Combined Meta-analysis Research Articles

Genomic Association Analysis of Growth and Backfat Traits in Large White Pigs.

The pig industry is significantly influenced by complex traits such as growth rate and fat deposition, which have substantial implications for economic returns. Over the years, remarkable genetic advancements have been achieved through intense artificial selection to enhance these traits in pigs. In this study, we aimed to investigate the genetic factors that contribute to growth efficiency and lean meat percentages in Large White pigs. Specifically, we focused on analyzing two key traits: age at 100 kg live weight (AGE100) and backfat thickness at 100 kg (BF100), in three distinct Large White pig populations-500 Canadian, 295 Danish, and 1500 American Large White pigs. By employing population genomic techniques, we observed significant population stratification among these pig populations. Utilizing imputed whole-genome sequencing data, we conducted single population genome-wide association studies (GWAS) as well as a combined meta-analysis across the three populations to identify genetic markers associated with the aforementioned traits. Our analyses highlighted several candidate genes, such as CNTN1-which has been linked to weight loss in mice and is potentially influential for AGE100-and MC4R, which is associated with obesity and appetite and may impact both traits. Additionally, we identified other genes-namely, PDZRN4, LIPM, and ANKRD22-which play a partial role in fat growth. Our findings provide valuable insights into the genetic basis of these important traits in Large White pigs, which may inform breeding strategies for improved production efficiency and meat quality.

THE ASSOCIATION BETWEEN BLOOD PRESSURE VARIABILITY AND DEMENTIA: A TWO-SAMPLE MENDELIAN RANDOMIZATION STUDY

Objective: This study aims to investigate the causal inference by applying a mendelian randomization (MR) study using single-nucleotide polymorphisms (SNPs) from the genome-wide association study (GWAS) based on the UK biobank. Design and method: The genetic instruments were chosen from BPV GWAS based on UK Biobank data. Four GWA studies were used for the genetic evaluation of dementia, including (1) The International Genomic of Alzheimer's Project (IGAP) GWAS for dementia; (2) and (3) UK Biobank GWAS for proxy phenotypes of Alzheimer's dementia: the maternal and paternal family history (MFH and PFH-UKBB); (4) A combined GWAS meta-analysis from the abovementioned three GWAS results. The following exclusion criteria were applied for SNPs: (1) confounding SNPs by searching hypertension and artery stiffness GWAS; (2) significant SNPs that are associated with dementia in the datasets; (3) palindromic SNPs with an effect allele frequency between 0.4 and 0.7. Proxy SNPs were manually selected for some SNPs. (4) only SNPs with linkage disequilibrium r2 < 0.01 were selected as genetic instruments, also known as independent SNPs. The effect/reference alleles were checked to ensure the consistency of the base pair between BPV and dementia GWAS, which is also known as data harmonization. After data harmonization, four MR methods were employed to measure the causal effect: IVW-MR with random effect, IVW-MR with fixed effect, MR-Egger, and weighted median MR. Results: Finally, six independent SNPs were chosen as instrument variants for SBPV, and five for DBPV. Significant causal effects of SBPV on dementia were found in the PFH-UKBB dataset, and the odds ratio of dementia per 10-unit increase in SBPV was 1.028, 1.015, and 1.015 for MR-Egger, weighted median, and IVW-MR, respectively (Table 1). In contrast, only one significant result was found for DBPV in MFH-UKBB. No significant results were found on other datasets. Conclusions: Along with the evidence from different observational studies, this GWAS study demonstrates that systolic blood pressure variability is a potential causal risk factor for Alzheimer's dementia, while the evidence from diastolic blood pressure variability is still uncertain.

CtDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis.

Cell-free circulating tumor DNA (ctDNA) is synthesized by tumor cells, including metastatic tumors, and circulates in the bloodstream. Evidence suggests that ctDNA is a potential predictive and prognostic biomarker for colorectal cancer (CRC), but its predictive efficacy in detecting CRC liver metastasis (CLM) remains unclear. Additionally, its utility in the clinical setting needs further investigation. We conducted a meta-analysis to determine the utility of ctDNA as a biomarker for predicting the prognosis of CLM and investigate the relationship between CLM and ctDNA positivity. A literature search was performed in electronic databases to identify relevant studies published up to March 19, 2022. We retrieved data on overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) for both ctDNA-positive and ctDNA-negative colorectal liver metastasis (CLM) patients from the selected articles. Hazard ratios (HRs) were also calculated for these survival outcomes analysis was also performed. The stability of the combined meta-analysis was verified by sensitivity analysis and publication bias evaluation. Ten trials were included, and 615 patients were evaluated. In patients with CLM, pooled HRs revealed a substantial link between ctDNA positivity and RFS/DFS. Subgroup analysis revealed that ctDNA had a prospective detection value. Sensitivity analysis and publication bias evaluation indicated stable results. Although the results on pooled HR for OS suggested that ctDNA-positive patients had a shorter survival time, their pooled HRs had a relatively evident heterogeneity, and sensitivity analysis and publication bias evaluation indicated that pooled HRs were extremely unstable. In conclusion, our results demonstrate that ctDNA appears to be a prognostic biomarker for resectable CLM patients.

Low Circulating Valine Associate With High Risk of Hip Fractures.

Hip fractures constitute a major health concern. An adequate supply of amino acids is crucial to ensure optimal acquisition and remodeling of bone. Circulating amino acid levels have been proposed as markers of bone mineral density, but data on their ability to predict incident fractures are scarce. To investigate the associations between circulating amino acids and incident fractures. We used UK Biobank (n = 111 257; 901 hip fracture cases) as a discovery cohort and the Umeå Fracture and Osteoporosis (UFO) hip fracture study (hip fracture cases n = 2225; controls n = 2225) for replication. Associations with bone microstructure parameters were tested in a subsample of Osteoporotic Fractures in Men Sweden (n = 449). Circulating valine was robustly associated with hip fractures in the UK Biobank (HR per SD increase 0.79, 95% CI 0.73-0.84), and this finding was replicated in the UFO study (combined meta-analysis including 3126 incident hip fracture cases, odds ratio per SD increase 0.84, 95% CI 0.80-0.88). Detailed bone microstructure analyses showed that high circulating valine was associated with high cortical bone area and trabecular thickness. Low circulating valine is a robust predictor of incident hip fractures. We propose that circulating valine may add information for hip fracture prediction. Future studies are warranted to determine whether low valine is causally associated with hip fractures.

Racial differences in the major clinical symptom domains of bipolar disorder

BackgroundAcross clinical settings, black individuals are disproportionately less likely to be diagnosed with bipolar disorder compared to schizophrenia, a traditionally more severe and chronic disorder with lower expectations for remission. The causes of this disparity are likely multifactorial, ranging from the effects of implicit bias, to developmental and lifelong effects of structural racism, to differing cultural manifestations of psychiatric symptoms and distress. While prior studies examining differences have found a greater preponderance of specific psychotic symptoms (such as persecutory delusions and hallucinations) and a more dysphoric/mixed mania presentation in Black individuals, these studies have been limited by a lack of systematic phenotypic assessment and small sample sizes. In the current report, we have combined data from two large multi-ethnic studies of bipolar disorder with comparable semi-structured interviews to investigate differences in symptoms presentation across the major clinical symptom domains of bipolar disorder.ResultsIn the combined meta-analysis, there were 4423 patients diagnosed with bipolar disorder type I, including 775 of self-reported as Black race. When symptom presentations were compared in Black versus White individuals, differences were found across all the major clinical symptom domains of bipolar disorder. Psychotic symptoms, particularly persecutory hallucinations and both persecutory and mood-incongruent delusions, were more prevalent in Black individuals with bipolar disorder type I (ORs = 1.26 to 2.45). In contrast, Black individuals endorsed fewer prototypical manic symptoms, with a notably decreased likelihood of endorsing abnormally elevated mood (OR = 0.44). Within depression associated symptoms, we found similar rates of mood or cognitive related mood symptoms but higher rates of decreased appetite (OR = 1.32) and weight loss (OR = 1.40), as well as increased endorsement of initial, middle, and early-morning insomnia (ORs = 1.73 to 1.82). Concurrently, we found that black individuals with BP-1 were much less likely to be treated with mood stabilizers, such as lithium (OR = 0.45), carbamazepine (OR = 0.37) and lamotrigine (OR = 0.34), and moderately more likely to be on antipsychotic medications (OR = 1.25).ConclusionsIn two large studies spanning over a decade, we found highly consistent and enduring differences in symptoms across the major clinical symptom domains of bipolar disorder. These differences were marked by a greater burden of mood-incongruent psychotic symptoms, insomnia and irritability, and fewer prototypical symptoms of mania. While such symptoms warrant better recognition to reduce diagnostic disparities, they may also represent potential targets of treatment that can be addressed to mitigate persistent disparities in outcome.

Professional driver mortality in 9 countries: a systematic review and meta-analysis

A systematic review, combining analysis (on means after deleting outliers from samples) and meta-analysis for Standardized mortality ratio (SMR) versus the general population for total and all-cancer mortality for professional drivers (men only) of various countries (cohorts of Great Britain, Denmark, Iceland, Italy, Canada, Russia, Singapore, Switzerland and Sweden (1988–2002); data for the USA (1978) were not available; 13 papers in total) were conducted. The criteria for the search and selection of sources (PubMed, Google, Cochrane Systematic Reviews and reference lists of publications) were: a) a cohort of drivers only, without adding other employees of auto enterprises; b) the presence in the study of index of total mortality (‘all causes’) and/or mortality from all malignant neoplasms (‘all cancer’); c) the expression of mortality rates only in the SMR index.
 A combined analysis and meta-analysis showed a weak healthy worker effect (HWE; meta-analysis: SMR=0.92, 95% confidence intervals (CI): 0.85, 0.99, the presence of HWE was judged by the value of the upper CI<1.0). There are also trends towards HWE for overall mortality for taxi and truck drivers (SMR=0.9–0.93), but the samples are too small to draw conclusions. For other groups of drivers HWE was not found.
 In both types of synthetic studies, no SMR for HWE was observed for mortality from all malignancies, either for the general group of drivers (8 countries; 16 cohorts) or for individual occupational groups. There were slight increases in SMR (by 3–10%), the magnitude of which, according to epidemiological canons, is difficult to prove, and according to the risk scale by R.R. Monson corresponds to no effect.
 The absence of significant risks both in terms of the integral indicator of well-being (life expectancy, inversely proportional to SMR), and in terms of mortality from all types of malignant neoplasms for professional drivers makes it unlikely that the population of Russia will experience increased mortality due to ever-increasing mass motorization.

Abstract 3168: DE-meta: Revealing tumor gene expression by meta-analysis of RNASeq and proteomics datasets

Abstract Detecting differentially expressed genes under different biological conditions is crucial to characterize mechanisms of cancer development and identifying determinants of patient outcome. High throughput technologies such as RNA sequencing and mass spectrometry-based proteomics have been widely used to identify differentially expressed genes (DEG), on a transcript and on a peptide basis, respectively. However, both transcription and translation of genes provide information about gene expression. Thus, leveraging both RNA and protein expression data could potentially produce more accurate results. Various statistical tools have been developed to tackle the differential expression problem for a single platform, such as edgeR, DESeq2, etc. However, a tool that integrates both transcriptome and proteomics data for differential expression analysis has not yet been developed. Meta-analysis can potentially increase statistical power and generate a more consensus conclusion by combining multiple datasets. Here we present DE-Meta, a new tool developed using R, which performs combined meta-analysis of RNA-seq and MS-based proteomics on matched tumor specimens. To characterize the performance of our method using real world data, we utilized a published lung cancer dataset and set a truth standard of DEG between known two expression subtypes: terminal respiratory unit (TRU) and proximal proliferative (PP). Briefly, we restricted to 7,458 common genes detected by RNA-seq and MS-based proteomics. We then, randomly selected tumors as the truth sample set, n=20 TRU and n=20 PP tumors. With this truth sample set, DEGs were calculated separately by RNA or by protein, using DESeq2 and regression models. The union of these DEGs defined the truth DEG set. Using independent tumors (n=10 TRU and n=10 PP), we applied DE-meta to detect DEGs by RNA, by protein or joint RNA and protein data. Through receiver operating characteristic curve analysis, we show that the DE-meta joint model performed better than the single platform models (joint AUC=0.651, RNA AUC=0.610, protein AUC=0.623). Focusing genes relevant to tumor biology, we found that the DE-meta joint model called an 169 cancer-relevant DEGs, such as MSH2, CD4, WDR3, PIK3R1, and RPS6KA3. which were not detected by the RNA or protein models, at the same false discovery rate threshold of 0.05 (Benjamini-Hochberg procedure). In summary, our new DE-meta tool, by joint analysis of RNA-seq and MS-based proteomics datasets, yields more accurate and biologically-relevant results. The views expressed in this abstract are solely of the authors and do not reflect the official policy of the Departments of Army/Navy/Air Force, Department of Defense, USUHS, HJF, or U.S. Government. Citation Format: Xijun Zhang, Clifton L. Dalgard, Matthew D. Wilkerson. DE-meta: Revealing tumor gene expression by meta-analysis of RNASeq and proteomics datasets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3168.

Mushroom consumption and risk of gastric cancer: a pooled analysis within the stomach cancer pooling project and a combined meta-analysis with other observational studies.

Edible mushrooms have high concentrations of vitamins and minerals. They are considered 'functional foods' for their disease-prevention properties. Mushroom consumption may reduce the risk of gastric cancer, the fifth most common cancer worldwide. We investigated the association between mushroom consumption and gastric cancer risk in a pooled analysis within the Stomach Cancer Pooling (StoP) Project and in a meta-analysis that also included previously published studies. A total of 3900 gastric cancer cases and 7792 controls from 11 studies were included in the StoP analysis. Mushroom consumption was measured using food frequency questionnaires. Higher mushroom consumption was associated with a lower risk of gastric cancer [relative risk (RR) for the highest vs. lowest consumption categories, 0.82; 95% confidence interval (CI), 0.71-0.95]. The corresponding RRs were 0.59 (95% CI, 0.26-1.33) in a meta-analysis of four previously published studies and 0.77 for all studies combined (95% CI, 0.63-0.95; n = 15 studies). In geographic subgroup analysis, the pooled risk in Western Pacific countries was (RR, 0.59; 95% CI, 0.40-0.87; n = 6). The stronger effect in Asian countries may reflect high level of antioxidants in mushroom species consumed in Asia.

Revisiting Unified Theory of Technology and Use of Technology Using Meta-analytic Structural Equation Modelling

The Unified Theory of Technology and Use of Technology (UTAUT) has been widely used in information system studies since its introduction in 2003. The current study synthesizes 40 empirical studies based on UTAUT in educational contexts using the one-stage meta-analytic structural equation modelling method. While the study confirmed the initial findings by Ventakesh et al. (2003), the model in this study underperformed in the explained variance of behavioral intention. However, the explained variance of usage behavior performed better than the original UTAUT. After introducing new direct relationships between the UTAUT constructs, it was found that the construct, facilitating conditions, was a new predictor of behavioral intention. At the same time, effort expectancy and social influence were new predictors of usage behavior. There have been studies on the UTAUT model with many diverse findings since its inception in 2003. The method introduced in this study, a One-Stage combined Meta-Analysis and Structural Equation Modelling (OSMASEM), offers an approach for researchers to use past empirical data to examine the UTAUT framework without relying on replicating similar studies. As more empirical data from UTAUT research are added to train the data model using OSMASEM, researchers can now study how educational technology trends change over time.

Meta-Analysis of Human Leukocyte Antigen-G 3′UTR Polymorphisms Confer Susceptibility to Recurrent Miscarriage

Objectives: The current systematic review and meta-analysis have shown that specific HLA-G 3′ UTR variants are associated with recurrent miscarriage (RM). Our aim was to investigate the relevance of HLA-G 3′ UTR polymorphisms with the risk of RM. Design: A combined meta-analysis was implemented in this study. Participants/Materials, Setting, Methods: Common electronic databases including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Cochrane Library, and Google Scholar were used to seek eligible articles up to August 2021. Results: Forty-four eligible articles with 4,467 cases and 3,955 controls were finally enrolled. Our meta-results suggested that 14 bp insertion allele was associated with elevated risk of RM (allelic model: OR = 1.18, 95% CI = 1.07–1.31, p = 0.001). Besides, a significant heterogeneity was observed between studies. Further subgroup analyses based on ethnicity revealed similar positive results in both the Caucasian and Asian subgroups but not in the Middle East subgroup. Moreover, rs1063320 G allele conferred elevated susceptibility to RM in Asian group (allelic model: OR = 1.54, 95% CI = 1.17–2.03, p = 0.002). Additionally, pooled results showed a decreased risk of RM in mothers carrying rs1710 G allele (allelic model: OR = 0.68, 95% CI = 0.55–0.85, p < 0.001) and an increased risk with rs9380142 A allele (allelic model: OR = 1.45, 95% CI = 1.15–1.83, p = 0.002). Further stratified analyses by race showed that these positive results were mainly from the associations observed in Asian populations. Limitations: The main limitation is that the enrolled number of individuals was relatively small. Thus, the results should be cautiously considered. Conclusions: Although the current systematic review and meta-analysis have shown that specific HLA-G 3′ UTR variants are associated with RM, a high degree of bias is present and further studies are needed to validate this causative effect.

Open Surgical Thrombendarterectomy Versus Endovascular Treatment in Occlusive Processes of the Femoral Artery Bifurcation.

The standard treatment of occlusive processes of the femoral artery bifurcation is thrombendarterectomy (TEA). Endovascular techniques (ENDO) have recently been put forward as a potential alternative. It is unclear so far which modality yields better outcomes with respect to long-term revascularization and periprocedural complications. Method: Multiple databases were systematically searched for pertinent publications (publication date November 1965 to February 2022). From the included studies, individual patient data (IPD) were requested. Aggregate data (AD) were used when no IPD were available. Primary and secondary patency (PP and SP), perioperative morbidity/mortality, and further endpoints were determined separately for TEA and ENDO and compared with each other. AD for each modality were summarized in meta-analyses. Time-to-event analyses and comparative meta-analyses with PP as primary endpoint were carried out using IPD. Results: 42 studies (3 IPD, 39 AD; 27 TEA, 12 ENDO, 3 comparisons of TEA versus ENDO) were included. In the combined meta-analysis of IPD and AD, PP for TEA was 97% at 6 months and 92% at 12 months, while PP for ENDO was 84% at 6 months and 85% at 12 months. The differences were not statistically significant. The comparative meta-analysis regarding PP did not reveal any significant differences either (TEA versus ENDO: HR 0.30 [0.06; 1.48]). SP at 12 months was 97% (TEA) and 93% (ENDO). The periprocedural morbidity was 16% for TEA and 9% for ENDO. Conclusion: In light of a higher PP, even without formal statistical proof of superiority, TEA can still be considered the standard treatment for occlusive processes of the femoral artery bifurcation. Multiple databases were systematically searched for pertinent publications (publication date November 1965 to February 2022). From the included studies, individual patient data (IPD) were requested. Aggregate data (AD) were used when no IPD were available. Primary and secondary patency (PP and SP), perioperative morbidity/mortality, and further endpoints were determined separately for TEA and ENDO and compared with each other. AD for each modality were summarized in meta-analyses. Time-to-event analyses and comparative meta-analyses with PP as primary endpoint were carried out using IPD. 42 studies (3 IPD, 39 AD; 27 TEA, 12 ENDO, 3 comparisons of TEA versus ENDO) were included. In the combined meta-analysis of IPD and AD, PP for TEA was 97% at 6 months and 92% at 12 months, while PP for ENDO was 84% at 6 months and 85% at 12 months. The differences were not statistically significant. The comparative meta-analysis regarding PP did not reveal any significant differences either (TEA versus ENDO: HR 0.30 [0.06; 1.48]). SP at 12 months was 97% (TEA) and 93% (ENDO). The periprocedural morbidity was 16% for TEA and 9% for ENDO. In light of a higher PP, even without formal statistical proof of superiority, TEA can still be considered the standard treatment for occlusive processes of the femoral artery bifurcation.

Association of an intronic SNP rs9939609 in FTO gene with type 2 diabetes mellitus among Bangladeshi population: A case–control study combined with updated meta-analysis

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder, caused by both genetic and environmental variables. The rs9939609 variant with a T > A mutation of the Fat mass obesity (FTO) gene has been known to have a strong association with T2DM and extensively investigated for its role in T2DM in different populations. In this study we conducted a case–control study based on the Bangladeshi population and a combined updated meta-analysis using the data of previous studies from different populations and our study to investigate the association of rs9939609 with T2DM. A total of 156 diabetic patients and 144 healthy non-diabetic controls were recruited. ARMS (Amplification Refractory Mutation System) PCR method was used for genotyping and sequencing was done to validate the PCR results. Our study found a significant association (p < 0.05) of rs9939609 with T2DM in co-dominant AA vs. TT (OR = 2.64) dominant TA + AA vs. TT (OR = 2.12) and additive 2(AA) + TA(OR = 2.224) genetic models. From the meta-analysis, we found significant association of rs9939609 with T2DM in the overall population for all genetic models. However, subgroup analysis showed negligible association in the Caucasian population unlike the Asian population. This is the first case–control study conducted on rs9939609 in the Bangladeshi population that revealed significant association with T2DM and also imply that the connection between them may be mediated by mechanisms other than obesity and increased BMI which was supported by results found in most of the Asian populations. This study could be used as a foundation for future association studies involving larger populations.

074 Investigation of gene-environment interactions in atopic eczema using data from 200,000 European cohort participants

Gene-environment (GxE) interactions are thought to play a role in the pathogenesis of atopic eczema, but specific genes and environmental factors remain to be elucidated. We analysed data from 25 European studies from 7 countries to test for interaction between 24 loci identified by genome-wide association studies and 10 early-life environmental exposures, on atopic eczema as an outcome. Fourteen of the 240 pairwise interactions reached nominal significance (P<0.05) in the discovery analysis (N=25,300), one was nominally significant in replication analysis (N=198,000) and four were nominally significant in the combined meta-analysis of discovery and replication data (N>200,000).

Direct, Indirect, and Combined Extracranial-to-Intracranial Bypass for Adult Moyamoya Disease: An Updated Systematic Review and Meta-Analysis.

Moyamoya disease is a chronic, progressive cerebrovascular disease involving occlusion or stenosis of the terminal portion of the internal carotid artery. We conducted an updated systematic review and meta-analysis to investigate clinical and angiographic outcomes comparing direct, combined, and indirect bypass for the treatment of moyamoya disease in adults. Two independent authors performed Preferred Reporting Items for Systematic reviews and Meta-Analyses guided literature searches in December 2021 to identify articles reporting clinical/angiographic outcomes in adult moyamoya disease patients undergoing bypass. Primary end points used were ischemic and hemorrhagic strokes, clinical outcomes, and angiographic revascularization. Study quality was evaluated with Newcastle-Ottawa and the Oxford Center for Evidence-Based Medicine scales. Four thousand four hundred fifty seven articles were identified in the initial search; 143 articles were analyzed. There were 3827 direct, 3826 indirect, and 3801 combined bypasses. Average length of follow-up was 3.59±2.93 years. Pooled analysis significantly favored direct (odds ratio [OR], 0.62 [0.48-0.79]; P<0.0001; OR, 0.44 [0.32-0.59]; P<0.0001; OR, 0.56 [0.42-0.74]; P<0.0001; OR, 3.1 [2.5-3.8]; P=0.0001) and combined (OR, 0.53 [0.41-0.69]; P<0.0001; OR, 0.28 [0.2-0.41]; P<0.0001; OR, 0.41 [0.3-0.56]; P<0.0001; OR, 3.1 [2.8-4.3]; P=0.0001) over indirect bypass for early stroke, late stroke, late intracerebral hemorrhage, and favorable outcomes, respectively. Indirect bypass was favored over combined (OR, 3.1 [1.7-5.6]; P<0.0001) and direct (OR, 4.12 [2.34-7.25]; P<0.0001) for early intracerebral hemorrhage. The meta-analysis significantly favored direct (OR, 0.37 [0.23-0.60]; P<0.001; OR, 0.49 [0.31-0.77]; P=0.002) and combined (OR, 0.23 [0.12-0.43]; P<0.00001; OR, 0.30 [0.18-0.49]; P<0.00001) bypass over indirect bypass for late stroke and late hemorrhage, respectively. Combined bypass was favored over indirect bypass for favorable outcomes (OR, 2.06 [1.18-3.58]; P=0.01). Based on combined meta-analysis (43 articles) and pooled analysis (143 articles), the existing literature indicates that combined and direct bypasses have significant benefits for patients suffering from late stroke and hemorrhage versus indirect bypass. Combined bypass was favored over indirect bypass for favorable outcomes. This is a strong recommendation based on low-quality evidence when utilizing the Grades of Recommendation, Assessment, Development, and Evaluation system. These findings have important implications for bypass strategy selection.

Identification of Key Gene Network Modules and Hub Genes Associated with Wheat Response to Biotic Stress Using Combined Microarray Meta-analysis and WGCN Analysis.

Wheat (Triticum aestivum) is one of the major crops worldwide and a primary source of calories for human food. Biotic stresses such as fungi, bacteria, and diseases limit wheat production. Althoughplant breeding and genetic engineeringforbiotic stress resistance have been suggested as promising solutions to handle losses caused by biotic stress factors, a comprehensive understanding of molecular mechanisms and identifying key genes is a critical step to obtaining success. Here, a network-based meta-analysis approach based on two main statistical methods was used to identify key genes and molecular mechanisms of the wheat response to biotic stress. A total of 163 samples (21,792 genes) from 10 datasets were analyzed. Fisher Z test based on the p-value and REM method based on effect size resulted in 533 differentially expressed genes (p < 0.001 and FDR < 0.001). WGCNA analysis using a dynamic tree-cutting algorithm was used to construct a co-expression network and three significant modules were detected. The modules were significantly enriched by 16 BP terms and 4 KEGG pathways (Benjamini-Hochberg FDR < 0.001). A total of nine hub genes (a top 1.5% of genes with the highest degree) were identified from the constructed network. The identification of DE genes, gene-gene co-expressing network, and hub genes may contribute to uncovering the molecular mechanisms of the wheat response to biotic stress.

Predicting cancer immunotherapy response from gut microbiomes using machine learning models.

Cancer immunotherapy has significantly improved patient survival. Yet, half of patients do not respond to immunotherapy. Gut microbiomes have been linked to clinical responsiveness of melanoma patients on immunotherapies; however, different taxa have been associated with response status with implicated taxa inconsistent between studies. We used a tumor-agnostic approach to find common gut microbiome features of response among immunotherapy patients with different advanced stage cancers. A combined meta-analysis of 16S rRNA gene sequencing data from our mixed tumor cohort and three published immunotherapy gut microbiome datasets from different melanoma patient cohorts found certain gut bacterial taxa correlated with immunotherapy response status regardless of tumor type. Using multivariate selbal analysis, we identified two separate groups of bacterial genera associated with responders versus non-responders. Statistical models of gut microbiome community features showed robust prediction accuracy of immunotherapy response in amplicon sequencing datasets and in cross-sequencing platform validation with shotgun metagenomic datasets. Results suggest baseline gut microbiome features may be predictive of clinical outcomes in oncology patients on immunotherapies, and some of these features may be generalizable across different tumor types, patient cohorts, and sequencing platforms. Findings demonstrate how machine learning models can reveal microbiome-immunotherapy interactions that may ultimately improve cancer patient outcomes.

Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

ObjectiveHepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account...

O-254 Oral dydrogesterone (OD) versus micronized vaginal progesterone (MVP) for luteal phase support (LPS): impact on endometrium and genital tract microbiota

Abstract Study question Is there a difference in the endometrial transcriptome and/or reproductive tract microbiota composition when OD versus MVP is used as LPS for fresh embryo transfer? Summary answer Endometrial transcriptome signatures and microbiota composition at the vaginal, cervical or intra-uterine site presented no significant differences following OD versus MVP. What is known already Adequate LPS is crucial to achieve a successful pregnancy following ovarian stimulation (OS) and fresh embryo transfer. OD has been proven to be non-inferior compared to MVP in two phase III clinical RCTs. Additionally, a combined individual participant data and aggregate data meta-analysis showed an odds ratio in favor of OD for live birth. Little information is available on the potential differences at the molecular level of the reproductive organs following the administration of either LPS strategies. Given the potential immunomodulating properties of OD, of main interest is the endometrial functionality and microbiota composition of the female genital tract. Study design, size, duration Thirty oocyte donors were planned to have two OS-cycles followed by one week of LPS (OD or MVP) in a randomized, cross-over, double-blind, double-dummy fashion. An endometrial biopsy, as well as vaginal/cervical/intra-uterine samples were collected. Endometrial RNA-sequencing was performed, raw reads were processed using STAR/htseq-count, differential gene expression was evaluated with EdgeR. Microbiota profiles were obtained by 16S-rRNA-sequencing using the DADA2-pipeline with RDP-classifier. Comparative analysis of genera relative abundances was performed in R. Participants/materials, setting, methods All oocyte donors were &amp;lt;35 years old, had regular menstrual cycles, no intra-uterine contraceptive device, AMH within normal range and BMI≤ 29 kg/m2. OS was performed in a GnRH antagonist protocol followed by dual triggering (1000U hCG + 0.2mg triptorelin) as soon as ≥ 3 follicles of 20mm were present. Following oocyte retrieval, subjects initiated LPS consisting of MVP 200 mg (Utrogestan®) or OD 10 mg (Duphaston®), both three times daily. Main results and the role of chance Subject and stimulation characteristics were comparable between the groups. For endometrial RNA-sequencing, 21 pairs (n = 42 biopsies) were available with the same oocyte donor having a biopsy after OD as well as after MVP (the remaining 9 subjects were excluded due to late follicular progesterone elevation/drop-out after one cycle). After correction for multiple hypothesis testing, no differentially expressed genes could be withheld and the principal component analysis plot showed one mixed OD/MVP cluster (PCA1 25% variance, PCA2 16% variance). The average Euclidean distance between samples of the OD group was significantly lower than for the MVP group (respectively 12.1 vs 18.8, comparison of the two-group wise Euclidean distributions results in p = 6.98e-14 using the Mann-Whitney test). Microbiota profiling was performed before and after OD/MVP (4 collections per subject). Samples with insufficient high-quality reads were excluded, resulting in 42 intra-uterine samplings, 82 cervical and 84 vaginal swabs used for analysis. No difference was seen at any site of the female reproductive tract following OD versus MVP in microbiota diversity, richness, genera abundances (delta contrasts [Mann–Whitney U test], padj &amp;gt; 0.1), nor community composition (dbRDA genus-level Euclidean distances in vagina [R2= 0.22%, padj=0.26], cervix [R2= 0.36%, padj=0.20], uterus [R2= -0.06%, padj=0.45]). Limitations, reasons for caution Sample size was limited. Whole tissue endometrial transcriptomics was performed on individual biopsies without accounting for the potential bias of different tissue compartment compositions among biopsies. As it was a double blind, double dummy study design, the impact of not administering medication via the vaginal route could not be evaluated. Wider implications of the findings This is the first molecular study comparing OD/MVP. Results show that there is no difference between OD/MVP’s ability to give rise to the receptive state, which corresponds with the clinical trial data. As the inter-sample distance of RNA-profiles was smaller following OD, interindividual variations could be lower for this approach. Trial registration number EUDRACT 2018-000105-23

Evidence for non-selective response inhibition in uncertain contexts revealed by combined meta-analysis and Bayesian analysis of fMRI data

Response inhibition is typically considered a brain mechanism selectively triggered by particular “inhibitory” stimuli or events. Based on recent research, an alternative non-selective mechanism was proposed by several authors. Presumably, the inhibitory brain activity may be triggered not only by the presentation of “inhibitory” stimuli but also by any imperative stimuli, including Go stimuli, when the context is uncertain. Earlier support for this notion was mainly based on the absence of a significant difference between neural activity evoked by equiprobable Go and NoGo stimuli. Equiprobable Go/NoGo design with a simple response time task limits potential confounds between response inhibition and accompanying cognitive processes while not preventing prepotent automaticity. However, previous neuroimaging studies used classical null hypothesis significance testing, making it impossible to accept the null hypothesis. Therefore, the current research aimed to provide evidence for the practical equivalence of neuronal activity in the Go and NoGo trials using Bayesian analysis of functional magnetic resonance imaging (fMRI) data. Thirty-four healthy participants performed a cued Go/NoGo task with an equiprobable presentation of Go and NoGo stimuli. To independently localize brain areas associated with response inhibition in similar experimental conditions, we performed a meta-analysis of fMRI studies using equal-probability Go/NoGo tasks. As a result, we observed overlap between response inhibition areas and areas that demonstrate the practical equivalence of neuronal activity located in the right dorsolateral prefrontal cortex, parietal cortex, premotor cortex, and left inferior frontal gyrus. Thus, obtained results favour the existence of non-selective response inhibition, which can act in settings of contextual uncertainty induced by the equal probability of Go and NoGo stimuli.

Genome-wide association analysis reveals insights into the genetic architecture of right ventricular structure and function.

Right ventricular (RV) structure and function influence the morbidity and mortality from coronary artery disease (CAD), dilated cardiomyopathy (DCM), pulmonary hypertension and heart failure. Little is known about the genetic basis of RV measurements. Here we perform genome-wide association analyses of four clinically relevant RV phenotypes (RV end-diastolic volume, RV end-systolic volume, RV stroke volume, RV ejection fraction) from cardiovascular magnetic resonance images, using a state-of-the-art deep learning algorithm in 29,506 UK Biobank participants. We identify 25 unique loci associated with at least one RV phenotype at P < 2.27 ×10-8, 17 of which are validated in a combined meta-analysis (n = 41,830). Several candidate genes overlap with Mendelian cardiomyopathy genes and are involved in cardiac muscle contraction and cellular adhesion. The RV polygenic risk scores (PRSs) are associated with DCM and CAD. The findings substantially advance our understanding of the genetic underpinning of RV measurements.