Browsing by Subject "meta-analysis"

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  • Service, S. K.; Verweij, K. J. H.; Lahti, J.; Congdon, E.; Ekelund, J.; Hintsanen, M.; Räikkönen, Katri; Lehtimaki, T.; Kahonen, M.; Widen, E.; Taanila, A.; Veijola, J.; Heath, A. C.; Madden, P. A. F.; Montgomery, G. W.; Sabatti, C.; Jarvelin, M-R; Palotie, A.; Raitakari, O.; Viikari, J.; Martin, N. G.; Eriksson, J. G.; Keltikangas-Järvinen, Liisa; Wray, N. R.; Freimer, N. B. (2012)
  • Soininen, Janne; Heino, Jani; Wang, Jianjun (2018)
    Aim: The number of studies investigating the nestedness and turnover components of beta diversity has increased substantially, but our general understanding of the drivers of turnover and nestedness remains elusive. Here, we examined the effects of species traits, spatial extent, latitude and ecosystem type on the nestedness and turnover components of beta diversity. Location: Global. Time period: 1968-2017. Major taxa studied: From bacteria to mammals. Methods: From the 99 studies that partition total beta diversity into its turnover and nestedness components, we assembled 269 and 259 data points for the pairwise and multiple site beta-diversity metrics, respectively. Our data covered a broad variation in species dispersal type, body size and trophic position. The data were from freshwater, marine and terrestrial realms, and encompassed geographical areas from the tropics to near polar regions. We used linear modelling as a meta-regression tool to analyse the data. Results: Pairwise turnover, multiple site turnover and total beta diversity all decreased significantly with latitude. In contrast, multiple site nestedness showed a positive relationship with latitude. Beta-diversity components did not generally differ among the realms. The turnover component and total beta diversity increased with spatial extent, whereas nestedness was scale invariant for pairwise metrics. Multiple site beta-diversity components did not vary with spatial extent. Surprisingly, passively dispersed organisms had lower turnover and total beta diversity than flying organisms. Body size showed a relatively weak relationship with beta diversity but had important interactions with trophic position, thus also affecting beta diversity via interactive effects. Producers had significantly higher average pairwise turnover and total beta diversity than carnivores. Main conclusions: The present results provide evidence that species turnover, being consistently the larger component of total beta diversity, and nestedness are related to the latitude of the study area and intrinsic organismal features. We showed that two beta-diversity components had generally opposing patterns with regard to latitude. We highlight that beta-diversity partition may give additional insights into the underlying causes of spatial variability in biotic communities compared with total beta diversity alone.
  • Malanchini, Margherita; Smith-Woolley, Emily; Ayorech, Ziada; Rimfeld, Kaili; Krapohl, Eva; Vuoksimaa, Eero; Korhonen, Tellervo; Bartels, Meike; van Beijsterveldt, Toos C. E. M.; Rose, Richard J.; Lundstrom, Sebastian; Anckarsater, Henrik; Kaprio, Jaakko; Lichtenstein, Paul; Boomsma, Dorret I.; Plomin, Robert (2019)
    Background Maternal smoking during pregnancy (MSDP) has been linked to offspring's externalizing problems. It has been argued that socio-demographic factors (e.g. maternal age and education), co-occurring environmental risk factors, or pleiotropic genetic effects may account for the association between MSDP and later outcomes. This study provides a comprehensive investigation of the association between MSDP and a single harmonized component of externalizing: aggressive behaviour, measured throughout childhood and adolescence. Methods Data came from four prospective twin cohorts - Twins Early Development Study, Netherlands Twin Register, Childhood and Adolescent Twin Study of Sweden, and FinnTwin12 study - who collaborate in the EU-ACTION consortium. Data from 30 708 unrelated individuals were analysed. Based on item level data, a harmonized measure of aggression was created at ages 9-10; 12; 14-15 and 16-18. Results MSDP predicted aggression in childhood and adolescence. A meta-analysis across the four samples found the independent effect of MSDP to be 0.4% (r = 0.066), this remained consistent when analyses were performed separately by sex. All other perinatal factors combined explained 1.1% of the variance in aggression across all ages and samples (r = 0.112). Paternal smoking and aggressive parenting strategies did not account for the MSDP-aggression association, consistent with the hypothesis of a small direct link between MSDP and aggression. Conclusions Perinatal factors, including MSDP, account for a small portion of the variance in aggression in childhood and adolescence. Later experiences may play a greater role in shaping adolescents' aggressive behaviour.
  • Raubenheimer, Marie-Claire (Helsingin yliopisto, 2020)
    Oil spillages represent a serious environmental hazard for flora and fauna of marine and coastal ecosystems. Though marine oil spills have decreased since the 1970s, the increasing production of petroleum goods remains a potential source of pollution due to its use and transportation. When aquatic organisms, including fish, are exposed to toxic oil compounds, this can cause sublethal morphological changes and increase mortality. In this context, herring have been frequently studied, and results suggest that particularly herrings eggs and larvae are highly susceptible to oil toxicity. In this thesis, a Bayesian meta-analysis was conducted to investigate the effects of crude and fuel oil on the mortality of herring eggs from the genus Clupea. Observations from laboratory studies, collected during a literature review, served as input for the statistical analysis. To this end, Bayesian inference modeling was applied to generate posterior probability distributions for additional mortality caused by exposure to oil mixtures. Also, oil concentration, oil type, exposure time, and temperature were analyzed to study possible correlations with mortality impacts. The results of this study suggest that acute mortality of exposed herring eggs is similar to mortality observed for individuals exposed to only small concentrations or none at all. Of all evaluated oil types, medium grade crude oil caused the most significant change in instantaneous mortality with increasing oil concentration. Generally, distinct oil types had a greater influence on mortality outcomes than temperatures at the given concentrations. For the lowest temperatures, some correlations for increased mortality were found. Overall, the unexplained variability between the reviewed studies has a relatively small influence on mortality outcomes. In conclusion, the mortality of exposed herrings eggs is most likely delayed due to sublethal effects, rather than immediate, at the modeled concentrations. Altogether, uncertainty amongst the posterior probability distributions is high, indicating a wide possibility range for the monitored parameters' actual values. The reasons for elevated uncertainty likely stem from diverse experimental setups, biological differences between tested species, relatively small sample sizes, and model-related issues. Thus, future research could consider additional variables, information from observational studies and other fish species to reduce uncertainty in mortality outcomes.
  • Honkalampi, Kirsi; Jokela, Markus; Lehto, Soili M.; Kivimäki, Mika; Virtanen, Marianna (2022)
    Alexithymia has been associated with substance use, but the magnitude of the association has not been evaluated and sub-group differences, if any, are unknown. The aim of this meta-analysis is to systematically review the association between alexithymia and substance use (alcohol or illicit drugs). We identified studies through a systematic review of PubMed and Web of Science and obtained a total of 52 publications using the Toronto Alexithymia Scale-20 scale. Random effects meta-analysis was used to evaluate the overall and sub-group associations. Of the studies, 50 were cross-sectional and two longitudinal. Alexithymia was associated with any substance use (Cohen's d = 0.62, 95% confidence interval [CI] 0.49-0.76), with little difference between estimates for use of alcohol or illicit drugs. A stronger association was observed for the alexithymia dimension "Difficulty in Identifying Feelings" (d = 0.64, 95% CI = 0.47-0.81) and "Difficulty in Describing Feelings" (d = 0.44, 95% CI = 0.32-0.55) than for "Externally Oriented Thinking" (d = 0.19, 95% CI = 0.09-0.28). The association was stronger in studies with clinical patient populations (d = 0.83, 95% CI = 0.62-1.05) than in those investigating general or student populations, and in studies with a majority of male rather than female participants. These findings suggest a strong overall association between alexithymia and substance use and a very strong association among clinical patient populations. The association may be stronger with the emotion-related dimensions than with the cognition-related dimension of alexithymia. As nearly all the studies were cross-sectional, more longitudinal studies are needed.
  • Schillemans, Tessa; Tragante, Vinicius; Maitusong, Buamina; Gigante, Bruna; Cresci, Sharon; Laguzzi, Federica; Vikstrom, Max; Richards, Mark; Pilbrow, Anna; Cameron, Vicky; Foco, Luisa; Doughty, Robert N.; Kuukasjarvi, Pekka; Allayee, Hooman; Hartiala, Jaana A.; Tang, W. H. Wilson; Lyytikainen, Leo-Pekka; Nikus, Kjell; Laurikka, Jari O.; Srinivasan, Sundararajan; Mordi, Ify R.; Trompet, Stella; Kraaijeveld, Adriaan; van Setten, Jessica; Gijsberts, Crystel M.; Maitland-van der Zee, Anke H.; Saely, Christoph H.; Gong, Yan; Johnson, Julie A.; Cooper-DeHoff, Rhonda M.; Pepine, Carl J.; Casu, Gavino; Leiherer, Andreas; Drexel, Heinz; Horne, Benjamin D.; van der Laan, Sander W.; Marziliano, Nicola; Hazen, Stanley L.; Sinisalo, Juha; Kahonen, Mika; Lehtimaki, Terho; Lang, Chim C.; Burkhardt, Ralph; Scholz, Markus; Jukema, J. Wouter; Eriksson, Niclas; Akerblom, Axel; James, Stefan; Held, Claes; Hagstrom, Emil; Spertus, John A.; Algra, Ale; de Faire, Ulf; Akesson, Agneta; Asselbergs, Folkert W.; Patel, Riyaz S.; Leander, Karin (2022)
    Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD.Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed.Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98-1.05 and rs7672915, HR: 0.97, 95% CI 0.94-1.00; rs3755863, HR: 1.02, 95% CI 0.99-1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged >= 65, 2) individuals with renal impairment, and 3) antiplatelet users.Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline.
  • Broderick, David T. J.; Waite, David W.; Marsh, Robyn L.; Camargo, Carlos A.; Cardenas, Paul; Chang, Anne B.; Cookson, William O. C.; Cuthbertson, Leah; Dai, Wenkui; Everard, Mark L.; Gervaix, Alain; Harris, J. Kirk; Hasegawa, Kohei; Hoffman, Lucas R.; Hong, Soo-Jong; Josset, Laurence; Kelly, Matthew S.; Kim, Bong-Soo; Kong, Yong; Li, Shuai C.; Mansbach, Jonathan M.; Mejias, Asuncion; O'Toole, George A.; Paalanen, Laura; Perez-Losada, Marcos; Pettigrew, Melinda M.; Pichon, Maxime; Ramilo, Octavio; Ruokolainen, Lasse; Sakwinska, Olga; Seed, Patrick C.; van der Gast, Christopher J.; Wagner, Brandie D.; Yi, Hana; Zemanick, Edith T.; Zheng, Yuejie; Pillarisetti, Naveen; Taylor, Michael W. (2021)
    Introduction: The airway microbiota has been linked to specific paediatric respiratory diseases, but studies are often small. It remains unclear whether particular bacteria are associated with a given disease, or if a more general, non-specific microbiota association with disease exists, as suggested for the gut. We investigated overarching patterns of bacterial association with acute and chronic paediatric respiratory disease in an individual participant data (IPD) meta-analysis of 16S rRNA gene sequences from published respiratory microbiota studies.Methods: We obtained raw microbiota data from public repositories or via communication with corresponding authors. Cross-sectional analyses of the paediatric (10 case subjects were included. Sequence data were processed using a uniform bioinformatics pipeline, removing a potentially substantial source of variation. Microbiota differences across diagnoses were assessed using alpha- and beta-diversity approaches, machine learning, and biomarker analyses.Results: We ultimately included 20 studies containing individual data from 2624 children. Disease was associated with lower bacterial diversity in nasal and lower airway samples and higher relative abundances of specific nasal taxa including Streptococcus and Haemophilus. Machine learning success in assigning samples to diagnostic groupings varied with anatomical site, with positive predictive value and sensitivity ranging from 43 to 100 and 8 to 99%, respectively.Conclusion: IPD meta-analysis of the respiratory microbiota across multiple diseases allowed identification of a non-specific disease association which cannot be recognised by studying a single disease. Whilst imperfect, machine learning offers promise as a potential additional tool to aid clinical diagnosis.
  • Heliste, Maria; Pettilä, Ville; Berger, David; Jakob, Stephan M.; Wilkman, Erika (2022)
    Background Critical illness may lead to activation of the sympathetic system. The sympathetic stimulation may be further increased by exogenous catecholamines, such as vasopressors and inotropes. Excessive adrenergic stress has been associated with organ dysfunction and higher mortality. beta-Blockers may reduce the adrenergic burden, but they may also compromise perfusion to vital organs thus worsening organ dysfunction. To assess the effect of treatment with beta-blockers in critically ill adults, we conducted a systematic review and meta-analysis of randomized controlled trials. Materials and methods We conducted a search from three major databases: Ovid Medline, the Cochrane Central Register for Controlled Trials and Scopus database. Two independent reviewers screened, selected, and assessed the included articles according to prespecified eligibility criteria. We assessed risk of bias of eligible articles according to the Cochrane guidelines. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Sixteen randomized controlled trials comprising 2410 critically ill patients were included in the final review. A meta-analysis of 11 trials including 2103 patients showed a significant reduction in mortality in patients treated with beta-blockers compared to control (risk ratio 0.65, 95%CI 0.53-0.79; p < .0001). There was no significant difference in mean arterial pressure or vasopressor load. Quality of life, biventricular ejection fraction, blood lactate levels, cardiac biomarkers and mitochondrial function could not be included in meta-analysis due to heterogenous reporting of outcomes. Conclusions In this systematic review we found that beta-blocker treatment reduced mortality in critical illness. Use of beta-blockers in critical illness thus appears safe after initial hemodynamic stabilization. High-quality RCT's are needed to answer the questions concerning optimal target group of patients, timing of beta-blocker treatment, choice of beta-blocker, and choice of physiological and hemodynamic parameters to target during beta-blocker treatment in critical illness. KEY MESSAGES A potential outcome benefit of beta-blocker treatment in critical illness exists according to the current review and meta-analysis. Administration of beta-blockers to resuscitated patients in the ICU seems safe in terms of hemodynamic stability and outcome, even during concomitant vasopressor administration. However, further studies, preferably large RCTs on beta-blocker treatment in the critically ill are needed to answer the questions concerning timing and choice of beta-blocker, patient selection, and optimal hemodynamic targets.
  • Ritzel, Robert; Roussel, Ronan; Giaccari, Andrea; Vora, Jiten; Brulle-Wohlhueter, Claire; Yki-Järvinen, Hannele (2018)
    AimsTo investigate the efficacy and safety of insulin glargine 300U/mL (Gla-300) vs insulin glargine 100U/mL (Gla-100) over 12months in a patient-level meta-analysis, using data from the EDITION studies in people with type 2 diabetes (T2DM). Methods EDITION 1, 2 and 3 were multicentre, randomized, open-label, 2-arm, parallel-group, treat-to-target phase IIIa studies. Similar study designs and endpoints enabled a meta-analysis to be conducted. ResultsReductions in glycated haemoglobin (HbA1c) were better sustained over 12months with Gla-300 than with Gla-100 (least squares [LS] mean difference in change from baseline: -0.10 % [95% confidence interval {CI} -0.18 to -0.02] or -1.09mmol/mol [95% CI -2.01 to -0.20]; P=.0174). Risk of confirmed (3.9mmol/L) or severe hypoglycaemia was 15% lower with Gla-300 vs Gla-100 at night (relative risk 0.85 [95% CI 0.77-0.92]) and 6% lower at any time of day (relative risk 0.94 [95% CI 0.90-0.98]). Rates of hypoglycaemia were 18% lower with Gla-300 vs Gla-100 at night (rate ratio 0.82 [95% CI 0.67-0.99]), but comparable at any time of day. HbA1c ConclusionsIn a broad population of people with T2DM over 12months, use of Gla-300 provided more sustained glycaemic control and significantly lower hypoglycaemia risk at night and at any time of day compared with Gla-100.
  • Hemilä, Harri; Chalker, Elizabeth (2022)
    Evidence has shown unambiguously that, in certain contexts, vitamin C is effective against the common cold. However, in mainstream medicine, the views on vitamin C and infections have been determined by eminence-based medicine rather than evidence-based medicine. The rejection of the demonstrated benefits of vitamin C is largely explained by three papers published in 1975-two published in JAMA and one in the American Journal of Medicine-all of which have been standard citations in textbooks of medicine and nutrition and in nutritional recommendations. Two of the papers were authored by Thomas Chalmers, an influential expert in clinical trials, and the third was authored by Paul Meier, a famous medical statistician. In this paper, we summarize several flaws in the three papers. In addition, we describe problems with two recent randomized trial reports published in JAMA which were presented in a way that misled readers. We also discuss shortcomings in three recent JAMA editorials on vitamin C. While most of our examples are from JAMA, it is not the only journal with apparent bias against vitamin C, but it illustrates the general views in mainstream medicine. We also consider potential explanations for the widespread bias against vitamin C.
  • Hemilä, Harri; Chalker, Elizabeth (2021)
    In this individual patient data meta-analysis we examined datasets of two randomized placebo-controlled trials which investigated the effect of nasal carrageenan separately on children and adults. In both trials, iota-carrageenan was administered nasally three times per day for 7 days for patients with the common cold and follow-up lasted for 21 days. We used Cox regression to estimate the effect of carrageenan on recovery rate. We also used quantile regression to calculate the effect of carrageenan on colds of differing lengths. Nasal carrageenan increased the recovery rate from all colds by 54% (95% CI 15%-105%; p = .003). The increase in recovery rate was 139% for coronavirus infections, 119% for influenza A infections, and 70% for rhinovirus infections. The mean duration of all colds in the placebo groups of the first four quintiles were 4.0, 6.8, 8.8, and 13.7 days, respectively. The fifth quintile contained patients with censored data. The 13.7-day colds were shortened by 3.8 days (28% reduction), and 8.8-day colds by 1.3 days (15% reduction). Carrageenan had no meaningful effect on shorter colds. In the placebo group, 21 patients had colds lasting over 20 days, compared with six patients in the carrageenan group, which corresponds to a 71% (p = .003) reduction in the risk of longer colds. Given that carrageenan has an effect on diverse virus groups, and effects at the clinical level on two old coronaviruses, it seems plausible that carrageenan may have an effect on COVID-19. Further research on nasal iota-carrageenan is warranted.
  • Rueegg, Corina S.; Stenehjem, Jo S.; Egger, Matthias; Ghiasvand, Reza; Cho, Eunyoung; Lund, Eiliv; Weiderpass, Elisabete; Green, Adele C.; Veierod, Marit B. (2019)
    Whether sunscreen use affects melanoma risk has been widely studied with contradictory results. To answer this question we performed a systematic review of all published studies, accounting for sources of heterogeneity and bias. We searched for original articles investigating the sunscreen-melanoma association in humans to February 28, 2018. We then used random-effects meta-analysis to combine estimates of the association, stratified by study design. Stratified meta-analysis and meta-regression were used to identify sources of heterogeneity. We included 21,069 melanoma cases from 28 studies published 1979-2018: 23 case-control (11 hospital-based, 12 population-based), 1 ecological, 3 cohort and 1 randomised controlled trial (RCT). There was marked heterogeneity across study designs and among case-control studies but adjustment for confounding by sun exposure, sunburns and phenotype systematically moved estimates toward decreased melanoma risk among sunscreen users. Ever- vs. never-use of sunscreen was inversely associated with melanoma in hospital-based case-control studies (adjusted odds ratio (OR) = 0.57, 95%confidence interval (CI) 0.37-0.87, p(heterogeneity) <0.001), the ecological study (rate ratio = 0.48, 95%CI 0.35-0.66), and the RCT (hazard ratio (HR) = 0.49, 95%CI 0.24-1.01). It was not associated in population-based case-control studies (OR = 1.17, 95%CI 0.90-1.51, p(heterogeneity) <0.001) and was positively associated in the cohort studies (HR = 1.27, 95%CI 1.07-1.51, p(heterogeneity) = 0.236). The association differed by latitude (p(interaction) = 0.042), region (p(interaction) = 0.008), adjustment for naevi/freckling (p(interaction) = 0.035), and proportion of never-sunscreen-users (p(interaction) = 0012). Evidence from observational studies on sunscreen use and melanoma risk was weak and heterogeneous, consistent with the challenges of controlling for innate confounding by indication. The only RCT showed a protective effect of sunscreen. What's new? Effectiveness of sunscreen in reducing UV-induced skin damage has been proven in experimental studies, but effectiveness in reducing melanoma in humans remains inconclusive. This is the first meta-analysis to analyze data from four study designs, stratify hospital- and population-based case-control studies, and include as many as five prospective studies. Evidence from observational studies on the sunscreen-melanoma association was heterogeneous, consistent with the challenges of controlling for innate confounding by indication. The only randomized controlled trial showed a protective effect. Public health recommendations should place greater emphasis on the proper use of sunscreen in conjunction with other means of sun protection.
  • Kaartinen, Niina E.; Knekt, Paul; Kanerva, Noora Karoliina; Valsta, Liisa M.; Eriksson, Johan Gunnar; Rissanen, Harri; Jaaskelainen, Tuija; Männistö, Satu (2016)
    Background: The relationship between carbohydrate intake, dietary glycaemic index (GI) and load (GL), and obesity remains unsolved. Sugar intake and obesity represent a timely topic, but studies on sugar subcategories are scarce. We aimed to study whether total carbohydrate, sucrose, lactose, fibre, dietary GI, and GL are associated with obesity in 25-79-year-old Finns. Methods: Our pooled analysis included three cross-sectional population-based studies: the DILGOM Study (n = 4842), the Helsinki Birth Cohort Study (n =1979), and the Health 2000 Survey (n = 5521). Diet was assessed by a validated food-frequency questionnaire, and anthropometric measurements were collected by standardised protocols. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression analysis. Results: In the model, which included sex, age, education, smoking, physical activity, and energy intake, the likelihood of being obese (body mass index >= 30 kg/m(2)) appeared lower in the highest quartiles of total carbohydrate (OR 0.65; 95% CI 0.57-0.74; P for trend <0.0001), sucrose (OR 0.53; 95% CI 0.47-0.61; P <0.0001), and dietary GL (OR 0.64; 95% CI 0.56-0.73; P <0.0001) compared to the lowest quartiles. In contrast, dietary GI did not associate with obesity. Fibre intake associated inversely with abdominal obesity (OR 0.80; 95% CI 0.71-0.90; P <0.001). The inverse sucrose obesity relationship appeared stronger in high fruit consumers compared to low fruit consumers (P for interaction 0.02). Conclusions: Although most of the studied carbohydrate exposures were associated with a diminished likelihood of being obese, prospective studies are needed to assess temporal relations to support causal inference.
  • Stroke Thrombolysis Trialists' (2018)
    Background The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5h. Methods We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0-1) at 3-6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality. Results Alteplase increased the odds of modified Rankin score 0-1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (odds ratio 1.42, 95% CI 1.21-1.68 and 1.43, 1.23-1.65, respectively), but not in those outside the age-revised label (1.06, 0.90-1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76-1.25 and 1.01, 0.86-1.19, respectively) but mortality remained higher outside the age-revised label (1.19, 0.99-1.42). Similarly, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19-2.01 and 1.37, 1.17-1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97-1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77-1.26 and 1.02, 0.87-1.20, respectively) but mortality remained higher outside the 4.5-h revised approval (1.17, 0.98-1.41). Conclusions An age-revised European Union label or 4.5-h-revised United States label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.
  • Jia, Qiong; Han, Yi; Huang, Pin; Woodward, Nicholas C.; Gukasyan, Janet; Kettunen, Johannes; Ala-Korpela, Mika; Anufrieva, Olga; Wang, Qin; Perola, Markus; Raitakari, Olli; Lehtimaki, Terho; Viikari, Jorma; Jarvelin, Marjo-Riitta; Boehnke, Michael; Laakso, Markku; Mohlke, Karen L.; Fiehn, Oliver; Wang, Zeneng; Tang, W. H. Wilson; Hazen, Stanley L.; Hartiala, Jaana A.; Allayee, Hooman (2019)
    Background-Recent studies have revealed sexually dimorphic associations between the carbamoyl-phosphate synthase 1 locus, intermediates of the metabolic pathway leading from choline to urea, and risk of coronary artery disease (CAD) in women. Based on evidence from the literature, the atheroprotective association with carbamoyl-phosphate synthase 1 could be mediated by the strong genetic effect of this locus on increased circulating glycine levels. Methods and Results-We sought to identify additional genetic determinants of circulating glycine levels by carrying out a metaanalysis of genome-wide association study data in up to 30 118 subjects of European ancestry. Mendelian randomization and other analytical approaches were used to determine whether glycine-associated variants were associated with CAD and traditional risk factors. Twelve loci were significantly associated with circulating glycine levels, 7 of which were not previously known to be involved in glycine metabolism (ACADM, PHGDH, COX1 8-ADAMTS3, PSPH, TRIB 1 , PTPRD, and ABO). Glycine-raising alleles at several loci individually exhibited directionally consistent associations with decreased risk of CAD. However, these effects could not be attributed directly to glycine because of associations with other CAD-related traits. By comparison, genetic models that only included the 2 variants directly involved in glycine degradation and for which there were no other pleiotropic associations were not associated with risk of CAD or blood pressure, lipid levels, and obesity-related traits. Conclusions-These results provide additional insight into the genetic architecture of glycine metabolism, but do not yield conclusive evidence for a causal relationship between circulating levels of this amino acid and risk of CAD in humans.
  • Singh, Sonal; Warren, Helen R.; Hiltunen, Timo P.; McDonough, Caitrin W.; El Rouby, Nihal; Salvi, Erika; Wang, Zhiying; Garofalidou, Tatiana; Fyhrquist, Frej; Kontula, Kimmo K.; Glorioso, Valeria; Zaninello, Roberta; Glorioso, Nicola; Pepine, Carl J.; Munroe, Patricia B.; Turner, Stephan T.; Chapman, Arlene B.; Boerwinkle, Eric; Johnson, Julie A.; Gong, Yan; Cooper-DeHoff, Rhonda M. (2019)
    Background-There exists a wide interindividual variability in blood pressure (BP) response to beta(1)-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants beta(1)-influencing blocker BP response. Methods and Results-Genome-wide association analysis for systolic BP and diastolic BP response to beta(1)-blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta-analysis and single nucleotide polymorphisms (SNPs) with P Conclusions-Data from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST1 containing locus on chromosome 4 is associated with beta(1)-blocker BP response. Given the previous associations of this region with BP, this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.
  • Plassais, Jonathan; Gbikpi-Benissan, Guillaume; Figarol, Marine; Scheperjans, Filip; Gorochov, Guy; Derkinderen, Pascal; Cervino, Alessandra C. L. (2021)
    The gut-brain axis may play a central role in the pathogenesis of neurological disorders. Dozens of case-control studies have been carried out to identify bacterial markers by the use of targeted metagenomics. Alterations of several taxonomic profiles have been confirmed across several populations, however, no consensus has been made regarding alpha-diversity. A recent publication has described and validated a novel method based on richness and evenness measures of the gut microbiome in order to reduce the complexity and multiplicity of alpha-diversity indices. We used these recently described richness and evenness composite measures to investigate the potential link between gut microbiome alpha-diversity and neurological disorders and to determine to what extent it could be used as a marker to diagnose neurological disorders from stool samples. We performed an exhaustive review of the literature to identify original published clinical studies including 16S rRNA gene sequencing on Parkinson's disease, multiple Sclerosis and Alzheimer's disease. Richness and evenness factors loadings were quantified from sequencing files in addition with the Shannon diversity index. For each disease, we performed a meta-analysis comparing the indices between patients and healthy controls. Seven studies were meta-analysed for Parkinson's disease, corresponding to 1067 subjects (631 Parkinson's Disease/436 healthy controls). Five studies were meta-analysed for multiple sclerosis, corresponding to 303 subjects (164 Multiple Sclerosis/139 healthy controls). For Alzheimer's disease, the meta-analysis was not done as only two studies matched our criteria. Neither richness nor evenness was significantly altered in Parkinson's disease and multiple sclerosis patients in comparison to healthy controls (P-value > 0.05). Shannon index was neither associated with neurological disorders (P-value > 0.05). After adjusting for age and sex, none of the alpha-diversity measures were associated with Parkinson's Disease. This is the first report investigating systematically alpha-diversity and its potential link to neurological disorders. Our study has demonstrated that unlike in other gastro-intestinal, immune and metabolic disorders, loss of bacterial diversity is not associated with Parkinson's disease and multiple sclerosis.
  • Nevalainen, Terttu; Säily, Tanja; Vartiainen, Turo; Liimatta, Aatu; Lijffijt, Jefrey (2020)
    In this paper, we explore the rate of language change in the history of English. Our main focus is on detecting periods of accelerated change in Middle English (1150–1500), but we also compare the Middle English data with the Early Modern period (1500–1700) in order to establish a longer diachrony for the pace at which English has changed over time. Our study is based on a meta-analysis of existing corpus research, which is made available through a new linguistic resource, the Language Change Database (LCD). By aggregating the rates of 44 individual changes, we provide a critical assessment of how well the theory of punctuated equilibria (Dixon 1997) fits with our results. More specifically, by comparing the rate of language change with major language-external events, such as the Norman Conquest and the Black Death, we provide the first corpus-based meta-analysis of whether these events, which had significant societal consequences, also had an impact on the rate of language change. Our results indicate that major changes in the rate of linguistic change in the late medieval period could indeed be connected to the social and cultural after-effects of the Norman Conquest. We also make a methodological contribution to the field of English historical linguistics: by re-using data from existing research, linguists can start to ask new, fundamental questions about the ways in which language change progresses.
  • Wang, Haining; Liu, Ye; Tian, Qing; Yang, Jin; Lu, Ran; Zhan, Siyan; Haukka, Jari; Hong, Tianpei (2018)
    Aims: To perform a meta-analysis of randomized controlled trials (RCTs), including 6 recently published large-scale cardiovascular outcome trials (CVOTs), to evaluate the risk of pancreatic cancer with incretin-based therapies in patients with type 2 diabetes (T2DM). Materials and Methods: For the period January 1, 2007 to May 1, 2017, the PubMed, Embase, Cochrane Central Register and databases were searched for RCTs in people with T2DM that compared incretin drugs with placebo or other antidiabetic drugs, with treatment and follow-up durations of >= 52 weeks. Two reviewers screened the studies, extracted the data and assessed the risk of bias independently and in duplicate. Results: A total of 33 studies (n = 79971), including the 6 CVOTs, with 87 pancreatic cancer events were identified. Overall, the pancreatic cancer risk was not increased in patients administered incretin drugs compared with controls (Peto odds ratio [OR] 0.67, 95% confidence interval [CI] 0.44-1.02). In the 6 CVOTs, 79 pancreatic cancer events were identified in 55248 participants. Pooled estimates of the 6 CVOTs showed an identical tendency (Peto OR 0.65, 95% CI 0.42-1.01). Notably, in the subgroup of participants who received treatment and follow-up for >= 104 weeks, 84 pancreatic cancer events were identified in 59919 participants, and a lower risk of pancreatic cancer was associated with incretin-based therapies (Peto OR 0.62, 95% CI 0.41-0.95). Conclusions: Treatment with incretin drugs was not associated with an increased risk of pancreatic cancer in people with T2DM. Instead, it might protect against pancreatic malignancy in patients treated for 104 weeks.