dsMTL: a computational framework for privacy-preserving, distributed multi-task machine learning.

MOTIVATION: In multi-cohort machine learning studies, it is critical to differentiate between effects that are reproducible across cohorts and those that are cohort-specific. Multi-task learning (MTL) is a machine learning approach that facilitates this differentiation through the simultaneous learning of prediction tasks across cohorts. Since multi-cohort data can often not be combined into a single storage solution, there would be the substantial utility of an MTL application for geographically distributed data sources. RESULTS: Here, we describe the development of 'dsMTL', a computational framework for privacy-preserving, distributed multi-task machine learning that includes three supervised and one unsupervised algorithms. First, we derive the theoretical properties of these methods and the relevant machine learning workflows to ensure the validity of the software implementation. Second, we implement dsMTL as a library for the R programming language, building on the DataSHIELD platform that supports the federated analysis of sensitive individual-level data. Third, we demonstrate the applicability of dsMTL for comorbidity modeling in distributed data. We show that comorbidity modeling using dsMTL outperformed conventional, federated machine learning, as well as the aggregation of multiple models built on the distributed datasets individually. The application of dsMTL was computationally efficient and highly scalable when applied to moderate-size (n < 500), real expression data given the actual network latency. AVAILABILITY AND IMPLEMENTATION: dsMTL is freely available at https://github.com/transbioZI/dsMTLBase (server-side package) and https://github.com/transbioZI/dsMTLClient (client-side package). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Malnutrition defined by GLIM criteria identifies a higher incidence of malnutrition and is associated with pulmonary complications after oesophagogastric cancer surgery, compared to ICD-10-defined malnutrition.

BACKGROUND & OBJECTIVES: Low muscle mass, measured using computed tomography (CT), is associated with poor surgical outcomes. We aimed to include CT-muscle mass in malnutrition diagnosis using the Global Leadership Initiative on Malnutrition (GLIM) criteria, compare it to the International Classification of Diseases 10th Revision (ICD-10) criteria, and assess the impact on postoperative outcomes after oesophagogastric (OG) cancer surgery. METHODS: One hundred and eight patients who underwent radical OG cancer surgery and had preoperative abdominal CT imaging were included. GLIM and ICD-10 malnutrition data were assessed against complication and survival outcomes. Low CT-muscle mass was determined using predefined cut-points. RESULTS: GLIM-defined malnutrition prevalence was significantly higher than ICD-10-malnutrition (72.2% vs. 40.7%, p < 0.001). Of the 78 patients with GLIM-defined malnutrition, low muscle mass (84.6%) was the predominant phenotypic criterion. GLIM-defined malnutrition was associated with pneumonia (26.9% vs. 6.7%, p = 0.010) and pleural effusions (12.8% vs. 0%, p = 0.029). Postoperative complications did not correlate with ICD-10 malnutrition. Severe GLIM (HR: 2.51, p = 0.014) and ICD-10 (HR: 2.15, p = 0.039) malnutrition were independently associated with poorer 5-year survival. CONCLUSIONS: GLIM criteria appear to identify more malnourished patients and more closely relate to surgical risk than ICD-10 malnutrition, likely due to incorporating objective muscle mass assessment.

Proteome analysis of human adipocytes identifies depot-specific heterogeneity at metabolic control points.

Adipose tissue is a primary regulator of energy balance and metabolism. The distribution of adipose tissue depots is of clinical interest because the accumulation of upper-body subcutaneous (ASAT) and visceral adipose tissue (VAT) is associated with cardiometabolic diseases, whereas lower-body glutealfemoral adipose tissue (GFAT) appears to be protective. There is heterogeneity in morphology and metabolism of adipocytes obtained from different regions of the body, but detailed knowledge of the constituent proteins in each depot is lacking. Here, we determined the human adipocyte proteome from ASAT, VAT, and GFAT using high-resolution Sequential Window Acquisition of all Theoretical (SWATH) mass spectrometry proteomics. We quantified 4,220 proteins in adipocytes, and 2,329 proteins were expressed in all three adipose depots. Comparative analysis revealed significant differences between adipocytes from different regions (6% and 8% when comparing VAT vs. ASAT and GFAT, 3% when comparing the subcutaneous adipose tissue depots, ASAT and GFAT), with marked differences in proteins that regulate metabolic functions. The VAT adipocyte proteome was overrepresented with proteins of glycolysis, lipogenesis, oxidative stress, and mitochondrial dysfunction. The GFAT adipocyte proteome predicted the activation of peroxisome proliferator-activated receptor α (PPARα), fatty acid, and branched-chain amino acid (BCAA) oxidation, enhanced tricarboxylic acid (TCA) cycle flux, and oxidative phosphorylation, which was supported by metabolomic data obtained from adipocytes. Together, this proteomic analysis provides an important resource and novel insights that enhance the understanding of metabolic heterogeneity in the regional adipocytes of humans.NEW & NOTEWORTHY Adipocyte metabolism varies depending on anatomical location and the adipocyte protein composition may orchestrate this heterogeneity. We used SWATH proteomics in patient-matched human upper- (visceral and subcutaneous) and lower-body (glutealfemoral) adipocytes and detected 4,220 proteins and distinguishable regional proteomes. Upper-body adipocyte proteins were associated with glycolysis, de novo lipogenesis, mitochondrial dysfunction, and oxidative stress, whereas lower-body adipocyte proteins were associated with enhanced PPARα activation, fatty acid, and BCAA oxidation, TCA cycle flux, and oxidative phosphorylation.

Dietary Macronutrient Composition in Relation to Circulating HDL and Non-HDL Cholesterol: A Federated Individual-Level Analysis of Cross-Sectional Data from Adolescents and Adults in 8 European Studies.

BACKGROUND: Associations between increased dietary fat and decreased carbohydrate intake with circulating HDL and non-HDL cholesterol have not been conclusively determined. OBJECTIVE: We assessed these relations in 8 European observational human studies participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) using harmonized data. METHODS: Dietary macronutrient intake was recorded using study-specific dietary assessment tools. Main outcome measures were lipoprotein cholesterol concentrations: HDL cholesterol (mg/dL) and non-HDL cholesterol (mg/dL). A cross-sectional analysis on 5919 participants (54% female) aged 13-80 y was undertaken using the statistical platform DataSHIELD that allows remote/federated nondisclosive analysis of individual-level data. Generalized linear models (GLM) were fitted to assess associations between replacing 5% of energy from carbohydrates with equivalent energy from total fats, SFAs, MUFAs, or PUFAs with circulating HDL cholesterol and non-HDL cholesterol. GLM were adjusted for study source, age, sex, smoking status, alcohol intake and BMI. RESULTS: The replacement of 5% of energy from carbohydrates with total fats or MUFAs was statistically significantly associated with 0.67 mg/dL (95% CI: 0.40, 0.94) or 0.99 mg/dL (95% CI: 0.37, 1.60) higher HDL cholesterol, respectively, but not with non-HDL cholesterol concentrations. The replacement of 5% of energy from carbohydrates with SFAs or PUFAs was not associated with HDL cholesterol, but SFAs were statistically significantly associated with 1.94 mg/dL (95% CI: 0.08, 3.79) higher non-HDL cholesterol, and PUFAs with -3.91 mg/dL (95% CI: -6.98, -0.84) lower non-HDL cholesterol concentrations. A statistically significant interaction by sex for the association of replacing carbohydrates with MUFAs and non-HDL cholesterol was observed, showing a statistically significant inverse association in males and no statistically significant association in females. We observed no statistically significant interaction by age. CONCLUSIONS: The replacement of dietary carbohydrates with fats had favorable effects on lipoprotein cholesterol concentrations in European adolescents and adults when fats were consumed as MUFAs or PUFAs but not as SFAs.

Evaluation of the histological variability of core and wedge biopsies in nonalcoholic fatty liver disease in bariatric surgical patients.

BACKGROUND: Liver biopsy remains the gold standard for characterizing and evaluating treatment response in nonalcoholic fatty liver disease (NAFLD). Liver heterogeneity and sampling variability can affect the reliability of results. This study aimed to compare histological variability of intraoperative wedge and core liver biopsies from different lobes in bariatric patients, to better inform surgeons on biopsy method and guide interpretation of results. METHODS: We prospectively recruited bariatric surgical patients. Intraoperative core biopsies were taken from the left and right lobe, with a wedge biopsy taken from the left. All biopsies were graded by a specialist liver pathologist, blinded to clinical details and biopsy site. Concordance of histological findings between sites was evaluated. RESULTS: There were 91 participants (72.2% female), mean age 46.8 ± 12.0 years, body mass index 45.9 ± 9.4 kg/m2. There was no significant pattern for up- or down-grading disease dependent on biopsy technique. Moderate to strong agreement was seen in the presence of NAFLD and nonalcoholic steatohepatitis (NASH, κ = 0.609-0.865, p < 0.001) between biopsy sites. Individual components (steatosis, inflammation, ballooning) showed weaker agreement (κ = 0.386-0.656, p < 0.01). Fibrosis showed particularly poor agreement (κ = 0.223-0.496, p < 0.01). Detection of pathology improved with a combination of biopsy techniques, compared to a single biopsy method. CONCLUSION: Overall diagnosis of NAFLD or NASH shows good agreement between biopsy sites, but individual components, particularly fibrosis stage, vary significantly. Clinicians should consider biopsies from varied sites, to better assess liver disease severity. These data have important implications in fibrosis assessment of NAFLD and are relevant in the interpretation of histological efficacy of investigational pharmacotherapies. TRIAL REGISTRATION: ACTRN12615000875505 (Australian Clinical Trials Register).

Better governance, better access: practising responsible data sharing in the METADAC governance infrastructure.

BACKGROUND: Genomic and biosocial research data about individuals is rapidly proliferating, bringing the potential for novel opportunities for data integration and use. The scale, pace and novelty of these applications raise a number of urgent sociotechnical, ethical and legal questions, including optimal methods of data storage, management and access. Although the open science movement advocates unfettered access to research data, many of the UK's longitudinal cohort studies operate systems of managed data access, in which access is governed by legal and ethical agreements between stewards of research datasets and researchers wishing to make use of them. Amongst other things, these agreements aim to respect the reasonable expectations of the research participants who provided data and samples, as expressed in the consent process. Arguably, responsible data management and governance of data and sample use are foundational to the consent process in longitudinal studies and are an important source of trustworthiness in the eyes of those who contribute data to genomic and biosocial research. METHODS: This paper presents an ethnographic case study exploring the foundational principles of a governance infrastructure for Managing Ethico-social, Technical and Administrative issues in Data ACcess (METADAC), which are operationalised through a committee known as the METADAC Access Committee. METADAC governs access to phenotype, genotype and 'omic' data and samples from five UK longitudinal studies. FINDINGS: Using the example of METADAC, we argue that three key structural features are foundational for practising responsible data sharing: independence and transparency; interdisciplinarity; and participant-centric decision-making. We observe that the international research community is proactively working towards optimising the use of research data, integrating/linking these data with routine data generated by health and social care services and other administrative data services to improve the analysis, interpretation and utility of these data. The governance of these new complex data assemblages will require a range of expertise from across a number of domains and disciplines, including that of study participants. Human-mediated decision-making bodies will be central to ensuring achievable, reasoned and responsible decisions about the use of these data; the METADAC model described in this paper provides an example of how this could be realised.

Evaluating feasibility and accuracy of non-invasive tests for nonalcoholic fatty liver disease in severe and morbid obesity.

INTRODUCTION: In obese individuals, nonalcoholic fatty liver disease (NAFLD) is common but often goes undiagnosed, and therefore untreated. The presence of significant fibrosis is a key determinant of NAFLD progression, and liver steatosis has substantial cardiovascular implications. We aimed to determine the diagnostic accuracy of common noninvasive diagnostic tests for steatosis and fibrosis in the obese. METHODS: We recruited 182 severely and morbidly obese individuals undergoing bariatric surgery (age 44 ± 12 years, body mass index 45.1 ± 8.3 kg/m2). Medical history, blood tests and liver biopsy were taken on the day of surgery. Serum steatosis and fibrosis scores were calculated. In a subgroup of patients, transient elastography with controlled attenuation parameter (TE/CAP) (n = 82) and proton magnetic resonance spectroscopy (1H-MRS) (n = 49) were performed. RESULTS: 1H-MRS had excellent diagnostic accuracy for steatosis, with strong correlation to steatosis (r = 0.647, p < 0.001), good AUROC (0.852, p = 0.001), sensitivity (81.3%) and specificity (87.5%). However, due to low feasibility in this cohort (65.3% success), this was substantially decreased with intention-to-diagnose analysis (sensitivity 50.0%, specificity 60.9%). CAP had good feasibility (80.5%), and performed better in intention-to-diagnose analysis (AUROC 0.688, sensitivity 84.8%, specificity 47.2%). Serum steatosis scores performed poorly, with comparable accuracy to ALT. For significant fibrosis, TE had the best accuracy (AUROC 0.903, p = 0.007), which remained reasonable after intention-to-diagnose analysis (sensitivity 100%, specificity 59.0%). A combination approach using CAP with ALT for steatosis and TE with Forn index for fibrosis yielded reasonable overall accuracy. CONCLUSIONS: 1H-MRS and TE/CAP had greatest accuracy for NAFLD-related steatosis and fibrosis. Failure rates in obesity significantly diminished diagnostic ability. Use of a combination of serum and imaging tests improved overall feasibility of assessment and diagnostic accuracy in obese individuals.

Long-term exposure to road traffic noise, ambient air pollution, and cardiovascular risk factors in the HUNT and lifelines cohorts.

AIMS: Blood biochemistry may provide information on associations between road traffic noise, air pollution, and cardiovascular disease risk. We evaluated this in two large European cohorts (HUNT3, Lifelines). METHODS AND RESULTS: Road traffic noise exposure was modelled for 2009 using a simplified version of the Common Noise Assessment Methods in Europe (CNOSSOS-EU). Annual ambient air pollution (PM10, NO2) at residence was estimated for 2007 using a Land Use Regression model. The statistical platform DataSHIELD was used to pool data from 144 082 participants aged ≥20 years to enable individual-level analysis. Generalized linear models were fitted to assess cross-sectional associations between pollutants and high-sensitivity C-reactive protein (hsCRP), blood lipids and for (Lifelines only) fasting blood glucose, for samples taken during recruitment in 2006-2013. Pooling both cohorts, an inter-quartile range (IQR) higher day-time noise (5.1 dB(A)) was associated with 1.1% [95% confidence interval (95% CI: 0.02-2.2%)] higher hsCRP, 0.7% (95% CI: 0.3-1.1%) higher triglycerides, and 0.5% (95% CI: 0.3-0.7%) higher high-density lipoprotein (HDL); only the association with HDL was robust to adjustment for air pollution. An IQR higher PM10 (2.0 µg/m3) or NO2 (7.4 µg/m3) was associated with higher triglycerides (1.9%, 95% CI: 1.5-2.4% and 2.2%, 95% CI: 1.6-2.7%), independent of adjustment for noise. Additionally for NO2, a significant association with hsCRP (1.9%, 95% CI: 0.5-3.3%) was seen. In Lifelines, an IQR higher noise (4.2 dB(A)) and PM10 (2.4 µg/m3) was associated with 0.2% (95% CI: 0.1-0.3%) and 0.6% (95% CI: 0.4-0.7%) higher fasting glucose respectively, with both remaining robust to adjustment for air/noise pollution. CONCLUSION: Long-term exposures to road traffic noise and ambient air pollution were associated with blood biochemistry, providing a possible link between road traffic noise/air pollution and cardio-metabolic disease risk.

Ambient air pollution, traffic noise and adult asthma prevalence: a BioSHaRE approach.

We investigated the effects of both ambient air pollution and traffic noise on adult asthma prevalence, using harmonised data from three European cohort studies established in 2006-2013 (HUNT3, Lifelines and UK Biobank).Residential exposures to ambient air pollution (particulate matter with aerodynamic diameter ≤10 µm (PM10) and nitrogen dioxide (NO2)) were estimated by a pan-European Land Use Regression model for 2007. Traffic noise for 2009 was modelled at home addresses by adapting a standardised noise assessment framework (CNOSSOS-EU). A cross-sectional analysis of 646 731 participants aged ≥20 years was undertaken using DataSHIELD to pool data for individual-level analysis via a "compute to the data" approach. Multivariate logistic regression models were fitted to assess the effects of each exposure on lifetime and current asthma prevalence.PM10 or NO2 higher by 10 µg·m-3 was associated with 12.8% (95% CI 9.5-16.3%) and 1.9% (95% CI 1.1-2.8%) higher lifetime asthma prevalence, respectively, independent of confounders. Effects were larger in those aged ≥50 years, ever-smokers and less educated. Noise exposure was not significantly associated with asthma prevalence.This study suggests that long-term ambient PM10 exposure is associated with asthma prevalence in western European adults. Traffic noise is not associated with asthma prevalence, but its potential to impact on asthma exacerbations needs further investigation.

The ECOUTER methodology for stakeholder engagement in translational research.

BACKGROUND: Because no single person or group holds knowledge about all aspects of research, mechanisms are needed to support knowledge exchange and engagement. Expertise in the research setting necessarily includes scientific and methodological expertise, but also expertise gained through the experience of participating in research and/or being a recipient of research outcomes (as a patient or member of the public). Engagement is, by its nature, reciprocal and relational: the process of engaging research participants, patients, citizens and others (the many 'publics' of engagement) brings them closer to the research but also brings the research closer to them. When translating research into practice, engaging the public and other stakeholders is explicitly intended to make the outcomes of translation relevant to its constituency of users. METHODS: In practice, engagement faces numerous challenges and is often time-consuming, expensive and 'thorny' work. We explore the epistemic and ontological considerations and implications of four common critiques of engagement methodologies that contest: representativeness, communication and articulation, impacts and outcome, and democracy. The ECOUTER (Employing COnceptUal schema for policy and Translation Engagement in Research) methodology addresses problems of representation and epistemic foundationalism using a methodology that asks, "How could it be otherwise?" ECOUTER affords the possibility of engagement where spatial and temporal constraints are present, relying on saturation as a method of 'keeping open' the possible considerations that might emerge and including reflexive use of qualitative analytic methods. RESULTS: This paper describes the ECOUTER process, focusing on one worked example and detailing lessons learned from four other pilots. ECOUTER uses mind-mapping techniques to 'open up' engagement, iteratively and organically. ECOUTER aims to balance the breadth, accessibility and user-determination of the scope of engagement. An ECOUTER exercise comprises four stages: (1) engagement and knowledge exchange; (2) analysis of mindmap contributions; (3) development of a conceptual schema (i.e. a map of concepts and their relationship); and (4) feedback, refinement and development of recommendations. CONCLUSION: ECOUTER refuses fixed truths but also refuses a fixed nature. Its promise lies in its flexibility, adaptability and openness. ECOUTER will be formed and re-formed by the needs and creativity of those who use it.

ESPRESSO: taking into account assessment errors on outcome and exposures in power analysis for association studies.

MOTIVATION: Very large studies are required to provide sufficiently big sample sizes for adequately powered association analyses. This can be an expensive undertaking and it is important that an accurate sample size is identified. For more realistic sample size calculation and power analysis, the impact of unmeasured aetiological determinants and the quality of measurement of both outcome and explanatory variables should be taken into account. Conventional methods to analyse power use closed-form solutions that are not flexible enough to cater for all of these elements easily. They often result in a potentially substantial overestimation of the actual power. RESULTS: In this article, we describe the Estimating Sample-size and Power in R by Exploring Simulated Study Outcomes tool that allows assessment errors in power calculation under various biomedical scenarios to be incorporated. We also report a real world analysis where we used this tool to answer an important strategic question for an existing cohort. AVAILABILITY AND IMPLEMENTATION: The software is available for online calculation and downloads at http://espresso-research.org. The code is freely available at https://github.com/ESPRESSO-research. CONTACT: louqman@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Data Safe Havens in health research and healthcare.

MOTIVATION: The data that put the 'evidence' into 'evidence-based medicine' are central to developments in public health, primary and hospital care. A fundamental challenge is to site such data in repositories that can easily be accessed under appropriate technical and governance controls which are effectively audited and are viewed as trustworthy by diverse stakeholders. This demands socio-technical solutions that may easily become enmeshed in protracted debate and controversy as they encounter the norms, values, expectations and concerns of diverse stakeholders. In this context, the development of what are called 'Data Safe Havens' has been crucial. Unfortunately, the origins and evolution of the term have led to a range of different definitions being assumed by different groups. There is, however, an intuitively meaningful interpretation that is often assumed by those who have not previously encountered the term: a repository in which useful but potentially sensitive data may be kept securely under governance and informatics systems that are fit-for-purpose and appropriately tailored to the nature of the data being maintained, and may be accessed and utilized by legitimate users undertaking work and research contributing to biomedicine, health and/or to ongoing development of healthcare systems. RESULTS: This review explores a fundamental question: 'what are the specific criteria that ought reasonably to be met by a data repository if it is to be seen as consistent with this interpretation and viewed as worthy of being accorded the status of 'Data Safe Haven' by key stakeholders'? We propose 12 such criteria. CONTACT: paul.burton@bristol.ac.uk.

Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. OBJECTIVE: We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis. METHODS: We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD). RESULTS: Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1ß expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study. CONCLUSIONS: Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

Robotic versus laparoscopic gastric bypass in bariatric surgery: a systematic review and meta-analysis on perioperative outcomes.

BACKGROUND: Robotic-assisted surgery has emerged as a compelling approach to bariatric surgery. However, current literature has not consistently demonstrated superior outcomes to laparoscopic bariatric surgery to justify its higher cost. With its mechanical advantages, the potential gains from the robotic surgical platform are likely to be apparent in more complex cases such as gastric bypass, especially revisional cases. OBJECTIVE: This systematic review and meta-analysis aimed to summarize the literature and evaluate the peri-operative outcomes of patients with obesity undergoing robotic gastric bypass versus laparoscopic gastric bypass surgery. SETTING: Systematic review. METHODS: A literature search of Embase, Medline, Pubmed, Cochrane library, and Google Scholar was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing outcomes of robotic and laparoscopic gastric bypass for obesity were included. RESULTS: Twenty-eight eligible studies comprised a total of 82,155 patients; 9051 robotic bypass surgery (RBS) versus 73,104 laparoscopic bypass surgery (LBS) were included. All included studies compared Roux-en-Y gastric bypass. RBS was noted to have higher reoperation rate within 30 days (4.4% versus 3.4%; odds ratio 1.31 [95% CI, 1.04-1.66]; P = .027; I2 = 43.5%) than LBS. All other endpoints measured (complication rate, anastomotic leak, anastomotic stricture, surgical site infections, hospital readmission, length of stay, operative time, conversion rate and mortality) did not show any difference between RBS and LBS. CONCLUSION: This systematic review and meta-analysis showed that there was no significant difference in key outcome measures in robotic versus laparoscopic gastric bypass. RBS was associated with a slightly higher reoperation rate and there was no reduction in overall complication rate with the use of robotic platform.

Emerging multi-port soft tissue robotic systems: a systematic review of clinical outcomes.

Multiple novel multi-port robotic surgical systems have been introduced into clinical practice. This systematic review aims to evaluate the clinical outcomes of these novel robotic systems to conventional laparoscopic technique and established da Vinci robotic surgical platforms. A literature search of Embase, Medline, Pubmed, Cochrane library, and Google Scholar was performed according to the PRISMA guidelines from 2012 to May 2023. Studies comparing clinical outcomes of novel multi-port robotic surgical systems with laparoscopic or the da Vinci platforms were included. Case series with no comparison groups were excluded. Descriptive statistics were used to report patient and outcome data. A systematic narrative review was provided for each outcome. Twelve studies comprised of 1142 patients were included. A total of 6 novel multi-port robotic systems: Micro Hand S, Senhance, Revo-i MSR-5000, KangDuo, Versius, and Hugo™ RAS were compared against the laparoscopic or the da Vinci robotic platforms. Clinical outcomes of these novel robotic platforms were comparable to the established da Vinci platforms. When compared against conventional laparoscopic approaches, the robotic platforms demonstrated lower volume of blood loss, shorter length of stay but longer operative time. This systematic review highlighted the safe implementation and efficacy of 6 new robotic systems. The clinical outcomes achieved by these new robotic systems are comparable to the established da Vinci robotic system in simple to moderate case complexities. There is emerging evidence that these new robotic systems provide a viable alternative to currently available robotic platforms.

Liver-derived extracellular vesicles improve whole-body glycaemic control via inter-organ communication.

Small extracellular vesicles (EVs) are signalling messengers that regulate inter-tissue communication through delivery of their molecular cargo. Here, we show that liver-derived EVs are acute regulators of whole-body glycaemic control in mice. Liver EV secretion into the circulation is increased in response to hyperglycaemia, resulting in increased glucose effectiveness and insulin secretion through direct inter-organ EV signalling to skeletal muscle and the pancreas, respectively. This acute blood glucose lowering effect occurs in healthy and obese mice with non-alcoholic fatty liver disease, despite marked remodelling of the liver-derived EV proteome in obese mice. The EV-mediated blood glucose lowering effects were recapitulated by administration of liver EVs derived from humans with or without progressive non-alcoholic fatty liver disease, suggesting broad functional conservation of liver EV signalling and potential therapeutic utility. Taken together, this work reveals a mechanism whereby liver EVs act on peripheral tissues via endocrine signalling to restore euglycaemia in the postprandial state.

Modified One Anastomosis Gastric Bypass Following Sleeve Gastrectomy for Severe Reflux and Delayed Gastric Emptying: A Prospective Trial with Clinical and Physiological Outcome Measures.

BACKGROUND: Gastro-esophageal reflux (GORD) following sleeve gastrectomy (SG) is a central challenge, and precise indications for revisional surgery or the physiology have not been precisely defined. We aimed to determine whether OAGB performed for reflux post-SG (1) accelerates gastric emptying half-time, (2) reduces the frequency and severity of reflux events, and (3) improves reflux symptoms. METHODS: We undertook a prospective trial (ACTRN12616001089426). There were 22 participants who underwent measurement before and after revisional surgery with 29 optimal SG (patients with optimal outcome from their primary surgery) as controls. All participants underwent a protocolized nuclear scintigraphy, 24-h pH monitoring, and gastroscopy and completed objective questionnaires. RESULTS: Trial patients were 90.9% female, age 44.4 years. Conversion from SG to OAGB was at a median of 45.2 ± 19.6 months. Scintigraphy showed an increased rate of gastric emptying post-OAGB 34 (IQR 14) vs 24 (IQR 10.3) min, p-value 0.008, with decreased number of reflux events post-prandially (39 (IQR 13) vs 26 (IQR 7), p-value 0.001). This data correlated with the pH analysis; total acid events substantially reduced post-OAGB 58.5 (IQR 88) vs 12 (IQR 9.4) events, p-value 0.017. Endoscopic findings indicated a reduction in incidence of bile stasis 72.7% vs 40.9% post-OAGB, p-value < 0.00010. Post-OAGB, patients experienced less frequent regurgitation (12 ± 4.1 vs. 5.5 ± 3, p-value 0.012) and reflux (37.1 ± 15.7 vs. 16.8 ± 12.6, p-value 0.003). CONCLUSIONS: We found OAGB is an effective treatment for reflux associated with delayed gastric emptying post-SG. The likely mechanisms is by, an increase in the rate of gastric clearance and reduced reflux events and overall esophageal acid exposure. This suggests that some forms of post-SG reflux are driven by slower emptying of the residual stomach and are amenable to treatment with drainage above the incisura.