A trivariate additive regression model with arbitrary link functions and varying correlation matrix

In many empirical situations, modelling simultaneously three or more outcomes as well as their dependence structure can be of considerable relevance. Copulae provide a powerful framework to build multivariate distributions and allow one to view the specification of the marginal responses’ equations and their dependence as separate but related issues. We propose a generalizationof the trivariate additive probit model where the link functions can in principle be derived from any parametric distribution and the parameters describing the residual association between the responses can be made dependent on several types of covariate effects (such as linear, nonlinear, random, and spatial effects). All the coefficients of the model are estimated simultaneously within a penalized likelihood framework that uses a trust region algorithm with integrated automatic multiple smoothing parameter selection. The effectiveness of the model is assessed in simulation as well as empirically by modelling jointly three adverse birth binary outcomes in North Carolina. The approach can be easily employed via the gjrm() function in the R package GJRM

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

SomaScan Novartis proteins (construct, domain, expression) used in development of SomaScan, for PUBLIC disclosure on SomaLogic website

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Proteomic associations with forced expiratory volume – a Mendelian randomisation study

A decline in forced expiratory volume (FEV1) is a hallmark of obstructive respiratory diseases, an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1. Data from the general population-based AGES-Reykjavik study were used. Proteomic measurements were done using 4,782 DNA aptamers (SOMAmers). Data from 1,648 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5,368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102). In observational analyses, 473 SOMAmers were associated with FEV1 after multiple testing adjustment. The most significant were R-Spondin 4, Alkaline Phosphatase, Placental Like 2 and Retinoic Acid Receptor Responder 2. Of the 235 SOMAmers with genetic data, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta and Apolipoprotein M. THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments. In summary, this large scale proteogenomic analyses of FEV1 reveals protein markers of FEV1, as well as several proteins that are potentially causally related with lung function

Evaluation of a novel blood microsampling device for clinical trial sample collection and protein biomarker analysis

Aim: Evaluation of a novel microsampling device for its use in clinical sample collection and biomarker analysis. Methodology: Matching samples were collected from 16 healthy donors (ten females, six males; age 42 ± 20) via K2EDTA touch activated phlebotomy (TAP) device and phlebotomy. The protein profile differences between sampling groups was evaluated using aptamer-based proteomic assay SomaScan and selected ELISA. Conclusion: Somascan signal concordance between phlebotomy- and TAP-generated samples was studied and comparability of protein abundances between these blood sample collection methods was demonstrated. Statistically significant correlation in selected ELISA assays also confirmed the TAP device applicability to the quantitative analysis of protein biomarkers in clinical trials

PIKfyve, a class III lipid kinase, is required for TLR-induced Type i IFN production via modulation of ATF3

Type I IFN plays a key role in antiviral responses. It also has been shown that deregulation of type I IFN expression following abnormal activation of TLRs contributes to the pathogenesis of systemic lupus erythematosus. In this study, we find that PIKfyve, a class III lipid kinase, is required for endolysosomal TLR-induced expression of type I IFN in mouse and human cells. PIKfyve binds to phosphatidylinositol 3-phosphate and synthesizes phosphatidylinositol 3,5-bisphosphate, and plays a critical role in endolysosomal trafficking. However, PIKfyve modulates type I IFN production via mechanisms independent of receptor and ligand trafficking in endolysosomes. Instead, pharmacological or genetic inactivation of PIKfyve rapidly induces expression of the transcription repressor ATF3, which is necessary and sufficient for suppression of type I IFN expression by binding to its promoter and blocking its transcription. Thus, we have uncovered a novel phosphoinositide-mediated regulatory mechanism that controls TLRmediated induction of type I IFN, which may provide a new therapeutic indication for the PIKfyve inhibitor. The Journal of Immunology, 2014, 192: 3383-3389. © Copyright 2014 by The American Association of Immunologists, Inc. All rights reserved

Decentralized clinical trial design using blood microsampling technology for serum bioanalysis.

Background: Alternatives to phlebotomy in clinical trials increase options for patients and clinicians by simplifying and increasing accessibility to clinical trials. The authors investigated the technical and logistical considerations of one technology compared with phlebotomy. Methodology: Paired samples were collected from 16 donors via a second-generation serum gel microsampling device and conventional phlebotomy. Microsamples were subject to alternative sample handling conditions and were evaluated for quality, clinical testing and proteome profiling. Results: Timely centrifugation of blood serum microsamples largely preserved analyte stability. Conclusion: Centrifugation timing of serum microsamples impacts the quality of specific clinical chemistry and protein biomarkers. Microsampling devices with remote centrifugation and refrigerated shipping can decrease patient burden, expand clinical trial populations and aid clinical decisions

Differential proteins expression distinguished between patients with infectious and noninfectious uveitis

Uveitis is associated with a number of inflammatory diseases and can be infectious or noninfectious. The diagnosis of uveitis is usually based on typical clinical presentation, but sometimes the signs and symptoms are not clear, and the discovery of new biomarkers may help to distinguish between infectious and noninfectious uveitis. In the current study, we investigate the proteome of aqueous humor and associated blood plasma from patients with confirmed infectious or noninfectious uveitis. Aqueous humor (AH) and plasma were obtained from 28 patients with infectious uveitis (IU), 29 patients with noninfectious uveitis (NIU) and 35 healthy controls undergoing cataract surgery. The protein profiles were analyzed by SomaScan proteomic profiling technology. Our results showed proteins differentially expressed in the AH and plasma from IU and NIU patients in comparison with cataract patients. Importantly, 18 proteins were up-regulated and 1 protein was down-regulated in both AH and plasma from IU patients. Furthermore, in NIU patients, 142 proteins were up-regulated and 7 proteins down-regulated in both AH and blood plasma. The results of pathway enrichment analysis for both IU and NIU groups identified mostly to inflammatory and regulatory processes. In conclusion, SomaScan assay was able to detect novel AH and plasma protein biomarkers in IU and NIU patients. The unique proteins found in both AH and plasma suggests a protein signature that could distinguish between infectious and noninfectious uveitis patient populations

ADAMTSL2 protein and a soluble biomarker signature identify significant and advanced fibrosis in adults with NAFLD

Abstract Aims and background: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and inform treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD. Methods: We used aptamer-based proteomics to measure 4783 proteins in two cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modelling-logistic regression assessed the candidate proteins to classify fibrosis. Results: From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n=62) and B (n=98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n=71) and D (n=84). The protein A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) accurately distinguished NAFL/NASH with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4 with an AUROC of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3) with an AUROC of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROC 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROC 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and Fibrosis-4 score. Conclusion: The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis with superior performance to standard of care fibrosis scores. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in blood which may identify fibrosis without the need for a liver biopsy