L.; Knudsen, Beatrice S.; Chinnaiyan, Arul M.; Pienta, Kenneth J.; Morrissey, Colm; Tewari, Muneesh

    2013-01-01

    MicroRNAs (miRNAs) are small (∼22 nucleotide) non-coding RNAs that regulate a myriad of biological processes and are frequently dysregulated in cancer. Cancer-associated microRNAs have been detected in serum and plasma and hold promise as minimally invasive cancer biomarkers, potentially for assessing disease characteristics in patients with metastatic disease that is difficult to biopsy. Here we used miRNA profiling to identify cancer-associated miRNAs that are differentially expressed in sera from patients with metastatic castration resistant prostate cancer (mCRPC) as compared to healthy controls. Of 365 miRNAs profiled, we identified five serum miRNAs (miR-141, miR-200a, miR-200c, miR-210 and miR-375) that were elevated in cases compared to controls across two independent cohorts. One of these, miR-210, is a known transcriptional target of the hypoxia-responsive HIF-1α signaling pathway. Exposure of cultured prostate cancer cells to hypoxia led to induction of miR-210 and its release into the extracellular environment. Moreover, we found that serum miR-210 levels varied widely amongst mCRPC patients undergoing therapy, and correlated with treatment response as assessed by change in PSA. Our results suggest that (i) cancer-associated hypoxia is a frequent, previously under-appreciated characteristic of mCRPC, and (ii) serum miR-210 may be further developed as a predictive biomarker in patients with this distinct disease biology. PMID:23935962

  2. Application of a Drug-Induced Apoptosis Assay to Identify Treatment Strategies in Recurrent or Metastatic Breast Cancer

    PubMed Central

    Bosserman, Linda; Rogers, Karl; Willis, Carl; Davidson, Dirk; Whitworth, Pat; Karimi, Misagh; Upadhyaya, Gargi; Rutledge, James; Hallquist, Allan; Perree, Mathieu; Presant, Cary A.

    2015-01-01

    Background A drug-induced apoptosis assay has been developed to determine which chemotherapy drugs or regimens can produce higher cell killing in vitro. This study was done to determine if this assay could be performed in patients with recurrent or metastatic breast cancer patients, to characterize the patterns of drug-induced apoptosis, and to evaluate the clinical utility of the assay. A secondary goal was to correlate assay use with clinical outcomes. Methods In a prospective, non-blinded, multi institutional controlled trial, 30 evaluable patients with recurrent or metastatic breast cancer who were treated with chemotherapy had tumor samples submitted for the MiCK drug-induced apoptosis assay. After receiving results within 72 hours after biopsy, physicians could use the test to determine therapy (users), or elect to not use the test (non-users). Results The assay was able to characterize drug-induced apoptosis in tumor specimens from breast cancer patients and identified which drugs or combinations gave highest levels of apoptosis. Patterns of drug activity were also analyzed in triple negative breast cancer. Different drugs from a single class of agents often produced significantly different amounts of apoptosis. Physician frequently (73%) used the assay to help select chemotherapy treatments in patients, Patients whose physicians were users had a higher response (CR+PR) rate compared to non-users (38.1% vs 0%, p = 0.04) and a higher disease control (CR+PR+Stable) rate (81% vs 25%, p<0.01). Time to relapse was longer in users 7.4 mo compared to non-users 2.2 mo (p<0.01). Conclusions The MiCK assay can be performed in breast cancer specimens, and results are often used by physicians in breast cancer patients with recurrent or metastatic disease. These results from a good laboratory phase II study can be the basis for a future larger prospective multicenter study to more definitively establish the value of the assay. Trial Registration Clinicaltrials.gov NCT

  3. A BAYESIAN HIERARCHICAL SPATIAL POINT PROCESS MODEL FOR MULTI-TYPE NEUROIMAGING META-ANALYSIS

    PubMed Central

    Kang, Jian; Nichols, Thomas E.; Wager, Tor D.; Johnson, Timothy D.

    2014-01-01

    Neuroimaging meta-analysis is an important tool for finding consistent effects over studies that each usually have 20 or fewer subjects. Interest in meta-analysis in brain mapping is also driven by a recent focus on so-called “reverse inference”: where as traditional “forward inference” identifies the regions of the brain involved in a task, a reverse inference identifies the cognitive processes that a task engages. Such reverse inferences, however, requires a set of meta-analysis, one for each possible cognitive domain. However, existing methods for neuroimaging meta-analysis have significant limitations. Commonly used methods for neuroimaging meta-analysis are not model based, do not provide interpretable parameter estimates, and only produce null hypothesis inferences; further, they are generally designed for a single group of studies and cannot produce reverse inferences. In this work we address these limitations by adopting a non-parametric Bayesian approach for meta analysis data from multiple classes or types of studies. In particular, foci from each type of study are modeled as a cluster process driven by a random intensity function that is modeled as a kernel convolution of a gamma random field. The type-specific gamma random fields are linked and modeled as a realization of a common gamma random field, shared by all types, that induces correlation between study types and mimics the behavior of a univariate mixed effects model. We illustrate our model on simulation studies and a meta analysis of five emotions from 219 studies and check model fit by a posterior predictive assessment. In addition, we implement reverse inference by using the model to predict study type from a newly presented study. We evaluate this predictive performance via leave-one-out cross validation that is efficiently implemented using importance sampling techniques. PMID:25426185

  4. A BAYESIAN HIERARCHICAL SPATIAL POINT PROCESS MODEL FOR MULTI-TYPE NEUROIMAGING META-ANALYSIS.

    PubMed

    Kang, Jian; Nichols, Thomas E; Wager, Tor D; Johnson, Timothy D

    2014-09-01

    Neuroimaging meta-analysis is an important tool for finding consistent effects over studies that each usually have 20 or fewer subjects. Interest in meta-analysis in brain mapping is also driven by a recent focus on so-called "reverse inference": where as traditional "forward inference" identifies the regions of the brain involved in a task, a reverse inference identifies the cognitive processes that a task engages. Such reverse inferences, however, requires a set of meta-analysis, one for each possible cognitive domain. However, existing methods for neuroimaging meta-analysis have significant limitations. Commonly used methods for neuroimaging meta-analysis are not model based, do not provide interpretable parameter estimates, and only produce null hypothesis inferences; further, they are generally designed for a single group of studies and cannot produce reverse inferences. In this work we address these limitations by adopting a non-parametric Bayesian approach for meta analysis data from multiple classes or types of studies. In particular, foci from each type of study are modeled as a cluster process driven by a random intensity function that is modeled as a kernel convolution of a gamma random field. The type-specific gamma random fields are linked and modeled as a realization of a common gamma random field, shared by all types, that induces correlation between study types and mimics the behavior of a univariate mixed effects model. We illustrate our model on simulation studies and a meta analysis of five emotions from 219 studies and check model fit by a posterior predictive assessment. In addition, we implement reverse inference by using the model to predict study type from a newly presented study. We evaluate this predictive performance via leave-one-out cross validation that is efficiently implemented using importance sampling techniques.

  5. Incorporating Quality Scores in Meta-Analysis

    ERIC Educational Resources Information Center

    Ahn, Soyeon; Becker, Betsy Jane

    2011-01-01

    This paper examines the impact of quality-score weights in meta-analysis. A simulation examines the roles of study characteristics such as population effect size (ES) and its variance on the bias and mean square errors (MSEs) of the estimators for several patterns of relationship between quality and ES, and for specific patterns of systematic…

  6. A Bayesian Nonparametric Meta-Analysis Model

    ERIC Educational Resources Information Center

    Karabatsos, George; Talbott, Elizabeth; Walker, Stephen G.

    2015-01-01

    In a meta-analysis, it is important to specify a model that adequately describes the effect-size distribution of the underlying population of studies. The conventional normal fixed-effect and normal random-effects models assume a normal effect-size population distribution, conditionally on parameters and covariates. For estimating the mean overall…

  7. Meta-Analysis: A Case Study

    ERIC Educational Resources Information Center

    Briggs, Derek C.

    2005-01-01

    This article raises some questions about the usefulness of meta-analysis as a means of reviewing quantitative research in the social sciences. When a meta-analytic model for SAT coaching is used to predict results from future studies, the amount of prediction error is quite large. Interpretations of meta-analytic regressions and quantifications of…

  8. Organizational Identification: A Meta-Analysis

    ERIC Educational Resources Information Center

    Riketta, Michael

    2005-01-01

    The last two decades have witnessed a surge in interest in research on organizational identification (OI). This paper presents a comprehensive meta-analysis of this research (k=96). Results indicate that (a) OI is correlated with a wide range of work-related attitudes, behaviors, and context variables, (b) OI is empirically distinct from its…

  9. Smoking and Suicide: A Meta-Analysis

    PubMed Central

    Poorolajal, Jalal; Darvishi, Nahid

    2016-01-01

    Background Many studies have reported a positive association between smoking and suicide, but the results are inconsistent. This meta-analysis was carried out to estimate the association between smoking and suicidal ideation, suicide plan, suicide attempt, and suicide death. Methods Major electronic databases including PubMed, Web of Science, Scopus, and ScienceDirect were searched until May 2015. The reference lists of included studies were screened too. Epidemiological studies addressing the association between smoking and suicidal behaviors were enrolled. The heterogeneity across studies was explored by Q-test and I2 statistic. The possibility of publication bias was assessed using Begg's and Egger's tests and Trim & Fill analysis. The results were reported based on risk ratio (RR) and odds ratio (OR) with 95% confidence intervals (CI) using a random-effects model. Results We identified a total of 8062 references and included 63 studies with 8,063,634 participants. Compared to nonsmokers, the current smokers were at higher risk of suicidal ideation (OR = 2.05; 95% CI: 1.53, 2.58; 8 studies; I2 = 80.8%; P<0.001), suicide plan (OR = 2.36; 95% CI: 1.69, 3.02; 6 studies; I2 = 85.2%; P<0.001), suicide attempt (OR = 2.84; 95% CI: 1.49, 4.19; 5 studies; I2 = 89.6%; (P<0.001), and suicide death (RR = 1.83; 95% CI: 1.64, 2.02; 14 studies; I2 = 49.7%; P = 0.018). Conclusions There is sufficient evidence that smoking is associated with an increased risk of suicidal behaviors. Therefore, smoking is a contributing factor for suicide. Although this association does not imply causation, however, smoking prevention and cessation should be the target of suicide prevention programs. PMID:27391330

  10. Meta-analysis of genome-wide expression patterns associated with behavioral maturation in honey bees

    PubMed Central

    Adams, Heather A; Southey, Bruce R; Robinson, Gene E; Rodriguez-Zas, Sandra L

    2008-01-01

    Background The information from multiple microarray experiments can be integrated in an objective manner via meta-analysis. However, multiple meta-analysis approaches are available and their relative strengths have not been directly compared using experimental data in the context of different gene expression scenarios and studies with different degrees of relationship. This study investigates the complementary advantages of meta-analysis approaches to integrate information across studies, and further mine the transcriptome for genes that are associated with complex processes such as behavioral maturation in honey bees. Behavioral maturation and division of labor in honey bees are related to changes in the expression of hundreds of genes in the brain. The information from various microarray studies comparing the expression of genes at different maturation stages in honey bee brains was integrated using complementary meta-analysis approaches. Results Comparison of lists of genes with significant differential expression across studies failed to identify genes with consistent patterns of expression that were below the selected significance threshold, or identified genes with significant yet inconsistent patterns. The meta-analytical framework supported the identification of genes with consistent overall expression patterns and eliminated genes that exhibited contradictory expression patterns across studies. Sample-level meta-analysis of normalized gene-expression can detect more differentially expressed genes than the study-level meta-analysis of estimates for genes that were well described by similar model parameter estimates across studies and had small variation across studies. Furthermore, study-level meta-analysis was well suited for genes that exhibit consistent patterns across studies, genes that had substantial variation across studies, and genes that did not conform to the assumptions of the sample-level meta-analysis. Meta-analyses confirmed previously

  11. Prison Privatization: A Meta-Analysis of Cost and Quality of Confinement Indicators

    ERIC Educational Resources Information Center

    Lundahl, Brad W.; Kunz, Chelsea; Brownell, Cyndi; Harris, Norma; Van Vleet, Russ

    2009-01-01

    Objective: To examine the results of prison privatization. Method: In an effort to provide an empirical base from which decisions about privatization might be made, we conducted a meta-analysis of reports on head-to-head comparisons between an identifiable privately managed and publicly managed prison(s). Results: Our search identified 12 studies.…

  12. Delayed reward discounting and addictive behavior: a meta-analysis

    PubMed Central

    Amlung, Michael T.; Few, Lauren R.; Ray, Lara A.; Sweet, Lawrence H.; Munafò, Marcus R.

    2011-01-01

    Rationale Delayed reward discounting (DRD) is a behavioral economic index of impulsivity and numerous studies have examined DRD in relation to addictive behavior. To synthesize the findings across the literature, the current review is a meta-analysis of studies comparing DRD between criterion groups exhibiting addictive behavior and control groups. Objectives The meta-analysis sought to characterize the overall patterns of findings, systematic variability by sample and study type, and possible small study (publication) bias. Methods Literature reviews identified 310 candidate articles from which 46 studies reporting 64 comparisons were identified (total N=56,013). Results From the total comparisons identified, a small magnitude effect was evident (d=.15; p<.00001) with very high heterogeneity of effect size. Based on systematic observed differences, large studies assessing DRD with a small number of self-report items were removed and an analysis of 57 comparisons (n=3,329) using equivalent methods and exhibiting acceptable heterogeneity revealed a medium magnitude effect (d=.58; p<.00001). Further analyses revealed significantly larger effect sizes for studies using clinical samples (d=.61) compared with studies using nonclinical samples (d=.45). Indices of small study bias among the various comparisons suggested varying levels of influence by unpublished findings, ranging from minimal to moderate. Conclusions These results provide strong evidence of greater DRD in individuals exhibiting addictive behavior in general and particularly in individuals who meet criteria for an addictive disorder. Implications for the assessment of DRD and research priorities are discussed. PMID:21373791

  13. Game-based digital interventions for depression therapy: a systematic review and meta-analysis.

    PubMed

    Li, Jinhui; Theng, Yin-Leng; Foo, Schubert

    2014-08-01

    The aim of this study was to review the existing literature on game-based digital interventions for depression systematically and examine their effectiveness through a meta-analysis of randomized controlled trials (RCTs). Database searching was conducted using specific search terms and inclusion criteria. A standard meta-analysis was also conducted of available RCT studies with a random effects model. The standard mean difference (Cohen's d) was used to calculate the effect size of each study. Nineteen studies were included in the review, and 10 RCTs (eight studies) were included in the meta-analysis. Four types of game interventions-psycho-education and training, virtual reality exposure therapy, exercising, and entertainment-were identified, with various types of support delivered and populations targeted. The meta-analysis revealed a moderate effect size of the game interventions for depression therapy at posttreatment (d=-0.47 [95% CI -0.69 to -0.24]). A subgroup analysis showed that interventions based on psycho-education and training had a smaller effect than those based on the other forms, and that self-help interventions yielded better outcomes than supported interventions. A higher effect was achieved when a waiting list was used as the control. The review and meta-analysis support the effectiveness of game-based digital interventions for depression. More large-scale, high-quality RCT studies with sufficient long-term data for treatment evaluation are needed.

  14. Game-Based Digital Interventions for Depression Therapy: A Systematic Review and Meta-Analysis

    PubMed Central

    Theng, Yin-Leng; Foo, Schubert

    2014-01-01

    Abstract The aim of this study was to review the existing literature on game-based digital interventions for depression systematically and examine their effectiveness through a meta-analysis of randomized controlled trials (RCTs). Database searching was conducted using specific search terms and inclusion criteria. A standard meta-analysis was also conducted of available RCT studies with a random effects model. The standard mean difference (Cohen's d) was used to calculate the effect size of each study. Nineteen studies were included in the review, and 10 RCTs (eight studies) were included in the meta-analysis. Four types of game interventions—psycho-education and training, virtual reality exposure therapy, exercising, and entertainment—were identified, with various types of support delivered and populations targeted. The meta-analysis revealed a moderate effect size of the game interventions for depression therapy at posttreatment (d=−0.47 [95% CI −0.69 to −0.24]). A subgroup analysis showed that interventions based on psycho-education and training had a smaller effect than those based on the other forms, and that self-help interventions yielded better outcomes than supported interventions. A higher effect was achieved when a waiting list was used as the control. The review and meta-analysis support the effectiveness of game-based digital interventions for depression. More large-scale, high-quality RCT studies with sufficient long-term data for treatment evaluation are needed. PMID:24810933

  15. A Meta-Analysis of Mathematics and Working Memory: Moderating Effects of Working Memory Domain, Type of Mathematics Skill, and Sample Characteristics

    ERIC Educational Resources Information Center

    Peng, Peng; Namkung, Jessica; Barnes, Marcia; Sun, Congying

    2016-01-01

    The purpose of this meta-analysis was to determine the relation between mathematics and working memory (WM) and to identify possible moderators of this relation including domains of WM, types of mathematics skills, and sample type. A meta-analysis of 110 studies with 829 effect sizes found a significant medium correlation of mathematics and WM, r…

  16. Efficacy and Safety of HER2-Targeted Agents for Breast Cancer with HER2-Overexpression: A Network Meta-Analysis

    PubMed Central

    Yu, Qiuyan; Zhu, Zhenli; Liu, Yan; Zhang, Jun; Li, Ke

    2015-01-01

    Background Clinical trials of human epidermal growth factor receptor 2 (HER2)-targeted agents added to standard treatment have been efficacious for HER2-positive (HER2+) advanced breast cancer. To our knowledge, no meta-analysis has evaluated HER2-targeted therapy including trastuzumab emtansine (T-DM1) and pertuzumab for HER2-positive breast caner and ranked the targeted treatments. We performed a network meta-analysis of both direct and indirect comparisons to evaluate the effect of adding HER2-targeted agents to standard treatment and examined side effects. Methods We performed a Bayesian-framework network meta-analysis of randomized controlled trials to compare 6 HER2-targeted treatment regimens and 1 naïve standard treatment (NST, without any-targeted drugs) in targeted treatment of HER2+ breast cancer in adults. These treatment regimens were T-DM1, LC (lapatinib), HC (trastuzumab), PEC (pertuzumab), LHC (lapatinib and trastuzumab), and PEHC (pertuzumab and trastuzumab). The main outcomes were overall survival and response rates. We also examined side effects of rash, LVEF (left ventricular ejection fraction), fatigue, and gastrointestinal disorders, and performed subgroup analysis for the different treatment regimens in metastatic or advanced breast cancer. Results We identified 25 articles of 21 trials, with data for 11,276 participants. T-DM1 and PEHC were more efficient drug regimens with regard to overall survival as compared with LHC, LC, HC and PEC. The incidence of treatment-related rash occurs more frequently in the patients who received LC treatment regimen than PEHC and T-DM1 and HC. In subgroup analysis, T-DM1 was associated with increased overall survival as compared with LC and HC. PEHC was associated with increased overall response as compared with LC, HC, and NST. Conclusions Overall, the regimen of T-DM1 as well as pertuzumab in combination with trastuzumab and docetaxel is efficacious with fewer side effects as compared with other regimens

  17. Scientists Admitting to Plagiarism: A Meta-analysis of Surveys.

    PubMed

    Pupovac, Vanja; Fanelli, Daniele

    2015-10-01

    We conducted a systematic review and meta-analysis of anonymous surveys asking scientists whether they ever committed various forms of plagiarism. From May to December 2011 we searched 35 bibliographic databases, five grey literature databases and hand searched nine journals for potentially relevant studies. We included surveys that asked scientists if, in a given recall period, they had committed or knew of a colleague who committed plagiarism, and from each survey extracted the proportion of those who reported at least one case. Studies that focused on academic (i.e. student) plagiarism were excluded. Literature searches returned 12,460 titles from which 17 relevant survey studies were identified. Meta-analysis of studies reporting committed (N = 7) and witnessed (N = 11) plagiarism yielded a pooled estimate of, respectively, 1.7% (95% CI 1.2-2.4) and 30% (95% CI 17-46). Basic methodological factors, including sample size, year of survey, delivery method and whether survey questions were explicit rather than indirect made a significant difference on survey results. Even after controlling for these methodological factors, between-study differences in admission rates were significantly above those expected by sampling error alone and remained largely unexplained. Despite several limitations of the data and of this meta-analysis, we draw three robust conclusions: (1) The rate at which scientists report knowing a colleague who committed plagiarism is higher than for data fabrication and falsification; (2) The rate at which scientists report knowing a colleague who committed plagiarism is correlated to that of fabrication and falsification; (3) The rate at which scientists admit having committed either form of misconduct (i.e. fabrication, falsification and plagiarism) in surveys has declined over time. PMID:25352123

  18. Scientists Admitting to Plagiarism: A Meta-analysis of Surveys.

    PubMed

    Pupovac, Vanja; Fanelli, Daniele

    2015-10-01

    We conducted a systematic review and meta-analysis of anonymous surveys asking scientists whether they ever committed various forms of plagiarism. From May to December 2011 we searched 35 bibliographic databases, five grey literature databases and hand searched nine journals for potentially relevant studies. We included surveys that asked scientists if, in a given recall period, they had committed or knew of a colleague who committed plagiarism, and from each survey extracted the proportion of those who reported at least one case. Studies that focused on academic (i.e. student) plagiarism were excluded. Literature searches returned 12,460 titles from which 17 relevant survey studies were identified. Meta-analysis of studies reporting committed (N = 7) and witnessed (N = 11) plagiarism yielded a pooled estimate of, respectively, 1.7% (95% CI 1.2-2.4) and 30% (95% CI 17-46). Basic methodological factors, including sample size, year of survey, delivery method and whether survey questions were explicit rather than indirect made a significant difference on survey results. Even after controlling for these methodological factors, between-study differences in admission rates were significantly above those expected by sampling error alone and remained largely unexplained. Despite several limitations of the data and of this meta-analysis, we draw three robust conclusions: (1) The rate at which scientists report knowing a colleague who committed plagiarism is higher than for data fabrication and falsification; (2) The rate at which scientists report knowing a colleague who committed plagiarism is correlated to that of fabrication and falsification; (3) The rate at which scientists admit having committed either form of misconduct (i.e. fabrication, falsification and plagiarism) in surveys has declined over time.

  19. Multiplicative interaction in network meta-analysis.

    PubMed

    Piepho, Hans-Peter; Madden, Laurence V; Williams, Emlyn R

    2015-02-20

    Meta-analysis of a set of clinical trials is usually conducted using a linear predictor with additive effects representing treatments and trials. Additivity is a strong assumption. In this paper, we consider models for two or more treatments that involve multiplicative terms for interaction between treatment and trial. Multiplicative models provide information on the sensitivity of each treatment effect relative to the trial effect. In developing these models, we make use of a two-way analysis-of-variance approach to meta-analysis and consider fixed or random trial effects. It is shown using two examples that models with multiplicative terms may fit better than purely additive models and provide insight into the nature of the trial effect. We also show how to model inconsistency using multiplicative terms.

  20. A Bayesian nonparametric meta-analysis model.

    PubMed

    Karabatsos, George; Talbott, Elizabeth; Walker, Stephen G

    2015-03-01

    In a meta-analysis, it is important to specify a model that adequately describes the effect-size distribution of the underlying population of studies. The conventional normal fixed-effect and normal random-effects models assume a normal effect-size population distribution, conditionally on parameters and covariates. For estimating the mean overall effect size, such models may be adequate, but for prediction, they surely are not if the effect-size distribution exhibits non-normal behavior. To address this issue, we propose a Bayesian nonparametric meta-analysis model, which can describe a wider range of effect-size distributions, including unimodal symmetric distributions, as well as skewed and more multimodal distributions. We demonstrate our model through the analysis of real meta-analytic data arising from behavioral-genetic research. We compare the predictive performance of the Bayesian nonparametric model against various conventional and more modern normal fixed-effects and random-effects models.

  1. Chest Compression-Only CPR: A Meta-Analysis

    PubMed Central

    Hüpfl, Michael; Selig, Harald F; Nagele, Peter

    2010-01-01

    Summary Background Evidence suggests that dispatcher-assisted chest compression-only bystander CPR may be superior to standard CPR (chest compressions and rescue ventilation) in out-of-hospital cardiac arrest, yet recent clinical trials did not observe improved outcomes. The goal of the study was to determine the association between chest compression-only CPR and survival after out-of-hospital cardiac arrest. Methods Studies published until August 2010 were systematically searched and identified in MEDLINE and EMBASE databases. For the primary meta-analysis only clinical trials were included that prospectively randomized dispatcher instructions to chest compression-only versus standard bystander CPR in out-of-hospital adult cardiac arrest patients; for the secondary meta-analysis observational cohort studies were included that distinguished between standard CPR and chest compression-only CPR. All studies were required to contain survival data. Data on study characteristics, methods and outcomes (return of spontaneous circulation, survival to discharge, 30-day survival, and favourable neurologic outcome) were extracted. A fixed-effects model was used for both meta-analyses for lack of heterogeneity among the studies (I2 0%). Findings All three published randomized clinical trials were included in the meta-analysis. The pooled analyses shows that dispatcher-assisted chest compression-only bystander CPR for adult out-of-hospital cardiac arrest was associated with a 22% improved chance of survival (risk ratio [RR] 1.22 [95% confidence interval {CI}, 1.01 – 1.47]; I2, 0%) compared to standard CPR. The absolute increase in survival was 2.4%; the number needed to treat was 41. The secondary meta-analysis included seven observational studies of bystander-CPR (not dispatcher-assisted) and showed no difference between the two CPR techniques (RR, 0.96 [95% CI, 0.83 – 1.11]; I2, 0%). Interpretation Dispatcher-assisted chest compression-only bystander CPR is associated with

  2. MODEL-DRIVEN META-ANALYSES FOR INFORMING HEALTH CARE: A DIABETES META-ANALYSIS AS AN EXEMPLAR

    PubMed Central

    Brown, Sharon A.; Becker, Betsy Jane; García, Alexandra A.; Brown, Adama; Ramírez, Gilbert

    2015-01-01

    A relatively novel type of meta-analysis, a model-driven meta-analysis, involves the quantitative synthesis of descriptive, correlational data and is useful for identifying key predictors of health outcomes and informing clinical guidelines. Few such meta-analyses have been conducted and thus, large bodies of research remain unsynthesized and uninterpreted for application in health care. We describe the unique challenges of conducting a model-driven meta-analysis, focusing primarily on issues related to locating a sample of published and unpublished primary studies, extracting and verifying descriptive and correlational data, and conducting analyses. A current meta-analysis of the research on predictors of key health outcomes in diabetes is used to illustrate our main points. PMID:25142707

  3. Model-driven meta-analyses for informing health care: a diabetes meta-analysis as an exemplar.

    PubMed

    Brown, Sharon A; Becker, Betsy Jane; García, Alexandra A; Brown, Adama; Ramírez, Gilbert

    2015-04-01

    A relatively novel type of meta-analysis, a model-driven meta-analysis, involves the quantitative synthesis of descriptive, correlational data and is useful for identifying key predictors of health outcomes and informing clinical guidelines. Few such meta-analyses have been conducted and thus, large bodies of research remain unsynthesized and uninterpreted for application in health care. We describe the unique challenges of conducting a model-driven meta-analysis, focusing primarily on issues related to locating a sample of published and unpublished primary studies, extracting and verifying descriptive and correlational data, and conducting analyses. A current meta-analysis of the research on predictors of key health outcomes in diabetes is used to illustrate our main points.

  4. Identifying metastatic breast tumors using textural kinetic features of a contrast based habitat in DCE-MRI

    NASA Astrophysics Data System (ADS)

    Chaudhury, Baishali; Zhou, Mu; Goldgof, Dmitry B.; Hall, Lawrence O.; Gatenby, Robert A.; Gillies, Robert J.; Drukteinis, Jennifer S.

    2015-03-01

    The ability to identify aggressive tumors from indolent tumors using quantitative analysis on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) would dramatically change the breast cancer treatment paradigm. With this prognostic information, patients with aggressive tumors that have the ability to spread to distant sites outside of the breast could be selected for more aggressive treatment and surveillance regimens. Conversely, patients with tumors that do not have the propensity to metastasize could be treated less aggressively, avoiding some of the morbidity associated with surgery, radiation and chemotherapy. We propose a computer aided detection framework to determine which breast cancers will metastasize to the loco-regional lymph nodes as well as which tumors will eventually go on to develop distant metastses using quantitative image analysis and radiomics. We defined a new contrast based tumor habitat and analyzed textural kinetic features from this habitat for classification purposes. The proposed tumor habitat, which we call combined-habitat, is derived from the intersection of two individual tumor sub-regions: one that exhibits rapid initial contrast uptake and the other that exhibits rapid delayed contrast washout. Hence the combined-habitat represents the tumor sub-region within which the pixels undergo both rapid initial uptake and rapid delayed washout. We analyzed a dataset of twenty-seven representative two dimensional (2D) images from volumetric DCE-MRI of breast tumors, for classification of tumors with no lymph nodes from tumors with positive number of axillary lymph nodes. For this classification an accuracy of 88.9% was achieved. Twenty of the twenty-seven patients were analyzed for classification of distant metastatic tumors from indolent cancers (tumors with no lymph nodes), for which the accuracy was 84.3%.

  5. Gene expression identifies heterogeneity of metastatic behavior among high-grade non-translocation associated soft tissue sarcomas

    PubMed Central

    2014-01-01

    Background The biologic heterogeneity of soft tissue sarcomas (STS), even within histological subtypes, complicates treatment. In earlier studies, gene expression patterns that distinguish two subsets of clear cell renal carcinoma (RCC), serous ovarian carcinoma (OVCA), and aggressive fibromatosis (AF) were used to separate 73 STS into two or four groups with different probabilities of developing metastatic disease (PrMet). This study was designed to confirm our earlier observations in a larger independent data set. Methods We utilized these gene sets, hierarchical clustering (HC), and Kaplan-Meier analysis, to examine 309 STS, using Affymetrix chip expression profiling. Results HC using the combined AF-, RCC-, and OVCA-gene sets identified subsets of the STS samples. Analysis revealed differences in PrMet between the clusters defined by the first branch point of the clustering dendrogram (p = 0.048), and also among the four different clusters defined by the second branch points (p < 0.0001). Analysis also revealed differences in PrMet between the leiomyosarcomas (LMS), dedifferentiated liposarcomas (LipoD), and undifferentiated pleomorphic sarcomas (UPS) (p = 0.0004). HC of both the LipoD and UPS sample sets divided the samples into two groups with different PrMet (p = 0.0128, and 0.0002, respectively). HC of the UPS samples also showed four groups with different PrMet (p = 0.0007). HC found no subgroups of the LMS samples. Conclusions These data confirm our earlier studies, and suggest that this approach may allow the identification of more than two subsets of STS, each with distinct clinical behavior, and may be useful to stratify STS in clinical trials and in patient management. PMID:24950699

  6. In-depth Characterization of the Secretome of Colorectal Cancer Metastatic Cells Identifies Key Proteins in Cell Adhesion, Migration, and Invasion*

    PubMed Central

    Barderas, Rodrigo; Mendes, Marta; Torres, Sofia; Bartolomé, Rubén A.; López-Lucendo, María; Villar-Vázquez, Roi; Peláez-García, Alberto; Fuente, Eduardo; Bonilla, Félix; Casal, J. Ignacio

    2013-01-01

    Liver metastasis in colorectal cancer is the major cause of cancer-related deaths. To identify and characterize proteins associated with colon cancer metastasis, we have compared the conditioned serum-free medium of highly metastatic KM12SM colorectal cancer cells with the parental, poorly metastatic KM12C cells using quantitative stable isotope labeling by amino acids in cell culture (SILAC) analyses on a linear ion trap-Orbitrap Velos mass spectrometer. In total, 1337 proteins were simultaneously identified in SILAC forward and reverse experiments. For quantification, 1098 proteins were selected in both experiments, with 155 proteins showing >1.5-fold change. About 52% of these proteins were secreted directly or using alternative secretion pathways. GDF15, S100A8/A9, and SERPINI1 showed capacity to discriminate cancer serum samples from healthy controls using ELISAs. In silico analyses of deregulated proteins in the secretome of metastatic cells showed a major abundance of proteins involved in cell adhesion, migration, and invasion. To characterize the tumorigenic and metastatic properties of some top up- and down-regulated proteins, we used siRNA silencing and antibody blocking. Knockdown expression of NEO1, SERPINI1, and PODXL showed a significant effect on cellular adhesion. Silencing or blocking experiments with SOSTDC1, CTSS, EFNA3, CD137L/TNFSF9, ZG16B, and Midkine caused a significant decrease in migration and invasion of highly metastatic cells. In addition, silencing of SOSTDC1, EFNA3, and CD137L/TNFSF9 reduced liver colonization capacity of KM12SM cells. Finally, the panel of six proteins involved in invasion showed association with poor prognosis and overall survival after dataset analysis of gene alterations. In summary, we have defined a collection of proteins that are relevant for understanding the mechanisms underlying adhesion, migration, invasion, and metastasis in colorectal cancer. PMID:23443137

  7. GWA meta-analysis of personality in Korean cohorts.

    PubMed

    Kim, Bo-Hye; Kim, Han-Na; Roh, Seung-Ju; Lee, Mi Kyeong; Yang, Sarah; Lee, Seung Ku; Sung, Yeon-Ah; Chung, Hye Won; Cho, Nam H; Shin, Chol; Sung, Joohon; Kim, Hyung-Lae

    2015-08-01

    Personality is a determinant of behavior and lifestyle that is associated with health and human diseases. Despite the heritability of personality traits is well established, the understanding of the genetic contribution to personality trait variation is extremely limited. To identify genetic variants associated with each of the five dimensions of personality, we performed a genome-wide association (GWA) meta-analysis of three cohorts, followed by comparison of a family cohort. Personality traits were measured with the Revised NEO Personality Inventory for the five-factor model (FFM) of personality. We investigated the top five single-nucleotide polymorphisms (SNPs) for each trait, and revealed the most highly association with neuroticism and TACC2 (rs1010657, P=8.79 × 10(-7)), extraversion and PTPN12 (rs12537271, P=1.47 × 10(-7)), openness and IMPAD1 (rs16921695, P=5 × 10(-8)), agreeableness and RPS29 (rs8015351, P=1.27 × 10(-6)) and conscientiousness and LMO4 (rs912765, P=2.91 × 10(-6)). It had no SNP reached the GWA study threshold (P<5 × 10(-8)). When expanded the SNPs up to top 100, the correlation of PTPRD (rs1029089) and agreeableness was confirmed in Healthy Twin cohort with other 13 SNPs. This GWA meta-analysis on FFM personality traits is meaningful as it was the first on a non-Caucasian population targeted to FFM of personality traits.

  8. A Meta-Analysis of Writing Instruction for Students in the Elementary Grades

    ERIC Educational Resources Information Center

    Graham, Steve; McKeown, Debra; Kiuhara, Sharlene; Harris, Karen R.

    2012-01-01

    In an effort to identify effective instructional practices for teaching writing to elementary grade students, we conducted a meta-analysis of the writing intervention literature, focusing our efforts on true and quasi-experiments. We located 115 documents that included the statistics for computing an effect size (ES). We calculated an average…

  9. Meta-Analysis of Biofeedback for Tension-Type Headache: Efficacy, Specificity, and Treatment Moderators

    ERIC Educational Resources Information Center

    Nestoriuc, Yvonne; Rief, Winfried; Martin, Alexandra

    2008-01-01

    The aims of the present meta-analysis were to investigate the short- and long-term efficacy, multidimensional outcome, and treatment moderators of biofeedback as a behavioral treatment option for tension-type headache. A literature search identified 74 outcome studies, of which 53 were selected according to predefined inclusion criteria.…

  10. A Decade of EEG Theta/Beta Ratio Research in ADHD: A Meta-Analysis

    ERIC Educational Resources Information Center

    Arns, Martijn; Conners, C. Keith; Kraemer, Helena C.

    2013-01-01

    Objective: Many EEG studies have reported that ADHD is characterized by elevated Theta/Beta ratio (TBR). In this study we conducted a meta-analysis on the TBR in ADHD. Method: TBR data during Eyes Open from location Cz were analyzed from children/adolescents 6-18 years of age with and without ADHD. Results: Nine studies were identified with a…

  11. Writing Characteristics of Students with Attention Deficit Hyperactive Disorder: A Meta-Analysis

    ERIC Educational Resources Information Center

    Graham, Steve; Fishman, Evan J.; Reid, Robert; Hebert, Michael

    2016-01-01

    Students with Attention Deficit Hyperactivity Disorders (ADHD) frequently experience significant difficulty mastering basic academic skills. This meta-analysis focuses on one specific potential area of learning difficulties for these students: namely, writing. To identify the extent and depth of the potential writing challenges faced by students…

  12. Individual and Work-Related Factors Influencing Burnout of Mental Health Professionals: A Meta-Analysis

    ERIC Educational Resources Information Center

    Lim, Nayoung; Kim, Eun Kyoung; Kim, Hyunjung; Yang, Eunjoo; Lee, Sang Min

    2010-01-01

    The current study identifies and assesses individual and work-related factors as correlates of burnout among mental health professionals. Results of a meta-analysis indicate that age and work setting variables are the most significant indicators of emotional exhaustion and depersonalization. In terms of level of personal accomplishment, the age…

  13. The Characteristics of Persistent Sexual Offenders: A Meta-Analysis of Recidivism Studies

    ERIC Educational Resources Information Center

    Hanson, R. Karl; Morton-Bourgon, Kelly E.

    2005-01-01

    A meta-analysis of 82 recidivism studies (1,620 findings from 29,450 sexual offenders) identified deviant sexual preferences and antisocial orientation as the major predictors of sexual recidivism for both adult and adolescent sexual offenders. Antisocial orientation was the major predictor of violent recidivism and general (any) recidivism. The…

  14. A Meta-Analysis of Predictors of Offender Treatment Attrition and Its Relationship to Recidivism

    ERIC Educational Resources Information Center

    Olver, Mark E.; Stockdale, Keira C.; Wormith, J. Stephen

    2011-01-01

    Objective: The failure of offenders to complete psychological treatment can pose significant concerns, including increased risk for recidivism. Although a large literature identifying predictors of offender treatment attrition has accumulated, there has yet to be a comprehensive quantitative review. Method: A meta-analysis of the offender…

  15. Discrimination against Latina/os: A Meta-Analysis of Individual-Level Resources and Outcomes

    ERIC Educational Resources Information Center

    Lee, Debbiesiu L.; Ahn, Soyeon

    2012-01-01

    This meta-analysis synthesizes the findings of 60 independent samples from 51 studies examining racial/ethnic discrimination against Latina/os in the United States. The purpose was to identify individual-level resources and outcomes that most strongly relate to discrimination. Discrimination against Latina/os significantly results in outcomes…

  16. A Meta-Analysis on Teaching Mathematics to Students with Significant Cognitive Disabilities

    ERIC Educational Resources Information Center

    Browder, Diane M.; Spooner, Fred; Ahlgrim-Delzell, Lynn; Harris, Amber A.; Wakeman, Shawnee

    2008-01-01

    This article reports on a comprehensive literature review and meta-analysis of 68 experiments on teaching mathematics to individuals with significant cognitive disabilities. Most of the studies in the review addressed numbers and computation or measurement. Within the computation studies identified, most focused on counting, calculation, or number…

  17. A Meta-Analysis of the Effectiveness of Intervention Programs Designed to Support Autonomy

    ERIC Educational Resources Information Center

    Su, Yu-Lan; Reeve, Johnmarshall

    2011-01-01

    The twofold purpose of the present study was, first, to determine whether training intervention programs designed to help people support the autonomy of others are effective and, second, to identify the set of conditions that allowed these interventions to be most effective. A meta-analysis of the findings from 19 studies with 20 effect sizes…

  18. Soy Consumption and Colorectal Cancer Risk in Humans: A Meta-Analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of the present study was to determine the relationship between soy consumption and colorectal cancer risk in humans by conducting a meta-analysis of available epidemiologic studies. We systematically reviewed publications obtained through a Medline literature search and identified four ...

  19. Weight change and all-cause mortality in older adults: A meta-analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This meta-analysis of observational cohort studies examined the association between weight change (weight loss, weight gain, and weight fluctuation) and all-cause mortality among older adults. We used PubMed (MEDLINE), Web of Science, and Cochrane Library to identify prospective studies published in...

  20. Meta-Analysis of Genome-Wide Linkage Studies in Celiac Disease

    PubMed Central

    Forabosco, Paola; Neuhausen, Susan L.; Greco, Luigi; Naluai, Åsa Torinsson; Wijmenga, Cisca; Saavalainen, Päivi; Houlston, Richard S.; Ciclitira, Paul J.; Babron, Marie-Claude; Lewis, Cathryn M.

    2009-01-01

    Objective A meta-analysis of genome-wide linkage studies allows us to summarize the extensive information available from family-based studies, as the field moves into genome-wide association studies. Methods Here we apply the genome scan meta-analysis (GSMA) method, a rank-based, model-free approach, to combine results across eight independent genome-wide linkages performed on celiac disease (CD), including 554 families with over 1,500 affected individuals. We also investigate the agreement between signals we identified from this meta-analysis of linkage studies and those identified from genome-wide association analysis using a hypergeometric distribution. Results Not surprisingly, the most significant result was obtained in the HLA region. Outside the HLA region, suggestive evidence for linkage was obtained at the telomeric region of chromosome 10 (10q26.12-qter; p = 0.00366), and on chromosome 8 (8q22.2-q24.21; p = 0.00491). Testing signals of association and linkage within bins showed no significant evidence for co-localization of results. Conclusion This meta-analysis allowed us to pool the results from available genome-wide linkage studies and to identify novel regions potentially harboring predisposing genetic variation contributing to CD. This study also shows that linkage and association studies may identify different types of disease-predisposing variants. PMID:19622889

  1. How Will DSM-5 Affect Autism Diagnosis? A Systematic Literature Review and Meta-Analysis

    ERIC Educational Resources Information Center

    Kulage, Kristine M.; Smaldone, Arlene M.; Cohn, Elizabeth G.

    2014-01-01

    We conducted a systematic review and meta-analysis to determine the effect of changes to the Diagnostic and Statistical Manual (DSM)-5 on autism spectrum disorder (ASD) and explore policy implications. We identified 418 studies; 14 met inclusion criteria. Studies consistently reported decreases in ASD diagnosis (range 7.3-68.4%) using DSM-5…

  2. Meta-Analysis of Randomized, Controlled Treatment Trials for Pediatric Obsessive-Compulsive Disorder

    ERIC Educational Resources Information Center

    Watson, Hunna J.; Rees, Clare S.

    2008-01-01

    Objective: To conduct a meta-analysis on randomized, controlled treatment trials of pediatric obsessive-compulsive disorder (OCD). Method: Studies were included if they employed randomized, controlled methodology and treated young people (19 years or under) with OCD. A comprehensive literature search identified 13 RCTs containing 10…

  3. Gender Differences in Academic Self-Efficacy: A Meta-Analysis

    ERIC Educational Resources Information Center

    Huang, Chiungjung

    2013-01-01

    A meta-analysis of 187 studies containing 247 independent studies (N = 68,429) on gender differences in academic self-efficacy identified an overall effect size of 0.08, with a small difference favoring males. Moderator analysis demonstrated that content domain was a significant moderator in explaining effect size variation. Females displayed…

  4. Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schafer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J. L.; Langely, Kate; O'Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of…

  5. How to Conduct a Good Meta-Analysis in Gifted Education

    ERIC Educational Resources Information Center

    Steenbergen-Hu, Saiying; Olszewski-Kubilius, Paula

    2016-01-01

    This methodological brief introduces basic procedures and issues for conducting a high-quality meta-analysis in gifted education. Specifically, we discuss issues such as how to select a topic and formulate research problems, search for and identify qualified studies, code studies and extract data, choose and calculate effect sizes, analyze data,…

  6. Does Music Instruction Help Children Learn to Read?: Evidence of a Meta-Analysis

    ERIC Educational Resources Information Center

    Standley, Jayne M.

    2008-01-01

    This meta-analysis of 30 studies using a variety of music interventions to affect reading skills resulted in a moderately strong, significant, overall effect size of d = 0.32. When music activities incorporate specific reading skills matched to the needs of identified children (d = 0.44) or contingent music is used to reinforce reading behavior (d…

  7. Effects of Deficient Reporting on Meta-Analysis: A Conceptual Framework and Reanalysis

    ERIC Educational Resources Information Center

    Orwin, Robert G.; Cordray, David S.

    1985-01-01

    Identifies three sources of reporting deficiency for meta-analytic results: quality (adequacy) of publicizing; quality of macrolevel reporting, and quality of microlevel reporting. Reanalysis of 25 reports from the Smith, Glass and Miller (1980) psychotherapy meta-analysis established two sources of misinformation, interrater reliabilities and…

  8. The "Freshman 5": A Meta-Analysis of Weight Gain in the Freshman Year of College

    ERIC Educational Resources Information Center

    Vella-Zarb, Rachel A.; Elgar, Frank J.

    2009-01-01

    Objective: (1) To use the available research to estimate the amount of weight gained by college freshman during their first year of college. (2) To identify potential predictors of freshman weight gain. Methods: A meta-analysis was conducted in November 2008. The analysis focused on articles published in English scientific journals between 1985…

  9. Strategy-Oriented Web-Based English Instruction--A Meta-Analysis

    ERIC Educational Resources Information Center

    Chang, Mei-Mei; Lin, Mei-Chen

    2013-01-01

    In this meta-analysis study, a total of thirty-one studies related to strategy use of students in Taiwan in a web-based English context were identified, collected, and analysed. Three criteria for selecting the appropriate studies are (a) they must have applied web-based instruction; (b) they must be related to English learning; and (c) they had…

  10. Dynamic Geometry Software Improves Mathematical Achievement: Systematic Review and Meta-Analysis

    ERIC Educational Resources Information Center

    Chan, Kan Kan; Leung, Siu Wai

    2014-01-01

    Dynamic geometry software (DGS) aims to enhance mathematics education. This systematic review and meta-analysis evaluated the quasi-experimental studies on the effectiveness of DGS-based instruction in improving students' mathematical achievement. Research articles published between 1990 and 2013 were identified from major databases according to a…

  11. Cinnamon intake lowers fasting blood glucose: an updated meta-analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    OBJECTIVE – To determine if meta-analysis of recent clinical studies of cinnamon intake by people with Type II diabetes and/or prediabetes resulted in significant changes in fasting blood glucose. RESEARCH DESIGN AND METHODS -- Published clinical studies were identified using a literature search (P...

  12. Indirect health costs in ulcerative colitis and Crohn's disease: a systematic review and meta-analysis.

    PubMed

    Kawalec, Paweł; Malinowski, Krzysztof Piotr

    2015-04-01

    The aim of this systematic review was to collect all current data on indirect costs related to inflammatory bowel disease as well as assessing homogeneity and comparability, and conducting a meta-analysis. Costs were collected using databases from Medline, Embase and Centre for Reviews and Dissemination databases, then average annual cost per patient was calculated and expressed in 2013-rate USD using the consumer price index and purchasing power parity (scenario 1) and then adjusted to specific gross domestic product (scenario 2) to make them comparable. The studies were then included in quantitative synthesis using the meta-analysis and bootstrap methods. This systematic review was carried out and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. From 18 publications, overall annual indirect costs per patient as a result of the quantitative synthesis among all studies eligible for meta-analysis ranged from US$2425.01-US$9622.15 depending on the scenario and model used for analysis. The cost of presenteeism was assessed in only two studies. Considering heterogeneity among all identified studies random-effect model presented the most accurate results of meta-analysis equal to US$7189.27 and US$9622.15 per patient per year for scenario 1 and scenario 2, respectively. This systematic review revealed the existence of a relatively small number of studies that reported on the great economic burden of the disease upon society. A great variety of methodologies and cost components resulted in a very large discrepancy in indirect costs and made meta-analysis difficult to perform, so two scenarios were considered and meta-analysis conducted in subgroups to make data more comparable. PMID:25656310

  13. A Guide to Conducting a Meta-Analysis.

    PubMed

    Cheung, Mike W-L; Vijayakumar, Ranjith

    2016-06-01

    Meta-analysis is widely accepted as the preferred method to synthesize research findings in various disciplines. This paper provides an introduction to when and how to conduct a meta-analysis. Several practical questions, such as advantages of meta-analysis over conventional narrative review and the number of studies required for a meta-analysis, are addressed. Common meta-analytic models are then introduced. An artificial dataset is used to illustrate how a meta-analysis is conducted in several software packages. The paper concludes with some common pitfalls of meta-analysis and their solutions. The primary goal of this paper is to provide a summary background to readers who would like to conduct their first meta-analytic study.

  14. DNA methylation and leukemia susceptibility in China: Evidence from an updated meta-analysis

    PubMed Central

    Jiang, Danjie; Li, Yirun; Hong, Qingxiao; Shen, Yusheng; Xu, Chunjing; Xu, Yan; Zhu, Huangkai; Dai, Dongjun; Ouyang, Guifang; Duan, Shiwei

    2016-01-01

    Mounting evidence supports a role for DNA methylation in the pathogenesis of leukemia; however, there no overview of these results in the Chinese population. The present study performed a comprehensive meta-analysis to establish candidate genes with an altered methylation status in Chinese leukemia patients. Eligible studies were identified through searching the National Center of Biotechnology Information PubMed and Wanfang databases. Studies were pooled and overall odds ratios with corresponding confidence intervals were calculated. A total of 4,325 leukemia patients and 2,010 controls from 94 studies on 53 genes were included in this meta-analysis, and 47 genes were found to be aberrantly methylated in leukemia patients. A further subgroup meta-analysis by leukemia subtype demonstrated that hypermethylation of 5 genes, namely cyclin-dependent kinase (CDKN)2A, DNA-binding protein inhibitor-4, CDKN2B, glioma pathogenesis-related protein 1 and p73, contributed to the risk of various subtypes of leukemia. In addition, a strong association between CDKN2A and leukemia was identified in Chinese (P<0.00001) but not in European patients. The aberrantly methylated genes identified in the present meta-analysis may help elucidate the mechanisms underlying the development of leukemia in Chinese patients. PMID:27588182

  15. Global meta-analysis of transcriptomics studies.

    PubMed

    Caldas, José; Vinga, Susana

    2014-01-01

    Transcriptomics meta-analysis aims at re-using existing data to derive novel biological hypotheses, and is motivated by the public availability of a large number of independent studies. Current methods are based on breaking down studies into multiple comparisons between phenotypes (e.g. disease vs. healthy), based on the studies' experimental designs, followed by computing the overlap between the resulting differential expression signatures. While useful, in this methodology each study yields multiple independent phenotype comparisons, and connections are established not between studies, but rather between subsets of the studies corresponding to phenotype comparisons. We propose a rank-based statistical meta-analysis framework that establishes global connections between transcriptomics studies without breaking down studies into sets of phenotype comparisons. By using a rank product method, our framework extracts global features from each study, corresponding to genes that are consistently among the most expressed or differentially expressed genes in that study. Those features are then statistically modelled via a term-frequency inverse-document frequency (TF-IDF) model, which is then used for connecting studies. Our framework is fast and parameter-free; when applied to large collections of Homo sapiens and Streptococcus pneumoniae transcriptomics studies, it performs better than similarity-based approaches in retrieving related studies, using a Medical Subject Headings gold standard. Finally, we highlight via case studies how the framework can be used to derive novel biological hypotheses regarding related studies and the genes that drive those connections. Our proposed statistical framework shows that it is possible to perform a meta-analysis of transcriptomics studies with arbitrary experimental designs by deriving global expression features rather than decomposing studies into multiple phenotype comparisons. PMID:24586684

  16. Identification of potential transcriptomic markers in developing ankylosing spondylitis: a meta-analysis of gene expression profiles.

    PubMed

    Fang, Fang; Pan, Jian; Xu, Lixiao; Li, Gang; Wang, Jian

    2015-01-01

    The goal of this study was to identify potential transcriptomic markers in developing ankylosing spondylitis by a meta-analysis of multiple public microarray datasets. Using the INMEX (integrative meta-analysis of expression data) program, we performed the meta-analysis to identify consistently differentially expressed (DE) genes in ankylosing spondylitis and further performed functional interpretation (gene ontology analysis and pathway analysis) of the DE genes identified in the meta-analysis. Three microarray datasets (26 cases and 29 controls in total) were collected for meta-analysis. 905 consistently DE genes were identified in ankylosing spondylitis, among which 482 genes were upregulated and 423 genes were downregulated. The upregulated gene with the smallest combined rank product (RP) was GNG11 (combined RP=299.64). The downregulated gene with the smallest combined RP was S100P (combined RP=335.94). In the gene ontology (GO) analysis, the most significantly enriched GO term was "immune system process" (P=3.46×10(-26)). The most significant pathway identified in the pathway analysis was antigen processing and presentation (P=8.40×10(-5)). The consistently DE genes in ankylosing spondylitis and biological pathways associated with those DE genes identified provide valuable information for studying the pathophysiology of ankylosing spondylitis.

  17. Chronic hepatitis B infection and risk of preterm labor: a meta-analysis of observational studies.

    PubMed

    Huang, Qi-tao; Wei, Shan-shan; Zhong, Mei; Hang, Li-lin; Xu, Yu-yuan; Cai, Geng-xi; Liu, Qing; Yu, Yan-hong

    2014-09-01

    Many epidemiological studies have found a positive association between chronic hepatitis B virus (CHB) infection and the risk of preterm labor, but the magnitude of this association varies and independent studies have reported conflicting findings. We performed a meta-analysis to ascertain the relationship between CHB infection and preterm labor. The PubMed and Embase databases were searched up to May 1st, 2014, for relevant observational studies on an association between CHB infection and the risk of preterm labor. Data were extracted and analyzed independently by two authors. The meta-analysis was performed using Stata version 10.0 software. Six observational case-control studies and 4 cohort studies, involving 6781 women with preterm labor, were identified. Based on a random-effects meta-analysis, no association between CHB infection and preterm labor was identified (odds ratio=1.12, 95% confidence interval CI, 0.94-1.33). Our meta-analysis suggested that CHB infection is not associated with an increased risk of preterm labor.

  18. A Meta-Analysis on Prehypertension and Chronic Kidney Disease

    PubMed Central

    Li, Yang; Xia, Peng; Xu, Lubin; Wang, Yang; Chen, Limeng

    2016-01-01

    Background Recent studies have demonstrated that there is an association between prehypertension and an increased risk of end-stage renal disease. However, there is conflicting evidence regarding the relationship between prehypertension and chronic kidney disease (CKD). This meta-analysis aimed to demonstrate the association between prehypertension and the incidence of CKD and identify the impacts of gender and ethnic differences. Methods MEDLINE, EMBASE, Cochrane Library (from inception through March 2016) and article reference lists were searched for relevant studies regarding blood pressure and CKD. Blood pressure (BP) measurements were classified as follows: optimal BP (less than 120/80 mmHg), prehypertension (120-139/80-89 mmHg) and hypertension (over 140/90 mmHg). CKD was defined by estimated glomerular filtration rate (eGFR)<60 ml/min/1.73 m2 or proteinuria. Two investigators independently extracted the data and assessed the quality of studies enrolled in this meta-analysis using the Newcastle-Ottawa Scale (NOS). We performed the meta-analysis using Stata/SE 12.0 (StataCorp LP). The random-effect models were used in the heterogeneous analyses. Results After retrieving data from 4,537 potentially relevant articles, we identified 7 cohort studies including 261,264 subjects, according to the predefined selection criteria. Five studies were conducted in Mongolians from East Asia, and the other two studies were performed in Indo-Europeans from Austria and Iran. The participants ranged in age from 20 to 89 years, and the proportion of females ranged from 27.2% to 63.8%. The follow-up period ranged from 2 to 11 years. Compared with the optimal BP values, prehypertension showed an increased risk of CKD (pooled RR = 1.28; 95% CI = 1.13–1.44; P = 0.000; I2 = 77.9%). In the sex-stratified analysis, we found a similar trend in women (pooled RR = 1.29; 95% CI = 1.01–1.63; P = 0.039; I2 = 76.1%) but not in men. This effect was observed only in Mongolians from East

  19. Comparing Active Pediatric Obesity Treatments Using Meta-Analysis

    ERIC Educational Resources Information Center

    Gilles, Allyson; Cassano, Michael; Shepherd, Elizabeth J.; Higgins, Diana; Hecker, Jeffrey E.; Nangle, Douglas W.

    2008-01-01

    The current meta-analysis reviews research on the treatment of pediatric obesity focusing on studies that have been published since 1994. Eleven studies (22 comparisons, 115 effect sizes, N = 447) were included in the present meta-analysis. Results indicated that comprehensive behavioral interventions may be improved in at least two ways:…

  20. Methods for the Joint Meta-Analysis of Multiple Tests

    ERIC Educational Resources Information Center

    Trikalinos, Thomas A.; Hoaglin, David C.; Small, Kevin M.; Terrin, Norma; Schmid, Christopher H.

    2014-01-01

    Existing methods for meta-analysis of diagnostic test accuracy focus primarily on a single index test. We propose models for the joint meta-analysis of studies comparing multiple index tests on the same participants in paired designs. These models respect the grouping of data by studies, account for the within-study correlation between the tests'…

  1. Classroom Communication and Instructional Processes: Advances through Meta-Analysis

    ERIC Educational Resources Information Center

    Gayle, Barbara Mae, Ed.; Preiss, Raymond W., Ed.; Burrell, Nancy, Ed.; Allen, Mike, Ed.

    2006-01-01

    This volume offers a systematic review of the literature on communication education and instruction. Making meta-analysis findings accessible and relevant, the editors of this volume approach the topic from the perspective that meta-analysis serves as a useful tool for summarizing experiments and for determining how and why specific teaching and…

  2. Comprehensive School Reform and Student Achievement: A Meta-Analysis.

    ERIC Educational Resources Information Center

    Borman, Geoffrey D.; Hewes, Gina M.; Overman, Laura T.; Brown, Shelly

    Using 232 studies, this meta analysis reviewed the research on the achievement effects of the nationally disseminated and externally developed school improvement programs known as "whole-school" or "comprehensive" reforms. In addition to reviewing the overall achievement effects of comprehensive school reform (CSR), the meta analysis considered…

  3. Pesticide exposure and risk of Alzheimer’s disease: a systematic review and meta-analysis

    NASA Astrophysics Data System (ADS)

    Yan, Dandan; Zhang, Yunjian; Liu, Liegang; Yan, Hong

    2016-09-01

    Evidence suggests that lifelong cumulative exposure to pesticides may generate lasting toxic effects on the central nervous system and contribute to the development of Alzheimer’s disease (AD). A number of reports indicate a potential association between long-term/low-dose pesticide exposure and AD, but the results are inconsistent. Therefore, we conducted a meta-analysis to clarify this association. Relevant studies were identified according to inclusion criteria. Summary odds ratios (ORs) were calculated using fixed-effects models. A total of seven studies were included in our meta-analysis. A positive association was observed between pesticide exposure and AD (OR = 1.34 95% confidence interval [CI] = 1.08, 1.67; n = 7). The summary ORs with 95% CIs from the crude and adjusted effect size studies were 1.14 (95% CI = 0.94, 1.38; n = 7) and 1.37 (95% CI = 1.09, 1.71; n = 5), respectively. The sensitivity analyses of the present meta-analysis did not substantially modify the association between pesticide exposure and AD. Subgroup analyses revealed that high-quality studies tended to show significant relationships. The present meta-analysis suggested a positive association between pesticide exposure and AD, confirming the hypothesis that pesticide exposure is a risk factor for AD. Further high-quality cohort and case-control studies are required to validate a causal relationship.

  4. Assessing Police Classifications of Sexual Assault Reports: A Meta-Analysis of False Reporting Rates.

    PubMed

    Ferguson, Claire E; Malouff, John M

    2016-07-01

    The objective of the study was to determine, through meta-analysis, the rate of confirmed false reports of sexual assault to police. The meta-analysis initially involved a search for relevant articles. The search identified seven studies where researchers or their trained helpers evaluated reported sexual assault cases to determine the rate of confirmed false reports. The meta-analysis calculated an overall rate and tested for possible moderators of effect size. The meta-analytic rate of false reports of sexual assault was .052 (95 % CI .030, .089). The rates for the individual studies were heterogeneous, suggesting the possibility of moderators of rate. However, the four possible moderators examined-year of publication, whether the data set used had information in addition to police reports, whether the study was completed in the U.S. or elsewhere, and whether inter-rater reliabilities were reported-were all not significant. The meta-analysis of seven relevant studies shows that confirmed false allegations of sexual assault made to police occur at a significant rate. The total false reporting rate, including both confirmed and equivocal cases, would be greater than the 5 % rate found here. PMID:26679304

  5. A Meta-Analysis of Renal Function After Adult Cardiac Surgery With Pulsatile Perfusion.

    PubMed

    Nam, Myung Ji; Lim, Choon Hak; Kim, Hyun-Jung; Kim, Yong Hwi; Choi, Hyuk; Son, Ho Sung; Lim, Hae Ja; Sun, Kyung

    2015-09-01

    The aim of this meta-analysis was to determine whether pulsatile perfusion during cardiac surgery has a lesser effect on renal dysfunction than nonpulsatile perfusion after cardiac surgery in randomized controlled trials. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were used to identify available articles published before April 25, 2014. Meta-analysis was conducted to determine the effects of pulsatile perfusion on postoperative renal functions, as determined by creatinine clearance (CrCl), serum creatinine (Cr), urinary neutrophil gelatinase-associated lipocalin (NGAL), and the incidences of acute renal insufficiency (ARI) and acute renal failure (ARF). Nine studies involving 674 patients that received pulsatile perfusion and 698 patients that received nonpulsatile perfusion during cardiopulmonary bypass (CPB) were considered in the meta-analysis. Stratified analysis was performed according to effective pulsatility or unclear pulsatility of the pulsatile perfusion method in the presence of heterogeneity. NGAL levels were not significantly different between the pulsatile and nonpulsatile groups. However, patients in the pulsatile group had a significantly higher CrCl and lower Cr levels when the analysis was restricted to studies on effective pulsatile flow (P < 0.00001, respectively). The incidence of ARI was significantly lower in the pulsatile group (P < 0.00001), but incidences of ARF were similar. In conclusion, the meta-analysis suggests that the use of pulsatile flow during CPB results in better postoperative renal function.

  6. Pesticide exposure and risk of Alzheimer’s disease: a systematic review and meta-analysis

    PubMed Central

    Yan, Dandan; Zhang, Yunjian; Liu, Liegang; Yan, Hong

    2016-01-01

    Evidence suggests that lifelong cumulative exposure to pesticides may generate lasting toxic effects on the central nervous system and contribute to the development of Alzheimer’s disease (AD). A number of reports indicate a potential association between long-term/low-dose pesticide exposure and AD, but the results are inconsistent. Therefore, we conducted a meta-analysis to clarify this association. Relevant studies were identified according to inclusion criteria. Summary odds ratios (ORs) were calculated using fixed-effects models. A total of seven studies were included in our meta-analysis. A positive association was observed between pesticide exposure and AD (OR = 1.34; 95% confidence interval [CI] = 1.08, 1.67; n = 7). The summary ORs with 95% CIs from the crude and adjusted effect size studies were 1.14 (95% CI = 0.94, 1.38; n = 7) and 1.37 (95% CI = 1.09, 1.71; n = 5), respectively. The sensitivity analyses of the present meta-analysis did not substantially modify the association between pesticide exposure and AD. Subgroup analyses revealed that high-quality studies tended to show significant relationships. The present meta-analysis suggested a positive association between pesticide exposure and AD, confirming the hypothesis that pesticide exposure is a risk factor for AD. Further high-quality cohort and case-control studies are required to validate a causal relationship. PMID:27581992

  7. Pesticide exposure and risk of Alzheimer's disease: a systematic review and meta-analysis.

    PubMed

    Yan, Dandan; Zhang, Yunjian; Liu, Liegang; Yan, Hong

    2016-01-01

    Evidence suggests that lifelong cumulative exposure to pesticides may generate lasting toxic effects on the central nervous system and contribute to the development of Alzheimer's disease (AD). A number of reports indicate a potential association between long-term/low-dose pesticide exposure and AD, but the results are inconsistent. Therefore, we conducted a meta-analysis to clarify this association. Relevant studies were identified according to inclusion criteria. Summary odds ratios (ORs) were calculated using fixed-effects models. A total of seven studies were included in our meta-analysis. A positive association was observed between pesticide exposure and AD (OR = 1.34; 95% confidence interval [CI] = 1.08, 1.67; n = 7). The summary ORs with 95% CIs from the crude and adjusted effect size studies were 1.14 (95% CI = 0.94, 1.38; n = 7) and 1.37 (95% CI = 1.09, 1.71; n = 5), respectively. The sensitivity analyses of the present meta-analysis did not substantially modify the association between pesticide exposure and AD. Subgroup analyses revealed that high-quality studies tended to show significant relationships. The present meta-analysis suggested a positive association between pesticide exposure and AD, confirming the hypothesis that pesticide exposure is a risk factor for AD. Further high-quality cohort and case-control studies are required to validate a causal relationship. PMID:27581992

  8. Childhood maltreatment and obesity: systematic review and meta-analysis.

    PubMed

    Danese, A; Tan, M

    2014-05-01

    Obesity is a prevalent global-health problem associated with substantial morbidity, impairment and economic burden. Because most readily available forms of treatment are ineffective in the long term, it is essential to advance knowledge of obesity prevention by identifying potentially modifiable risk factors. Findings from experimental studies in non-human primates suggest that adverse childhood experiences may influence obesity risk. However, observations from human studies showed heterogeneous results. To address these inconsistencies, we performed Medline, PsycInfo and Embase searches till 1 August 2012 for articles examining the association between childhood maltreatment and obesity. We then conducted a meta-analysis of the identified studies and explored the effects of various possible sources of bias. A meta-analysis of 41 studies (190 285 participants) revealed that childhood maltreatment was associated with elevated risk of developing obesity over the life-course (odds ratio=1.36; 95% confidence interval=1.26-1.47). Results were not explained by publication bias or undue influence of individual studies. Overall, results were not significantly affected by the measures or definitions used for maltreatment or obesity, nor by confounding by childhood or adult socioeconomic status, current smoking, alcohol intake or physical activity. However, the association was not statistically significant in studies of children and adolescents, focusing on emotional neglect, or adjusting for current depression. Furthermore, the association was stronger in samples including more women and whites, but was not influenced by study quality. Child maltreatment is a potentially modifiable risk factor for obesity. Future research should clarify the mechanisms through which child maltreatment affects obesity risk and explore methods to remediate this effect.

  9. Passive Smoking and Inflammatory Bowel Disease: A Meta-analysis

    PubMed Central

    Jones, Deborah T.; Osterman, Mark T.; Bewtra, Meenakshi; Lewis, James D.

    2009-01-01

    Objectives Active smoking has a well-documented role in the etiology of inflammatory bowel disease (IBD), but the role of passive smoking has been unclear. This meta-analysis examined the relationship between prenatal smoke exposure and childhood passive smoke exposure and the development of IBD. Methods We searched the MEDLINE and EMBASE databases to identify observational studies regarding the relationship between prenatal and/or childhood passive smoke exposure and the development of Crohn’s disease (CD) and/or ulcerative colitis (UC). Pooled odds ratios were calculated for each relationship. Results A total of 534 and 699 potential studies were identified from MEDLINE and EMBASE, respectively, of which 13 met all of our inclusion criteria. Overall we did not observe a positive relationship between childhood passive smoke exposure and CD (OR, 1.10; 95% CI, 0.92–1.30) or UC (OR, 1.01; 95% CI, 0.85–1.20). Likewise, we did not observe an association between prenatal smoke exposure and CD (OR, 1.10; 95% CI, 0.67–1.80), or prenatal smoke exposure and UC (OR, 1.11; 95% CI, 0.63–1.97). Conclusions Our meta-analysis suggests that there is not a strong association between childhood passive smoke exposure and the development of CD. We found no evidence that childhood passive smoke exposure exerts a protective effect against UC, as is the case in active smoke exposure. Heterogeneity among the small number of studies limited the ability to draw conclusions about prenatal smoke exposure. PMID:18844625

  10. Cinnamon intake lowers fasting blood glucose: meta-analysis.

    PubMed

    Davis, Paul A; Yokoyama, Wallace

    2011-09-01

    Cinnamon, the dry bark and twig of Cinnamomum spp., is a rich botanical source of polyphenolics that has been used for centuries in Chinese medicine and has been shown to affect blood glucose and insulin signaling. Cinnamon's effects on blood glucose have been the subject of many clinical and animal studies; however, the issue of cinnamon intake's effect on fasting blood glucose (FBG) in people with type 2 diabetes and/or prediabetes still remains unclear. A meta-analysis of clinical studies of the effect of cinnamon intake on people with type 2 diabetes and/or prediabetes that included three new clinical trials along with five trials used in previous meta-analyses was done to assess cinnamon's effectiveness in lowering FBG. The eight clinical studies were identified using a literature search (Pub Med and Biosis through May 2010) of randomized, placebo-controlled trials reporting data on cinnamon and/or cinnamon extract and FBG. Comprehensive Meta-Analysis (Biostat Inc., Englewood, NJ, USA) was performed on the identified data for both cinnamon and cinnamon extract intake using a random-effects model that determined the standardized mean difference ([i.e., Change 1(control) - Change 2(cinnamon)] divided by the pooled SD of the post scores). Cinnamon intake, either as whole cinnamon or as cinnamon extract, results in a statistically significant lowering in FBG (-0.49±0.2 mmol/L; n=8, P=.025) and intake of cinnamon extract only also lowered FBG (-0.48 mmol/L±0.17; n=5, P=.008). Thus cinnamon extract and/or cinnamon improves FBG in people with type 2 diabetes or prediabetes.

  11. Childhood maltreatment and obesity: systematic review and meta-analysis.

    PubMed

    Danese, A; Tan, M

    2014-05-01

    Obesity is a prevalent global-health problem associated with substantial morbidity, impairment and economic burden. Because most readily available forms of treatment are ineffective in the long term, it is essential to advance knowledge of obesity prevention by identifying potentially modifiable risk factors. Findings from experimental studies in non-human primates suggest that adverse childhood experiences may influence obesity risk. However, observations from human studies showed heterogeneous results. To address these inconsistencies, we performed Medline, PsycInfo and Embase searches till 1 August 2012 for articles examining the association between childhood maltreatment and obesity. We then conducted a meta-analysis of the identified studies and explored the effects of various possible sources of bias. A meta-analysis of 41 studies (190 285 participants) revealed that childhood maltreatment was associated with elevated risk of developing obesity over the life-course (odds ratio=1.36; 95% confidence interval=1.26-1.47). Results were not explained by publication bias or undue influence of individual studies. Overall, results were not significantly affected by the measures or definitions used for maltreatment or obesity, nor by confounding by childhood or adult socioeconomic status, current smoking, alcohol intake or physical activity. However, the association was not statistically significant in studies of children and adolescents, focusing on emotional neglect, or adjusting for current depression. Furthermore, the association was stronger in samples including more women and whites, but was not influenced by study quality. Child maltreatment is a potentially modifiable risk factor for obesity. Future research should clarify the mechanisms through which child maltreatment affects obesity risk and explore methods to remediate this effect. PMID:23689533

  12. Phenotype-driven chemical screening in zebrafish for compounds that inhibit collective cell migration identifies multiple pathways potentially involved in metastatic invasion

    PubMed Central

    Gallardo, Viviana E.; Varshney, Gaurav K.; Lee, Minnkyong; Bupp, Sujata; Xu, Lisha; Shinn, Paul; Crawford, Nigel P.; Inglese, James; Burgess, Shawn M.

    2015-01-01

    ABSTRACT In the last decade, high-throughput chemical screening has become the dominant approach for discovering novel compounds with therapeutic properties. Automated screening using in vitro or cultured cell assays have yielded thousands of candidate drugs for a variety of biological targets, but these approaches have not resulted in an increase in drug discovery despite major increases in expenditures. In contrast, phenotype-driven screens have shown a much stronger success rate, which is why we developed an in vivo assay using transgenic zebrafish with a GFP-marked migrating posterior lateral line primordium (PLLp) to identify compounds that influence collective cell migration. We then conducted a high-throughput screen using a compound library of 2160 annotated bioactive synthetic compounds and 800 natural products to identify molecules that block normal PLLp migration. We identified 165 compounds that interfere with primordium migration without overt toxicity in vivo. Selected compounds were confirmed in their migration-blocking activity by using additional assays for cell migration. We then proved the screen to be successful in identifying anti-metastatic compounds active in vivo by performing orthotopic tumor implantation assays in mice. We demonstrated that the Src inhibitor SU6656, identified in our screen, can be used to suppress the metastatic capacity of a highly aggressive mammary tumor cell line. Finally, we used CRISPR/Cas9-targeted mutagenesis in zebrafish to genetically validate predicted targets of compounds. This approach demonstrates that the migrating PLLp in zebrafish can be used for large-scale, high-throughput screening for compounds that inhibit collective cell migration and, potentially, anti-metastatic compounds. PMID:25810455

  13. How Acute Total Sleep Loss Affects the Attending Brain: A Meta-Analysis of Neuroimaging Studies

    PubMed Central

    Ma, Ning; Dinges, David F.; Basner, Mathias; Rao, Hengyi

    2015-01-01

    Study Objectives: Attention is a cognitive domain that can be severely affected by sleep deprivation. Previous neuroimaging studies have used different attention paradigms and reported both increased and reduced brain activation after sleep deprivation. However, due to large variability in sleep deprivation protocols, task paradigms, experimental designs, characteristics of subject populations, and imaging techniques, there is no consensus regarding the effects of sleep loss on the attending brain. The aim of this meta-analysis was to identify brain activations that are commonly altered by acute total sleep deprivation across different attention tasks. Design: Coordinate-based meta-analysis of neuroimaging studies of performance on attention tasks during experimental sleep deprivation. Methods: The current version of the activation likelihood estimation (ALE) approach was used for meta-analysis. The authors searched published articles and identified 11 sleep deprivation neuroimaging studies using different attention tasks with a total of 185 participants, equaling 81 foci for ALE analysis. Results: The meta-analysis revealed significantly reduced brain activation in multiple regions following sleep deprivation compared to rested wakefulness, including bilateral intraparietal sulcus, bilateral insula, right prefrontal cortex, medial frontal cortex, and right parahippocampal gyrus. Increased activation was found only in bilateral thalamus after sleep deprivation compared to rested wakefulness. Conclusion: Acute total sleep deprivation decreases brain activation in the fronto-parietal attention network (prefrontal cortex and intraparietal sulcus) and in the salience network (insula and medial frontal cortex). Increased thalamic activation after sleep deprivation may reflect a complex interaction between the de-arousing effects of sleep loss and the arousing effects of task performance on thalamic activity. Citation: Ma N, Dinges DF, Basner M, Rao H. How acute total

  14. μFE models can represent microdamaged regions of healthy and metastatically involved whole vertebrae identified through histology and contrast enhanced μCT imaging.

    PubMed

    Choudhari, Chetan; Chan, Katelyn; Akens, Margarete K; Whyne, Cari M

    2016-05-01

    Micro-damage formation within the skeleton is an important stimulant for bone remodeling, however abnormal build-up of micro-damage can lead to skeletal fragility. In this study, µCT imaging based micro finite element (μFE) models were used to evaluate tissue level damage criteria in whole healthy and metastatically-involved vertebrae. T13-L2 spinal segments were excised from osteolytic (n=3) and healthy (n=3) female athymic rnu/rnu rats. Osteolytic metastasis was generated by intercardiac injection of HeLa cancer cells. Micro-mechanical axial loading was applied to the spinal motion segments under μCT imaging. Vertebral samples underwent BaSO4 staining and sequential calcein/fuchsin staining to identify load induced micro-damage. μCT imaging was used generate specimen specific μFE models of the healthy and osteolytic whole rat vertebrae. Model boundary conditions were generated through deformable image registration of loaded and unloaded scans. Elevated stresses and strains were detected in regions of micro-damage identified through histological and BaSO4 staining within healthy and osteolytic vertebral models, as compared to undamaged regions. Additionally, damaged regions of metastatic vertebrae experienced significantly higher local stresses and strains than those in the damaged regions of healthy specimens. Areas identified by BaSO4 staining, however, yielded lower levels of stress and strain in damaged and undamaged regions of healthy and metastatic vertebrae as compared to fuschin staining. The multimodal (experimental, image-based and computational) techniques used in this study demonstrated the ability of local stresses and strains computed through µFE analysis to identify trabecular micro-damage, that can be applied to biomechanical analyses of healthy and diseased whole bones. PMID:26947031

  15. Meta-Analysis: Overweight, Obesity, and Parkinson's Disease

    PubMed Central

    Guan, Zhenlong; Wang, Liqin; Song, Guangyao; Ma, Boqing; Wang, Yanqin

    2014-01-01

    Objective. Parkinson's disease (PD) is a severe neurological disease and its risk factors remain largely unknown. A meta-analysis was carried out to investigate the relationship of overweight and obesity with PD. Methods. We used PubMed, EMBASE, and the Chinese National Knowledge Infrastructure (CNKI) databases to identify studies of associations between overweight/obesity and PD. Overweight, obesity, and PD were used as keywords, and published works were retrieved until September 30, 2013. The extracted data were classified (BMI ≥ 30, 25 ≤ BMI < 30, and BMI < 25) according to BMI values and analyzed using RevMan5.2 and Stata11.0. Results. Four cohort studies and three case-control studies were used to evaluate the association between overweight/obesity and PD, including 2857 PD patients and 5, 683, 939 cases of non-PD controls. There was a statistically significant difference between 25 ≤ BMI < 30  and BMI < 25 in the cohort study (RR = 1.17, 95% CI, 1.03–1.32,  P = 0.03), but there was no difference between BMI ≥ 30  and BMI < 25 or BMI ≥ 30  and 25 ≤ BMI < 30, where the respective RR was 1.16 and 0.84; the respective 95% CI was 0.67–2.01 and 0.61–1.15, respectively, and the P values were 0.60 and 0.28, respectively. Case-control studies showed that there was no statistical difference between any two groups. Conclusion. Meta-analysis showed that overweight might be a potential risk factor of PD. Demonstration of a causal role of overweight/obesity in PD development could have important therapeutic implications. PMID:24672544

  16. Biological risk factors for suicidal behaviors: a meta-analysis.

    PubMed

    Chang, B P; Franklin, J C; Ribeiro, J D; Fox, K R; Bentley, K H; Kleiman, E M; Nock, M K

    2016-01-01

    Prior studies have proposed a wide range of potential biological risk factors for future suicidal behaviors. Although strong evidence exists for biological correlates of suicidal behaviors, it remains unclear if these correlates are also risk factors for suicidal behaviors. We performed a meta-analysis to integrate the existing literature on biological risk factors for suicidal behaviors and to determine their statistical significance. We conducted a systematic search of PubMed, PsycInfo and Google Scholar for studies that used a biological factor to predict either suicide attempt or death by suicide. Inclusion criteria included studies with at least one longitudinal analysis using a biological factor to predict either of these outcomes in any population through 2015. From an initial screen of 2541 studies we identified 94 cases. Random effects models were used for both meta-analyses and meta-regression. The combined effect of biological factors produced statistically significant but relatively weak prediction of suicide attempts (weighted mean odds ratio (wOR)=1.41; CI: 1.09-1.81) and suicide death (wOR=1.28; CI: 1.13-1.45). After accounting for publication bias, prediction was nonsignificant for both suicide attempts and suicide death. Only two factors remained significant after accounting for publication bias-cytokines (wOR=2.87; CI: 1.40-5.93) and low levels of fish oil nutrients (wOR=1.09; CI: 1.01-1.19). Our meta-analysis revealed that currently known biological factors are weak predictors of future suicidal behaviors. This conclusion should be interpreted within the context of the limitations of the existing literature, including long follow-up intervals and a lack of tests of interactions with other risk factors. Future studies addressing these limitations may more effectively test for potential biological risk factors. PMID:27622931

  17. Personality Consistency in Dogs: A Meta-Analysis

    PubMed Central

    Fratkin, Jamie L.; Sinn, David L.; Patall, Erika A.; Gosling, Samuel D.

    2013-01-01

    Personality, or consistent individual differences in behavior, is well established in studies of dogs. Such consistency implies predictability of behavior, but some recent research suggests that predictability cannot be assumed. In addition, anecdotally, many dog experts believe that ‘puppy tests’ measuring behavior during the first year of a dog's life are not accurate indicators of subsequent adult behavior. Personality consistency in dogs is an important aspect of human-dog relationships (e.g., when selecting dogs suitable for substance-detection work or placement in a family). Here we perform the first comprehensive meta-analysis of studies reporting estimates of temporal consistency of dog personality. A thorough literature search identified 31 studies suitable for inclusion in our meta-analysis. Overall, we found evidence to suggest substantial consistency (r = 0.43). Furthermore, personality consistency was higher in older dogs, when behavioral assessment intervals were shorter, and when the measurement tool was exactly the same in both assessments. In puppies, aggression and submissiveness were the most consistent dimensions, while responsiveness to training, fearfulness, and sociability were the least consistent dimensions. In adult dogs, there were no dimension-based differences in consistency. There was no difference in personality consistency in dogs tested first as puppies and later as adults (e.g., ‘puppy tests’) versus dogs tested first as puppies and later again as puppies. Finally, there were no differences in consistency between working versus non-working dogs, between behavioral codings versus behavioral ratings, and between aggregate versus single measures. Implications for theory, practice, and future research are discussed. PMID:23372787

  18. Biological risk factors for suicidal behaviors: a meta-analysis.

    PubMed

    Chang, B P; Franklin, J C; Ribeiro, J D; Fox, K R; Bentley, K H; Kleiman, E M; Nock, M K

    2016-01-01

    Prior studies have proposed a wide range of potential biological risk factors for future suicidal behaviors. Although strong evidence exists for biological correlates of suicidal behaviors, it remains unclear if these correlates are also risk factors for suicidal behaviors. We performed a meta-analysis to integrate the existing literature on biological risk factors for suicidal behaviors and to determine their statistical significance. We conducted a systematic search of PubMed, PsycInfo and Google Scholar for studies that used a biological factor to predict either suicide attempt or death by suicide. Inclusion criteria included studies with at least one longitudinal analysis using a biological factor to predict either of these outcomes in any population through 2015. From an initial screen of 2541 studies we identified 94 cases. Random effects models were used for both meta-analyses and meta-regression. The combined effect of biological factors produced statistically significant but relatively weak prediction of suicide attempts (weighted mean odds ratio (wOR)=1.41; CI: 1.09-1.81) and suicide death (wOR=1.28; CI: 1.13-1.45). After accounting for publication bias, prediction was nonsignificant for both suicide attempts and suicide death. Only two factors remained significant after accounting for publication bias-cytokines (wOR=2.87; CI: 1.40-5.93) and low levels of fish oil nutrients (wOR=1.09; CI: 1.01-1.19). Our meta-analysis revealed that currently known biological factors are weak predictors of future suicidal behaviors. This conclusion should be interpreted within the context of the limitations of the existing literature, including long follow-up intervals and a lack of tests of interactions with other risk factors. Future studies addressing these limitations may more effectively test for potential biological risk factors.

  19. Biological risk factors for suicidal behaviors: a meta-analysis

    PubMed Central

    Chang, B P; Franklin, J C; Ribeiro, J D; Fox, K R; Bentley, K H; Kleiman, E M; Nock, M K

    2016-01-01

    Prior studies have proposed a wide range of potential biological risk factors for future suicidal behaviors. Although strong evidence exists for biological correlates of suicidal behaviors, it remains unclear if these correlates are also risk factors for suicidal behaviors. We performed a meta-analysis to integrate the existing literature on biological risk factors for suicidal behaviors and to determine their statistical significance. We conducted a systematic search of PubMed, PsycInfo and Google Scholar for studies that used a biological factor to predict either suicide attempt or death by suicide. Inclusion criteria included studies with at least one longitudinal analysis using a biological factor to predict either of these outcomes in any population through 2015. From an initial screen of 2541 studies we identified 94 cases. Random effects models were used for both meta-analyses and meta-regression. The combined effect of biological factors produced statistically significant but relatively weak prediction of suicide attempts (weighted mean odds ratio (wOR)=1.41; CI: 1.09–1.81) and suicide death (wOR=1.28; CI: 1.13–1.45). After accounting for publication bias, prediction was nonsignificant for both suicide attempts and suicide death. Only two factors remained significant after accounting for publication bias—cytokines (wOR=2.87; CI: 1.40–5.93) and low levels of fish oil nutrients (wOR=1.09; CI: 1.01–1.19). Our meta-analysis revealed that currently known biological factors are weak predictors of future suicidal behaviors. This conclusion should be interpreted within the context of the limitations of the existing literature, including long follow-up intervals and a lack of tests of interactions with other risk factors. Future studies addressing these limitations may more effectively test for potential biological risk factors. PMID:27622931

  20. MICA polymorphisms and cancer risk: a meta-analysis.

    PubMed

    Ji, Mengyao; Wang, Jun; Yuan, Lei; Zhang, Yunting; Zhang, Jixiang; Dong, Weiguo; Peng, Xiulan

    2015-01-01

    The major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism has been implicated in susceptibility to cancer. However, the results are inconsistent. The aim of this meta-analysis is to evaluate the association between the MICA-TM polymorphisms and cancer risk. All eligible case-control studies published up to August 20, 2014 were identified by searching PubMed, Web of Science, CNKI and Wanfang databases. The cancer risk associated with the MICA polymorphism was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively. 21 studies from 19 publications with 3620 cases and 4903 controls were included. Overall, no significant associations between the MICA-TM polymorphism and cancer risk were found (A4 allele: OR = 0.97, 95% CI: 0.88-1.07; A5 allele: OR = 0.91, 95% CI: 0.81-1.04; A5.1 allele: OR = 1.03, 95% CI: 0.89-1.18; A6 allele: OR = 1.05, 95% CI: 0.95-1.15; A9 allele: OR = 0.96, 95% CI: 0.80-1.14; A10 allele: OR = 0.88, 95% CI: 0.43-1.79; del: OR = 2.50, 95% CI: 0.73-8.58; A7 allele: OR = 0.93, 95% CI: 0.43-2.00). When stratified by ethnicity, similar results were observed among Asians; however, there were significant association in Caucasian population for A5 (OR = 0.77, 95% CI: 0.68-0.87) and A9 allele (OR = 0.75, 95% CI: 0.66-0.85). This meta-analysis suggests that the MICA-TM A5 and A9 alleles may be an important protective factor for cancer in Caucasian populations.

  1. Dietary acrylamide and cancer risk: an updated meta-analysis.

    PubMed

    Pelucchi, Claudio; Bosetti, Cristina; Galeone, Carlotta; La Vecchia, Carlo

    2015-06-15

    The debate on the potential carcinogenic effect of dietary acrylamide is open. In consideration of the recent findings from large prospective investigations, we conducted an updated meta-analysis on acrylamide intake and the risk of cancer at several sites. Up to July 2014, we identified 32 publications. We performed meta-analyses to calculate the summary relative risk (RR) of each cancer site for the highest versus lowest level of intake and for an increment of 10 µg/day of dietary acrylamide, through fixed-effects or random-effects models, depending on the heterogeneity test. Fourteen cancer sites could be examined. No meaningful associations were found for most cancers considered. The summary RRs for high versus low acrylamide intake were 0.87 for oral and pharyngeal, 1.14 for esophageal, 1.03 for stomach, 0.94 for colorectal, 0.93 for pancreatic, 1.10 for laryngeal, 0.88 for lung, 0.96 for breast, 1.06 for endometrial, 1.12 for ovarian, 1.00 for prostate, 0.93 for bladder and 1.13 for lymphoid malignancies. The RR was of borderline significance only for kidney cancer (RR = 1.20; 95% confidence interval, CI, 1.00-1.45). All the corresponding continuous estimates ranged between 0.95 and 1.03, and none of them was significant. Among never-smokers, borderline associations with dietary acrylamide emerged for endometrial (RR = 1.23; 95% CI, 1.00-1.51) and ovarian (RR = 1.39; 95% CI, 0.97-2.00) cancers. This systematic review and meta-analysis of epidemiological studies indicates that dietary acrylamide is not related to the risk of most common cancers. A modest association for kidney cancer, and for endometrial and ovarian cancers in never smokers only, cannot be excluded.

  2. Meta-analysis of SUMO1

    PubMed Central

    Wilson, Brian J

    2008-01-01

    An abundantly growing body of literature implicates conjugation of SUMO in the regulation of many proteins and processes, yet the regulation of SUMO pathways is poorly understood. To gain insight into the players in the SUMO1 pathway I have performed an in-silico co-expression meta-analysis of SUMO1, comparing many different multi-microarray studies of various normal and human tumour tissues, from the Oncomine database. This serves as a data-driven predictor of pathway partners of SUMO1. While the data obtained need to be confirmed by future independent experiments and can currently only be considered a hypothesis, results implicate defender against cell death (DAD1) and the anti-apoptotic DEK oncogene as new pathway partners of SUMO1. PMID:18710513

  3. Cognitive Expertise: An ALE Meta-Analysis.

    PubMed

    Neumann, Nicola; Lotze, Martin; Eickhoff, Simon B

    2016-01-01

    Expert performance constitutes the endpoint of skill acquisition and is accompanied by widespread neuroplastic changes. To reveal common mechanisms of reorganization associated with long-term expertise in a cognitive domain (mental calculation, chess, language, memory, music without motor involvement), we used activation likelihood estimation meta-analysis and compared brain activation of experts to nonexperts. Twenty-six studies matched inclusion criteria, most of which reported an increase and not a decrease of activation foci in experts. Increased activation occurred in the left rolandic operculum (OP 4) and left primary auditory cortex and in bilateral premotor cortex in studies that used auditory stimulation. In studies with visual stimulation, experts showed enhanced activation in the right inferior parietal cortex (area PGp) and the right lingual gyrus. Experts' brain activation patterns seem to be characterized by enhanced or additional activity in domain-specific primary, association, and motor structures, confirming that learning is localized and very specialized. PMID:26467981

  4. Vitamin D receptor polymorphisms and susceptibility to Parkinson's disease and Alzheimer's disease: a meta-analysis.

    PubMed

    Lee, Young Ho; Kim, Jae-Hoon; Song, Gwan Gyu

    2014-12-01

    The goal of this study was to examine whether vitamin D receptor (VDR) polymorphisms are associated with susceptibility to Parkinson's disease (PD) and Alzheimer's disease (AD). A meta-analysis was performed to investigate the association between VDR FokI, BsmI, TaqI, ApaI, rs4334089, or rs11568820 polymorphism and susceptibility to PD or AD. Thirteen studies, including seven on PD and six on AD, were included in this meta-analysis. The meta-analysis revealed an association between the BB + Bb genotype and PD in the Asian population (OR 0.478, 95 % CI 0.259-0.884, p = 0.018). We also observed a significant association between PD and the FokI F allele (OR 1.413, 95 % CI 1.144-1.746, p = 0.001). Meta-analysis of the A allele, the AA vs. Aa + aa, and the AA vs. aa for the ApaI polymorphism revealed significant associations with AD (OR 0.729, 95 % CI 0.0.591-0.900, p = 0.034; OR 0.591, 95 % CI 0.431-0.810, p = 0.001; OR 0.580, 95 % CI 0.361-0.931, p = 0.024, respectively). This meta-analysis demonstrates that the VDR BsmI polymorphism is associated with PD susceptibility in Asians, and the FokI polymorphism is associated with PD. Furthermore, we identified associations between the VDR TaqI and ApaI polymorphisms and AD susceptibility.

  5. A direct quantification method for measuring plasma MicroRNAs identified potential biomarkers for detecting metastatic breast cancer.

    PubMed

    Zhao, Qian; Deng, Shengqiong; Wang, Guangxue; Liu, Cuicui; Meng, Lingyu; Qiao, Shanshan; Shen, Lei; Zhang, Yue; Lü, Jinhui; Li, Wenshu; Zhang, Yuzhen; Wang, Min; Pestell, Richard G; Liang, Chunli; Yu, Zuoren

    2016-04-19

    Circulating miRNAs are protected from ribonuclease degradation by assembly into microvesicles and exosomes. Releasing miRNAs completely from these particles is the key step to quantify the circulating miRNAs. Currently purified RNA-based quantitative analysis is widely used while it is time and cost consuming with high risk for those circulating miRNAs with low abundance due to partial loss of RNA during the steps of total RNA extraction and small RNA enrichment. Herein, we optimized a simple, effective and time-saving method to directly measure plasma miRNAs without RNA isolation. It is based on complete miRNA release from the protein complexes, followed by miRNA-specific reverse transcription and quantitative real-time PCR amplification. By comparison to the RNA-based approach, the direct quantification method showed more efficiency for circulating miRNA analysis, higher accuracy and specificity. By application of the direct quantification method to clinical samples combined with the RNA-based miRNA screening analysis, upregulation of miR-106a in blood was validated in metastatic breast cancer patients, indicating miR-106a are a potential biomarker for metastatic breast cancer. PMID:26967564

  6. A direct quantification method for measuring plasma MicroRNAs identified potential biomarkers for detecting metastatic breast cancer

    PubMed Central

    Liu, Cuicui; Meng, Lingyu; Qiao, Shanshan; Shen, Lei; Zhang, Yue; Lü, Jinhui; Li, Wenshu; Zhang, Yuzhen; Wang, Min; Pestell, Richard G.; Liang, Chunli; Yu, Zuoren

    2016-01-01

    Circulating miRNAs are protected from ribonuclease degradation by assembly into microvesicles and exosomes. Releasing miRNAs completely from these particles is the key step to quantify the circulating miRNAs. Currently purified RNA-based quantitative analysis is widely used while it is time and cost consuming with high risk for those circulating miRNAs with low abundance due to partial loss of RNA during the steps of total RNA extraction and small RNA enrichment. Herein, we optimized a simple, effective and time-saving method to directly measure plasma miRNAs without RNA isolation. It is based on complete miRNA release from the protein complexes, followed by miRNA-specific reverse transcription and quantitative real-time PCR amplification. By comparison to the RNA-based approach, the direct quantification method showed more efficiency for circulating miRNA analysis, higher accuracy and specificity. By application of the direct quantification method to clinical samples combined with the RNA-based miRNA screening analysis, upregulation of miR-106a in blood was validated in metastatic breast cancer patients, indicating miR-106a are a potential biomarker for metastatic breast cancer. PMID:26967564

  7. The choice of prior distribution for a covariance matrix in multivariate meta-analysis: a simulation study.

    PubMed

    Hurtado Rúa, Sandra M; Mazumdar, Madhu; Strawderman, Robert L

    2015-12-30

    Bayesian meta-analysis is an increasingly important component of clinical research, with multivariate meta-analysis a promising tool for studies with multiple endpoints. Model assumptions, including the choice of priors, are crucial aspects of multivariate Bayesian meta-analysis (MBMA) models. In a given model, two different prior distributions can lead to different inferences about a particular parameter. A simulation study was performed in which the impact of families of prior distributions for the covariance matrix of a multivariate normal random effects MBMA model was analyzed. Inferences about effect sizes were not particularly sensitive to prior choice, but the related covariance estimates were. A few families of prior distributions with small relative biases, tight mean squared errors, and close to nominal coverage for the effect size estimates were identified. Our results demonstrate the need for sensitivity analysis and suggest some guidelines for choosing prior distributions in this class of problems. The MBMA models proposed here are illustrated in a small meta-analysis example from the periodontal field and a medium meta-analysis from the study of stroke. Copyright © 2015 John Wiley & Sons, Ltd.

  8. The choice of prior distribution for a covariance matrix in multivariate meta-analysis: a simulation study.

    PubMed

    Hurtado Rúa, Sandra M; Mazumdar, Madhu; Strawderman, Robert L

    2015-12-30

    Bayesian meta-analysis is an increasingly important component of clinical research, with multivariate meta-analysis a promising tool for studies with multiple endpoints. Model assumptions, including the choice of priors, are crucial aspects of multivariate Bayesian meta-analysis (MBMA) models. In a given model, two different prior distributions can lead to different inferences about a particular parameter. A simulation study was performed in which the impact of families of prior distributions for the covariance matrix of a multivariate normal random effects MBMA model was analyzed. Inferences about effect sizes were not particularly sensitive to prior choice, but the related covariance estimates were. A few families of prior distributions with small relative biases, tight mean squared errors, and close to nominal coverage for the effect size estimates were identified. Our results demonstrate the need for sensitivity analysis and suggest some guidelines for choosing prior distributions in this class of problems. The MBMA models proposed here are illustrated in a small meta-analysis example from the periodontal field and a medium meta-analysis from the study of stroke. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26303671

  9. Graphical Tools for Network Meta-Analysis in STATA

    PubMed Central

    Chaimani, Anna; Higgins, Julian P. T.; Mavridis, Dimitris; Spyridonos, Panagiota; Salanti, Georgia

    2013-01-01

    Network meta-analysis synthesizes direct and indirect evidence in a network of trials that compare multiple interventions and has the potential to rank the competing treatments according to the studied outcome. Despite its usefulness network meta-analysis is often criticized for its complexity and for being accessible only to researchers with strong statistical and computational skills. The evaluation of the underlying model assumptions, the statistical technicalities and presentation of the results in a concise and understandable way are all challenging aspects in the network meta-analysis methodology. In this paper we aim to make the methodology accessible to non-statisticians by presenting and explaining a series of graphical tools via worked examples. To this end, we provide a set of STATA routines that can be easily employed to present the evidence base, evaluate the assumptions, fit the network meta-analysis model and interpret its results. PMID:24098547

  10. Graphical tools for network meta-analysis in STATA.

    PubMed

    Chaimani, Anna; Higgins, Julian P T; Mavridis, Dimitris; Spyridonos, Panagiota; Salanti, Georgia

    2013-01-01

    Network meta-analysis synthesizes direct and indirect evidence in a network of trials that compare multiple interventions and has the potential to rank the competing treatments according to the studied outcome. Despite its usefulness network meta-analysis is often criticized for its complexity and for being accessible only to researchers with strong statistical and computational skills. The evaluation of the underlying model assumptions, the statistical technicalities and presentation of the results in a concise and understandable way are all challenging aspects in the network meta-analysis methodology. In this paper we aim to make the methodology accessible to non-statisticians by presenting and explaining a series of graphical tools via worked examples. To this end, we provide a set of STATA routines that can be easily employed to present the evidence base, evaluate the assumptions, fit the network meta-analysis model and interpret its results.

  11. Garlic intake lowers fasting blood glucose: meta-analysis of randomized controlled trials.

    PubMed

    Hou, Li-qiong; Liu, Yun-hui; Zhang, Yi-yi

    2015-01-01

    Garlic is a common spicy flavouring agent also used for certain therapeutic purposes. Garlic's effects on blood glucose have been the subject of many clinical and animal studies, however, studies reporting hypoglycemic effects of garlic in humans are conflicting. A comprehensive literature search was conducted to identify relevant trials of garlic or garlic extracts on markers of glycemic control [fasting blood glucose (FBG), postprandial glucose (PPG), glycosylated haemoglobin (HbA1c)]. A meta-analysis of the effect of garlic intake on human was done to assess garlic's effectiveness in lowering glucose levels. Two reviewers extracted data from each of the identified studies. Seven eligible randomized controlled trials with 513 subjects were identified. Pooled analyses showed that garlic intake results in a statistically significant lowering in FBG [SMD=-1.67; 95% CI (-2.80, -0.55), p=0.004]. Our pooled analyses did not include PPG control and HbA1c outcomes. Because only 1 study included in the meta-analysis reported PPG variables and only 2 studies reported HbA1c variables. In conclusion, the current meta-analysis showed that the administration of garlic resulted in a significant reduction in FBG concentrations. More trials are needed to investigate the effectiveness of garlic on HbA1c and PPG.

  12. Can retention forestry help conserve biodiversity? A meta-analysis

    PubMed Central

    Fedrowitz, Katja; Koricheva, Julia; Baker, Susan C; Lindenmayer, David B; Palik, Brian; Rosenvald, Raul; Beese, William; Franklin, Jerry F; Kouki, Jari; Macdonald, Ellen; Messier, Christian; Sverdrup-Thygeson, Anne; Gustafsson, Lena

    2014-01-01

    Industrial forestry typically leads to a simplified forest structure and altered species composition. Retention of trees at harvest was introduced about 25 years ago to mitigate negative impacts on biodiversity, mainly from clearcutting, and is now widely practiced in boreal and temperate regions. Despite numerous studies on response of flora and fauna to retention, no comprehensive review has summarized its effects on biodiversity in comparison to clearcuts as well as un-harvested forests. Using a systematic review protocol, we completed a meta-analysis of 78 studies including 944 comparisons of biodiversity between retention cuts and either clearcuts or un-harvested forests, with the main objective of assessing whether retention forestry helps, at least in the short term, to moderate the negative effects of clearcutting on flora and fauna. Retention cuts supported higher richness and a greater abundance of forest species than clearcuts as well as higher richness and abundance of open-habitat species than un-harvested forests. For all species taken together (i.e. forest species, open-habitat species, generalist species and unclassified species), richness was higher in retention cuts than in clearcuts. Retention cuts had negative impacts on some species compared to un-harvested forest, indicating that certain forest-interior species may not survive in retention cuts. Similarly, retention cuts were less suitable for some open-habitat species compared with clearcuts. Positive effects of retention cuts on richness of forest species increased with proportion of retained trees and time since harvest, but there were not enough data to analyse possible threshold effects, that is, levels at which effects on biodiversity diminish. Spatial arrangement of the trees (aggregated vs. dispersed) had no effect on either forest species or open-habitat species, although limited data may have hindered our capacity to identify responses. Results for different comparisons were largely

  13. [Basic concepts for network meta-analysis].

    PubMed

    Catalá-López, Ferrán; Tobías, Aurelio; Roqué, Marta

    2014-12-01

    Systematic reviews and meta-analyses have long been fundamental tools for evidence-based clinical practice. Initially, meta-analyses were proposed as a technique that could improve the accuracy and the statistical power of previous research from individual studies with small sample size. However, one of its main limitations has been the fact of being able to compare no more than two treatments in an analysis, even when the clinical research question necessitates that we compare multiple interventions. Network meta-analysis (NMA) uses novel statistical methods that incorporate information from both direct and indirect treatment comparisons in a network of studies examining the effects of various competing treatments, estimating comparisons between many treatments in a single analysis. Despite its potential limitations, NMA applications in clinical epidemiology can be of great value in situations where there are several treatments that have been compared against a common comparator. Also, NMA can be relevant to a research or clinical question when many treatments must be considered or when there is a mix of both direct and indirect information in the body of evidence.

  14. Network Meta-Analysis of Onychomycosis Treatments

    PubMed Central

    Gupta, Aditya K.; Daigle, Deanne; Foley, Kelly A.

    2015-01-01

    Background Many onychomycosis treatments have not been directly compared in head-to-head clinical trials. Objective: To determine the relative efficacy of onychomycosis treatments using network meta-analysis (NMA). Methods We conducted a systematic review and NMA of mycological cure rates. Results Nineteen trials were included in the network. Terbinafine 250 mg was significantly superior to all treatments except itraconazole 400 mg pulse therapy. The itraconazole 400 mg pulse regimen was significantly superior to all topicals except efinaconazole 10% nail solution. Itraconazole 200 mg was significantly superior to all topical treatments, while fluconazole 150-450 mg, efinaconazole 10% nail solution, tavaborole 5% nail solution, ciclopirox nail lacquer 8%, terbinafine nail solution, and amorolfine 5% nail lacquer were significantly superior to placebo. Conclusions Newly developed topicals have improved the odds ratios (ORs) of mycological cure, yet these ORs were not significantly greater than preexisting topical treatments. Further experience with these agents will reveal their clinical significance, and head-to-head trials are warranted. © 2015 S. Karger AG, Basel PMID:27170937

  15. Psychotherapy for subclinical depression: meta-analysis

    PubMed Central

    Cuijpers, Pim; Koole, Sander L.; van Dijke, Annemiek; Roca, Miquel; Li, Juan; Reynolds, Charles F.

    2014-01-01

    Background There is controversy about whether psychotherapies are effective in the treatment of subclinical depression, defined by clinically relevant depressive symptoms in the absence of a major depressive disorder. Aims To examine whether psychotherapies are effective in reducing depressive symptoms, reduce the risk of developing major depressive disorder and have comparable effects to psychological treatment of major depression. Method We conducted a meta-analysis of 18 studies comparing a psychological treatment of subclinical depression with a control group. Results The target groups, therapies and characteristics of the included studies differed considerably from each other, and the quality of many studies was not optimal. Psychotherapies did have a small to moderate effect on depressive symptoms against care as usual at the post-test assessment (g = 0.35, 95% CI 0.23-0.47; NNT = 5, 95% CI 4-8) and significantly reduced the incidence of major depressive episodes at 6 months (RR = 0.61) and possibly at 12 months (RR = 0.74). The effects were significantly smaller than those of psychotherapy for major depressive disorder and could be accounted for by non-specific effects of treatment. Conclusions Psychotherapy may be effective in the treatment of subclinical depression and reduce the incidence of major depression, but more high-quality research is needed. PMID:25274315

  16. Disclosure of sensitive behaviors across self-administered survey modes: a meta-analysis.

    PubMed

    Gnambs, Timo; Kaspar, Kai

    2015-12-01

    In surveys, individuals tend to misreport behaviors that are in contrast to prevalent social norms or regulations. Several design features of the survey procedure have been suggested to counteract this problem; particularly, computerized surveys are supposed to elicit more truthful responding. This assumption was tested in a meta-analysis of survey experiments reporting 460 effect sizes (total N =125,672). Self-reported prevalence rates of several sensitive behaviors for which motivated misreporting has been frequently observed were compared across self-administered paper-and-pencil versus computerized surveys. The results revealed that computerized surveys led to significantly more reporting of socially undesirable behaviors than comparable surveys administered on paper. This effect was strongest for highly sensitive behaviors and surveys administered individually to respondents. Moderator analyses did not identify interviewer effects or benefits of audio-enhanced computer surveys. The meta-analysis highlighted the advantages of computerized survey modes for the assessment of sensitive topics.

  17. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials.

    PubMed

    Krebs, Teri S; Johansen, Pål-Ørjan

    2012-07-01

    Assessments of lysergic acid diethylamide (LSD) in the treatment of alcoholism have not been based on quantitative meta-analysis. Hence, we performed a meta-analysis of randomized controlled trials in order to evaluate the clinical efficacy of LSD in the treatment of alcoholism. Two reviewers independently extracted the data, pooling the effects using odds ratios (ORs) by a generic inverse variance, random effects model. We identified six eligible trials, including 536 participants. There was evidence for a beneficial effect of LSD on alcohol misuse (OR, 1.96; 95% CI, 1.36-2.84; p = 0.0003). Between-trial heterogeneity for the treatment effects was negligible (I² = 0%). Secondary outcomes, risk of bias and limitations are discussed. A single dose of LSD, in the context of various alcoholism treatment programs, is associated with a decrease in alcohol misuse.

  18. Vancomycin-associated nephrotoxicity: A meta-analysis of administration by continuous versus intermittent infusion.

    PubMed

    Hanrahan, Timothy; Whitehouse, Tony; Lipman, Jeffrey; Roberts, Jason A

    2015-09-01

    Vancomycin is a glycopeptide antibiotic widely used in the management of meticillin-resistant Staphylococcus aureus (MRSA). Guidelines currently recommend vancomycin be administered by intermittent infusion, despite recent research suggesting that continuous infusion (CI) may be associated with lower rates of vancomycin-associated nephrotoxicity. In 2012, Cataldo et al. presented a meta-analysis supporting the use of CI. Here we present an updated meta-analysis, inclusive of a recently published large-scale retrospective study. PubMed, EMBASE and Cochrane Reviews databases were searched using the keywords 'vancomycin' and 'continuous' or 'intermittent' or 'infusion' or 'discontinuous' or 'administration'. Seven studies were included in the final analysis. Using a random-effects model, a non-significant trend of reduced nephrotoxicity in those who received vancomycin by CI (risk ratio=0.799, 95% confidence interval 0.523-1.220; P=0.299) was identified. A large, randomised controlled trial is necessary to confirm these results.

  19. Survival benefit from S-1 as compared to Fluorouracil in Asian patients with advanced gastrointestinal cancer: a meta-analysis.

    PubMed

    Cao, Chunxiang; Zhang, Xunlei; Kuang, Meng; Gu, Dongying; He, Mingliang; Chen, Jinfei; Tang, Cuiju

    2014-08-01

    Whether S-1 could replace 5-Fluorouracil (5-Fu) or not in the treatment of advanced gastrointestinal (GI) cancer (including advanced gastric cancer [AGS] and metastatic colorectal cancer [mCRC]) in Asian patients has been controversial. This meta-analysis was performed to compare the activity, efficacy and toxicity of S-1-based versus 5-Fu-based chemotherapy in those Asian patients. Randomized controlled trials (RCTs) were identified by electronic search of Pubmed. Relevant abstracts were manually searched to identify relevant trials. A total of 2182 patients from eight RCTs were included, and our results demonstrated that S-1-based chemotherapy significantly improved overall survival (OS) (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.77-1.00) and overall response rate (ORR) (odds ratio [OR], 1.72; 95% CI, 1.09-2.70), but no significant progression-free survival (PFS) benefit was found between arms (HR, 0.87; 95% CI, 0.72-1.06). Subgroup analyses revealed that S-1-based chemotherapy significantly improved OS and ORR in subgroups of patients with non-platinum containing regimens (P = 0.041; P = 0.034) and patients with no prior chemotherapy history (P = 0.025; P = 0.016). Statistically significant improvements of PFS and ORR in the S-1-based chemotherapy were observed in the subgroup of patients with AGC (P < 0.001; P = 0.005). S-1-based chemotherapy was characterized by significantly higher incidences of diarrhea, fatigue and thrombocytopenia, and a lower incidence of nausea. This analysis provided strong evidence for survival benefits of S-1, and S-1-based chemotherapy could be considered to replace 5-Fu-based therapy for the treatment of advanced GI cancer in Asian patients.

  20. Identification of Pathways for Bipolar Disorder A Meta-analysis

    PubMed Central

    Nurnberger, John I.; Koller, Daniel L.; Jung, Jeesun; Edenberg, Howard J.; Foroud, Tatiana; Guella, Ilaria; Vawter, Marquis P.; Kelsoe, John R.

    2015-01-01

    IMPORTANCE Genome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders. OBJECTIVE To identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS). DATA SOURCES Four independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data. STUDY SELECTION The 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample. DATA EXTRACTION AND SYNTHESIS We identified 966 genes that contained 2 or more variants associated with BP at P < .05 in 3 of 4 GWAS data sets (n = 12 127 [5253 cases, 6874 controls]). Simulations using 10 000 replicates of these data sets corrected for gene size and allowed the calculation of an empirical P value for each gene; empirically significant genes were entered into a pathway analysis. Each of these pathways was then tested in the replication sample (n = 8396 [3507 cases, 4889 controls]) using gene set enrichment analysis for single-nucleotide polymorphisms. The 226 genes were also compared with results from a meta-analysis of gene expression in the dorsolateral prefrontal cortex. MAIN OUTCOMES AND MEASURES Empirically significant genes and biological pathways. RESULTS Among 966 genes, 226 were empirically significant (P < .05). Seventeen pathways were overrepresented in analyses of the initial data set. Six of the 17 pathways were associated with BP in both the initial and replication samples: corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac

  1. Depression and anxiety in ovarian cancer: a systematic review and meta-analysis of prevalence rates

    PubMed Central

    Watts, Sam; Prescott, Philip; Mason, Jessica; McLeod, Natalie; Lewith, George

    2015-01-01

    Objectives To systematically review the literature pertaining to the prevalence of depression and anxiety in patients with ovarian cancer as a function of treatment stage. Design Systematic review and meta-analysis. Participants 3623 patients with ovarian cancer from primary research investigations. Primary outcome measure The prevalence of depression and anxiety in patients with ovarian cancer as a function of treatment stage. Results We identified 24 full journal articles that met the inclusion criteria for entry into the meta-analysis resulting in a pooled sample size of 3623 patients. The meta-analysis of prevalence rates identified pretreatment, on-treatment and post-treatment depression prevalences of 25.34% (CI 22.79% to 28.07%), 22.99% (CI 19.85% to 26.46%) and 12.71% (CI 10.14% to 15.79%), respectively. Pretreatment, on-treatment and post-treatment anxiety prevalences were 19.12% (CI 17.11% to 21.30%), 26.23% (CI 22.30% to 30.56%) and 27.09% (CI 23.10% to 31.49%). Conclusions Our findings suggest that the prevalence of depression and anxiety in women with ovarian cancer, across the treatment spectrum, is significantly greater than in the healthy female population. With the growing emphasis on improving the management of survivorship and quality of life, we conclude that further research is warranted to ensure psychological distress in ovarian cancer is not underdiagnosed and undertreated. PMID:26621509

  2. Predicting Pilot Performance in Off-Nominal Conditions: A Meta-Analysis and Model Validation

    NASA Technical Reports Server (NTRS)

    Wickens, C.D.; Hooey, B.L.; Gore, B.F.; Sebok, A.; Koenecke, C.; Salud, E.

    2009-01-01

    Pilot response to off-nominal (very rare) events represents a critical component to understanding the safety of next generation airspace technology and procedures. We describe a meta-analysis designed to integrate the existing data regarding pilot accuracy of detecting rare, unexpected events such as runway incursions in realistic flight simulations. Thirty-five studies were identified and pilot responses were categorized by expectancy, event location, and whether the pilot was flying with a highway-in-the-sky display. All three dichotomies produced large, significant effects on event miss rate. A model of human attention and noticing, N-SEEV, was then used to predict event noticing performance as a function of event salience and expectancy, and retinal eccentricity. Eccentricity is predicted from steady state scanning by the SEEV model of attention allocation. The model was used to predict miss rates for the expectancy, location and highway-in-the-sky (HITS) effects identified in the meta-analysis. The correlation between model-predicted results and data from the meta-analysis was 0.72.

  3. Passive smoke exposure and risk of diabetes: a meta-analysis of prospective studies.

    PubMed

    Sun, Kan; Liu, Dan; Wang, Chuan; Ren, Men; Yang, Chuan; Yan, Li

    2014-11-01

    Epidemiological evidence suggests that passive smoke exposure is related to the development of diabetes. However, data on this issue are controversial. We conducted a meta-analysis to provide a quantitative assessment of the association between passive smoking and the risk of diabetes. We searched the Medline and Embase databases up to October 2013 to identify prospective cohort studies related to passive smoke exposure and incident diabetes. Summary effect estimates with 95 % confidence intervals (CI) were derived using a fixed or random effects model, depending on the heterogeneity of the included studies. Six prospective studies that span three continents involving 154,406 participants (ages 18-74) with 7,116 new diabetes cases were included in the meta-analysis. On the basis of the Newcastle Ottawa Scale system, five studies were identified as relatively high-quality. In our primary analysis, compared to never smokers without passive smoke exposure, never smokers reporting passive smoke exposure was associated with increased risk of diabetes (pooled relative risk 1.21, 95 % CI 1.07-1.38). Such association persisted in the dose-response analysis. No indications of significant heterogeneity and publication bias were detected. Estimates of total effects were generally consistent in the sensitivity and subgroup analyses. Findings of the present meta-analysis suggest that passive smoke exposure is independently associated with the risk of diabetes. The conclusion may have a far-reaching significance for public health in countries of high smoking intensity and high incident diabetes.

  4. Common and distinct neural correlates of personal and vicarious reward: A quantitative meta-analysis

    PubMed Central

    Morelli, Sylvia A.; Sacchet, Matthew D.; Zaki, Jamil

    2015-01-01

    Individuals experience reward not only when directly receiving positive outcomes (e.g., food or money), but also when observing others receive such outcomes. This latter phenomenon, known as vicarious reward, is a perennial topic of interest among psychologists and economists. More recently, neuroscientists have begun exploring the neuroanatomy underlying vicarious reward. Here we present a quantitative whole-brain meta-analysis of this emerging literature. We identified 25 functional neuroimaging studies that included contrasts between vicarious reward and a neutral control, and subjected these contrasts to an activation likelihood estimate (ALE) meta-analysis. This analysis revealed a consistent pattern of activation across studies, spanning structures typically associated with the computation of value (especially ventromedial prefrontal cortex) and mentalizing (including dorsomedial prefrontal cortex and superior temporal sulcus). We further quantitatively compared this activation pattern to activation foci from a previous meta-analysis of personal reward. Conjunction analyses yielded overlapping VMPFC activity in response to personal and vicarious reward. Contrast analyses identified preferential engagement of the nucleus accumbens in response to personal as compared to vicarious reward, and in mentalizing-related structures in response to vicarious as compared to personal reward. These data shed light on the common and unique components of the reward that individuals experience directly and through their social connections. PMID:25554428

  5. Risk of renal cancer in liver transplant recipients: A systematic review and meta-analysis.

    PubMed

    Zhu, Xun; Wang, Jing-zhe; Zhang, Yi; Xu, Min; Chen, Pen; Wang, Cun-zu

    2016-01-01

    Liver transplantation is associated with a significantly increased risk of de novo malignancies, but for renal cancer this risk is less clear. We therefore performed a meta-analysis of published studies to determine whether renal cancer risk in liver transplant recipients (LTRs) was increased. To obtain a more precise conclusion, a systematic search was performed in PubMed and Web of Science databases until June 10, 2015. Standardized incidence ratio (SIR) corresponding 95% confidence interval (CI) were used to estimate risk of renal cancer in LTRs. Heterogeneity test, sensitivity analysis, and publishing bias were also performed. We identified 8 eligible studies and performed a meta-analysis on data of 49,654 LTRs with a total follow-up of 121,514.6 patient-years. The SIR for renal cancer was identified a 3.275-fold higher SIR (95% CI: 1.857-5.777; P < 0.001) in LTRs compared with the general population. This systematic review and meta-analysis demonstrated that the LTRs was associated with a significant increase in the incidence of renal cancer. Such association suggests that yearly routine post-transplant surveillance is need for renal cancer in LTRs.

  6. A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure

    PubMed Central

    Zhang, Xiaojian; Shen, Chengwu; Zhai, Shujun; Liu, Yukun; Yue, Wen-Wei; Han, Li

    2016-01-01

    Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease. PMID:27703506

  7. A Western Dietary Pattern Increases Prostate Cancer Risk: A Systematic Review and Meta-Analysis

    PubMed Central

    Fabiani, Roberto; Minelli, Liliana; Bertarelli, Gaia; Bacci, Silvia

    2016-01-01

    Dietary patterns were recently applied to examine the relationship between eating habits and prostate cancer (PC) risk. While the associations between PC risk with the glycemic index and Mediterranean score have been reviewed, no meta-analysis is currently available on dietary patterns defined by “a posteriori” methods. A literature search was carried out (PubMed, Web of Science) to identify studies reporting the relationship between dietary patterns and PC risk. Relevant dietary patterns were selected and the risks estimated were calculated by a random-effect model. Multivariable-adjusted odds ratios (ORs), for a first-percentile increase in dietary pattern score, were combined by a dose-response meta-analysis. Twelve observational studies were included in the meta-analysis which identified a “Healthy pattern” and a “Western pattern”. The Healthy pattern was not related to PC risk (OR = 0.96; 95% confidence interval (CI): 0.88–1.04) while the Western pattern significantly increased it (OR = 1.34; 95% CI: 1.08–1.65). In addition, the “Carbohydrate pattern”, which was analyzed in four articles, was positively associated with a higher PC risk (OR = 1.64; 95% CI: 1.35–2.00). A significant linear trend between the Western (p = 0.011) pattern, the Carbohydrate (p = 0.005) pattern, and the increment of PC risk was observed. The small number of studies included in the meta-analysis suggests that further investigation is necessary to support these findings. PMID:27754328

  8. Meta-analysis of functional brain imaging in specific phobia.

    PubMed

    Ipser, Jonathan C; Singh, Leesha; Stein, Dan J

    2013-07-01

    Although specific phobia is a prevalent anxiety disorder, evidence regarding its underlying functional neuroanatomy is inconsistent. A meta-analysis was undertaken to identify brain regions that were consistently responsive to phobic stimuli, and to characterize changes in brain activation following cognitive behavioral therapy (CBT). We searched the PubMed, SCOPUS and PsycINFO databases to identify positron emission tomography and functional magnetic resonance imaging studies comparing brain activation in specific phobia patients and healthy controls. Two raters independently extracted study data from all the eligible studies, and pooled coordinates from these studies using activation likelihood estimation, a quantitative meta-analytic technique. Resulting statistical parametric maps were compared between patients and healthy controls, in response to phobic versus fear-evoking stimuli, and before and after therapy. Thirteen studies were included, comprising 327 participants. Regions that were consistently activated in response to phobic stimuli included the left insula, amygdala, and globus pallidus. Compared to healthy controls, phobic subjects had increased activation in response to phobic stimuli in the left amygdala/globus pallidus, left insula, right thalamus (pulvinar), and cerebellum. Following exposure-based therapy widespread deactivation was observed in the right frontal cortex, limbic cortex, basal ganglia and cerebellum, with increased activation detected in the thalamus. Exposure to phobia-specific stimuli elicits brain activation that is consistent with current understandings of the neuroanatomy of fear conditioning and extinction. There is evidence that the effects of CBT in specific phobia may be mediated through the same underlying neurocircuitry.

  9. Acute exercise and subsequent energy intake. A meta-analysis.

    PubMed

    Schubert, Matthew M; Desbrow, Ben; Sabapathy, Surendran; Leveritt, Michael

    2013-04-01

    The precise magnitude of the effect of acute exercise on subsequent energy intake is not well understood. Identifying how large a deficit exercise can produce in energy intake and whether this is compensated for, is important in design of long-term exercise programs for weight loss and weight maintenance. Thus, this paper sought to review and perform a meta-analysis on data from the existing literature. Twenty-nine studies, consisting of 51 trials, were identified for inclusion. Exercise duration ranged from 30 to 120min at intensities of 36-81% VO(2)max, with trials ranging from 2 to 14h, and ad libitum test meals offered 0-2h post-exercise. The outcome variables included absolute energy intake and relative energy intake. A random effects model was employed for analysis due to expected heterogeneity. Results indicated that exercise has a trivial effect on absolute energy intake (n=51; ES=0.14, 95% CI: -0.005 to 0.29) and a large effect on relative energy intake (creating an energy deficit, n=25; ES=-1.35, 95% CI: -1.64 to -1.05). Despite variability among studies, results suggest that exercise is effective for producing a short-term energy deficit and that individuals tend not to compensate for the energy expended during exercise in the immediate hours after exercise by altering food intake.

  10. The impact of soil compaction on runoff - a meta analysis

    NASA Astrophysics Data System (ADS)

    Rogger, Magdalena; Blöschl, Günter

    2016-04-01

    Soil compaction caused by intensive agricultural practices is known to influence runoff processes at the local scale and is often speculated to have an impact on flood events at much larger scales. Due to the complex and diverse mechanisms related to soil compaction, the key processes influencing runoff at different scales are still poorly understood. The impacts of soil compaction are, however, not only investigated by hydrologists, but also by agricultural scientists since changes in the soil structure and water availability have a direct impact on agricultural yield. Results from these studies are also of interest to hydrologists. This study presents a meta analysis of such agricultural studies with the aim to analyse and bring together the results related to runoff processes. The study identifies the most important parameters used to describe soil compaction effects and compares the observed impacts under different climatic and soil conditions. The specific type of agricultural practice causing the soil compaction is also taken into account. In a further step the results of this study shall be used to derive a toy model for scenario analysis in order to identify the potential impacts of soil compaction on runoff processes at larger scales then the plot scale.

  11. Dealing with Feeling: A Meta-Analysis of the Effectiveness of Strategies Derived from the Process Model of Emotion Regulation

    ERIC Educational Resources Information Center

    Webb, Thomas L.; Miles, Eleanor; Sheeran, Paschal

    2012-01-01

    The present meta-analysis investigated the effectiveness of strategies derived from the process model of emotion regulation in modifying emotional outcomes as indexed by experiential, behavioral, and physiological measures. A systematic search of the literature identified 306 experimental comparisons of different emotion regulation (ER)…

  12. A Meta-Analysis of Distributed Leadership from 2002 to 2013: Theory Development, Empirical Evidence and Future Research Focus

    ERIC Educational Resources Information Center

    Tian, Meng; Risku, Mika; Collin, Kaija

    2016-01-01

    This article provides a meta-analysis of research conducted on distributed leadership from 2002 to 2013. It continues the review of distributed leadership commissioned by the English National College for School Leadership (NCSL) ("Distributed Leadership: A Desk Study," Bennett et al., 2003), which identified two gaps in the research…

  13. Meta-analysis method for discovering reliable biomarkers by integrating statistical and biological approaches: An application to liver toxicity.

    PubMed

    Cho, Hyeyoung; Kim, Hyosil; Na, Dokyun; Kim, So Youn; Jo, Deokyeon; Lee, Doheon

    2016-03-01

    Biomarkers that are identified from a single study often appear to be biologically irrelevant or false positives. Meta-analysis techniques allow integrating data from multiple studies that are related but independent in order to identify biomarkers across multiple conditions. However, existing biomarker meta-analysis methods tend to be sensitive to the dataset being analyzed. Here, we propose a meta-analysis method, iMeta, which integrates t-statistic and fold change ratio for improved robustness. For evaluation of predictive performance of the biomarkers identified by iMeta, we compare our method with other meta-analysis methods. As a result, iMeta outperforms the other methods in terms of sensitivity and specificity, and especially shows robustness to study variance increase; it consistently shows higher classification accuracy on diverse datasets, while the performance of the others is highly affected by the dataset being analyzed. Application of iMeta to 59 drug-induced liver injury studies identified three key biomarker genes: Zwint, Abcc3, and Ppp1r3b. Experimental evaluation using RT-PCR and qRT-PCR shows that their expressional changes in response to drug toxicity are concordant with the result of our method. iMeta is available at http://imeta.kaist.ac.kr/index.html. PMID:26820531

  14. Meta-analysis method for discovering reliable biomarkers by integrating statistical and biological approaches: An application to liver toxicity.

    PubMed

    Cho, Hyeyoung; Kim, Hyosil; Na, Dokyun; Kim, So Youn; Jo, Deokyeon; Lee, Doheon

    2016-03-01

    Biomarkers that are identified from a single study often appear to be biologically irrelevant or false positives. Meta-analysis techniques allow integrating data from multiple studies that are related but independent in order to identify biomarkers across multiple conditions. However, existing biomarker meta-analysis methods tend to be sensitive to the dataset being analyzed. Here, we propose a meta-analysis method, iMeta, which integrates t-statistic and fold change ratio for improved robustness. For evaluation of predictive performance of the biomarkers identified by iMeta, we compare our method with other meta-analysis methods. As a result, iMeta outperforms the other methods in terms of sensitivity and specificity, and especially shows robustness to study variance increase; it consistently shows higher classification accuracy on diverse datasets, while the performance of the others is highly affected by the dataset being analyzed. Application of iMeta to 59 drug-induced liver injury studies identified three key biomarker genes: Zwint, Abcc3, and Ppp1r3b. Experimental evaluation using RT-PCR and qRT-PCR shows that their expressional changes in response to drug toxicity are concordant with the result of our method. iMeta is available at http://imeta.kaist.ac.kr/index.html.

  15. Epistasis Test in Meta-Analysis: A Multi-Parameter Markov Chain Monte Carlo Model for Consistency of Evidence.

    PubMed

    Lin, Chin; Chu, Chi-Ming; Su, Sui-Lung

    2016-01-01

    Conventional genome-wide association studies (GWAS) have been proven to be a successful strategy for identifying genetic variants associated with complex human traits. However, there is still a large heritability gap between GWAS and transitional family studies. The "missing heritability" has been suggested to be due to lack of studies focused on epistasis, also called gene-gene interactions, because individual trials have often had insufficient sample size. Meta-analysis is a common method for increasing statistical power. However, sufficient detailed information is difficult to obtain. A previous study employed a meta-regression-based method to detect epistasis, but it faced the challenge of inconsistent estimates. Here, we describe a Markov chain Monte Carlo-based method, called "Epistasis Test in Meta-Analysis" (ETMA), which uses genotype summary data to obtain consistent estimates of epistasis effects in meta-analysis. We defined a series of conditions to generate simulation data and tested the power and type I error rates in ETMA, individual data analysis and conventional meta-regression-based method. ETMA not only successfully facilitated consistency of evidence but also yielded acceptable type I error and higher power than conventional meta-regression. We applied ETMA to three real meta-analysis data sets. We found significant gene-gene interactions in the renin-angiotensin system and the polycyclic aromatic hydrocarbon metabolism pathway, with strong supporting evidence. In addition, glutathione S-transferase (GST) mu 1 and theta 1 were confirmed to exert independent effects on cancer. We concluded that the application of ETMA to real meta-analysis data was successful. Finally, we developed an R package, etma, for the detection of epistasis in meta-analysis [etma is available via the Comprehensive R Archive Network (CRAN) at https://cran.r-project.org/web/packages/etma/index.html]. PMID:27045371

  16. Epistasis Test in Meta-Analysis: A Multi-Parameter Markov Chain Monte Carlo Model for Consistency of Evidence.

    PubMed

    Lin, Chin; Chu, Chi-Ming; Su, Sui-Lung

    2016-01-01

    Conventional genome-wide association studies (GWAS) have been proven to be a successful strategy for identifying genetic variants associated with complex human traits. However, there is still a large heritability gap between GWAS and transitional family studies. The "missing heritability" has been suggested to be due to lack of studies focused on epistasis, also called gene-gene interactions, because individual trials have often had insufficient sample size. Meta-analysis is a common method for increasing statistical power. However, sufficient detailed information is difficult to obtain. A previous study employed a meta-regression-based method to detect epistasis, but it faced the challenge of inconsistent estimates. Here, we describe a Markov chain Monte Carlo-based method, called "Epistasis Test in Meta-Analysis" (ETMA), which uses genotype summary data to obtain consistent estimates of epistasis effects in meta-analysis. We defined a series of conditions to generate simulation data and tested the power and type I error rates in ETMA, individual data analysis and conventional meta-regression-based method. ETMA not only successfully facilitated consistency of evidence but also yielded acceptable type I error and higher power than conventional meta-regression. We applied ETMA to three real meta-analysis data sets. We found significant gene-gene interactions in the renin-angiotensin system and the polycyclic aromatic hydrocarbon metabolism pathway, with strong supporting evidence. In addition, glutathione S-transferase (GST) mu 1 and theta 1 were confirmed to exert independent effects on cancer. We concluded that the application of ETMA to real meta-analysis data was successful. Finally, we developed an R package, etma, for the detection of epistasis in meta-analysis [etma is available via the Comprehensive R Archive Network (CRAN) at https://cran.r-project.org/web/packages/etma/index.html].

  17. Activation Likelihood Estimation meta-analysis revisited

    PubMed Central

    Eickhoff, Simon B.; Bzdok, Danilo; Laird, Angela R.; Kurth, Florian; Fox, Peter T.

    2011-01-01

    A widely used technique for coordinate-based meta-analysis of neuroimaging data is activation likelihood estimation (ALE), which determines the convergence of foci reported from different experiments. ALE analysis involves modelling these foci as probability distributions whose width is based on empirical estimates of the spatial uncertainty due to the between-subject and between-template variability of neuroimaging data. ALE results are assessed against a null-distribution of random spatial association between experiments, resulting in random-effects inference. In the present revision of this algorithm, we address two remaining drawbacks of the previous algorithm. First, the assessment of spatial association between experiments was based on a highly time-consuming permutation test, which nevertheless entailed the danger of underestimating the right tail of the null-distribution. In this report, we outline how this previous approach may be replaced by a faster and more precise analytical method. Second, the previously applied correction procedure, i.e. controlling the false discovery rate (FDR), is supplemented by new approaches for correcting the family-wise error rate and the cluster-level significance. The different alternatives for drawing inference on meta-analytic results are evaluated on an exemplary dataset on face perception as well as discussed with respect to their methodological limitations and advantages. In summary, we thus replaced the previous permutation algorithm with a faster and more rigorous analytical solution for the null-distribution and comprehensively address the issue of multiple-comparison corrections. The proposed revision of the ALE-algorithm should provide an improved tool for conducting coordinate-based meta-analyses on functional imaging data. PMID:21963913

  18. The Flynn Effect: A Meta-analysis

    PubMed Central

    Trahan, Lisa; Stuebing, Karla K.; Hiscock, Merril K.; Fletcher, Jack M.

    2014-01-01

    The “Flynn effect” refers to the observed rise in IQ scores over time, resulting in norms obsolescence. Although the Flynn effect is widely accepted, most approaches to estimating it have relied upon “scorecard” approaches that make estimates of its magnitude and error of measurement controversial and prevent determination of factors that moderate the Flynn effect across different IQ tests. We conducted a meta-analysis to determine the magnitude of the Flynn effect with a higher degree of precision, to determine the error of measurement, and to assess the impact of several moderator variables on the mean effect size. Across 285 studies (N = 14,031) since 1951 with administrations of two intelligence tests with different normative bases, the meta-analytic mean was 2.31, 95% CI [1.99, 2.64], standard score points per decade. The mean effect size for 53 comparisons (N = 3,951) (excluding three atypical studies that inflate the estimates) involving modern (since 1972) Stanford-Binet and Wechsler IQ tests (2.93, 95% CI [2.3, 3.5], IQ points per decade) was comparable to previous estimates of about 3 points per decade, but not consistent with the hypothesis that the Flynn effect is diminishing. For modern tests, study sample (larger increases for validation research samples vs. test standardization samples) and order of administration explained unique variance in the Flynn effect, but age and ability level were not significant moderators. These results supported previous estimates of the Flynn effect and its robustness across different age groups, measures, samples, and levels of performance. PMID:24979188

  19. The Flynn effect: a meta-analysis.

    PubMed

    Trahan, Lisa H; Stuebing, Karla K; Fletcher, Jack M; Hiscock, Merrill

    2014-09-01

    The Flynn effect refers to the observed rise in IQ scores over time, which results in norms obsolescence. Although the Flynn effect is widely accepted, most efforts to estimate it have relied upon "scorecard" approaches that make estimates of its magnitude and error of measurement controversial and prevent determination of factors that moderate the Flynn effect across different IQ tests. We conducted a meta-analysis to determine the magnitude of the Flynn effect with a higher degree of precision, to determine the error of measurement, and to assess the impact of several moderator variables on the mean effect size. Across 285 studies (N = 14,031) since 1951 with administrations of 2 intelligence tests with different normative bases, the meta-analytic mean was 2.31, 95% CI [1.99, 2.64], standard score points per decade. The mean effect size for 53 comparisons (N = 3,951, excluding 3 atypical studies that inflate the estimates) involving modern (since 1972) Stanford-Binet and Wechsler IQ tests (2.93, 95% CI [2.3, 3.5], IQ points per decade) was comparable to previous estimates of about 3 points per decade but was not consistent with the hypothesis that the Flynn effect is diminishing. For modern tests, study sample (larger increases for validation research samples vs. test standardization samples) and order of administration explained unique variance in the Flynn effect, but age and ability level were not significant moderators. These results supported previous estimates of the Flynn effect and its robustness across different age groups, measures, samples, and levels of performance.

  20. The Flynn effect: a meta-analysis.

    PubMed

    Trahan, Lisa H; Stuebing, Karla K; Fletcher, Jack M; Hiscock, Merrill

    2014-09-01

    The Flynn effect refers to the observed rise in IQ scores over time, which results in norms obsolescence. Although the Flynn effect is widely accepted, most efforts to estimate it have relied upon "scorecard" approaches that make estimates of its magnitude and error of measurement controversial and prevent determination of factors that moderate the Flynn effect across different IQ tests. We conducted a meta-analysis to determine the magnitude of the Flynn effect with a higher degree of precision, to determine the error of measurement, and to assess the impact of several moderator variables on the mean effect size. Across 285 studies (N = 14,031) since 1951 with administrations of 2 intelligence tests with different normative bases, the meta-analytic mean was 2.31, 95% CI [1.99, 2.64], standard score points per decade. The mean effect size for 53 comparisons (N = 3,951, excluding 3 atypical studies that inflate the estimates) involving modern (since 1972) Stanford-Binet and Wechsler IQ tests (2.93, 95% CI [2.3, 3.5], IQ points per decade) was comparable to previous estimates of about 3 points per decade but was not consistent with the hypothesis that the Flynn effect is diminishing. For modern tests, study sample (larger increases for validation research samples vs. test standardization samples) and order of administration explained unique variance in the Flynn effect, but age and ability level were not significant moderators. These results supported previous estimates of the Flynn effect and its robustness across different age groups, measures, samples, and levels of performance. PMID:24979188

  1. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis

    PubMed Central

    D'Souza, Aloysius L; Rajkumar, Chakravarthi; Cooke, Jonathan; Bulpitt, Christopher J

    2002-01-01

    Objective To evaluate efficacy of probiotics in prevention and treatment of diarrhoea associated with the use of antibiotics. Design Meta-analysis; outcome data (proportion of patients not getting diarrhoea) were analysed, pooled, and compared to determine odds ratios in treated and control groups. Identification Studies identified by searching Medline between 1966 and 2000 and the Cochrane Library. Studies reviewed Nine randomised, double blind, placebo controlled trials of probiotics. Results Two of the nine studies investigated the effects of probiotics in children. Four trials used a yeast (Saccharomyces boulardii), four used lactobacilli, and one used a strain of enterococcus that produced lactic acid. Three trials used a combination of probiotic strains of bacteria. In all nine trials, the probiotics were given in combination with antibiotics and the control groups received placebo and antibiotics. The odds ratio in favour of active treatment over placebo in preventing diarrhoea associated with antibiotics was 0.39 (95% confidence interval 0.25 to 0.62; P<0.001) for the yeast and 0.34 (0.19 to 0.61; P<0.01 for lactobacilli. The combined odds ratio was 0.37 (0.26 to 0.53; P<0.001) in favour of active treatment over placebo. Conclusions The meta-analysis suggests that probiotics can be used to prevent antibiotic associated diarrhoea and that S boulardii and lactobacilli have the potential to be used in this situation. The efficacy of probiotics in treating antibiotic associated diarrhoea remains to be proved. A further large trial in which probiotics are used as preventive agents should look at the costs of and need for routine use of these agents. What is already known on this topicProbiotics are well known for their microbiological properties and have been used to treat gastrointestinal and vaginal mucosal infectionsConflicting results have prevented probiotics from being accepted as viable alternatives to conventional treatments for antibiotic associated

  2. Association of thyroid carcinoma with pregnancy: A meta-analysis

    PubMed Central

    ZHOU, Y.Q.; ZHOU, Z.; QIAN, M.F.; GONG, T.; WANG, J.D.

    2015-01-01

    A number of scholars reported that reproductive factors play a significant role in thyroid cancer and the correlation between the two may affect the diagnosis and treatment of thyroid carcinoma during pregnancy. To determine whether pregnancy reproductive factors affect thyroid carcinoma, we conducted a meta-analysis of studies that investigated the association between pregnancy factors and thyroid carcinoma. PubMed, OVID and the Cochrane Library were searched from their inception to April 1st, 2013. The searched publications mainly investigated reproductive factors and the morbidity or prognosis of female thyroid carcinoma. The studies were filtered by predetermined standards and the quality of the included studies was evaluated by the Newcastle-Ottawa scale inventory. Two researchers independently extracted information on first author, year of publication, study design (case-control or prospective cohort), compared populations, inclusion and exclusion criteria and total sample size. Other researchers assessed the studies for publication bias and performed statistical analyses. Discrepancies were resolved by consensus. A total of 21 studies were selected for the meta-analysis, including 406,329 cases in total. Compared to the control group, the risk of thyroid carcinoma in women with a history of pregnancy was not significantly discrepant, [odds ratio (OR)=1.00, 95% confidence interval (CI): 0.91-1.11]. However, the risk of thyroid carcinoma in women with a history of ≥ 3 pregnancies was significantly increased (OR=1.39, 95% CI: 1.21-1.59). Furthermore, an interval of ≤ 5 years since the last pregnancy was closely associated with thyroid carcinoma (OR=1.53, 95% CI: 1.29-1.81). The patients developed thyroid carcinoma during pregnancy did not exhibit an increased risk of lymphatic metastasis (OR=0.94, 95% CI: 0.53-1.67); the risk of distant metastasis also did not increase significantly (OR=1.03, 95% CI: 0.86-1.24). Therefore, multiple pregnancies and a ≤ 5

  3. A surprising cross-species conservation in the genomic landscape of mouse and human oral cancer identifies a transcriptional signature predicting metastatic disease

    PubMed Central

    Onken, Michael D.; Winkler, Ashley E.; Kanchi, Krishna-Latha; Chalivendra, Varun; Law, Jonathan H.; Rickert, Charles G.; Kallogjeri, Dorina; Judd, Nancy P.; Dunn, Gavin P.; Piccirillo, Jay F.; Lewis, James S.; Mardis, Elaine R.; Uppaluri, Ravindra

    2014-01-01

    Purpose Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance. Experimental Design Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature and we assessed its representation in 4 independent human datasets comprising 324 patients using weighted voting and Gene Set Enrichment Analysis (GSEA). Kaplan-Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A qRT-PCR assay based on the mouse signature coupled to a machine-learning algorithm was developed and used to stratify an independent set of 31 patients with respect to metastatic lymphadenopathy. Results NGS revealed conservation of human driver pathway mutations in mouse OSCC including in Trp53, MAPK, PI3K, NOTCH, JAK/STAT and FAT1–4. Moreover, comparative analysis between The Cancer Genome Atlas (TCGA) and mouse samples defined AKAP9, MED12L and MYH6 as novel putative cancer genes. Expression analysis identified a transcriptional signature predicting aggressiveness and clinical outcomes, which were validated in 4 independent human OSCC datasets. Finally, we harnessed the translational potential of this signature by creating a clinically feasible assay that stratified OSCC patients with a 93.5% accuracy. Conclusions These data demonstrate surprising cross-species genomic conservation that has translational relevance for human oral squamous cell cancer. PMID:24668645

  4. Behavioural Activation for Depression; An Update of Meta-Analysis of Effectiveness and Sub Group Analysis

    PubMed Central

    Ekers, David; Webster, Lisa; Van Straten, Annemieke; Cuijpers, Pim; Richards, David; Gilbody, Simon

    2014-01-01

    Background Depression is a common, disabling condition for which psychological treatments are recommended. Behavioural activation has attracted increased interest in recent years. It has been over 5 years since our meta-analyses summarised the evidence supporting and this systematic review updates those findings and examines moderators of treatment effect. Method Randomised trials of behavioural activation for depression versus controls or anti-depressant medication were identified using electronic database searches, previous reviews and reference lists. Data on symptom level and study level moderators were extracted and analysed using meta-analysis, sub-group analysis and meta-regression respectively. Results Twenty six randomised controlled trials including 1524 subjects were included in this meta-analysis. A random effects meta-analysis of symptom level post treatment showed behavioural activation to be superior to controls (SMD −0.74 CI −0.91 to −0.56, k = 25, N = 1088) and medication (SMD −0.42 CI −0.83 to-0.00, k = 4, N = 283). Study quality was low in the majority of studies and follow- up time periods short. There was no indication of publication bias and subgroup analysis showed limited association between moderators and effect size. Conclusions The results in this meta-analysis support and strengthen the evidence base indicating Behavioural Activation is an effective treatment for depression. Further high quality research with longer term follow-up is needed to strengthen the evidence base. PMID:24936656

  5. Effects of Allopurinol on Arterial Stiffness: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Deng, Gang; Qiu, Zhandong; Li, Dayong; Fang, Yu; Zhang, Suming

    2016-01-01

    Background Several studies have tested the effects of allopurinol on arterial stiffness, but the results have been inconclusive. We aimed to conduct a meta-analysis to investigate the impacts of allopurinol treatment on arterial stiffness, as measured by pulse wave velocity (PWV) and augmentation index (AIx). Material/Methods Randomized controlled trials (RCTs) assessing the effects of allopurinol on arterial stiffness were identified through searching PubMed, Web of Science, EMBASE, the Cochrane Library for Central Register of Clinical Trials, and China National Knowledge Infrastructure up to December 2015. The primary endpoints were the change of PWV and AIx after allopurinol treatment. The weighted mean difference (WMD) or standardized mean difference (SMD) and the 95% confidence interval (CI) of each study were pooled for meta-analysis. Results A total of 11 RCTs met the inclusion criteria and were included in the final meta-analysis. Eight RCTs with 1,111 patients were pooled for PWV; eight RCTs with 397 patients were pooled for PWV. Allopurinol administration did not significantly change PWV (WMD=−0.19 m/s, 95% CI: −0.49 to 0.12, Z=1.21, p=0.23), but significantly reduced AIx (SMD=−0.34, 95% CI: −0.54 to −0.14, Z=3.35, p=0.0008). Conclusions Although our meta-analysis showed some favorable effects of allopurinol treatment on improving AIx, its impact on arterial stiffness must be tested in more large-scale RCTs. PMID:27110924

  6. Circulating adiponectin levels and risk of endometrial cancer: Systematic review and meta-analysis

    PubMed Central

    LI, ZHI-JUN; YANG, XUE-LING; YAO, YAN; HAN, WEI-QING; LI, BO

    2016-01-01

    Previous epidemiological studies have presented conflicting results regarding associations between circulating adiponectin (APN) levels and the risk of endometrial cancer. Thus a meta-analysis was performed to investigate the association between these factors. Multiple electronic sources, including PubMed, SpringerLink and Google Scholar databases were searched to identify relevant studies for the present meta-analysis. All of the selected studies examined the correlation between circulating APN levels and endometrial cancer. The standardized mean difference (SMD) and 95% confidence intervals (CIs) were estimated and pooled using meta-analysis methods. Overall, 18 case-control studies met the inclusion criteria. A total of 5,692 participants and 2,337 cases of endometrial cancer were included in this meta-analysis. The SMD of the pooled analysis (95% CI) were −1.96 (−2.60, −1.31), P=0.000. When the cancer grades were compared, the APN values were not significantly different between the grades of endometrial cancer [G1 vs. G3, 1.02 (−0.68, 2.72), P>0.05; G1 vs. G2, 0.34 (−0.86, 1.54), P>0.05]. However, there was a significant association between high APN levels and postmenopausal endometrial cancer cases with an SMD (95% CI) of −2.27 (−4.36, −0.18) and P<0.05, however, no association was observed in premenopausal endometrial cancer cases with an SMD (95% CI) of −1.52 (−3.49, 0.45) and P>0.05. The low circulating APN level increases the risk of endometrial cancer, whereas the high APN level decreases this risk in postmenopausal women. Circulating APN as simple biomarkers may be a promising tool for the prevention, early diagnosis and disease monitoring of endometrial cancer. PMID:27284314

  7. Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

    PubMed

    Huang, Ruixue; Wang, Ke; Hu, Jianan

    2016-01-01

    It has been reported that gut probiotics play a major role in the bidirectional communication between the gut and the brain. Probiotics may be essential to people with depression, which remains a global health challenge, as depression is a metabolic brain disorder. However, the efficacy of probiotics for depression is controversial. This study aimed to systematically review the existing evidence on the effect of probiotics-based interventions on depression. Randomized, controlled trials, identified through screening multiple databases and grey literature, were included in the meta-analysis. The meta-analysis was performed using Review Manager 5.3 software using a fixed-effects model. The meta-analysis showed that probiotics significantly decreased the depression scale score (MD (depressive disorder) = -0.30, 95% CI (-0.51--0.09), p = 0.005) in the subjects. Probiotics had an effect on both the healthy population (MD = -0.25, 95% CI (-0.47--0.03), p = 0.03) and patients with major depressive disorder (MDD) (MD = -0.73, 95% CI (-1.37--0.09), p = 0.03). Probiotics had an effect on the population aged under 60 (MD = -0.43, 95% CI (-0.72--0.13), p = 0.005), while it had no effect on people aged over 65 (MD = -0.18, 95% CI (-0.47-0.11), p = 0.22). This is the first systematic review and meta-analysis with the goal of determining the effect of probiotics on depression. We found that probiotics were associated with a significant reduction in depression, underscoring the need for additional research on this potential preventive strategy for depression. PMID:27509521

  8. Effects of low power laser irradiation on bone healing in animals: a meta-analysis

    PubMed Central

    2010-01-01

    Purpose The meta-analysis was performed to identify animal research defining the effects of low power laser irradiation on biomechanical indicators of bone regeneration and the impact of dosage. Methods We searched five electronic databases (MEDLINE, EMBASE, PubMed, CINAHL, and Cochrane Database of Randomised Clinical Trials) for studies in the area of laser and bone healing published from 1966 to October 2008. Included studies had to investigate fracture healing in any animal model, using any type of low power laser irradiation, and use at least one quantitative biomechanical measures of bone strength. There were 880 abstracts related to the laser irradiation and bone issues (healing, surgery and assessment). Five studies met our inclusion criteria and were critically appraised by two raters independently using a structured tool designed for rating the quality of animal research studies. After full text review, two articles were deemed ineligible for meta-analysis because of the type of injury method and biomechanical variables used, leaving three studies for meta-analysis. Maximum bone tolerance force before the point of fracture during the biomechanical test, 4 weeks after bone deficiency was our main biomechanical bone properties for the Meta analysis. Results Studies indicate that low power laser irradiation can enhance biomechanical properties of bone during fracture healing in animal models. Maximum bone tolerance was statistically improved following low level laser irradiation (average random effect size 0.726, 95% CI 0.08 - 1.37, p 0.028). While conclusions are limited by the low number of studies, there is concordance across limited evidence that laser improves the strength of bone tissue during the healing process in animal models. PMID:20047683

  9. Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Huang, Ruixue; Wang, Ke; Hu, Jianan

    2016-01-01

    It has been reported that gut probiotics play a major role in the bidirectional communication between the gut and the brain. Probiotics may be essential to people with depression, which remains a global health challenge, as depression is a metabolic brain disorder. However, the efficacy of probiotics for depression is controversial. This study aimed to systematically review the existing evidence on the effect of probiotics-based interventions on depression. Randomized, controlled trials, identified through screening multiple databases and grey literature, were included in the meta-analysis. The meta-analysis was performed using Review Manager 5.3 software using a fixed-effects model. The meta-analysis showed that probiotics significantly decreased the depression scale score (MD (depressive disorder) = −0.30, 95% CI (−0.51–−0.09), p = 0.005) in the subjects. Probiotics had an effect on both the healthy population (MD = −0.25, 95% CI (−0.47–−0.03), p = 0.03) and patients with major depressive disorder (MDD) (MD = −0.73, 95% CI (−1.37–−0.09), p = 0.03). Probiotics had an effect on the population aged under 60 (MD = −0.43, 95% CI (−0.72–−0.13), p = 0.005), while it had no effect on people aged over 65 (MD = −0.18, 95% CI (−0.47–0.11), p = 0.22). This is the first systematic review and meta-analysis with the goal of determining the effect of probiotics on depression. We found that probiotics were associated with a significant reduction in depression, underscoring the need for additional research on this potential preventive strategy for depression. PMID:27509521

  10. Biopersistent Granular Dust and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis

    PubMed Central

    Brüske, Irene; Thiering, Elisabeth; Heinrich, Joachim; Huster, Katharina; Nowak, Dennis

    2013-01-01

    Objective Applying a systematic review to identify studies eligible for meta-analysis of the association between occupational exposure to inorganic dust and the development of chronic obstructive pulmonary disease (COPD), and conducting a meta-analysis. Data Sources Searches of PubMed and Embase for the time period 1970–2010 yielded 257 cross-sectional and longitudinal studies on people exposed to inorganic dust at the workplace with data on lung function. These studies were independently abstracted and evaluated by two authors; any disagreement was resolved by a third reviewer. Of 55 publications accepted for meta-analysis, 27 investigated the effects of occupational exposure to biopersistent granular dust (bg-dust). Methods A random effects meta-analysis allowed us to provide an estimate of the average exposure effect on spirometric parameters presented in forest plots. Between-study heterogeneity was assessed by using I2 statistics, with I2>25% indicating significant heterogeneity. Publication bias was investigated by visual inspection of funnel plots. The influence of individual studies was assessed by dropping the respective study before pooling study-specific estimates. Results The mean FEV1 of workers exposed to bg-dust was 160 ml lower or 5.7% less than predicted compared to workers with no/low exposure. The risk of an obstructive airway disease—defined as FEV1/FVC < 70%—increased by 7% per 1 mg· m-3 respirable bg-dust. Conclusion Occupational inhalative exposure to bg-dust was associated with a statistically significant decreased FEV1 and FEV1/FVC revealing airway obstruction consistent with COPD. PMID:24278358

  11. Toxoplasmosis in immunocompromised patients in Iran: a systematic review and meta-analysis.

    PubMed

    Ahmadpour, Ehsan; Daryani, Ahmad; Sharif, Mahdi; Sarvi, Shahabeddin; Aarabi, Mohsen; Mizani, Azadeh; Rahimi, Mohammad Taghi; Shokri, Azar

    2014-12-15

    Although toxoplasmosis in immunocompetent individuals is generally asymptomatic, in immunocompromised patients (HIV/AIDS, cancer, and transplant patients), it can lead to serious pathological effects. This study included a systematic review and meta-analysis to comprehensively assess the seroprevalence rate of Toxoplasma infection in immunocompromised patients in Iran. Electronic English and Persian databases (PubMed, Google Scholar, ScienceDirect, Scopus, Magiran, Scientific Information Database [SID], IranMedex, and IranDoc), parasitology congresses, and projects and theses of Iranian medical universities, were systematically searched from 1997 to 2013 (published or unpublished data). In this paper, several studies that used serological methods for diagnosis of toxoplasmosis were selected. Analysis of seroprevalence estimates was pooled using a random-effects meta-analysis. Twenty-two studies, comprising 2,805 individuals, were included in the meta-analysis. Overall seroprevalence rate of Toxoplasma infection in Iranian immunocompromised patients was 50.01% (95% confidence interval, 43.85 to 56.17); however, there was significant heterogeneity among study groups. The results showed that seroprevalence rate of toxoplasmosis among transplant recipients, HIV/AIDS, and cancer patients in Iran was 55.1%, 50.05%, and 45.06%, respectively. In addition, IgM seroprevalence rate was estimated to be 4.85% (95% confidence interval, 2.22 to 8.41). This systematic review and meta-analysis identified a high seroprevalence rate of Toxoplasma infection among immunocompromised patients (50%). Consideration of management, design and provision of appropriate control measures of toxoplasmosis is highly recommended.

  12. Exposure to organochlorine pesticides and non-Hodgkin lymphoma: a meta-analysis of observational studies

    PubMed Central

    Luo, Dan; Zhou, Tingting; Tao, Yun; Feng, Yaqian; Shen, Xiaoli; Mei, Surong

    2016-01-01

    Growing evidence indicates that exposure to organochlorine pesticides (OCPs) could increase non-Hodgkin lymphoma (NHL) risk. However, results from epidemiological studies investigating this association remain controversial. We thus conducted a meta-analysis to quantitatively evaluate the association between OCP exposure and NHL risk. Relevant publications were searched in PubMed, Web of Science, and Embase and identified according to the inclusion criteria. Thirteen studies (6 nested case-control, 1 case-cohort, and 6 case-control) were selected for this meta-analysis. We used odds ratios (ORs) with 95% confidence intervals (CIs) to estimate the relationship between OCPs exposure and NHL risk. The summary OR for included studies was 1.40 (95% CI 1.27 to 1.56). No overall significant heterogeneity in the OR was observed (Ph = 0.253, I2 = 12.6%). Furthermore, OR estimates in subgroup analyses were discussed, and strong associations were observed for dichlorodiphenyldichloroethylene (DDE, OR = 1.38, 95% CI 1.14 to 1.66), hexachlorocyclohexane (HCH, OR = 1.42, 95% CI 1.08 to 1.87), chlordane (OR = 1.93, 95% CI 1.51 to 2.48), and hexachlorobenzene (HCB, OR = 1.54, 95% CI 1.20 to 1.99). This meta-analysis had suggested that total OCPs of interest was significantly positively associated with NHL risk. PMID:27185567

  13. Fire-Needle Moxibustion for the Treatment of Knee Osteoarthritis: A Meta-Analysis.

    PubMed

    Wang, Yidan; Xie, Xiaohua; Zhu, Xiaoyue; Chu, Minjie; Lu, Yihua; Tian, Tian; Zhuang, Xun; Jiang, Liying

    2016-01-01

    Objectives. The aim of this study was to evaluate the effectiveness of fire-needle moxibustion as an intervention in the treatment of knee osteoarthritis (KOA). Methods. An updated meta-analysis of randomized controlled trials (RCTs) on fire-needle moxibustion in treating KOA was conducted by searching PubMed, Embase, the Cochrane Library, Web of Science, Wanfang database, and the Chinese Medical Database (CNKI) since their inception through March 2016. The meta-analysis was performed using RevMan 5.3. Results. Thirteen RCTs were identified in the systematic study which consisted of 1179 participants. Fire-needle moxibustion treatment group had a statistical significance on recovery rate as well as recovery and marked-improvement rate compared with control group. Subgroup analysis indicated that there was significant difference between fire-needle moxibustion group and control group. However, GRADE analysis indicated that the quality of evidence for all outcomes was relatively low. Only two of 13 studies reported adverse reactions (difficulty in movement and intolerance of cold). Conclusion. This meta-analysis suggests that fire-needle moxibustion is more effective than control group in symptom management of KOA. Further high quality trials should be conducted to evaluate the effectiveness of fire-needle moxibustion on KOA. PMID:27403195

  14. Hypertension and risk of prostate cancer: a systematic review and meta-analysis

    PubMed Central

    Liang, Zhen; Xie, Bo; Li, Jiangfeng; Wang, Xiao; Wang, Song; Meng, Shuai; Ji, Alin; Zhu, Yi; Xu, Xin; Zheng, Xiangyi; Xie, Liping

    2016-01-01

    The previously reported association between hypertension and prostate cancer risk was controversial. We performed this systematic review and meta-analysis of all available studies to summarize evidence on this association. Studies were identified by searching PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases through January 2016. Pooled relative risks (RRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. A total of 21 published studies were included in this meta-analysis. A significant increase in the risk of prostate cancer (RR 1.08, 95% CI 1.02–1.15, P = 0.014) was observed among individuals with hypertension. There was statistically significant heterogeneity among included studies (P < 0.001 for heterogeneity, I2 = 72.1%). No obvious evidence of significant publication bias was detected by either Begg’s test (P = 0.174) or Egger’s test (P = 0.277). In conclusion, this meta-analysis indicates that hypertension may be associated with an increased risk of prostate cancer. Considering the substantial heterogeneity and residual confounding among included studies, further large-scale, well-designed prospective cohorts, as well as mechanistic studies, are urgently needed to confirm our preliminary findings. PMID:27511796

  15. Red meat and processed meat consumption and all-cause mortality: a meta-analysis.

    PubMed

    Larsson, Susanna C; Orsini, Nicola

    2014-02-01

    High consumption of red meat and processed meat has been associated with increased risk of several chronic diseases. We conducted a meta-analysis to summarize the evidence from prospective studies on red meat and processed meat consumption in relationship to all-cause mortality. Pertinent studies were identified by searching PubMed through May 2013 and by reviewing the reference lists of retrieved articles. Prospective studies that reported relative risks with 95% confidence intervals for the association of red meat or processed meat consumption with all-cause mortality were eligible. Study-specific results were combined by using a random-effects model. Nine prospective studies were included in the meta-analysis. The summary relative risks of all-cause mortality for the highest versus the lowest category of consumption were 1.10 (95% confidence interval (CI): 0.98, 1.22; n = 6 studies) for unprocessed red meat, 1.23 (95% CI: 1.17, 1.28; n = 6 studies) for processed meat, and 1.29 (95% CI: 1.24, 1.35; n = 5 studies) for total red meat. In a dose-response meta-analysis, consumption of processed meat and total red meat, but not unprocessed red meat, was statistically significantly positively associated with all-cause mortality in a nonlinear fashion. These results indicate that high consumption of red meat, especially processed meat, may increase all-cause mortality.

  16. Risk of malignancy in ankylosing spondylitis: a systematic review and meta-analysis

    PubMed Central

    Deng, Chuiwen; Li, Wenli; Fei, Yunyun; Li, Yongzhe; Zhang, Fengchun

    2016-01-01

    Current knowledge about the overall and site-specific risk of malignancy associated with ankylosing spondylitis (AS) is inconsistent. We conducted a systematic review and meta-analysis to address this knowledge gap. Five databases (PubMed, EMBASE, Web of Science, the Cochrane library and the virtual health library) were systematically searched. A manual search of publications within the last 2 years in key journals in the field (Annals of the Rheumatic Diseases, Rheumatology and Arthritis & rheumatology) was also performed. STATA 11.2 software was used to conduct the meta-analysis. After screening, twenty-three studies, of different designs, were eligible for meta-analysis. AS is associated with a 14% (pooled RR 1.14; 95% CI 1.03–1.25) increase in the overall risk for malignancy. Compared to controls, patients with AS are at a specific increased risk for malignancy of the digestive system (pooled RR 1.20; 95% CI 1.01 to 1.42), multiple myelomas (pooled RR 1.92; 95% CI 1.37 to 3.69) and lymphomas (pooled RR 1.32; 95% CI 1.11 to 1.57). On subgroup analysis, evidence from high quality cohort studies indicated that AS patients from Asia are at highest risk for malignancy overall. Confirmation of findings from large-scale longitudinal studies is needed to identify specific risk factors and to evaluate treatment effects. PMID:27534810

  17. Dietary Patterns and Chronic Obstructive Pulmonary Disease: A Meta-analysis.

    PubMed

    Zheng, Pei-Fen; Shu, Long; Si, Cai-Juan; Zhang, Xiao-Yan; Yu, Xiao-Long; Gao, Wei

    2016-08-01

    Investigation of the relationship between dietary patterns and some chronic noncommunicable diseases has become appealing in nutritional epidemiology. Some studies have reported potential associations between dietary patterns and the risk of chronic obstructive pulmonary disease; however, the results remain conflicting. Thus, we conducted this meta-analysis to pool the results of studies to clarify the associations between dietary patterns and the risk of chronic obstructive pulmonary disease. A literature search of MEDLINE and EBSCO databases was performed to identify relevant studies published from January 1990 up to June 2015. A total of 13 studies met the inclusion criteria and were included in this meta-analysis. The highest category of healthy/prudent dietary patterns when compared with the lowest category was apparently associated with a decreased risk (OR = 0.55; CI: 0.46, 0.66; P < 0.0001). An increase in the risk of chronic obstructive pulmonary disease was shown for the highest compared with the lowest categories of "unhealthy/western-style" dietary patterns (OR = 2.12; CI: 1.64, 2.74; P < (0.0001). The results of this meta-analysis indicate that different dietary pattern may be associated with the risk of chronic obstructive pulmonary disease.

  18. Prophylactic Mesh Application during Colostomy to Prevent Parastomal Hernia: A Meta-Analysis

    PubMed Central

    2016-01-01

    Background. Parastomal hernia is a common complication after stoma formation, especially in permanent colostomy. The present meta-analysis aimed to evaluate the effectiveness of prophylactic mesh application during permanent colostomy for preventing parastomal hernia. Methods. Randomized controlled trials comparing outcomes in patients who underwent colostomy with or without prophylactic mesh application were identified from PubMed, EMBASE, Science Citation Index, and the Cochrane Libraries. Results. This meta-analysis included 8 randomized controlled trials with 522 participants. Our pooled results showed that prophylactic mesh application (mesh group) reduced the incidence of clinically detected parastomal hernia (risk ratio [RR]: 0.22; 95% confidence interval [CI]: 0.13–0.38; P < 0.00001), radiologically detected parastomal hernia (RR: 0.62; 95% CI: 0.47–0.82; P = 0.0008), and surgical repair for herniation (RR: 0.34; 95% CI: 0.14–0.83; P = 0.02) when compared with conventional permanent colostomy formation (control group). The incidence of complications, including wound infection, peristomal infection, mesh infection, stomal necrosis and stenosis, stoma site pain, and fistula, was not higher in the mesh group than in the control group. Conclusions. Our meta-analysis demonstrated that prophylactic mesh application at the time of primary colostomy formation is a promising method for the prevention of parastomal herniation.

  19. Association Between BRCA Status and P53 Status in Breast Cancer: A Meta-Analysis

    PubMed Central

    Peng, Lin; Xu, Tao; Long, Ting; Zuo, Huaiquan

    2016-01-01

    Background Research on BRCA mutation has meaningful clinical implications, such as identifying risk of second primary cancers and risk of hereditary cancers. This study seeks to summarize available data to investigate the association between BRCA status and P53 status by meta-analysis. Material/Methods We searched PubMed, Embase, and Cochrane library databases for relevant studies. Meta-analysis was conducted using STATA software. We summarized odds ratios by fixed-effects or random-effects models. Results This study included a total of 4288 cases from 16 articles, which including 681 BRCA1 mutation carriers (BRCA1Mut), 366 carriers of BRCA2 mutation (BRCA2Mut), and 3241 carriers of normal versions of these genes. BRCA1Mut was significantly associated with P53 over-expression compared with BRCA2Mut (OR 1.851, 95% CI=1.393–2.458) or non-carriers (OR=2.503, 95% CI=1.493–4.198). No difference was found between p53 protein expression in BRCA2 Mut carriers and non-carriers (OR=0.881, 95% CI=0.670–1.158). Conclusions Our meta-analysis suggests that BRCA1Mut breast cancer patients are more likely to have P53 overexpression compared with BRCA2Mut and non-carriers. This information provides valuable information for clinicians who perform related studies in the future. PMID:27272763

  20. Fire-Needle Moxibustion for the Treatment of Knee Osteoarthritis: A Meta-Analysis

    PubMed Central

    Wang, Yidan; Xie, Xiaohua; Zhu, Xiaoyue; Chu, Minjie; Lu, Yihua; Tian, Tian

    2016-01-01

    Objectives. The aim of this study was to evaluate the effectiveness of fire-needle moxibustion as an intervention in the treatment of knee osteoarthritis (KOA). Methods. An updated meta-analysis of randomized controlled trials (RCTs) on fire-needle moxibustion in treating KOA was conducted by searching PubMed, Embase, the Cochrane Library, Web of Science, Wanfang database, and the Chinese Medical Database (CNKI) since their inception through March 2016. The meta-analysis was performed using RevMan 5.3. Results. Thirteen RCTs were identified in the systematic study which consisted of 1179 participants. Fire-needle moxibustion treatment group had a statistical significance on recovery rate as well as recovery and marked-improvement rate compared with control group. Subgroup analysis indicated that there was significant difference between fire-needle moxibustion group and control group. However, GRADE analysis indicated that the quality of evidence for all outcomes was relatively low. Only two of 13 studies reported adverse reactions (difficulty in movement and intolerance of cold). Conclusion. This meta-analysis suggests that fire-needle moxibustion is more effective than control group in symptom management of KOA. Further high quality trials should be conducted to evaluate the effectiveness of fire-needle moxibustion on KOA. PMID:27403195

  1. Altered resting-state functional activity in posttraumatic stress disorder: A quantitative meta-analysis

    PubMed Central

    Wang, Ting; Liu, Jia; Zhang, Junran; Zhan, Wang; Li, Lei; Wu, Min; Huang, Hua; Zhu, Hongyan; Kemp, Graham J.; Gong, Qiyong

    2016-01-01

    Many functional neuroimaging studies have reported differential patterns of spontaneous brain activity in posttraumatic stress disorder (PTSD), but the findings are inconsistent and have not so far been quantitatively reviewed. The present study set out to determine consistent, specific regional brain activity alterations in PTSD, using the Effect Size Signed Differential Mapping technique to conduct a quantitative meta-analysis of resting-state functional neuroimaging studies of PTSD that used either a non-trauma (NTC) or a trauma-exposed (TEC) comparison control group. Fifteen functional neuroimaging studies were included, comparing 286 PTSDs, 203 TECs and 155 NTCs. Compared with NTC, PTSD patients showed hyperactivity in the right anterior insula and bilateral cerebellum, and hypoactivity in the dorsal medial prefrontal cortex (mPFC); compared with TEC, PTSD showed hyperactivity in the ventral mPFC. The pooled meta-analysis showed hypoactivity in the posterior insula, superior temporal, and Heschl’s gyrus in PTSD. Additionally, subgroup meta-analysis (non-medicated subjects vs. NTC) identified abnormal activation in the prefrontal-limbic system. In meta-regression analyses, mean illness duration was positively associated with activity in the right cerebellum (PTSD vs. NTC), and illness severity was negatively associated with activity in the right lingual gyrus (PTSD vs. TEC). PMID:27251865

  2. Association between lutein and zeaxanthin status and the risk of cataract: a meta-analysis.

    PubMed

    Liu, Xiao-Hong; Yu, Rong-Bin; Liu, Rong; Hao, Zhen-Xuan; Han, Cheng-Cheng; Zhu, Zhong-Hai; Ma, Le

    2014-01-22

    The purpose of this meta-analysis was to evaluate the relationship between blood lutein and zeaxanthin concentration and the risk of age-related cataract (ARC). MEDLINE, EMBASE, ISI and Cochrane Library were searched to identify relevant studies up to April 2013. Meta-analysis was conducted to obtain pooled relative risks (RRs) for the highest-versus-lowest categories of blood lutein and zeaxanthin concentrations. One cohort study and seven cross-sectional studies were included in the meta-analysis. There were significant inverse associations between nuclear cataract and blood lutein and zeaxanthin concentrations, with the pooled RRs ranging from 0.63 (95% confidence interval (CI): 0.49, 0.77) for zeaxanthin to 0.73 (95% CI: 0.59, 0.87) for lutein. A stronger association between nuclear cataract and blood zeaxanthin might be noted for the studies conducted in the European Nations. Blood lutein and zeaxanthin were also noted to lead towards a decrease in the risk of cortical cataract and subcapsular cataract; however, these pooled RRs were not statistically significant, with the exception of a marginal association between lutein and subcapsular cataract. Our results suggest that high blood lutein and zeaxanthin are significantly associated with a decrease in the risk of nuclear cataract. However, no significant associations were found for ARC in other regions of the lens.

  3. Long-term prognosis of tooth autotransplantation: a systematic review and meta-analysis.

    PubMed

    Machado, L A; do Nascimento, R R; Ferreira, D M T P; Mattos, C T; Vilella, O V

    2016-05-01

    The aim of this study was to systematically review the prognosis of autotransplanted teeth followed up for a period of 6 years or more. A literature search was conducted in five databases and the eligibility criteria were established. The outcomes evaluated were the survival rate, percentage of abnormal mobility, pulpal conditions, and percentage of root resorption. The searches identified 1848 articles, and after evaluation against the eligibility criteria, six were included. Data related to outcome measures were extracted from the studies and a meta-analysis was performed. Survival rates ranged from 75.3% to 91% and the meta-analysis showed an effect size of 81% (P<0.0001). The percentage ankylosis ranged from 4.2% to 18.2% and the effect size was 4.8% (P<0.0001). Root resorption percentages ranged from 3% to 10% and the effect size was equal to 4% (P<0.0001). It was not possible to perform a meta-analysis of data on pulpal conditions and percentage of teeth with abnormal mobility. The results of this study showed the survival rate to be excellent, considering the observation period. The rates of ankylosis and root resorption, despite their low values, influence the prognosis of transplanted teeth.

  4. Risk of malignancy in ankylosing spondylitis: a systematic review and meta-analysis.

    PubMed

    Deng, Chuiwen; Li, Wenli; Fei, Yunyun; Li, Yongzhe; Zhang, Fengchun

    2016-01-01

    Current knowledge about the overall and site-specific risk of malignancy associated with ankylosing spondylitis (AS) is inconsistent. We conducted a systematic review and meta-analysis to address this knowledge gap. Five databases (PubMed, EMBASE, Web of Science, the Cochrane library and the virtual health library) were systematically searched. A manual search of publications within the last 2 years in key journals in the field (Annals of the Rheumatic Diseases, Rheumatology and Arthritis &rheumatology) was also performed. STATA 11.2 software was used to conduct the meta-analysis. After screening, twenty-three studies, of different designs, were eligible for meta-analysis. AS is associated with a 14% (pooled RR 1.14; 95% CI 1.03-1.25) increase in the overall risk for malignancy. Compared to controls, patients with AS are at a specific increased risk for malignancy of the digestive system (pooled RR 1.20; 95% CI 1.01 to 1.42), multiple myelomas (pooled RR 1.92; 95% CI 1.37 to 3.69) and lymphomas (pooled RR 1.32; 95% CI 1.11 to 1.57). On subgroup analysis, evidence from high quality cohort studies indicated that AS patients from Asia are at highest risk for malignancy overall. Confirmation of findings from large-scale longitudinal studies is needed to identify specific risk factors and to evaluate treatment effects. PMID:27534810

  5. Chlorination, chlorination by-products, and cancer: a meta-analysis.

    PubMed Central

    Morris, R D; Audet, A M; Angelillo, I F; Chalmers, T C; Mosteller, F

    1992-01-01

    OBJECTIVES. Individual epidemiological investigations into the association between chlorination by-products in drinking water and cancer have been suggestive but inconclusive. Enough studies exist to provide the basis for a meaningful meta-analysis. METHODS. An extensive literature search was performed to identify pertinent case-control studies and cohort studies. Consumption of chlorinated water, surface water, or water with high levels of chloroform was used as a surrogate for exposure to chlorination by-products. Relative risk estimates were abstracted from the individual studies and pooled. RESULTS. A simple meta-analysis of all cancer sites yielded a relative risk estimate for exposure to chlorination by-products of 1.15 (95% CI: 1.09, 1.20). Pooled relative risk estimates for organ-specific neoplasms were 1.21 (95% CI: 1.09, 1.34) for bladder cancer and 1.38 (95% CI: 1.01, 1.87) for rectal cancer. When studies that adjusted for potential confounders were pooled separately, estimates of relative risks did not change substantially. CONCLUSIONS. The results of this meta-analysis suggest a positive association between consumption of chlorination by-products in drinking water and bladder and rectal cancer in humans. PMID:1535181

  6. Milk, yogurt, and lactose intake and ovarian cancer risk: a meta-analysis.

    PubMed

    Liu, Jing; Tang, Wenru; Sang, Lei; Dai, Xiaoli; Wei, Danping; Luo, Ying; Zhang, Jihong

    2015-01-01

    Inconclusive information for the role of dairy food intake in relation to ovarian cancer risk may associate with adverse effects of lactose, which has been hypothesized to increase gonadotropin levels in animal models and ecological studies. Up to now, several studies have indicated the association between dairy food intake and risk of ovarian cancer, but no identified founding was reported. We performed this meta-analysis to derive a more precise estimation of the association between dairy food intake and ovarian cancer risk. Using the data from 19 available publications, we examined dairy food including low-fat/skim milk, whole milk, yogurt and lactose in relation to risk of ovarian cancer by meta-analysis. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to assess the association. We observed a slightly increased risk of ovarian cancer with high intake of whole milk, but has no statistical significance (OR = 1.228, 95% CI = 1.031-1.464, P = 0.022). The results of other milk models did not provide evidence of positive association with ovarian cancer risk. This meta-analysis suggests that low-fat/skim milk, whole milk, yogurt and lactose intake has no associated with increased risk of ovarian cancer. Further studies with larger participants worldwide are needed to validate the association between dairy food intake and ovarian cancer.

  7. Interleukin-18 promoter polymorphism and asthma risk: a meta-analysis.

    PubMed

    Ma, Ying; Zhang, Bo; Tang, Ren-Kuan; Liu, Yun; Peng, Guo-Guang

    2012-02-01

    Some studies have shown that IL-18 was associated with aetiology and progression of asthma. However, the association between single-nucleotide polymorphisms -607C/A (rs1946518) and -137G/C (rs187238) located in the IL-18 gene promoter and asthma risk was still controversial and ambiguous. To derive a more precise effect on the association between these polymorphisms and asthma risk, we performed a meta-analysis based on the currently available evidence of the literature. A total of 5 studies with 1411 cases and 1525 controls for -607C/A polymorphism and 5 studies with 1883 cases and 6645 controls for -137G/C polymorphism were identified to perform a meta-analysis, up to October 2010. Summary ORs and corresponding 95% CIs for IL-18 polymorphisms and asthma were estimated using fixed- and random-effects models when appropriate. Heterogeneity and publication bias were evaluated. We found that individuals carrying AC/CC genotype of -607C/A polymorphism were associated with an increased asthma risk in recessive model (OR = 1.278; 95% CI, 1.073-1.522). However, no significant association was observed between -137G/C polymorphism and asthma risk under different contrast models. There was no evidence of publication bias. The present meta-analysis suggested that IL-18 -607C/A polymorphism in promoter region was associated with asthma risk. PMID:21611751

  8. Quality and severity of depression in borderline personality disorder: A systematic review and meta-analysis.

    PubMed

    Köhling, Johanna; Ehrenthal, Johannes C; Levy, Kenneth N; Schauenburg, Henning; Dinger, Ulrike

    2015-04-01

    Depression in borderline personality disorder (BPD) is hypothesized to be distinct in quality and severity. This paper provides a systematic review of depression quality, and a meta-analysis of depression severity in BPD patients compared to those with depressive disorders (DeDs) only. Based on a systematic literature search, 26 studies were identified for systematic review and 35 studies (3425 participants) were included for meta-analysis. The review focused on different forms of depressive symptoms, affective impairment, self-evaluation, and negative interpersonal experiences. The meta-analysis examined age, gender, presence of comorbid DeDs in BPD patients, and type of depression scale as moderators of effect sizes. Findings indicate that depression quality in BPD is characterized by higher anger/hostility and self-criticism. There was no significant difference in depression severity between BPD and DeD groups, and a high level of heterogeneity. Moderator analyses revealed lower depression severity in BPD patients without comorbid DeDs, but higher severity in BPD patients with comorbid DeDs compared to depressed controls. Our results suggest high variability in depression severity across BPD patients, point toward the consideration of comorbid DeDs, and lend partial support to a BPD-specific depression quality. We discuss difficulties in research on depression in BPD, and offer directions for future studies. PMID:25723972

  9. Association of T174M polymorphism of angiotensinogen gene with essential hypertension: A meta-analysis.

    PubMed

    Liao, Xiaoyang; Yang, Zhiyi; Peng, Daqing; Dai, Hua; Lei, Yi; Zhao, Qian; Han, Yanbing; Wang, Weiwen

    2014-09-01

    The association between T174M polymorphism of angiotensinogen gene and essential hypertension risk remains controversial. We herein performed a meta-analysis to achieve a reliable estimation of their relationship. All the studies published up to May 2013 on the association between T174M polymorphism and essential hypertension risk were identified by searching the electronic repositories PubMed, MEDLINE and EMBASE, Springer, Elsevier Science Direct, Cochrane Library and Google Scholar. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Ultimately, nine eligible studies, including 2188 essential hypertension cases and 2459 controls, were enrolled in this meta-analysis. No significant associations were found under the overall ORs for M-allele comparison (M vs. T, pooled OR 0.92, 95% CI 0.62-1.37), MM vs. TT (pooled OR 0.86, 95% CI 0.29-2.51), TM vs. TT n (pooled OR 0.91, 95% CI 0.63-1.32), recessive model (MM vs. TT+TM, pooled OR 0.89, 95% CI 0.35-2.30), dominant model (MM+TM vs. TT, pooled OR 0.91, 95% CI 0.60-1.38) between T174M polymorphism and risk for essential hypertension. This meta-analysis suggested that the T174M polymorphism of the angiotensinogen gene might not be associated with the susceptibility of essential hypertension in Asian or European populations.

  10. Green tea, black tea consumption and risk of lung cancer: a meta-analysis.

    PubMed

    Tang, Naping; Wu, Yuemin; Zhou, Bo; Wang, Bin; Yu, Rongbin

    2009-09-01

    Studies investigating the association of green tea and black tea consumption with lung cancer risk have reported inconsistent findings. To provide a quantitative assessment of this association, we conducted a meta-analysis on the topic. Studies were identified by a literature search in PubMed from 1966 to November 2008 and by searching the reference lists of relevant studies. Summary relative risk (RR) estimates and their corresponding 95% confidence intervals (CIs) were calculated based on random-effects model. Our meta-analysis included 22 studies provided data on consumption of green tea or black tea, or both related to lung cancer risk. For green tea, the summary RR indicated a borderline significant association between highest green tea consumption and reduced risk of lung cancer (RR=0.78, 95% CI=0.61-1.00). Furthermore, an increase in green tea consumption of two cups/day was associated with an 18% decreased risk of developing lung cancer (RR=0.82, 95% CI=0.71-0.96). For black tea, no statistically significant association was observe through the meta-analysis (highest versus non/lowest, RR=0.86, 95% CI=0.70-1.05; an increment of two cups/day, RR=0.82, 95% CI=0.65-1.03). In conclusion, our data suggest that high or an increase in consumption of green tea but not black tea may be related to the reduction of lung cancer risk.

  11. Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis.

    PubMed

    Marconi, Arianna; Di Forti, Marta; Lewis, Cathryn M; Murray, Robin M; Vassos, Evangelos

    2016-09-01

    Cannabis use has been reported to induce long-lasting psychotic disorders and a dose-response relationship has been observed. We performed a systematic review of studies that investigate the association between the degree of cannabis consumption and psychosis and a meta-analysis to quantify the magnitude of effect. Published studies were identified through search of electronic databases, supplemented by manual searches of bibliographies. Studies were considered if they provided data on cannabis consumption prior to the onset of psychosis using a dose criterion (frequency/amount used) and reported psychosis-related outcomes. We performed random effects meta-analysis of individual data points generated with a simulation method from the summary data of the original studies. From 571 references, 18 studies fulfilled inclusion criteria for the systematic review and 10 were inserted in the meta-analysis, enrolling a total of 66 816 individuals. Higher levels of cannabis use were associated with increased risk for psychosis in all the included studies. A logistic regression model gave an OR of 3.90 (95% CI 2.84 to 5.34) for the risk of schizophrenia and other psychosis-related outcomes among the heaviest cannabis users compared to the nonusers. Current evidence shows that high levels of cannabis use increase the risk of psychotic outcomes and confirms a dose-response relationship between the level of use and the risk for psychosis. Although a causal link cannot be unequivocally established, there is sufficient evidence to justify harm reduction prevention programs.

  12. Alcohol use and antiretroviral adherence: Review and meta-analysis

    PubMed Central

    Hendershot, Christian S.; Stoner, Susan A.; Pantalone, David W.; Simoni, Jane M.

    2009-01-01

    Background Alcohol use is frequently implicated as a factor in nonadherence to highly active antiretroviral therapy (HAART). There have not been efforts to systematically evaluate findings across studies. This meta-analysis provides a quantitative evaluation of the alcohol-adherence association by aggregating findings across studies and examining potential moderators. Methods Literature searches identified 40 qualifying studies totaling over 25,000 participants. Studies were coded on several methodological variables. Results In the combined analysis, alcohol drinkers were approximately 50–60% as likely to be classified as adherent [OR = 0.548, 95% CI: 0.490–0.612] compared to abstainers (or those who drank relatively less). Effect sizes for problem drinking, defined as meeting the National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria for at-risk drinking or criteria for an alcohol use disorder, were greater [OR = 0.474, 95% CI = 0.408–0.550] than those reflecting any or global drinking [OR = 0.604, 95% CI = 0.531–0.687]. Several variables moderated the alcohol-adherence association. Conclusions Results support a significant and reliable association of alcohol use and medication nonadherence. Methodological variables appear to moderate this association and could contribute to inconsistencies across studies. Future research would benefit from efforts to characterize theoretical mechanisms as well as mediators and moderators of the alcohol-adherence association. PMID:19668086

  13. Quality of life in eating disorders: a meta-analysis.

    PubMed

    Winkler, Laura Al-Dakhiel; Christiansen, Erik; Lichtenstein, Mia Beck; Hansen, Nina Beck; Bilenberg, Niels; Støving, René Klinkby

    2014-09-30

    Eating disorders (EDs) comprise a variety of symptoms and have a profound impact on everyday life. They are associated with high morbidity and mortality. The objective of this study was to analyse published data on health-related quality of life (HRQoL) in EDs so as to compare the results to general population norm data and to investigate potential differences between ED diagnostic groups. A systematic review of the current literature was conducted using a keyword-based search in PubMed and PsychInfo. The search covered anorexia nervosa (AN), bulimia nervosa (BN), eating disorders not otherwise specified (EDNOS) and binge eating disorder (BED) and used the Medical Outcomes Study Short Form-36 Health Survey (SF-36) as a measure of HRQoL. Of the 102 citations identified, 85 abstracts were reviewed and seven studies were included in the meta-analysis. AN patients were included in five studies (n=227), BN in four studies (n=216), EDNOS in two studies (n=166) and BED in four studies (n=148). We tested for between-study variation and significant differences between the diagnostic groups. The results confirmed a significantly lower level of HRQoL in all EDs compared to a population mean. It was not possible to establish any differences between the diagnostic groups.

  14. Reward, punishment, and cooperation: a meta-analysis.

    PubMed

    Balliet, Daniel; Mulder, Laetitia B; Van Lange, Paul A M

    2011-07-01

    How effective are rewards (for cooperation) and punishment (for noncooperation) as tools to promote cooperation in social dilemmas or situations when immediate self-interest and longer term collective interest conflict? What variables can promote the impact of these incentives? Although such questions have been examined, social and behavioral scientists provide different answers. To date, there is no theoretical and/or quantitative review of rewards and punishments as incentives for cooperation in social dilemmas. Using a novel interdependence-theoretic framework, we propose that rewards and punishments should both promote cooperation, and we identify 2 variables—cost of incentives and source of incentives—that are predicted to magnify the effectiveness of these incentives in promoting cooperation.A meta-analysis involving 187 effect sizes revealed that rewards and punishments exhibited a statistically equivalent positive effect on cooperation (d =0.51 and 0.70, respectively). The effectiveness of incentives was stronger when the incentives were costly to administer, compared to free. Centralization of incentives did not moderate the effect size. Punishments were also more effective during iterated dilemmas when participants continued to interact in the same group, compared to both (a) iterated dilemmas with reassignment to a new group after each trial and (b) one-shot dilemmas. We also examine several other potential moderators, such as iterations, partner matching, group size, country, and participant payment. We discuss broad conclusions, consider implications for theory, and suggest directions for future research on rewards and punishment in social dilemmas.

  15. Meta-Analysis of the Prevalence of Unacknowledged Rape.

    PubMed

    Wilson, Laura C; Miller, Katherine E

    2016-04-01

    Many sexual violence survivors do not label their experiences as rape but instead use more benign labels, such as "bad sex" or "miscommunication." A meta-analysis was conducted to estimate the mean prevalence of unacknowledged rape and to inform our understanding of methodological factors that influence the detection of this phenomenon. Studies were identified using PsycINFO, PubMED, and PILOTS and were required to report the percentage of unacknowledged rape that had occurred since the age of 14 among female survivors. Moderator variables included mean participant age, recruitment source, rape definition, and unacknowledged rape definition. Twenty-eight studies (30 independent samples) containing 5,917 female rape survivors met the inclusion criteria. Based on a random effects model, the overall weighted mean percentage of unacknowledged rape was 60.4% (95% confidence interval [55.0%, 65.6%]). There was a large amount of heterogeneity, Q(29) = 445.11, p < .001, and inconsistency (I(2) = 93.5%) among included studies. The prevalence was significantly higher among college student participants compared to noncollege participants. The findings supported that over half of all female rape survivors do not acknowledge that they have been raped. The results suggest that screening tools should use behaviorally descriptive items about sexual contact, rather than using terms such as "rape." PMID:25784571

  16. Reward, punishment, and cooperation: a meta-analysis.

    PubMed

    Balliet, Daniel; Mulder, Laetitia B; Van Lange, Paul A M

    2011-07-01

    How effective are rewards (for cooperation) and punishment (for noncooperation) as tools to promote cooperation in social dilemmas or situations when immediate self-interest and longer term collective interest conflict? What variables can promote the impact of these incentives? Although such questions have been examined, social and behavioral scientists provide different answers. To date, there is no theoretical and/or quantitative review of rewards and punishments as incentives for cooperation in social dilemmas. Using a novel interdependence-theoretic framework, we propose that rewards and punishments should both promote cooperation, and we identify 2 variables—cost of incentives and source of incentives—that are predicted to magnify the effectiveness of these incentives in promoting cooperation.A meta-analysis involving 187 effect sizes revealed that rewards and punishments exhibited a statistically equivalent positive effect on cooperation (d =0.51 and 0.70, respectively). The effectiveness of incentives was stronger when the incentives were costly to administer, compared to free. Centralization of incentives did not moderate the effect size. Punishments were also more effective during iterated dilemmas when participants continued to interact in the same group, compared to both (a) iterated dilemmas with reassignment to a new group after each trial and (b) one-shot dilemmas. We also examine several other potential moderators, such as iterations, partner matching, group size, country, and participant payment. We discuss broad conclusions, consider implications for theory, and suggest directions for future research on rewards and punishment in social dilemmas. PMID:21574679

  17. Association between Arsenic Exposure and Diabetes: A Meta-Analysis

    PubMed Central

    Sung, Tzu-Ching; Huang, Jhih-Wei; Guo, How-Ran

    2015-01-01

    Studies on the association between arsenic exposure and diabetes mellitus (DM) yielded inconsistent results. Epidemiologic data on the associations between arsenic exposures via inhalation and DM are limited. Therefore, we conducted a meta-analysis to evaluate the risk of DM associated with arsenic exposure. We searched the related literature through a systematic approach and analyzed the data according to the exposure route (inhalation and ingestion). We used random-effect models to estimate the summary relative risks (RRs) for DM associated with arsenic exposure and used I2 statistics to assess the heterogeneity of studies. We identified 38 relevant studies, of which the 32 on the ingestion route showed a significant association between arsenic exposure and DM (RR = 1.57; 95% CI 1.27–1.93). Focusing on the 24 studies in which the diagnosis of DM was confirmed using laboratory tests or medical records, we found that the summary RR was 1.71 (95% CI 1.32–2.23), very close to the overall estimates. We concluded that ingested arsenic is associated with the development of DM, but the heterogeneity among the studies may affect the results. PMID:26000288

  18. The psychological effects of meditation: a meta-analysis.

    PubMed

    Sedlmeier, Peter; Eberth, Juliane; Schwarz, Marcus; Zimmermann, Doreen; Haarig, Frederik; Jaeger, Sonia; Kunze, Sonja

    2012-11-01

    In this meta-analysis, we give a comprehensive overview of the effects of meditation on psychological variables that can be extracted from empirical studies, concentrating on the effects of meditation on nonclinical groups of adult meditators. Mostly because of methodological problems, almost ¾ of an initially identified 595 studies had to be excluded. Most studies appear to have been conducted without sufficient theoretical background. To put the results into perspective, we briefly summarize the major theoretical approaches from both East and West. The 163 studies that allowed the calculation of effect sizes exhibited medium average effects (r = .28 for all studies and r = .27 for the n = 125 studies from reviewed journals), which cannot be explained by mere relaxation or cognitive restructuring effects. In general, results were strongest (medium to large) for changes in emotionality and relationship issues, less strong (about medium) for measures of attention, and weakest (small to medium) for more cognitive measures. However, specific findings varied across different approaches to meditation (transcendental meditation, mindfulness meditation, and other meditation techniques). Surprisingly, meditation experience only partially covaried with long-term impact on the variables examined. In general, the dependent variables used cover only some of the content areas about which predictions can be made from already existing theories about meditation; still, such predictions lack precision at present. We conclude that to arrive at a comprehensive understanding of why and how meditation works, emphasis should be placed on the development of more precise theories and measurement devices.

  19. Meta-Analysis of the First Facial Expression Recognition Challenge.

    PubMed

    Valstar, M F; Mehu, M; Bihan Jiang; Pantic, M; Scherer, K

    2012-08-01

    Automatic facial expression recognition has been an active topic in computer science for over two decades, in particular facial action coding system action unit (AU) detection and classification of a number of discrete emotion states from facial expressive imagery. Standardization and comparability have received some attention; for instance, there exist a number of commonly used facial expression databases. However, lack of a commonly accepted evaluation protocol and, typically, lack of sufficient details needed to reproduce the reported individual results make it difficult to compare systems. This, in turn, hinders the progress of the field. A periodical challenge in facial expression recognition would allow such a comparison on a level playing field. It would provide an insight on how far the field has come and would allow researchers to identify new goals, challenges, and targets. This paper presents a meta-analysis of the first such challenge in automatic recognition of facial expressions, held during the IEEE conference on Face and Gesture Recognition 2011. It details the challenge data, evaluation protocol, and the results attained in two subchallenges: AU detection and classification of facial expression imagery in terms of a number of discrete emotion categories. We also summarize the lessons learned and reflect on the future of the field of facial expression recognition in general and on possible future challenges in particular.

  20. Independent Replication and Meta-Analysis for Endometriosis Risk Loci.

    PubMed

    Sapkota, Yadav; Fassbender, Amelie; Bowdler, Lisa; Fung, Jenny N; Peterse, Daniëlle; O, Dorien; Montgomery, Grant W; Nyholt, Dale R; D'Hooghe, Thomas M

    2015-10-01

    Endometriosis is a complex disease that affects 6-10% of women in their reproductive years and 20-50% of women with infertility. Genome-wide and candidate-gene association studies for endometriosis have identified 10 independent risk loci, and of these, nine (rs7521902, rs13394619, rs4141819, rs6542095, rs1519761, rs7739264, rs12700667, rs1537377, and rs10859871) are polymorphic in European populations. Here we investigate the replication of nine SNP loci in 998 laparoscopically and histologically confirmed endometriosis cases and 783 disease-free controls from Belgium. SNPs rs7521902, rs13394619, and rs6542095 show nominally significant (p < .05) associations with endometriosis, while the directions of effect for seven SNPs are consistent with the original reports. Association of rs6542095 at the IL1A locus with 'All' (p = .066) and 'Grade_B' (p = .01) endometriosis is noteworthy because this is the first successful replication in an independent population. Meta-analysis with the published results yields genome-wide significant evidence for rs7521902, rs13394619, rs6542095, rs12700667, rs7739264, and rs1537377. Notably, three coding variants in GREB1 (near rs13394619) and CDKN2B-AS1 (near rs1537377) also showed nominally significant associations with endometriosis. Overall, this study provides important replication in a uniquely characterized independent population, and indicates that the majority of the original genome-wide association findings are not due to chance alone.

  1. Orthokeratology to Control Myopia Progression: A Meta-Analysis

    PubMed Central

    Zhang, Ting; Liu, Manli; Wang, Danyang; Chen, Yile; Liu, Quan

    2015-01-01

    Objective To evaluate the clinical treatment effects of orthokeratology to slow the progression of myopia. Methods Several well-designed controlled studies have investigated the effects of orthokeratology in school-aged children. We conducted this meta-analysis to better evaluate the existing evidence. Relevant studies were identified in the Medline and Embase database without language limitations. The main outcomes included axial length and vitreous chamber depth reported as the mean ± standard deviation. The results were pooled and assessed with a fixed-effects model analysis. Subgroup analyses were performed according to geographical location and study design. Results Of the seven eligible studies, all reported axial length changes after 2 years, while two studies reported vitreous chamber depth changes. The pooled estimates indicated that change in axial length in the ortho-k group was 0.27 mm (95% confidence interval [CI]: 0.22, 0.32) less than the control group. Myopic progression was reduced by approximately 45%. The combined results revealed that the difference in vitreous chamber depth between the two groups was 0.22 mm (95% confidence interval [CI]: 0.14, 0.31). None of the studies reported severe adverse events. Conclusion The overall findings suggest that ortho-k can slow myopia progression in school-aged children. PMID:25855979

  2. Meta-Analysis of the Prevalence of Unacknowledged Rape.

    PubMed

    Wilson, Laura C; Miller, Katherine E

    2016-04-01

    Many sexual violence survivors do not label their experiences as rape but instead use more benign labels, such as "bad sex" or "miscommunication." A meta-analysis was conducted to estimate the mean prevalence of unacknowledged rape and to inform our understanding of methodological factors that influence the detection of this phenomenon. Studies were identified using PsycINFO, PubMED, and PILOTS and were required to report the percentage of unacknowledged rape that had occurred since the age of 14 among female survivors. Moderator variables included mean participant age, recruitment source, rape definition, and unacknowledged rape definition. Twenty-eight studies (30 independent samples) containing 5,917 female rape survivors met the inclusion criteria. Based on a random effects model, the overall weighted mean percentage of unacknowledged rape was 60.4% (95% confidence interval [55.0%, 65.6%]). There was a large amount of heterogeneity, Q(29) = 445.11, p < .001, and inconsistency (I(2) = 93.5%) among included studies. The prevalence was significantly higher among college student participants compared to noncollege participants. The findings supported that over half of all female rape survivors do not acknowledge that they have been raped. The results suggest that screening tools should use behaviorally descriptive items about sexual contact, rather than using terms such as "rape."

  3. Meta-analysis of nitrogen removal in riparian buffers.

    PubMed

    Mayer, Paul M; Reynolds, Steven K; McCutchen, Marshall D; Canfield, Timothy J

    2007-01-01

    Riparian buffers, the vegetated region adjacent to streams and wetlands, are thought to be effective at intercepting and reducing nitrogen loads entering water bodies. Riparian buffer width is thought to be positively related to nitrogen removal effectiveness by influencing nitrogen retention or removal. We surveyed the scientific literature containing data on riparian buffers and nitrogen concentration in streams and groundwater to identify trends between nitrogen removal effectiveness and buffer width, hydrological flow path, and vegetative cover. Nitrogen removal effectiveness varied widely. Wide buffers (>50 m) more consistently removed significant portions of nitrogen entering a riparian zone than narrow buffers (0-25 m). Buffers of various vegetation types were equally effective at removing nitrogen but buffers composed of herbaceous and forest/herbaceous vegetation were more effective when wider. Subsurface removal of nitrogen was efficient, but did not appear to be related to buffer width, while surface removal of nitrogen was partly related to buffer width. The mass of nitrate nitrogen removed per unit length of buffer did not differ by buffer width, flow path, or buffer vegetation type. Our meta-analysis suggests that buffer width is an important consideration in managing nitrogen in watersheds. However, the inconsistent effects of buffer width and vegetation on nitrogen removal suggest that soil type, subsurface hydrology (e.g., soil saturation, groundwater flow paths), and subsurface biogeochemistry (organic carbon supply, nitrate inputs) also are important factors governing nitrogen removal in buffers.

  4. Association between susceptibility to rheumatoid arthritis and PADI4 polymorphisms: a meta-analysis.

    PubMed

    Lee, Young Ho; Bae, Sang-Cheol

    2016-04-01

    The objective of the study was to determine by meta-analysis whether polymorphisms of the gene encoding peptidylarginine deiminase 4 (PADI4) are associated with susceptibility to rheumatoid arthritis (RA). A literature review was conducted to identify data sets that described analyses of genetic association between PADI4 polymorphisms and RA. Data sets were collated and a meta-analysis was performed, with a specific focus on associations within Caucasian and Asian populations. A total of 15,947 RA cases and 22,696 controls that were taken from 28 studies in 24 papers were included in this study. Meta-analysis showed a significant association between allele 2 of the PADI4_94 polymorphism and RA in the overall population (odds ratio [OR] = 1.155, 95 % confidence interval [CI] = 1.069-1.249, p = 2.7 × 10(-5)). Stratification by ethnicity revealed an association between PADI4_94 allele 2 and RA in Asians (OR = 1.273, 95 % CI = 1.193-1.359, p < 1.0 × 10(-9)), but not in Caucasians (OR = 1.024, 95 % CI = 0.973-1.078, p = 0.358). However, meta-analysis using homozygote contrast showed an association between PADI4_94 allele 2 and RA in both Asians (OR = 2.311, 95 % CI = 1.1.858-2.875, p < 1.0 × 10(-9)) and Caucasians (OR = 1.523, 95 % CI = 1.157-2.004, p = 0.008). Meta-analysis also revealed an association between allele 2 of the PADI4_104 polymorphism and RA in both Asians (OR = 1.547, 95 % CI = 1.247-1.919, p = 7.1 × 10(-6)) and Caucasians (OR = 1.096, 95 % CI = 1.025-1.172, p = 0.008). Finally, meta-analysis showed an association between allele 2 of the PADI4_92 polymorphism and RA in Asians (OR = 1.263, 95 % CI = 1.153-1.384, p = 5.8 × 10(-8)), but not in Caucasians (OR = 1.123, 95 % CI = 0.980-1.287, p = 0.095). Meta-analysis indicated no association between allele 2 of either the PADI4_90 or PADI4_89 polymorphisms and RA in

  5. Association between susceptibility to rheumatoid arthritis and PADI4 polymorphisms: a meta-analysis.

    PubMed

    Lee, Young Ho; Bae, Sang-Cheol

    2016-04-01

    The objective of the study was to determine by meta-analysis whether polymorphisms of the gene encoding peptidylarginine deiminase 4 (PADI4) are associated with susceptibility to rheumatoid arthritis (RA). A literature review was conducted to identify data sets that described analyses of genetic association between PADI4 polymorphisms and RA. Data sets were collated and a meta-analysis was performed, with a specific focus on associations within Caucasian and Asian populations. A total of 15,947 RA cases and 22,696 controls that were taken from 28 studies in 24 papers were included in this study. Meta-analysis showed a significant association between allele 2 of the PADI4_94 polymorphism and RA in the overall population (odds ratio [OR] = 1.155, 95 % confidence interval [CI] = 1.069-1.249, p = 2.7 × 10(-5)). Stratification by ethnicity revealed an association between PADI4_94 allele 2 and RA in Asians (OR = 1.273, 95 % CI = 1.193-1.359, p < 1.0 × 10(-9)), but not in Caucasians (OR = 1.024, 95 % CI = 0.973-1.078, p = 0.358). However, meta-analysis using homozygote contrast showed an association between PADI4_94 allele 2 and RA in both Asians (OR = 2.311, 95 % CI = 1.1.858-2.875, p < 1.0 × 10(-9)) and Caucasians (OR = 1.523, 95 % CI = 1.157-2.004, p = 0.008). Meta-analysis also revealed an association between allele 2 of the PADI4_104 polymorphism and RA in both Asians (OR = 1.547, 95 % CI = 1.247-1.919, p = 7.1 × 10(-6)) and Caucasians (OR = 1.096, 95 % CI = 1.025-1.172, p = 0.008). Finally, meta-analysis showed an association between allele 2 of the PADI4_92 polymorphism and RA in Asians (OR = 1.263, 95 % CI = 1.153-1.384, p = 5.8 × 10(-8)), but not in Caucasians (OR = 1.123, 95 % CI = 0.980-1.287, p = 0.095). Meta-analysis indicated no association between allele 2 of either the PADI4_90 or PADI4_89 polymorphisms and RA in

  6. Goodness-of-fit test for meta-analysis

    NASA Astrophysics Data System (ADS)

    Chen, Zhongxue; Zhang, Guoyi; Li, Jing

    2015-11-01

    Meta-analysis is a very useful tool to combine information from different sources. Fixed effect and random effect models are widely used in meta-analysis. Despite their popularity, they may give us misleading results if the models don’t fit the data but are blindly used. Therefore, like any statistical analysis, checking the model fitting is an important step. However, in practice, the goodness-of-fit in meta-analysis is rarely discussed. In this paper, we propose some tests to check the goodness-of-fit for the fixed and random effect models with assumption of normal distributions in meta-analysis. Through simulation study, we show that the proposed tests control type I error rate very well. To demonstrate the usefulness of the proposed tests, we also apply them to some real data sets. Our study shows that the proposed tests are useful tools in checking the goodness-of-fit of the normal models used in meta-analysis.

  7. Methods for the joint meta-analysis of multiple tests.

    PubMed

    Trikalinos, Thomas A; Hoaglin, David C; Small, Kevin M; Terrin, Norma; Schmid, Christopher H

    2014-12-01

    Existing methods for meta-analysis of diagnostic test accuracy focus primarily on a single index test. We propose models for the joint meta-analysis of studies comparing multiple index tests on the same participants in paired designs. These models respect the grouping of data by studies, account for the within-study correlation between the tests' true-positive rates (TPRs) and between their false-positive rates (FPRs) (induced because tests are applied to the same participants), and allow for between-study correlations between TPRs and FPRs (such as those induced by threshold effects). We estimate models in the Bayesian setting. We demonstrate using a meta-analysis of screening for Down syndrome with two tests: shortened humerus (arm bone), and shortened femur (thigh bone). Separate and joint meta-analyses yielded similar TPR and FPR estimates. For example, the summary TPR for a shortened humerus was 35.3% (95% credible interval (CrI): 26.9, 41.8%) versus 37.9% (27.7, 50.3%) with joint versus separate meta-analysis. Joint meta-analysis is more efficient when calculating comparative accuracy: the difference in the summary TPRs was 0.0% (-8.9, 9.5%; TPR higher for shortened humerus) with joint versus 2.6% (-14.7, 19.8%) with separate meta-analyses. Simulation and empirical analyses are needed to refine the role of the proposed methodology.

  8. Network meta-analysis of survival data with fractional polynomials

    PubMed Central

    2011-01-01

    Background Pairwise meta-analysis, indirect treatment comparisons and network meta-analysis for aggregate level survival data are often based on the reported hazard ratio, which relies on the proportional hazards assumption. This assumption is implausible when hazard functions intersect, and can have a huge impact on decisions based on comparisons of expected survival, such as cost-effectiveness analysis. Methods As an alternative to network meta-analysis of survival data in which the treatment effect is represented by the constant hazard ratio, a multi-dimensional treatment effect approach is presented. With fractional polynomials the hazard functions of interventions compared in a randomized controlled trial are modeled, and the difference between the parameters of these fractional polynomials within a trial are synthesized (and indirectly compared) across studies. Results The proposed models are illustrated with an analysis of survival data in non-small-cell lung cancer. Fixed and random effects first and second order fractional polynomials were evaluated. Conclusion (Network) meta-analysis of survival data with models where the treatment effect is represented with several parameters using fractional polynomials can be more closely fitted to the available data than meta-analysis based on the constant hazard ratio. PMID:21548941

  9. Cortisol levels and suicidal behavior: A meta-analysis.

    PubMed

    O'Connor, Daryl B; Ferguson, Eamonn; Green, Jessica A; O'Carroll, Ronan E; O'Connor, Rory C

    2016-01-01

    Suicide is a major cause of death worldwide, responsible for 1.5% of all mortality. The causes of suicidal behavior are not fully understood. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, is one potential risk factor. This meta-analytic review aimed (i) to estimate the strength and variability of the association between naturally fluctuating cortisol levels and suicidal behavior and (ii) to identify moderators of this relationship. A systematic literature search identified 27 studies (N=2226; 779 suicide attempters and 1447 non-attempters) that met the study eligibility criteria from a total of 417 unique records initially examined. Estimates of effect sizes (r) obtained from these studies were analysed using Comprehensive Meta-Analysis. In these analyses, we compared participants identified as having a past history of suicide attempt(s) to those with no such history. Study quality, mean age of sample and percentage of male participants were examined as potential moderators. Overall, there was no significant effect of suicide group on cortisol. However, significant associations between cortisol and suicide attempts were observed as a function of age. In studies where the mean age of the sample was below 40 years the association was positive (i.e., higher cortisol was associated with suicide attempts; r=.234, p<.001), and where the mean age was 40 or above the association was negative (i.e., lower cortisol was associated with suicide attempts; r=-.129, p<.001). These findings confirm that HPA axis activity, as indicated by age-dependent variations in cortisol levels, is associated with suicidal behavior. The challenge for theory and clinical practice is to explain the complete reversal of the association with age and to identify its clinical implications.

  10. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

    PubMed

    Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A; Barnes, Michael R; Li, Xiaohui; Warren, Helen R; Chasman, Daniel I; Zhou, Kaixin; Arsenault, Benoit J; Donnelly, Louise A; Wiggins, Kerri L; Avery, Christy L; Griffin, Paula; Feng, QiPing; Taylor, Kent D; Li, Guo; Evans, Daniel S; Smith, Albert V; de Keyser, Catherine E; Johnson, Andrew D; de Craen, Anton J M; Stott, David J; Buckley, Brendan M; Ford, Ian; Westendorp, Rudi G J; Slagboom, P Eline; Sattar, Naveed; Munroe, Patricia B; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C; O'Brien, Eoin; Shaw-Hawkins, Sue; Chen, Y-D Ida; Nickerson, Deborah A; Smith, Joshua D; Dubé, Marie Pierre; Boekholdt, S Matthijs; Hovingh, G Kees; Kastelein, John J P; McKeigue, Paul M; Betteridge, John; Neil, Andrew; Durrington, Paul N; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C; Rice, Kenneth; Smith, Nicholas L; Lumley, Thomas; Whitsel, Eric A; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S; O'Donnell, Christopher J; Vasan, Ramachandran S; Wei, Wei-Qi; Wilke, Russell A; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M; Stafford, Jeanette M; Ding, Jingzhong; Herrington, David M; Kritchevsky, Stephen B; Eiriksdottir, Gudny; Launer, Leonore J; Harris, Tamara B; Chu, Audrey Y; Giulianini, Franco; MacFadyen, Jean G; Barratt, Bryan J; Nyberg, Fredrik; Stricker, Bruno H; Uitterlinden, André G; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H; Ridker, Paul M; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C; Ballantyne, Christie M; Rotter, Jerome I; Adrienne Cupples, L; Psaty, Bruce M; Palmer, Colin N A; Tardif, Jean-Claude; Colhoun, Helen M; Hitman, Graham; Krauss, Ronald M; Wouter Jukema, J; Caulfield, Mark J

    2014-10-28

    Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

  11. Abnormal COX2 Protein Expression May Be Correlated with Poor Prognosis in Oral Cancer: A Meta-Analysis

    PubMed Central

    Wang, Zhi-Ming; Liu, Jie; Liu, Hong-Bo; Ye, Ming; Zhang, Yu-Fei; Yang, Dong-Sheng

    2014-01-01

    Background. The prognostic significance of COX2 for survival of patients with oral cancer remains controversial. Thus, the meta-analysis was performed in order to identify COX2 expression impact on prognosis of oral cancer. Method. Relevant literatures were searched using the following electronic databases without any language restrictions: Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and CBM. Version 12.0 STATA software (Stata Corporation, College Station, Texas, USA) was used for the current meta-analysis. Odds ratios (ORs) and hazard ratios (HRs) with their corresponding 95% confidence interval (95% CI) were also calculated to clarify the correlation between COX2 expression and prognosis of oral cancer. Results. Final analysis of 979 oral cancer patients from 12 clinical cohort studies was performed. The meta-analysis results show that COX2 expression in cancer tissues was significantly higher than those in normal and benign tissues (all P < 0.05). Combined HR of COX2 suggests that positive COX2 expression has a shorter overall survival (OS) than those of negative COX2 expression (P < 0.05). Conclusion. The meta-analysis study shows that elevated COX2 expression may be associated with the pathogenesis of oral cancer and with a worse prognosis in oral cancer patients. PMID:25028647

  12. Transcranial direct current stimulation facilitates motor learning post-stroke: a systematic review and meta-analysis.

    PubMed

    Kang, Nyeonju; Summers, Jeffery J; Cauraugh, James H

    2016-04-01

    Transcranial direct current stimulation (tDCS) is an attractive protocol for stroke motor recovery. The current systematic review and meta-analysis investigated the effects of tDCS on motor learning post-stroke. Specifically, we determined long-term learning effects by examining motor improvements from baseline to at least 5 days after tDCS intervention and motor practise. 17 studies reported long-term retention testing (mean retention interval=43.8 days; SD=56.6 days) and qualified for inclusion in our meta-analysis. Assessing primary outcome measures for groups that received tDCS and motor practise versus sham control groups created 21 valid comparisons: (1) 16 clinical assessments and (2) 5 motor skill acquisition tests. A random effects model meta-analysis showed a significant overall effect size=0.59 (p<0.0001; low heterogeneity, T(2)=0.04; I(2)=22.75%; and high classic fail-safe N=240). 4 moderator variable analyses revealed beneficial effects of tDCS on long-term motor learning: (1) stimulation protocols: anodal on the ipsilesional hemisphere, cathodal on the contralesional hemisphere, or bilateral; (2) recovery stage: subacute or chronic stroke; (3) stimulation timing: tDCS before or during motor practise; and (4) task-specific training or conventional rehabilitation protocols. This robust meta-analysis identified novel long-term motor learning effects with tDCS and motor practise post-stroke. PMID:26319437

  13. An association between -866G/A polymorphism in the promoter of UCP2 and obesity: a meta-analysis.

    PubMed

    Liu, Lingling; Zhao, Xinxin; Kang, Shan; Zhang, Dongfeng

    2013-02-01

    -866G/A polymorphism in the promoter of UCP2 gene has been reported to be associated with obesity, but the results remain inconclusive. To assess the relation of UCP2 -866G/A polymorphism and obesity susceptibility, a meta-analysis was performed. PubMed, ISI, Wanfang database, VIP and CBM were searched to identify relevant studies up to July 31, 2012. Odds ratios (OR) and 95% confidence interval (95% CI) were pooled using fixed or random effect models. Subgroup analysis was performed by ethnicity (categorized as Asian and European). Heterogeneity and publication bias evaluation were performed to validate the credibility. Meta-regression and the 'leave one out' sensitive analysis were used to explore the potential sources of between-study heterogeneity. 14 studies were included in this meta-analysis. After exclusion of articles that deviated from the HWE in controls, and were the key contributors to between-study heterogeneity, the meta-analysis showed a significant association of the A allele with reduced risk of obesity in overall analysis and in European in the dominant, codominant and additional models. In Asian, no significant association was found between the -866G/A in UCP2 gene and obesity susceptibility. The meta-analysis suggested that UCP2 -866G/A polymorphism was associated with obesity. The A allele may be an important protective factor for obesity in European, but not in Asian. Further studies are needed to elucidate the relationship.

  14. Efficacy of Vitamin C Supplements in Prevention of Cancer: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Lee, Bobae; Oh, Seung-Won

    2015-01-01

    Background Previous randomized controlled trials (RCTs) have reported inconsistent findings regarding the association between vitamin C supplementation and the risk of cancer. Methods We performed a meta-analysis of RCTs to investigate the efficacy of vitamin C supplements for prevention of cancer. We searched the PubMed, EMBASE, and Cochrane Library databases in November 2014 using common keywords related to vitamin C supplements and cancer. Results Among 785 articles, a total of seven trials were identified, which included 62,619 participants; 31,326 and 31,293 were randomized to vitamin C supplementation and control or placebo groups, respectively, which were included in the final analysis. A fixed-effects meta-analysis of all seven RCTs revealed no significant association between vitamin C supplementation and cancer (relative risk, 1.00; 95% confidence intervals, 0.95-1.05). Similarly, subgroup meta-analysis by dose of vitamin C administered singly or in combination with other supplements, follow-up period, methodological quality, cancer mortality, gender, smoking status, country, and type of cancer also showed no efficacy of vitamin C supplementation for cancer prevention. Conclusion This meta-analysis shows that there is no evidence to support the use of vitamin C supplements for prevention of cancer. PMID:26634093

  15. Meta-analysis of the association between GSTT1 null genotype and risk of nasopharyngeal carcinoma in Chinese.

    PubMed

    Jin, Bin; Dong, Pin; Li, Keyong; Shen, Bin; Xie, Jin

    2014-01-01

    Glutathione S-transferase T1 (GSTT1) null genotype has been proven to be associated with risks of many cancers. There were also many studies assessing on the association between GSTT1 null genotype and nasopharyngeal carcinoma risk in Chinese, but the findings from those studies were inconsistent. We performed a meta-analysis to provide a more precise assessment on the effect of GSTT1 null genotype on nasopharyngeal carcinoma risk. The PubMed and Wanfang databases were searched to identify eligible case-control studies on the association between GSTT1 null genotype and risk of nasopharyngeal carcinoma in Chinese. The pooled odds ratios (OR) with corresponding 95% confidence intervals (95% CI) were used to assess the association. Eight case-control studies with a total of 3,702 individuals were finally included in the meta-analysis. Meta-analysis of a total of eight studies showed that GSTT1 null genotype was significantly associated with increased risk of nasopharyngeal carcinoma in Chinese (OR = 2.27; 95% CI 1.41-3.67; P = 0.001). The finding from cumulative meta-analysis showed that there was a trend of more obvious association between GSTT1 null genotype and risk of nasopharyngeal carcinoma in Chinese as data accumulated by publication year. Therefore, the GSTT1 null genotype is significantly associated with increased risk of nasopharyngeal carcinoma in Chinese.

  16. Transcranial direct current stimulation facilitates motor learning post-stroke: a systematic review and meta-analysis.

    PubMed

    Kang, Nyeonju; Summers, Jeffery J; Cauraugh, James H

    2016-04-01

    Transcranial direct current stimulation (tDCS) is an attractive protocol for stroke motor recovery. The current systematic review and meta-analysis investigated the effects of tDCS on motor learning post-stroke. Specifically, we determined long-term learning effects by examining motor improvements from baseline to at least 5 days after tDCS intervention and motor practise. 17 studies reported long-term retention testing (mean retention interval=43.8 days; SD=56.6 days) and qualified for inclusion in our meta-analysis. Assessing primary outcome measures for groups that received tDCS and motor practise versus sham control groups created 21 valid comparisons: (1) 16 clinical assessments and (2) 5 motor skill acquisition tests. A random effects model meta-analysis showed a significant overall effect size=0.59 (p<0.0001; low heterogeneity, T(2)=0.04; I(2)=22.75%; and high classic fail-safe N=240). 4 moderator variable analyses revealed beneficial effects of tDCS on long-term motor learning: (1) stimulation protocols: anodal on the ipsilesional hemisphere, cathodal on the contralesional hemisphere, or bilateral; (2) recovery stage: subacute or chronic stroke; (3) stimulation timing: tDCS before or during motor practise; and (4) task-specific training or conventional rehabilitation protocols. This robust meta-analysis identified novel long-term motor learning effects with tDCS and motor practise post-stroke.

  17. Meta-Analysis of Oxidative Stress in Schizophrenia

    PubMed Central

    Flatow, Joshua; Buckley, Peter; Miller, Brian J.

    2014-01-01

    Background Schizophrenia is associated with impaired antioxidant defense, including abnormal serum, plasma, and red blood cell (RBC) oxidative stress parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment after an acute exacerbation of psychosis. Methods We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information, and the reference lists of identified studies. Results Forty-four studies met the inclusion criteria. Total antioxidant status seemed to be a state marker, because levels were significantly decreased in cross-sectional studies of serum and plasma in first-episode psychosis (FEP) and significantly increased in longitudinal studies of antipsychotic treatment for acute exacerbations of psychosis (p < .01 for each). The RBC catalase and plasma nitrite seemed to be state-related markers, because levels in cross-sectional studies were significantly decreased in FEP (p < .01) and significantly increased in stable outpatients (p = .01). In contrast, RBC superoxide dismutase seemed to be a trait marker for schizophrenia, because levels in cross-sectional studies were significantly decreased in acutely relapsed inpatients, FEP, and stable outpatients (p < .01 for each). Conclusions Oxidative stress abnormalities in FEP suggest an effect that might be independent of antipsychotic medications. Although some parameters (total antioxidant status, RBC catalase, and plasma nitrite) might be state markers for acute exacerbations of psychosis, others (RBC superoxide dismutase) might be trait markers; however, more longitudinal studies are needed. Our findings suggest that oxidative stress might serve as a potential biomarker in the etiopathophysiology and clinical course of schizophrenia. PMID:23683390

  18. Hepatitis E Seroprevalence in Europe: A Meta-Analysis

    PubMed Central

    Hartl, Johannes; Otto, Benjamin; Madden, Richie Guy; Webb, Glynn; Woolson, Kathy Louise; Kriston, Levente; Vettorazzi, Eik; Lohse, Ansgar W.; Dalton, Harry Richard; Pischke, Sven

    2016-01-01

    There have been large numbers of studies on anti-HEV IgG seroprevalence in Europe, however, the results of these studies have produced high variability of seroprevalence rates, making interpretation increasingly problematic. Therefore, the aim of this study was to develop a clearer understanding of anti-HEV IgG seroprevalence in Europe and identify risk groups for HEV exposure by a meta-analysis of published studies. Methods: All European HEV-seroprevalence studies from 2003 to 2015 were reviewed. Data were stratified by assay, geographical location, and patient cohort (general population, patients with HIV, solid-organ transplant recipients, chronic liver disease patients, and individuals in contact with swine/wild animals). Data were pooled using a mixed-effects model. Results: Four hundred thirty-two studies were initially identified, of which 73 studies were included in the analysis. Seroprevalence estimates ranged from 0.6% to 52.5%, increased with age, but were unrelated to gender. General population seroprevalence varied depending on assays: Wantai (WT): 17%, Mikrogen (MG): 10%, MP-diagnostics (MP): 7%, DiaPro: 4%, Abbott 2%. The WT assay reported significantly higher seroprevalence rates across all cohorts (p < 0.001). Individuals in contact with swine/wild animals had significantly higher seroprevalence rates than the general population, irrespective of assay (p < 0.0001). There was no difference between any other cohorts. The highest seroprevalence was observed in France (WT: 32%, MP: 16%) the lowest in Italy (WT: 7.5%, MP 0.9%). Seroprevalence varied between and within countries. The observed heterogeneity was attributed to geographical region (23%), assay employed (23%) and study cohort (7%). Conclusion: Seroprevalcence rates primarily depend on the seroassy that is used, followed by the geographical region and study cohort. Seroprevalence is higher in individuals exposed to swine and/or wild animals, and increases with age. PMID:27509518

  19. Empowerment of women for health promotion: a meta-analysis.

    PubMed

    Kar, S B; Pascual, C A; Chickering, K L

    1999-12-01

    The objective of this paper is to identify conditions, factors and methods, which empower women and mothers (WAM) for social action and health promotion movements. WAM are the primary caregivers in almost all cultures; they have demonstrated bold leadership under extreme adversity. Consequently, when empowered and involved, WAM can be effective partners in health promotion programs. The methodology includes a meta-analysis of 40 exemplary case studies from across the world, which meet predetermined criteria, to draw implications for social action and health promotion. Cases were selected from industrialized and less-industrialized nations and from four problem domains affecting quality of life and health: (1) human rights, (2) women's equal rights, (3) economic enhancement and (4) health promotion. Content analysis extracted data from all cases on six dimensions: (1) problem, (2) impetus/leadership, (3) macro-environment, (4) methods used, (5) partners/opponents and (6) impact. Analysis identified seven methods frequently used to EMPOWER (acronym): empowerment education and training, media use and advocacy, public education and participation, organizing associations and unions, work training and micro-enterprise, enabling services and support, and rights protection and promotion. Cochran's Q test confirmed significant differences in the frequencies of methods used. The seven EMPOWER methods were used in this order: enabling services, rights protection/promotion, public education, media use/advocacy, and organizing associations/unions, empowerment education, and work training and micro-enterprise. Media and public education were more frequently used by industrialized than non-industrialized societies (X2 tests). While frequencies of methods used varied in all other comparisons, these differences were not statistically significant, suggesting the importance of these methods across problem domains and levels of industrialization. The paper integrates key findings into

  20. Review of the Reporting of Survival Analyses within Randomised Controlled Trials and the Implications for Meta-Analysis

    PubMed Central

    Batson, Sarah; Greenall, Gemma; Hudson, Pollyanna

    2016-01-01

    Background Meta-analysis is a growing approach to evidence synthesis and network meta-analysis in particular represents an important and developing method within Health Technology Assessment (HTA). Meta-analysis of survival data is usually performed using the individual summary statistic—the hazard ratio (HR) from each randomised controlled trial (RCT). Objectives The objectives of this study are to: (i) review the methods and reporting of survival analyses in oncology RCTs; and (ii) assess the suitability and relevance of survival data reported in RCTs for inclusion into meta-analysis. Methods Five oncology journals were searched to identify Phase III RCTs published between April and July 2015. Eligible studies included those that analysed a survival outcome. Results Thirty-two RCTs reporting survival outcomes in cancer populations were identified. None of the publications reported details relating to a strategy for statistical model building, the goodness of fit of the final model, or final model validation for the analysis of survival outcomes. The majority of studies (88%) reported the use of Cox proportional hazards (PH) regression to analyse survival endpoints. However, most publications failed to report the validation of the statistical models in terms of the PH assumption. Conclusions This review highlights deficiencies in terms of reporting the methods and validity of survival analyses within oncology RCTs. We support previous recommendations to encourage authors to improve the reporting of survival analyses in journal publications. We also recommend that the final choice of a statistical model for survival should be informed by goodness of model fit to a given dataset, and that model assumptions are validated. The failure of trial investigators and statisticians to investigate the PH for RCT survival data is likely to result in clinical decisions based on inappropriate methods. The development of alternative approaches for the meta-analysis of survival

  1. Metastatic Colonization

    PubMed Central

    Massagué, Joan; Obenauf, Anna C.

    2016-01-01

    Metastasis is the main cause of death from cancer. To colonize distant organs, circulating cancer cells must overcome many obstacles through mechanisms that we are starting to understand. Infiltrating distant tissue, evading immune defences, adapting to supportive niches, surviving as latent tumour-initiating seeds, and eventually breaking out to replace the host tissue, are key steps for metastatic colonization. These obstacles make metastasis a highly inefficient process, but once metastases are established current treatments frequently fail to provide durable responses. A better understanding of the mechanistic determinants of metastatic colonization is needed to better prevent and treat metastatic cancer. PMID:26791720

  2. Meta-analysis of differential gene co-expression: application to lupus.

    PubMed

    Makashir, Sumit B; Kottyan, Leah C; Weirauch, Matthew T

    2015-01-01

    We present a novel statistical framework for meta-analysis of differential gene co-expression. In contrast to standard methods, which identify genes that are over or under expressed in disease vs controls, differential co-expression identifies gene pairs with correlated expression profiles specific to one state. We apply our differential co-expression meta-analysis method to identify genes specifically mis-expressed in blood-derived cells of systemic lupus erythematosus (SLE) patients. The resulting network is strongly enriched for genes genetically associated with SLE, and effectively identifies gene modules known to play important roles in SLE etiology, such as increased type 1 interferon response and response to wounding. Our results also strongly support previous preliminary studies suggesting a role for dysregulation of neutrophil extracellular trap formation in SLE. Strikingly, two of the gene modules we identify contain SLE-associated transcription factors that have binding sites significantly enriched in the promoter regions of their respective gene modules, suggesting a possible mechanism underlying the mis-expression of the modules. Thus, our general method is capable of identifying specific dysregulated gene expression programs, as opposed to large global responses. We anticipate that methods such as ours will be more and more useful as gene expression monitoring becomes increasingly common in clinical settings.

  3. Systemic Lupus Erythematous and Malignancy Risk: A Meta-Analysis

    PubMed Central

    Xu, Gaixiang; Liu, Ping; Meng, Haitao; Wang, Jinghan; Zhao, Xiaoying; Tang, Yongmin; Jin, Jie

    2015-01-01

    Background Pilot studies have estimated cancer incidence in patients with systemic lupus erythematous (SLE). However, the results have been inconclusive. To ascertain the correlation between SLE and malignancy more comprehensively and precisely, we conducted a meta-analysis. Methods PubMed, the Cochrane Library and Embase databases through June 2014, were searched to identify observational studies evaluating the association between SLE and malignancy. The outcomes from these studies were measured as relative risks (RRs). A random or fixed effects model was chosen to calculate the pooled RR according to heterogeneity test. Between-study heterogeneity was assessed by estimating I2 index. Publication bias was assessed by Egger’s test. Results A total of 16 papers, including 59,662 SLE patients, were suitable for the meta-analysis. Of these papers, 15 reported RRs for overall malignancy, 12 for non-Hodgkin lymphoma (NHL) and lung cancer, 7 for bladder cancer, 6 for Hodgkin lymphoma (HL) and leukemia, 5 for skin melanoma, and liver and thyroid cancers, 4 for multiple myeloma (MM), and esophageal and vaginal/vulvar cancers and 3 for laryngeal and non-melanoma skin cancers. The pooled RRs were 1.28 (95% CI, 1.17–1.41) for overall cancer, 5.40 (95% CI, 3.75–7.77) for NHL, 3.26(95% CI, 2.17–4.88) for HL, 2.01(95% CI, 1.61–2.52) for leukemia, 1.45(95% CI, 1.04–2.03) for MM, 4.19(95% CI, 1.98–8.87) for laryngeal cancer, 1.59 (95% CI, 1.44–1.76) for lung cancer, 1.86(95% CI, 1.21–2.88) for esophageal cancer, 3.21(95% CI, 1.70–6.05) for liver cancer, 3.67(95% CI, 2.80–4.81) for vaginal/vulvar cancer, 2.11(95% CI, 1.12–3.99) for bladder cancer, 1.51(95% CI, 1.12–2.03) for non-melanoma skin cancer, 1.78(95% CI, 1.35–2.33) for thyroid cancer, and 0.65(95% CI, 0.50–0.85) for skin melanoma. Only the meta-analyses of overall malignancy, NHL, and liver and bladder cancers produced substantial heterogeneity (I2, 57.6% vs 74.3% vs 67.7% vs 82.3%). No

  4. Meta-Analysis of Cognitive Preferences and Learning.

    ERIC Educational Resources Information Center

    Tamir, Pinchas

    1985-01-01

    Presents meta-analysis of 54 articles and dissertations dealing with cognitive preferences. Information provided includes: test reliability; comparisons by country, grade level, gender, disciplines, and curricula; relationships between cognitive preferences and career orientation, science achievement, interest, and aptitude; and effect sizes.…

  5. Maternal Smoking and Autism Spectrum Disorder: A Meta-Analysis

    ERIC Educational Resources Information Center

    Rosen, Brittany N.; Lee, Brian K.; Lee, Nora L.; Yang, Yunwen; Burstyn, Igor

    2015-01-01

    We conducted a meta-analysis of 15 studies on maternal prenatal smoking and ASD risk in offspring. Using a random-effects model, we found no evidence of an association (summary OR 1.02, 95% CI 0.93-1.12). Stratifying by study design, birth year, type of healthcare system, and adjustment for socioeconomic status or psychiatric history did not alter…

  6. Does College Teach Critical Thinking? A Meta-Analysis

    ERIC Educational Resources Information Center

    Huber, Christopher R.; Kuncel, Nathan R.

    2016-01-01

    Educators view critical thinking as an essential skill, yet it remains unclear how effectively it is being taught in college. This meta-analysis synthesizes research on gains in critical thinking skills and attitudinal dispositions over various time frames in college. The results suggest that both critical thinking skills and dispositions improve…

  7. Effectiveness of Secondary Pregnancy Prevention Programs: A Meta-Analysis

    ERIC Educational Resources Information Center

    Corcoran, Jacqueline; Pillai, Vijayan K.

    2007-01-01

    Because subsequent pregnancy in teen parents often worsens the impact of adolescent parenting; therefore, a common goal of teenage parent programs has been to reduce repeat pregnancy. To examine the impact of this goal, a meta-analysis was conducted on 16 control-comparison group studies that evaluated the effect of teenage pregnancy and parenting…

  8. Formative Assessment and Writing: A Meta-Analysis

    ERIC Educational Resources Information Center

    Graham, Steve; Hebert, Michael; Harris, Karen R.

    2015-01-01

    To determine whether formative writing assessments that are directly tied to everyday classroom teaching and learning enhance students' writing performance, we conducted a meta-analysis of true and quasi-experiments conducted with students in grades 1 to 8. We found that feedback to students about writing from adults, peers, self, and computers…

  9. A Meta-Analysis of Massage Therapy Research

    ERIC Educational Resources Information Center

    Moyer, Christopher A.; Rounds, James; Hannum, James W.

    2004-01-01

    Massage therapy (MT) is an ancient form of treatment that is now gaining popularity as part of the complementary and alternative medical therapy movement. A meta-analysis was conducted of studies that used random assignment to test the effectiveness of MT. Mean effect sizes were calculated from 37 studies for 9 dependent variables. Single…

  10. Visuo-Spatial Performance in Autism: A Meta-Analysis

    ERIC Educational Resources Information Center

    Muth, Anne; Hönekopp, Johannes; Falter, Christine M.

    2014-01-01

    Visuo-spatial skills are believed to be enhanced in autism spectrum disorders (ASDs). This meta-analysis tests the current state of evidence for Figure Disembedding, Block Design, Mental Rotation and Navon tasks in ASD and neurotypicals. Block Design (d = 0.32) and Figure Disembedding (d = 0.26) showed superior performance for ASD with large…

  11. The Relationship between Parenting and Delinquency: A Meta-Analysis

    ERIC Educational Resources Information Center

    Hoeve, Machteld; Dubas, Judith Semon; Eichelsheim, Veroni I.; van der Laan, Peter H.; Smeenk, Wilma; Gerris, Jan R. M.

    2009-01-01

    This meta-analysis of 161 published and unpublished manuscripts was conducted to determine whether the association between parenting and delinquency exists and what the magnitude of this linkage is. The strongest links were found for parental monitoring, psychological control, and negative aspects of support such as rejection and hostility,…

  12. Updated Meta-Analysis of Learner Control within Educational Technology

    ERIC Educational Resources Information Center

    Karich, Abbey C.; Burns, Matthew K.; Maki, Kathrin E.

    2014-01-01

    Giving a student control over their learning has theoretical and intuitive appeal, but its effects are neither powerful nor consistent in the empirical literature base. This meta-analysis updated previous meta-analytic research by Niemiec, Sikorski, and Walberg by studying the overall effectiveness of providing learner control within educational…

  13. Bilingual Language Assessment: A Meta-Analysis of Diagnostic Accuracy

    ERIC Educational Resources Information Center

    Dollaghan, Christine A.; Horner, Elizabeth A.

    2011-01-01

    Purpose: To describe quality indicators for appraising studies of diagnostic accuracy and to report a meta-analysis of measures for diagnosing language impairment (LI) in bilingual Spanish-English U.S. children. Method: The authors searched electronically and by hand to locate peer-reviewed English-language publications meeting inclusion criteria;…

  14. Guidelines for Using the "Q" Test in Meta-Analysis

    ERIC Educational Resources Information Center

    Maeda, Yukiko; Harwell, Michael R.

    2016-01-01

    The "Q" test is regularly used in meta-analysis to examine variation in effect sizes. However, the assumptions of "Q" are unlikely to be satisfied in practice prompting methodological researchers to conduct computer simulation studies examining its statistical properties. Narrative summaries of this literature are available but…

  15. The Paradox of Intragroup Conflict: A Meta-Analysis

    ERIC Educational Resources Information Center

    de Wit, Frank R. C.; Greer, Lindred L.; Jehn, Karen A.

    2012-01-01

    Since the meta-analysis by De Dreu and Weingart (2003b) on the effects of intragroup conflict on group outcomes, more than 80 new empirical studies of conflict have been conducted, often investigating more complex, moderated relationships between conflict and group outcomes, as well as new types of intragroup conflict, such as process conflict. To…

  16. Multivariate Meta-Analysis Using Individual Participant Data

    ERIC Educational Resources Information Center

    Riley, R. D.; Price, M. J.; Jackson, D.; Wardle, M.; Gueyffier, F.; Wang, J.; Staessen, J. A.; White, I. R.

    2015-01-01

    When combining results across related studies, a multivariate meta-analysis allows the joint synthesis of correlated effect estimates from multiple outcomes. Joint synthesis can improve efficiency over separate univariate syntheses, may reduce selective outcome reporting biases, and enables joint inferences across the outcomes. A common issue is…

  17. Instructional Animation versus Static Pictures: A Meta-Analysis

    ERIC Educational Resources Information Center

    Hoffler, Tim N.; Leutner, Detlev

    2007-01-01

    A meta-analysis of 26 primary studies, yielding 76 pair-wise comparisons of dynamic and static visualizations, reveals a medium-sized overall advantage of instructional animations over static pictures. The mean weighted effect size on learning outcome is d = 0.37 (95% CI 0.25-0.49). Moderator analyses indicate even more substantial effect sizes…

  18. Evaluative Conditioning in Humans: A Meta-Analysis

    ERIC Educational Resources Information Center

    Hofmann, Wilhelm; De Houwer, Jan; Perugini, Marco; Baeyens, Frank; Crombez, Geert

    2010-01-01

    This article presents a meta-analysis of research on "evaluative conditioning" (EC), defined as a change in the liking of a stimulus (conditioned stimulus; CS) that results from pairing that stimulus with other positive or negative stimuli (unconditioned stimulus; US). Across a total of 214 studies included in the main sample, the mean EC effect…

  19. A Meta-Analysis of Attachment to Parents and Delinquency

    ERIC Educational Resources Information Center

    Hoeve, Machteld; Stams, Geert Jan J. M.; van der Put, Claudia E.; Dubas, Judith Semon; van der Laan, Peter H.; Gerris, Jan R. M.

    2012-01-01

    To investigate the link between attachment to parents and delinquency, and the potential moderating effects of age and sex, 74 published and unpublished manuscripts (N = 55,537 participants) were subjected to a multilevel meta-analysis. A mean small to moderate effect size was found (r = 0.18). Poor attachment to parents was significantly linked…

  20. Reinforcement, Reward, and Intrinsic Motivation: A Meta-Analysis.

    ERIC Educational Resources Information Center

    Cameron, Judy; Pierce, W. David

    1994-01-01

    A meta-analysis including 96 experimental studies considers the effects of reinforcement/reward on intrinsic motivation. Results indicate that reward does not decrease intrinsic motivation, although interaction effects must be examined. An analysis with five studies also indicates that reinforcement does not harm intrinsic motivation. (SLD)

  1. Learning with Concept and Knowledge Maps: A Meta-Analysis

    ERIC Educational Resources Information Center

    Nesbit, John C.; Adesope, Olusola O.

    2006-01-01

    This meta-analysis reviews experimental and quasi-experimental studies in which students learned by constructing, modifying, or viewing node-link diagrams. Following an exhaustive search for studies meeting specified design criteria, 67 standardized mean difference effect sizes were extracted from 55 studies involving 5,818 participants. Students…

  2. Indirect orbital floor fractures: a meta-analysis.

    PubMed

    Gonzalez, Mithra O; Durairaj, Vikram D

    2010-04-01

    Orbit fractures are common in the context of orbital trauma. Fractures of the orbital floor without orbital rim involvement are known as indirect orbital floor fractures, pure internal floor fractures, and orbital blowout fractures. In this paper, we have reported a meta-analysis of orbital floor fractures focusing on indications and timing of surgical repair, outcomes, and complications. PMID:20616920

  3. Wilderness Therapy Programs for Juvenile Delinquents: A Meta-Analysis.

    ERIC Educational Resources Information Center

    Bedard, Rachel M.; Rosen, Lee A.; Vacha-Haase, Tami

    2003-01-01

    A study examining the effectiveness of wilderness therapy programs for rehabilitating delinquent adolescents analyzed 23 programs using meta-analysis. Moderate effect sizes in favor of wilderness therapy programs were found with respect to enhancing self-esteem/self-concept, improving interpersonal skills, and promoting behavior changes. A small…

  4. Demographic Faultlines: A Meta-Analysis of the Literature

    ERIC Educational Resources Information Center

    Thatcher, Sherry M. B.; Patel, Pankaj C.

    2011-01-01

    We propose and test a theoretical model focusing on antecedents and consequences of demographic faultlines. We also posit contingencies that affect overall team dynamics in the context of demographic faultlines, such as the study setting and performance measurement. Using meta-analysis structural equation modeling with a final data set consisting…

  5. Intelligent Tutoring Systems and Learning Outcomes: A Meta-Analysis

    ERIC Educational Resources Information Center

    Ma, Wenting; Adesope, Olusola O.; Nesbit, John C.; Liu, Qing

    2014-01-01

    Intelligent Tutoring Systems (ITS) are computer programs that model learners' psychological states to provide individualized instruction. They have been developed for diverse subject areas (e.g., algebra, medicine, law, reading) to help learners acquire domain-specific, cognitive and metacognitive knowledge. A meta-analysis was conducted on…

  6. Digital Simulation-Based Training: A Meta-Analysis

    ERIC Educational Resources Information Center

    Gegenfurtner, Andreas; Quesada-Pallarès, Carla; Knogler, Maximilian

    2014-01-01

    This study examines how design characteristics in digital simulation-based learning environments moderate self-efficacy and transfer of learning. Drawing on social cognitive theory and the cognitive theory of multimedia learning, the meta-analysis psychometrically cumulated k?=?15 studies of 25 years of research with a total sample size of…

  7. Effective Interventions on Test Anxiety Reduction: A Meta-Analysis.

    ERIC Educational Resources Information Center

    Ergene, Tuncay

    2003-01-01

    This meta-analysis synthesized results from test anxiety reduction programs. The treatment of test anxiety has been quite successful in reducing the test anxiety level of clients. The most effective treatments appear to be those that combine skill-focused approaches with behavior or cognitive approaches. Individually conducted programs, along with…

  8. Meta-Analysis of Scale Reliability Using Latent Variable Modeling

    ERIC Educational Resources Information Center

    Raykov, Tenko; Marcoulides, George A.

    2013-01-01

    A latent variable modeling approach is outlined that can be used for meta-analysis of reliability coefficients of multicomponent measuring instruments. Important limitations of efforts to combine composite reliability findings across multiple studies are initially pointed out. A reliability synthesis procedure is discussed that is based on…

  9. The Psychophysiology of Posttraumatic Stress Disorder: A Meta-Analysis

    ERIC Educational Resources Information Center

    Pole, Nnamdi

    2007-01-01

    This meta-analysis of 58 resting baseline studies, 25 startle studies, 17 standardized trauma cue studies, and 22 idiographic trauma cue studies compared adults with and without posttraumatic stress disorder (PTSD) on psychophysiological variables: facial electromyography (EMG), heart rate (HR), skin conductance (SC), and blood pressure.…

  10. Lead and Conduct Problems: A Meta-Analysis

    ERIC Educational Resources Information Center

    Marcus, David K.; Fulton, Jessica J.; Clarke, Erin J.

    2010-01-01

    This meta-analysis examined the association between conduct problems and lead exposure. Nineteen studies on 8,561 children and adolescents were included. The average "r" across all 19 studies was 0.19 (p less than 0.001), which is considered a medium effect size. Studies that assessed lead exposure using hair element analysis yielded considerably…

  11. Comprehensive School Reform and Achievement: A Meta-Analysis

    ERIC Educational Resources Information Center

    Borman, Geoffrey D.; Hewes, Gina M.; Overman, Laura T.; Brown, Shelly

    2003-01-01

    This meta-analysis reviews research on the achievement effects of comprehensive school reform (CSR) and summarizes the specific effects of 29 widely implemented models. There are limitations on the overall quantity and quality of the research base, but the overall effects of CSR appear promising. The combined quantity, quality, and statistical…

  12. A Noncentral "t" Regression Model for Meta-Analysis

    ERIC Educational Resources Information Center

    Camilli, Gregory; de la Torre, Jimmy; Chiu, Chia-Yi

    2010-01-01

    In this article, three multilevel models for meta-analysis are examined. Hedges and Olkin suggested that effect sizes follow a noncentral "t" distribution and proposed several approximate methods. Raudenbush and Bryk further refined this model; however, this procedure is based on a normal approximation. In the current research literature, this…

  13. Illustration of a Multilevel Model for Meta-Analysis

    ERIC Educational Resources Information Center

    de la Torre, Jimmy; Camilli, Gregory; Vargas, Sadako; Vernon, R. Fox

    2007-01-01

    In this article, the authors present a multilevel (or hierarchical linear) model that illustrates issues in the application of the model to data from meta-analytic studies. In doing so, several issues are discussed that typically arise in the course of a meta-analysis. These include the presence of non-zero between-study variability, how multiple…

  14. Achievement Goals and Achievement Emotions: A Meta-Analysis

    ERIC Educational Resources Information Center

    Huang, Chiungjung

    2011-01-01

    This meta-analysis synthesized 93 independent samples (N = 30,003) in 77 studies that reported in 78 articles examining correlations between achievement goals and achievement emotions. Achievement goals were meaningfully associated with different achievement emotions. The correlations of mastery and mastery approach goals with positive achievement…

  15. Learning Disabilities and Anxiety: A Meta-Analysis

    ERIC Educational Resources Information Center

    Nelson, Jason M.; Harwood, Hannah

    2011-01-01

    This article presents the results of a meta-analysis of the empirical literature on anxious symptomatology among school-aged students with learning disabilities (LD) in comparison to their non-LD peers. Fifty-eight studies met inclusion criteria. Results indicate that students with LD had higher mean scores on measures of anxiety than did non-LD…

  16. Intervention Studies on Forgiveness: A Meta-Analysis

    ERIC Educational Resources Information Center

    Baskin, Thomas W.; Enright, Robert D.

    2004-01-01

    In this meta-analysis, 9 published studies (N = 330) that investigated the efficacy of forgiveness interventions within counseling were examined. After a review of theories of forgiveness, it was discovered that the studies could logically be grouped into 3 categories: decision-based, process-based group, and process-based individual…

  17. Meta-analysis of osteoporosis: fracture risks, medication and treatment.

    PubMed

    Liu, W; Yang, L-H; Kong, X-C; An, L-K; Wang, R

    2015-08-01

    Osteoporosis is a brittle bone disease that can cause fractures mostly in older men and women. Meta-analysis is the statistical method which is applied in the frame work for the assessment of results obtained from various research studies conducted in several years. A meta-analysis of osteoporotic fracture risk with medication non-adherence has been described to assess the bone fracture risk among patients non-adherent versus adherent to therapy for osteoporosis by many researchers. Osteoporosis therapy reduces the risk of fracture in clinical trials, and real-world adherence to therapy which is suboptimal and can reduce the effectiveness of intervention. The methods of Medline, Embase, and CINAHL were literature searched for these observational studies from year 1998 to 2009, and up to 2015. The results of meta-analysis of osteoporosis research on fractures of postmenopausal women and men are presented. The use of bisphosphonate therapy for osteoporosis has been described with other drugs. The authors, design, studies (women %), years (data), follow-up (wks), fractures (types), and compliance or persistence results from years 2004 to 2009 from are shown in a brief table. The meta-analysis studies have been reviewed from other researchers on osteoporosis and fractures, medications and treatments.

  18. Meta-Analysis and Inadequate Responders to Intervention: A Reply

    ERIC Educational Resources Information Center

    Swanson, H. Lee

    2012-01-01

    A meta-analysis by Tran, Sanchez, Arellano, and Swanson (2011) of the published RTI literature found that the magnitude of effect size (ES) between responders and low responders at posttest was significantly moderated by the pretest ES and the type of dependent measure administered, whereas no significant moderating effects were found in the mixed…

  19. The Process Writing Approach: A Meta-Analysis

    ERIC Educational Resources Information Center

    Graham, Steve; Sandmel, Karin

    2011-01-01

    The process approach to writing instruction is one of the most popular methods for teaching writing. The authors conducted meta-analysis of 29 experimental and quasi-experimental studies conducted with students in Grades 1-12 to examine if process writing instruction improves the quality of students' writing and motivation to write. For students…

  20. The Categorical Perception Deficit in Dyslexia: A Meta-Analysis

    ERIC Educational Resources Information Center

    Noordenbos, Mark W.; Serniclaes, Willy

    2015-01-01

    Speech perception in dyslexia is characterized by a categorical perception (CP) deficit, demonstrated by weaker discrimination of acoustic differences between phonemic categories in conjunction with better discrimination of acoustic differences within phonemic categories. We performed a meta-analysis of studies that examined the reliability of the…

  1. Anti-Programmed Cell Death (PD)-1 Immunotherapy for Malignant Tumor: A Systematic Review and Meta-Analysis.

    PubMed

    Chen, Ran; Peng, Pei-Chun; Wen, Bin; Li, Fu-Ying; Xie, Sheng; Chen, Guozhong; Lu, Jiefu; Peng, Zhuoyu; Tang, Shao-Bo; Liang, Yu-Mei; Deng, Xin

    2016-02-01

    This systematic review and meta-analysis evaluated anti-programmed cell death (PD)-1 immunotherapy (nivolumab or pembrolizumab) for overall efficacy, safety, and effective dose relative to standard chemotherapy or other conventional drugs in the treatment of malignant tumors. We searched the following databases, PubMed, Medline, Embase, Cochrane, Wangfang Data, Weipu, and China National Knowledge Infrastructure, and the reference lists of the selected articles for randomized controlled trials (RCTs) of anti-PD-1 therapies in humans. The outcome measures were overall survival, treatment response, and adverse events. Only four randomized controlled trials met our inclusion criteria. Three of these evaluated responses to nivolumab, whereas one tested pembrolizumab. The result of our analysis suggested that nivolumab may improve the overall response rate in treating melanoma relative to chemotherapy and has few associated adverse events. Similarly, in metastatic melanoma patients, nivolumab had a significant advantage over dacarbazine in terms of 1-year survival, progression-free survival, and objective response rate. Regarding dose levels of nivolumab for patients with metastatic renal cell carcinoma, the outcomes in response to 2 and 10 mg/kg were similar, but both had significant advantages over 0.3 mg/kg. In addition, pembrolizumab showed similar outcomes in response to 2- and 10-mg/kg treatment. Anti-PD-1 immunotherapy appears to be safe and effective for patients with melanoma or metastatic renal cell carcinoma. Our meta-analysis is limited, but additional clinical trials are warranted to verify this preliminary evidence of positive outcomes and before anti-PD-1 therapy can be recommended for routine clinical use. PMID:26947879

  2. Meta-analysis of ionic liquid literature and toxicology.

    PubMed

    Heckenbach, Mary E; Romero, Felicia N; Green, Matthew D; Halden, Rolf U

    2016-05-01

    A meta-analysis was conducted to compare the total amount of ionic liquid (IL) literature (n = 39,036) to the body of publications dealing with IL toxicity (n = 213) with the goal of establishing the state of knowledge and existing information gaps. Additionally, patent literature pertaining to issued patents utilizing ILs (n = 3358) or dealing with IL toxicity (n = 112) were analyzed. Total publishing activity and patent count served to gauge research activity, industrial usage and toxicology knowledge of ILs. Five of the most commonly studied IL cations were identified and used to establish a relationship between toxicity data and potential of commercial use: imidazolium, ammonium, phosphonium, pyridinium, and pyrrolidinium. Toxicology publications for all IL cations represented 0.55% ± 0.27% of the total publishing activity; compared with other industrial chemicals, these numbers indicate that there is still a paucity of studies on the adverse effects of this class of chemical. Toxicity studies on ILs were dominated by the use of in vitro models (18%) and marine bacteria (15%) as studied biological systems. Whole animal studies (n = 87) comprised 31% of IL toxicity studies, with a subset of in vivo mammalian models consisting of 8%. Human toxicology data were found to be limited to in vitro analyses, indicating substantial knowledge gaps. Risks from long-term and chronic low-level exposure to ILs have not been established yet for any model organisms, reemphasizing the need to fill crucial knowledge gaps concerning human health effects and the environmental safety of ILs. Adding to the existing knowledge of the molecular toxicity characteristics of ILs can help inform the design of greener, less toxic and more benign IL technologies. PMID:26907595

  3. Does Music Training Enhance Literacy Skills? A Meta-Analysis

    PubMed Central

    Gordon, Reyna L.; Fehd, Hilda M.; McCandliss, Bruce D.

    2015-01-01

    Children's engagement in music practice is associated with enhancements in literacy-related language skills, as demonstrated by multiple reports of correlation across these two domains. Training studies have tested whether engaging in music training directly transfers benefit to children's literacy skill development. Results of such studies, however, are mixed. Interpretation of these mixed results is made more complex by the fact that a wide range of literacy-related outcome measures are used across these studies. Here, we address these challenges via a meta-analytic approach. A comprehensive literature review of peer-reviewed music training studies was built around key criteria needed to test the direct transfer hypothesis, including: (a) inclusion of music training vs. control groups; (b) inclusion of pre- vs. post-comparison measures, and (c) indication that reading instruction was held constant across groups. Thirteen studies were identified (n = 901). Two classes of outcome measures emerged with sufficient overlap to support meta-analysis: phonological awareness and reading fluency. Hours of training, age, and type of control intervention were examined as potential moderators. Results supported the hypothesis that music training leads to gains in phonological awareness skills. The effect isolated by contrasting gains in music training vs. gains in control was small relative to the large variance in these skills (d = 0.2). Interestingly, analyses revealed that transfer effects for rhyming skills tended to grow stronger with increased hours of training. In contrast, no significant aggregate transfer effect emerged for reading fluency measures, despite some studies reporting large training effects. The potential influence of other study design factors were considered, including intervention design, IQ, and SES. Results are discussed in the context of emerging findings that music training may enhance literacy development via changes in brain mechanisms that

  4. Meta-analysis of ionic liquid literature and toxicology.

    PubMed

    Heckenbach, Mary E; Romero, Felicia N; Green, Matthew D; Halden, Rolf U

    2016-05-01

    A meta-analysis was conducted to compare the total amount of ionic liquid (IL) literature (n = 39,036) to the body of publications dealing with IL toxicity (n = 213) with the goal of establishing the state of knowledge and existing information gaps. Additionally, patent literature pertaining to issued patents utilizing ILs (n = 3358) or dealing with IL toxicity (n = 112) were analyzed. Total publishing activity and patent count served to gauge research activity, industrial usage and toxicology knowledge of ILs. Five of the most commonly studied IL cations were identified and used to establish a relationship between toxicity data and potential of commercial use: imidazolium, ammonium, phosphonium, pyridinium, and pyrrolidinium. Toxicology publications for all IL cations represented 0.55% ± 0.27% of the total publishing activity; compared with other industrial chemicals, these numbers indicate that there is still a paucity of studies on the adverse effects of this class of chemical. Toxicity studies on ILs were dominated by the use of in vitro models (18%) and marine bacteria (15%) as studied biological systems. Whole animal studies (n = 87) comprised 31% of IL toxicity studies, with a subset of in vivo mammalian models consisting of 8%. Human toxicology data were found to be limited to in vitro analyses, indicating substantial knowledge gaps. Risks from long-term and chronic low-level exposure to ILs have not been established yet for any model organisms, reemphasizing the need to fill crucial knowledge gaps concerning human health effects and the environmental safety of ILs. Adding to the existing knowledge of the molecular toxicity characteristics of ILs can help inform the design of greener, less toxic and more benign IL technologies.

  5. Bullying and Suicidal Ideation and Behaviors: A Meta-Analysis

    PubMed Central

    Holt, Melissa K.; Vivolo-Kantor, Alana M.; Polanin, Joshua R.; Holland, Kristin M.; DeGue, Sarah; Matjasko, Jennifer L.; Wolfe, Misty; Reid, Gerald

    2015-01-01

    BACKGROUND AND OBJECTIVES Over the last decade there has been increased attention to the association between bullying involvement (as a victim, perpetrator, or bully-victim) and suicidal ideation/behaviors. We conducted a meta-analysis to estimate the association between bullying involvement and suicidal ideation and behaviors. METHODS We searched multiple online databases and reviewed reference sections of articles derived from searches to identify cross-sectional studies published through July 2013. Using search terms associated with bullying, suicide, and youth, 47 studies (38.3% from the United States, 61.7% in non-US samples) met inclusion criteria. Seven observers independently coded studies and met in pairs to reach consensus. RESULTS Six different meta-analyses were conducted by using 3 predictors (bullying victimization, bullying perpetration, and bully/victim status) and 2 outcomes (suicidal ideation and suicidal behaviors). A total of 280 effect sizes were extracted and multilevel, random effects meta-analyses were performed. Results indicated that each of the predictors were associated with risk for suicidal ideation and behavior (range, 2.12 [95% confidence interval (CI), 1.67–2.69] to 4.02 [95% CI, 2.39–6.76]). Significant heterogeneity remained across each analysis. The bullying perpetration and suicidal behavior effect sizes were moderated by the study’s country of origin; the bully/victim status and suicidal ideation results were moderated by bullying assessment method. CONCLUSIONS Findings demonstrated that involvement in bullying in any capacity is associated with suicidal ideation and behavior. Future research should address mental health implications of bullying involvement to prevent suicidal ideation/behavior. PMID:25560447

  6. The Prevalence of Vitiligo: A Meta-Analysis

    PubMed Central

    Zhang, Yuhui; Cai, Yunfei; Shi, Meihui; Jiang, Shibin; Cui, Shaoshan; Wu, Yan; Gao, Xing-Hua; Chen, Hong-Duo

    2016-01-01

    Objective To conduct a meta-analysis assessing the prevalence of vitiligo. Methods Literatures that reported prevalence rates of vitiligo were identified using EMBASE, PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang database and Weipu database for the period from inception to May 2016. We performed stratified analyses on possible sources of bias, including areas difference, years of publication, gender and age. Publication bias was assessed with Egger’s test method. Results A total of 103 studies were eligible for inclusion. The pooled prevalence of vitiligo from 82 population- or community-based studies was 0.2% (95%CI: 0.1%–0.2%) and from 22 hospital-based studies was 1.8% (95%CI: 1.4%–2.1%). A relatively high prevalence of vitiligo was found in Africa area and in female patients. For population- or community-based studies, the prevalence has maintained at a low level in recent 20 years and it has increased with age gradually. For hospital-based studies, the prevalence has showed a decreased trend from 60s till now or from young to old. No significant publication bias existed in hospital-based studies (t = 0.47, P = 0.643), while a significant publication bias existed in population- or community-based studies (t = 2.31, P = 0.026). Conclusion A relatively high prevalence of vitiligo was found in Africa area and in female patients. The prevalence has maintained at a low level in recent years. It showed an inverse trend with age increment in population- or community-based studies and hospital-based studies. PMID:27673680

  7. Does Music Training Enhance Literacy Skills? A Meta-Analysis.

    PubMed

    Gordon, Reyna L; Fehd, Hilda M; McCandliss, Bruce D

    2015-01-01

    Children's engagement in music practice is associated with enhancements in literacy-related language skills, as demonstrated by multiple reports of correlation across these two domains. Training studies have tested whether engaging in music training directly transfers benefit to children's literacy skill development. Results of such studies, however, are mixed. Interpretation of these mixed results is made more complex by the fact that a wide range of literacy-related outcome measures are used across these studies. Here, we address these challenges via a meta-analytic approach. A comprehensive literature review of peer-reviewed music training studies was built around key criteria needed to test the direct transfer hypothesis, including: (a) inclusion of music training vs. control groups; (b) inclusion of pre- vs. post-comparison measures, and (c) indication that reading instruction was held constant across groups. Thirteen studies were identified (n = 901). Two classes of outcome measures emerged with sufficient overlap to support meta-analysis: phonological awareness and reading fluency. Hours of training, age, and type of control intervention were examined as potential moderators. Results supported the hypothesis that music training leads to gains in phonological awareness skills. The effect isolated by contrasting gains in music training vs. gains in control was small relative to the large variance in these skills (d = 0.2). Interestingly, analyses revealed that transfer effects for rhyming skills tended to grow stronger with increased hours of training. In contrast, no significant aggregate transfer effect emerged for reading fluency measures, despite some studies reporting large training effects. The potential influence of other study design factors were considered, including intervention design, IQ, and SES. Results are discussed in the context of emerging findings that music training may enhance literacy development via changes in brain mechanisms that

  8. Energy Requirements of Adult Dogs: A Meta-Analysis

    PubMed Central

    Bermingham, Emma N.; Thomas, David G.; Cave, Nicholas J.; Morris, Penelope J.; Butterwick, Richard F.; German, Alexander J.

    2014-01-01

    A meta-analysis was conducted to determine the maintenance energy requirements of adult dogs. Suitable publications were first identified, and then used to generate relationships amongst energy requirements, husbandry, activity level, methodology, sex, neuter status, dog size, and age in healthy adult dogs. Allometric equations for maintenance energy requirements were determined using log-log linear regression. So that the resulting equations could readily be compared with equations reported by the National Research Council, maintenance energy requirements in the current study were determined in kcal/kg0.75 body weight (BW). Ultimately, the data of 70 treatment groups from 29 publications were used, and mean (± standard deviation) maintenance energy requirements were 142.8±55.3 kcal.kgBW−0.75.day−1. The corresponding allometric equation was 81.5 kcal.kgBW−0.93.day−1 (adjusted R2 = 0.64; 70 treatment groups). Type of husbandry had a significant effect on maintenance energy requirements (P<0.001): requirements were greatest in racing dogs, followed by working dogs and hunting dogs, whilst the energy requirements of pet dogs and kennel dogs were least. Maintenance energy requirements were less in neutered compared with sexually intact dogs (P<0.001), but there was no effect of sex. Further, reported activity level tended to effect the maintenance energy requirement of the dog (P = 0.09). This review suggests that estimating maintenance energy requirements based on BW alone may not be accurate, but that predictions that factor in husbandry, neuter status and, possibly, activity level might be superior. Additionally, more information on the nutrient requirements of older dogs, and those at the extremes of body size (i.e. giant and toy breeds) is needed. PMID:25313818

  9. Energy requirements of adult dogs: a meta-analysis.

    PubMed

    Bermingham, Emma N; Thomas, David G; Cave, Nicholas J; Morris, Penelope J; Butterwick, Richard F; German, Alexander J

    2014-01-01

    A meta-analysis was conducted to determine the maintenance energy requirements of adult dogs. Suitable publications were first identified, and then used to generate relationships amongst energy requirements, husbandry, activity level, methodology, sex, neuter status, dog size, and age in healthy adult dogs. Allometric equations for maintenance energy requirements were determined using log-log linear regression. So that the resulting equations could readily be compared with equations reported by the National Research Council, maintenance energy requirements in the current study were determined in kcal/kg(0.75) body weight (BW). Ultimately, the data of 70 treatment groups from 29 publications were used, and mean (± standard deviation) maintenance energy requirements were 142.8±55.3 kcal·kgBW(-0.75)·day(-1). The corresponding allometric equation was 81.5 kcal·kgBW(-0.9)·day(-1) (adjusted R2 = 0.64; 70 treatment groups). Type of husbandry had a significant effect on maintenance energy requirements (P<0.001): requirements were greatest in racing dogs, followed by working dogs and hunting dogs, whilst the energy requirements of pet dogs and kennel dogs were least. Maintenance energy requirements were less in neutered compared with sexually intact dogs (P<0.001), but there was no effect of sex. Further, reported activity level tended to effect the maintenance energy requirement of the dog (P = 0.09). This review suggests that estimating maintenance energy requirements based on BW alone may not be accurate, but that predictions that factor in husbandry, neuter status and, possibly, activity level might be superior. Additionally, more information on the nutrient requirements of older dogs, and those at the extremes of body size (i.e. giant and toy breeds) is needed.

  10. Does Music Training Enhance Literacy Skills? A Meta-Analysis.

    PubMed

    Gordon, Reyna L; Fehd, Hilda M; McCandliss, Bruce D

    2015-01-01

    Ch