(2010). Am. Compared with those individuals who had the lowest score (wGRS < 1.80), the trauma patients with a higher score had higher incidence of sepsis, with odds ratios of 1.47 (95%CI = 0.93–2.30, P = 0.10), 1.87 (95%CI = 1.20–2.92, P = 6.00 × 10–3), and 3.16 (95%CI = 2.05–4.88, P = 1.20 × 10–7), respectively (Ptrend = 6.81 × 10–8) (Table 2). The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. USA.gov. Acute Physiology and Chronic Health Evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores were carried out to evaluate the severity and organ failures after injury during the hospital days. S, AR, Segal Crit. (2019). The red line represents the nomogram. The discriminative ability of wGRS was evaluated by receiver operating characteristic (ROC) curves and the areas under the curve (AUC). INTRODUCTION Genetic, animal and epidemiological studies involving biomolecular and clinical endophenotypes implicate mitochondrial dysfunction in Alzheimer’s disease (AD) pathogenesis. The diagnosis criterion of sepsis was according to the Sepsis 2.0 for patients who met at least two of SIRS criteria plus infection (Jacome and Tatum, 2018). 20, R182–R188. , Tung et al; ABCTB Investigators; EMBRACE; GEMO Study Collaborators; HEBON; kConFab/AOCS Investigators; NBSC Collaborators. 44, 2199–2207. Mitochondrial pathway polygenic risk scores are associated with Alzheimer’s Disease, for the Alzheimer’s Disease Neuroimaging Initiative, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Mark and Mary Stevens Neuroimaging and Informatics Institute, USC Alzheimer’s Disease Research Center, Keck School of USC, University of Kansas Alzheimer’s Disease Center, Kansas City, Department of Neuroscience, Icahn School of Medicine at Mount Sinai. Virulence 5, 36–44. The AUCs of only wGRS and only ISS were 0.619 (95%CI = 0.586–0.651) and 0.734 (95%CI = 0.703–0.763), respectively. Patient selection using these criteria was performed before calculation of the 86-SNV score. Dr Lancaster reported being a previous employee of Myriad Genetics and a current employee of Regeneron Pharmaceuticals. Our current study indicated that increased wGRS was significantly associated with a higher risk of traumatic sepsis. (2016). BG. The effect size of the 86-SNV score in ATM (OR, 1.37; 95% CI, 1.21-1.55) and PALB2 (OR, 1.34; 95% CI, 1.16-1.55) PV carriers was similar to that observed for noncarriers.14,28. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. PD, Michailidou In the current study involving 883 trauma patients, 17 of 64 potential risk variants identified systematically by previous GWAS and candidate gene association studies were used to calculate wGRS based on the random forest algorithm. Development and validation of a new algorithm for the reclassification of genetic variants identified in the, Lee ORs for Developing Breast Cancer by BC Affected Status of a First-Degree Relative and by Carrier Status for a PV in a BC-Associated Gene, eFigure 4. Med. The AUC of the risk prediction model incorporating wGRS into the clinical variables was 0.768 (95% CI = 0.739–0.796), with an increase of 3.40% (P = 8.00 × 10–4) vs. clinical factor-only model. wGRS and ISS were identified as independent risk predictors of sepsis in trauma patients using the multivariate logistic regression algorithm (Supplementary Table S5). , Anglian Breast Cancer Study Group. In this study, stratification of breast cancer risk by an 86-SNV score in PV carriers of moderate-risk breast cancer genes was associated with risk changes for women at the lower and higher ends of the risk distribution. To determine this overall risk, we need to model how to sum the contribution of all of these variants together. I-squared and p value for heterogeneity were calculated using fixed effect meta-analysis. RESULTS Pathway-PRS for four mitochondrial pathways are significantly associated with increased AD risk: (i) response to oxidative stress (OR: 2.01 [95% Cl: 1.71, 2.37]); (ii) mitochondrial transport (OR: 1.81 [95% Cl: 1.55, 2.13]); (iii) hallmark oxidative phosphorylation (OR: 1.23 [95% Cl: 1.07, 1.41]); and (iv) mitochondrial membrane potential regulation (OR: 1.18 [95% Cl: 1.03, 1.36]). Effect sizes, expressed as standardized odds ratios (ORs) with 95% CIs, were assessed for carriers of PVs in each gene as well as for noncarriers. | , Hughes Breast cancer variant detection via next-generation sequencing has been described in detail elsewhere.29 Women were classified as positive for at least 1 PV in a gene associated with breast cancer (ie, BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, and BARD1) using American College of Medical Genetics and Genomics recommendations and Association for Molecular Pathology guidelines, as well as previously described statistical variant classification methods.30. Genetic polymorphisms in sepsis. None of the other variants was associated with sepsis. Wurfel, M. M., Gordon, A. C., Holden, T. D., Radella, F., Strout, J., Kajikawa, O., et al. 255, 147–157. Family history of breast cancer is a significant determinant in the development of the disease, and 3 types of genetic variation are known to contribute to the risk.1 First, high-risk pathogenic or likely pathogenic variants (PVs) in BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) (BRCA1/2) have been known since the mid-1990s to influence familial risk and are routinely tested for in families with a significant family history. Med. Breast cancer risk prediction using clinical models and 77 independent risk-associated SNPs for women aged under 50 years: Australian Breast Cancer Family Registry. However, polygenic scores do not provide a baseline or timeframe for the progression of a disease. Single-nucleotide variation genotyping by next-generation sequencing and details for calculating the 86-SNV score have been described previously.13 Briefly, from a panel of 94 previously identified breast cancer–associated SNVs published at the start of this study,11,12 86 variants were selected based on a ranking of informativeness for their contribution of breast cancer risk. J, Brentnall | Methods: Sixty-four genetic variants potential relating to sepsis were genotyped in Chinese trauma cohort. Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. DCA was recently considered as a novel analysis for evaluating clinical consequences the nomogram brings on decision-making. To date, our study is the first attempt to construct and comprehensively evaluate the capacity of wGRS for risk prediction of traumatic sepsis. (2017). Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. The area under the curve (AUC) and net reclassification improvement (NRI) were adopted to evaluate the discriminatory and reclassification ability of weighted genetic risk score (wGRS). R, Li Published: July 1, 2020. doi:10.1001/jamanetworkopen.2020.8501. TP, LaDuca AP, Tischkowitz S, Lash , Easton doi: 10.1097/sla.0000000000000687, Keywords: trauma, sepsis, prediction, genetic variants, weighted genetic risk score, Citation: Lu H, Wen D, Sun J, Du J, Qiao L, Zhang H, Zeng L, Zhang L, Jiang J and Zhang A (2020) Polygenic Risk Score for Early Prediction of Sepsis Risk in the Polytrauma Screening Cohort. Articles, https://doi.org/10.3389/fgene.2020.545564, https://www.researchsquare.com/article/rs-14628/v1, https://www.frontiersin.org/articles/10.3389/fgene.2020.545564/full#supplementary-material, Creative Commons Attribution License (CC BY). A case–control evaluation of 143 single nucleotide polymorphisms for breast cancer risk stratification with classical factors and mammographic density. All statistical analyses were performed with SPSS 17.0 and R statistical software version 3.6.1. The likelihood that a woman will develop breast cancer during her lifetime is influenced by her genetic inheritance. In addition, the combination of genetic and clinical factors into one model was feasible in clinical practice for trauma patients, which might enhance the discrimination of patients at high risk for sepsis. However, polygenic scores do not provide a baseline or timeframe for the progression of a disease. Larger data sets will permit analysis of PRS modification for less commonly mutated breast cancer genes and will refine risk modification associated with PVs in ATM and PALB2. (2014). et al. T, Leclair KB, Hopper We warmly thank Prof. Min Wu, University of North Dakota, and Daolin Tang, University of Pittsburgh, for the helpful discussions and Genesky Biotechnologies Inc., Shanghai, for genotyping of the samples and for technical support. C, Tybjaerg-Hansen Figure 1. (2017). Firstly, in our current study, only ISS was significantly different between sepsis and non-sepsis trauma patients and included into the prediction model, but other risk factors (antibiotic usage, blood transfusion, and tracheal cannula et al.) Michailidou Results J, The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. L, N, Domchek To examine relative risks by percentiles of the 86-SNV score, the noncarrier and BRCA1, BRCA2, CHEK2, and ATM PV-positive cohorts were each binned into quintiles based on the 86-SNV score. For example, consider two people with high polygenic risk scores for having coronary heart disease. Reclassification of predicted risk with the addition of wGRS using NRI. A., et al. P, Gallagher Stat. This study has several notable strengths. Age- and tumor subtype-specific breast cancer risk estimates for, Maxwell Polygenic risk score for early prediction of sepsis risk in the polytrauma screening cohort. . ORs for Developing Breast Cancer by 86-SNV Score Percentile and PV Carrier Status, Table 4. N, Seal 2020 Aug 14;21(16):5835. doi: 10.3390/ijms21165835. Eligible studies were searched from PubMed, Embase, Medline, Web of Science, and HuGE databases before March 13, 2016, by using the following keywords: associated or synonymous with “sepsis” and “polymorphism.” Moreover, we reviewed the full articles with the following criteria: (1) studies provided the number or frequency of genotypes in detail; and (2) these papers had an observational (case control or cohort) study design. P values were calculated from likelihood ratio χ2 test statistics and are reported as 2-sided; P < .05 was considered the level of significance. Get free access to newly published articles. EA, The associations of the four variants with sepsis were confirmed using logistic regression analysis, adjusting for age and sex. The information will be posted with your response. Available at: https://www.researchsquare.com/article/rs-14628/v1 (Accessed Feb 20, 2020), Mao, Q., Jay, M., Hoffman, J. L., Calvert, J., Barton, C., Shimabukuro, D., et al. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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