Compare and Contrast Meta Analysis (CCMA)

Genetic epidemiology has moved from linkage studies via candidate gene association studies towards genome wide association studies (GWAS), which use single nucleotide variants (SNVs), the smallest genetic entity, to map diseases to susceptibility loci in a hypothesis free way. The era of GWAS started in 2005, when high throughput genotyping became feasible and affordable, and it has since been a great success. GWAS have revealed many markers associated with complex diseases, and meta-analyses of several GWAS further increased the set of known disease-related variants. Besides the identification of disease specific effects, GWAS-based methods revealed susceptibility loci shared between several clinically related and also unrelated diseases. These pleiotropic loci are of high biological interest considering that they may mark shared or branching pathophysiological mechanisms. Customized genotyping arrays, e.g. the Immunochip, further supported the view that several diseases map to the same susceptibility loci showing agonistic and antagonistic effects. Some methods have been proposed for investigating and searching for genetic overlap between diseases, however there is still a need for sound statistical methods to address this issue. The aim of this thesis was to develop a method based on meta-analysis techniques to compare and contrast two complex diseases, in particular, to find agonistic and antagonistic loci that may contribute to the understanding of the genetic architecture of psoriasis and atopic eczema. This work presents a new method, the Compare & Contrast Meta Analysis (CCMA), which allows researchers to compare and contrast two diseases on a genetic basis. Meta-analysis techniques are used to impose a test statistic that allows for identifying agonistic and antagonistic effects. A closed form for the density and cumulative distribution function of the CCMA test statistic is presented, which, conveniently for practical reasons, turns out to be exponentially distributed. Hence, thresholds for suggestive and genome- wide significant association can easily be derived and, in contrast to the already reported Subset-Based Meta Analysis (SBMA), the mode of pleiotropy can be inferred directly. Modified versions of the test statistic allow incorporating study size, which, depending on the transformation matrix, improve the power for detecting agonistic or antagonistic effects. The power and type I error of the CCMA method are compared with those of the SBMA method by simulation. The CCMA method shows marginally lower power than SBMA but the type I error is better controlled. The CCMA method is applied to several published GWAS on atopic eczema and psoriasis. In order to compare it with the computer intensive multinomial regression models (MNM), the SBMA is used to reduce the vast amount of SNVs to those showing at least suggestive disease-specific or pleiotropic effects. These SNVs are reanalyzed using MNM, and their effect categorization (disease-specific or pleiotropic) is compared with the ones obtained by the CCMA method. The comparison reveals high agreement of 85.5% overall and 93.6% without the most complex Human Leukocyte Antigen (HLA) region, which demonstrates the usability of the new method. Finally, the CCMA is compared with the COMPARED & OVERLAP approach in terms of identification of associated SNVs and concordance of effect categorization with the MNM as gold standard. This work shows that the CCMA method is an appealing approach to identify disease-specific and pleiotropic loci using available GWAS data and effectively exploits additional cross-phenotype information. It shows comparable power to the SBMA method while better controlling the type 1 error and outperforms the COMPARED & OVERLAP approach. It shows high agreement with the MNM in terms of effect categorization. Finally, the CCMA method can also be applied to other genome-wide molecular data such as gene expression, epigenomics or metabolomics, as well as to other research questions that arise in environmental epidemiology. In that context, the influence of lifestyle factors or environmental exposures on two different diseases can be investigated with regard to their concordant or contrasting effect.Die genetische Epidemiologie hat sich in den letzten Jahren von Kopplungsstudien über Kandidatengen-Assoziationsstudien hin zu genomweiten Assoziationsstudien (GWAS) entwickelt, welche basierend auf der kleinsten genetischen Einheit, den Einzelnukleotidvari- anten (single nucleotide variants, SNVs), Erkrankungen auf agnostische Weise im Genom kartiert. Die Ära der GWAS, die 2005 begann, als die Hochdurchsatzgenotypisierung zu annehmbaren Kosten technisch realisierbar wurde, war ein großer Erfolg. GWAS haben viele Marker, die mit komplexen Erkrankungen assoziiert sind, identifiziert, und Meta-Analysen von mehreren GWAS zur gleichen Erkrankung haben die Menge der bekannten krankheitsbezogenen Varianten erweitert. Neben krankheitsspezifischen Effekten wurden mit GWAS-basierten Methoden gemeinsame Loci von klinisch verwandten und nicht verwandten Erkrankungen entdeckt. Diese pleiotropen Loci sind von großem biologis- chem Interesse, da sie gemeinsame und verzweigende pathophysiologische Mechanismen anzeigen. Die erfolgreiche Verwendung nutzerspezifischer Genchips, wie z.B. des Immunochip, belegen die Vermutung, dass verschiedenen Erkrankungen dieselben Suszeptibilitätsloci zugrunde liegen, die agonistische oder antagonistische Effekte aufweisen. Es wurden bereits statistische Methoden entwickelt, um gemeinsame genetische Komponenten verschiedener Erkrankungen zu identifizieren, jedoch besteht weiterhin Forschungsbedarf in diesem Bereich. Ziel dieser Arbeit ist es, eine auf Meta-Analyse basierende Methode zu entwickeln, um zwei komplexe Erkrankungen zu vergleichen und zu kontrastieren, insbesondere um agonistische und antagonistische Loci zu identifizieren, die zum Verständnis der genetischen Grundlage der Psoriasis und des atopischem Ekzems beitragen. Die vorliegende Arbeit präsentiert die Compare & Contrast Meta Analysis (CCMA) Methode, die es erlaubt, zwei Erkrankungen hinsichtlich ihrer genetischen Grundlage zu vergleichen und zu kontrastieren. Dazu wird eine Teststatistik basierend auf Meta-Analyse-Ergebnissen entwickelt, die agonistische und antagonistische Effekte untersucht. Für die Verteilung der Teststatistik kann eine geschlossene Form angegeben werden, die kritische Werte für suggestive und genomweite signifikante Assoziationen liefert. Analy- sen zur Power und zum Fehler 1. Art werden durchgeführt, um die CCMA-Methode mit der bereits bekannten Subset-Based Meta-Analyse (SBMA) zu vergleichen. Die CCMA-Methode wird auf verschiedene GWAS-Daten zur Psoriasis und zum atopischen Ekzem angewendet und selektiert SNVs mit krankheitsspezifischen oder pleiotropen Effekten, die die Signifikanzschranke für suggestive Assoziation unterschreiten. Diese SNVs werden mit Hilfe des multinomialen Regressionsmodells (MNM) erneut analysiert und die Kategorisierung in krankheitsspezifische oder pleiotrope Effekte mit jener der CCMA-Methode verglichen. Eine große Übereinstimmung beider Methoden von 85.5% insgesamt bzw. 93.6% ohne die komplexe humane Leukozytenantigenregion (HLA-Region) bestätigt die Verwendbarkeit der neuen Methode. Schließlich wird die CCMA mit der SBMA und der COMPARED & OVERLAP Methode hinsichtlich identifizierter SNVs und Übereinstimmung der Effektkategorisierung mit dem MNM als Goldstandard verglichen. Die CCMA-Methode basiert auf Meta-Analyse-Teststatistiken mit guter Power und ist schnell und einfach zu implementieren. Sie kann sowohl pleiotrope als auch krankheitsspezifische Marker identifizieren. Im Vergleich zu anderen Methoden liegen die Vorteile der CCMA in ihrer Einfachheit und Präzision, ohne individuelle Genotypdaten verwenden zu müssen. Die hohe Übereinstimmung mit dem multinomialen Regressionsmodell als Goldstandard bei der Effektkategorisierung unterstreicht die Nutzbarkeit der neuen Methode

The Effectiveness of Interventions to Reduce Sedentary Time in Different Target Groups and Settings in Germany: Systematic Review, Meta-Analysis and Recommendations on Interventions

Background: Sedentary behavior is an important risk factor for several chronic diseases and is associated with an increased risk of mortality. We assessed the effectiveness of interventions to reduce sedentary time in Germany and provide recommendations on interventions to reduce sedentary time in children and adults. Methods: We comprehensively searched PubMed, Web of Science and the German Clinical Trials Register up to April 2022 for intervention studies targeting sedentary behavior in Germany. We performed a systematic review and qualitative synthesis of the interventions and a meta-analysis in children. Results: We included 15 studies comprising data from 4588 participants. The results of included primary studies in adults and children showed inconsistent evidence regarding change in sedentary time, with a majority of studies reporting non-significant intervention effects. The meta-analysis in children showed an increase in sedentary time for children in the control and intervention groups. Conclusion: We found inconsistent evidence regarding the effectiveness of interventions to reduce time spent sedentary and our meta-analysis showed an increase in sedentary time in children. For children, we recommend physical and social environment interventions with an active involvement of families. For adults, we recommend physical environment interventions, such as height-adjustable desks at work

Supportig Information

Background Atopic dermatitis (AD) is driven by the interplay between a dysfunctional epidermal barrier and a skewed cutaneous immune dysregulation. As part of the complex skin barrier dysfunction, abnormalities in lipid organization and microbiome composition have been described. We set out to systematically investigate the composition of the stratum corneum lipidome, skin microbiome and skin physiology parameters at three different body sites in patients with AD and healthy volunteers. Methods We analysed tape strips from different body areas obtained from 10 adults with AD and 10 healthy volunteers matched for FLG mutation status for 361 skin lipid species using the Metabolon mass spectrometry platform. 16S rRNA data were available from all probands. Results Our study showed that the lipid composition differs significantly between body sites and between AD patients and healthy individuals. Ceramide species NS was significantly higher in AD patients compared to healthy volunteers and was also higher in AD patients with a FLG mutation compared to AD patients without a FLG mutation. The correlation analysis of skin lipid alterations with the microbiome showed that Staphylococcus colonization in AD is positively correlated with ceramide subspecies AS, ADS, NS and NDS. Conclusion This is the first study to reveal site-specific lipid alterations and correlations with the skin microbiome in AD

A Mendelian randomization study on the effect of 25‐hydroxyvitamin D levels on periodontitis

Abstract Background Twenty five‐hydroxy vitamin D (25OHD) levels have been proposed to protect against periodontitis based on in vitro and observational studies but evidence from long‐term randomized controlled trials (RCTs) is lacking. This study tested whether genetically proxied 25OHD is associated with periodontitis using Mendelian randomization (MR). Methods Genetic variants strongly associated with 25OHD in a genome‐wide association study (GWAS) of 417,580 participants of European ancestry were used as instrumental variables, and linked to GWAS summary data of 17,353 periodontitis cases and 28,210 controls. In addition to the main analysis using an inverse variance weighted (IVW) model, we applied additional robust methods to control for pleiotropy. We also undertook sensitivity analyses excluding single nucleotide polymorphisms (SNPs) used as instruments with potential pleiotropic effects and used a second 25OHD GWAS for replication. We identified 288 SNPs to be genome‐wide significant for 25OHD, explaining 7.0% of the variance of 25OHD levels and providing ≥90% power to detect an odds ratio (OR) of ≤ 0.97. Results MR analysis suggested that a 1 standard deviation increase in natural log‐transformed 25OHD was not associated with periodontitis risk (IVW OR = 1.04; 95% confidence interval (CI): 0.97–1.12; P‐value = 0.297). The robust models, replication, and sensitivity analyses were coherent with the primary analysis. Conclusions Collectively, our findings suggest that 25OHD levels are unlikely to have a substantial effect on the risk of periodontitis, but large long‐term RCTs are needed to derive definitive evidence on the causal role of 25OHD in periodontitis

Author Correction: Suicide risk and mortality among patients with cancer.

Correction to: Nature Medicine https://doi.org/10.1038/s41591-022-01745-y. Published online 28 March 2022. In the version of this article initially published, refs. 12 and 16 were duplicated as refs. 21 and 22, which have now been removed and the list renumbered. There were typographical errors in the Supplementary Information which are reflected in descriptions of the meta-analysis in the main text, as follows: the review included 47,035,065 patients with cancer (not 46,952,813, as stated previously), the number of whom died by suicide is 69,401 (not 69,298 as reported previously), encompassing 107,961,345 person-years of follow-up (not 107,691,796, as noted previously); the “Study population” section of the Results now reports 30 studies performed in the USA and 25 in Europe (not 31 and 24, respectively, as stated previously). The abstract and the “Study population,” “Sensitivity analyses using all 62 eligible studies” and “Assessment of publication bias” sections of the Results have been amended. The typographical errors in the Supplementary Information were corrected as follows: pages 6 and 12, Turaga et al., end-time of recruitment updated from 2015 to 2005; page 7, Patasius et al., standardized mortality ratio updated from 1.01 to 1.10; page 7, Levi et al., follow-up in person-years updated from 57,614 to 57,164; page 8, Alanee et al., number of suicide cases updated from 30 to 33; page 9, Osazuwa-Peters et al., study population count updated from 205,658 to 287,901; pages 7 and 11, Kaceniene et al., country of study updated from USA to Lithuania. The results of the metadata analysis remain unchanged. Updates have now been made in the HTML and PDF versions of the full text, Extended Data Figures 2, 4 and 5 and the Supplementary Information

Suicide risk and mortality among patients with cancer

Despite substantial progress in cancer therapy in recent decades, patients with cancer remain at high suicide risk. Data from individual studies have not been comprehensively quantified and specific risk factors are ill-defined. We assessed suicide mortality risk according to cancer prognosis, stage, time since diagnosis, gender, ethnicity, marital status, year of recruitment and geographic region. We searched EMBASE, MEDLINE, PsycINFO, Web of Science, CINAHL and Google Scholar for relevant articles up to February 2021. We used a random effects model, performed meta-regression meta-analysis and assessed heterogeneity and publication bias using I², funnel plots and Egger’s and Begg’s tests. We performed a systematic review including 62 studies and 46,952,813 patients. To avoid patient sample overlap, the meta-analysis was performed on 28 studies, involving 22,407,690 patients with cancer. Suicide mortality was significantly increased compared with the general population (standardized mortality ratio = 1.85, 95% confidence interval = 1.55–2.20). Risk was strongly related to cancer prognosis, cancer stage, time since diagnosis and geographic region. Patients with cancer, particularly those with specific risk factors, should be closely monitored for suicidality and need specialized care to reduce short- and long-term risks of suicide

Association between physical activity, grip strength and sedentary behaviour with incidence of malignant melanoma: results from the UK Biobank

Background Physical activity has been positively related to malignant melanoma. However, that association may be confounded by ultraviolet radiation (UV), a variable closely related to both outdoor physical activity and malignant melanoma. We examined physical activity, grip strength and sedentary behaviour in relation to risk of malignant melanoma, accounting for relevant confounders using data from a prospective cohort study. Methods In 350,512 UK Biobank participants aged 38–73 years at baseline, physical activity was assessed with a modified version of the International Physical Activity Questionnaire Short Form, grip strength was measured with a hand dynamometer, and sedentary behaviour was recorded with three specific questions. Multivariable hazard ratios (HR) and corresponding 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. Results During 7 years of follow-up, 1239 incident malignant melanoma diagnoses were recorded. Physical activity and sedentary behaviour were unrelated to malignant melanoma (HRs 1.01 (95% CI 0.95–1.07) and 1.04 (95% CI 0.97–1.12), respectively), and the initially positive association with grip strength in the basic model (HR 1.23, 95% CI 1.08–1.40) was attenuated after full adjustment (HR 1.10, 95% CI 0.96–1.26). Conclusion Physical activity, grip strength and sedentary behaviour are not associated with malignant melanoma risk

No bidirectional relationship between depression and periodontitis: A genetic correlation and Mendelian randomization study

BackgroundObservational and in-vivo research suggested a bidirectional relationship between depression and periodontitis. We estimated the genetic correlation and examined directionality of causation.MethodsThe study used summary statistics from published genome wide association studies, with sample sizes ranging from 45,563 to 797,563 individuals of European ancestry. We performed linkage disequilibrium score regression (LDSC) to estimate global correlation and used Heritability Estimation from Summary Statistics (ρ-HESS) to further examine local genetic correlation. Latent Heritable Confounder Mendelian randomization (LHC-MR), Causal Analysis using Summary Effect estimates (CAUSE), and conventional MR approaches assessed bidirectional causation.ResultsLDSC observed only weak genetic correlation (rg = 0.06, P-Value = 0.619) between depression and periodontitis. Analysis of local genetic correlation using ρ-HESS did not reveal loci of significant local genetic covariance. LHC-MR, CAUSE and conventional MR models provided no support for bidirectional causation between depression and periodontitis, with odds ratios ranging from 1.00 to 1.06 in either direction.ConclusionsResults do not support shared heritability or a causal connection between depression and periodontitis

Targeted therapies in patients with newly diagnosed glioblastoma - a systematic meta-analysis of randomized clinical trials

Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor-treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta-analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled in a random-effects meta-analysis. Twelve RCTs (n=3,941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti-angiogenic approaches, and poly (ADP-ribose) polymerase (PARP) inhibitors were included in the meta-analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR=0.98 [95% Confidence Interval (CI) 0.86-1.11, p=0.7731]. By comparison, targeted therapy showed a benefit for PFS (HR=0.83 [95% CI 0.74-0.94, p=0.0037], especially for patients with an unmethylated O6-Methylguanin-DNA-methyltransferase (MGMT) promoter (0.75 [95% CI 0.56-0.99, p=0.0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR=0.70 [95% CI 0.61-0.80, p=0.0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared with standard care. However, no improvement in OS was observed with any of the targeted agents