Individualized Polygenic Risk Score Identifies NASH in the Eastern Asia Region: A Derivation and Validation Study.
Ontology highlight
ABSTRACT: Introduction
Strong evidence indicates that multiple genetic and environmental risk factors play a role in the pathogenesis of nonalcoholic steatohepatitis (NASH). We aimed to develop and validate a novel nomogram, incorporating both genetic and clinical factors, for predicting NASH.Methods
A total of 1,070 Asian individuals with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) from 2 countries (China and South Korea) were recruited. The histological spectrum of NAFLD was classified according to the NASH clinical research network scoring system. The nomogram was developed in the Chinese training set (n = 402), and then, it was validated in both the Chinese internal validation set (n = 136) and the external Korean validation cohort (n = 532), respectively.Results
Sex, metabolic syndrome, insulin resistance, serum aspartate aminotransferase levels, and PNPLA3 (rs738409) and HSD17B13 (rs72613567) genetic variants were strongly associated with NASH. Based on their regression coefficients, we developed a nomogram with good discriminatory ability (area under the receiver operating characteristic curve: 0.81, 95% confidence interval [CI] 0.77-0.85) and good calibration (Hosmer-Lemeshow test, P = 0.794) for identifying NASH. In the 2 validation cohorts, the nomogram showed high area under the receiver operating characteristic curves (internal validation set: 0.80, 95% CI 0.72-0.88; external validation cohort: 0.76, 95% CI 0.72-0.80) and good calibration.Discussion
Our newly developed and externally validated nomogram, incorporating both genetic and clinical risk factors, may be conveniently used to predict NASH. Further validation studies in other ethnic groups are warranted to confirm its diagnostic utility to identify NASH, among patients with biopsy-proven NAFLD.
SUBMITTER: Gao F
PROVIDER: S-EPMC7954375 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background Despite advances in cardiovascular disease and risk factor management, mortality from ischemic heart failure (HF) in patients with coronary artery disease (CAD) remains high. Given the partial role of genetics in HF and lack of reliable risk stratification tools, we developed and validated a polygenic risk score for HF in patients with CAD, which we term HF-PRS. Methods and Results Using summary statistics from a recent genome-wide association study for HF, we developed candidate PRSs in the Mount Sinai BioMe CAD patient cohort (N=6274) by using the pruning and thresholding method and LDPred. We validated the best score in the Penn Medicine BioBank (N=7250) and performed a subgroup analysis in a high-risk cohort who had undergone coronary catheterization. We observed a significant association between HF-PRS score and ischemic HF even after adjusting for evidence of obstructive CAD in patients of European ancestry in both BioMe (odds ratio [OR], 1.14 per SD; 95% CI, 1.05-1.24; P=0.003) and Penn Medicine BioBank (OR, 1.07 per SD; 95% CI, 1.01-1.13; P=0.016). In European patients with CAD in Penn Medicine BioBank who had undergone coronary catheterization, individuals in the top 10th percentile of PRS had a 2-fold increased odds of ischemic HF (OR, 2.0; 95% CI, 1.1-3.7; P=0.02) compared with the bottom 10th percentile. Conclusions A PRS for HF enables risk stratification in patients with CAD. Future prospective studies aimed at demonstrating clinical utility are warranted for adoption in the patient setting.
| S-EPMC8751935 | biostudies-literature
Project description:Urinary tract stones have high heritability indicating a strong genetic component. However, genome-wide association studies (GWAS) have uncovered only a few genome wide significant single nucleotide polymorphisms (SNPs). Polygenic risk scores (PRS) sum cumulative effect of many SNPs and shed light on underlying genetic architecture. Using GWAS summary statistics from 361,141 participants in the United Kingdom Biobank, we generated a PRS and determined association with stone diagnosis in 28,877 participants in the Mount Sinai BioMe Biobank. In BioMe (1,071 cases and 27,806 controls), for every standard deviation increase, we observed a significant increment in adjusted odds ratio of a factor of 1.2 (95% confidence interval 1.13-1.26). In comparison, a risk score comprised of GWAS significant SNPs was not significantly associated with diagnosis. After stratifying individuals into low and high-risk categories on clinical risk factors, there was a significant increment in adjusted odds ratio of 1.3 (1.12-1.6) in the low- and 1.2 (1.1-1.2) in the high-risk group for every standard deviation increment in PRS. In a 14,348-participant validation cohort (Penn Medicine Biobank), every standard deviation increment was associated with a significant adjusted odds ratio of 1.1 (1.03 - 1.2). Thus, a genome-wide PRS is associated with urinary tract stones overall and in the absence of known clinical risk factors and illustrates their complex polygenic architecture.
| S-EPMC7606592 | biostudies-literature
Project description:BackgroundGenome-wide association studies have identified over 100 single-nucleotide polymorphisms (SNPs) associated with prostate cancer (PrCa), and polygenic risk scores (PRS) based on their combined genotypes have been developed for risk stratification. We aimed to assess the contribution of PRS to PrCa risk in a large multisite study.MethodsThe sample included 1972 PrCa cases and 1919 unaffected controls. Next-generation sequencing was used to assess pathogenic variants in 14 PrCa-susceptibility genes and 72 validated PrCa-associated SNPs. We constructed a population-standardized PRS and tested its association with PrCa using logistic regression adjusted for age and family history of PrCa.ResultsThe mean age of PrCa cases at diagnosis and age of controls at testing/last clinic visit was 59.5 ± 7.2 and 57.2 ± 13.0 years, respectively. Among 1740 cases with pathology data, 57.4% had Gleason score ≤ 6, while 42.6% had Gleason score ≥ 8. In addition, 39.6% cases and 20.1% controls had a family history of PrCa. The PRS was significantly higher in cases than controls (mean ± SD: 1.42 ± 1.11 vs 1.02 ± 0.76; P < .0001). Compared with men in the 1st quartile of age-adjusted PRS, those in the 2nd, 3rd, and 4th quartile were 1.58 (95% confidence interval [CI]: 1.31-1.90), 2.36 (95% CI: 1.96-2.84), and 3.98 (95% CI: 3.29-4.82) times as likely to have PrCa (all P < .0001). Adjustment for family history yielded similar results. PRS predictive performance was consistent with prior literature (area under the receiver operating curve = 0.64; 95% CI: 0.62-0.66).ConclusionsThese data suggest that a 72-SNP PRS is predictive of PrCa, supporting its potential use in clinical risk assessment.
| S-EPMC7590110 | biostudies-literature
Project description:BackgroundOne-carbon metabolism, which is crucial in DNA synthesis and genomic stability, is an interrelated network of biochemical reactions involved in several dietary and lifestyle factors. The development of the homocysteine score using these factors may be useful to reflect the status of one-carbon metabolism in large epidemiologic studies without biologic samples to measure homocysteine directly.ObjectiveThe aim of this study was to develop an homocysteine score that reflects one-carbon metabolism better than individual dietary or lifestyle factors.MethodsWe divided 2023 participants with measured plasma total homocysteine data in the Nurses' Health Study and the Health Professionals Follow-Up Study into training (n = 1619) and testing (n = 404) subsets. Using multivariable linear regression, we selected lifestyle determinants of plasma homocysteine in the training set and derived the homocysteine score weighted by the β coefficient for each predictor. The validation of the homocysteine score was assessed using the plasma homocysteine in the independent samples of the training set.ResultsIn the training set, smoking, multivitamin use, and caffeine, alcohol, and dietary and supplemental folate intake were significant independent determinants of plasma homocysteine in multivariable linear regression (P ≤ 0.01) and were included in the derivation of the homocysteine score. The Pearson correlation of the homocysteine score with plasma homocysteine was 0.30 in the testing subset (P < 0.001). The homocysteine score was positively associated with the plasma homocysteine concentration in the testing subset and in an independent population of women; the mean difference of plasma homocysteine concentration between the extreme quintiles of homocysteine score ranged from 0.83 μmol/L to 1.52 μmol/L. Population misclassification either from the lowest quintile of plasma homocysteine into the highest quintile of the homocysteine score or from the highest quintile of plasma homocysteine into the lowest quintile of the homocysteine score was ≤12%.ConclusionThese data indicate that the homocysteine score may be used with relatively inexpensive and simple questionnaires to rank an individual's one-carbon metabolism status when homocysteine data are not available.
| S-EPMC4264025 | biostudies-literature
Project description:Hippocampal subfield atrophy is a prime structural change in the brain, associated with cognitive aging and neurodegenerative diseases such as Alzheimer's disease. Recent developments in genome-wide association studies (GWAS) have identified genetic loci that characterize the risk of hippocampal volume loss based on the processes of normal and abnormal aging. Polygenic risk scores are the genetic proxies mimicking the genetic role of the pre-existing vulnerabilities of the underlying mechanisms influencing these changes. Discriminating the genetic predispositions of hippocampal subfield atrophy between cognitive aging and neurodegenerative diseases will be helpful in understanding the disease etiology. In this study, we evaluated the polygenic risk of Alzheimer's disease (AD PGRS) for hippocampal subfield atrophy in 1,086 individuals (319 cognitively normal (CN), 591 mild cognitively impaired (MCI), and 176 Alzheimer's disease dementia (ADD)). Our results showed a stronger association of AD PGRS effect on the left hemisphere than on the right hemisphere for all the hippocampal subfield volumes in a mixed clinical population (CN+MCI+ADD). The subfields CA1, CA4, hippocampal tail, subiculum, presubiculum, molecular layer, GC-ML-DG, and HATA showed stronger AD PGRS associations with the MCI+ADD group than with the CN group. The subfields CA3, parasubiculum, and fimbria showed moderately higher AD PGRS associations with the MCI+ADD group than with the CN group. Our findings suggest that the eight subfield regions, which were strongly associated with AD PGRS are likely involved in the early stage ADD and a specific focus on the left hemisphere could enhance the early prediction of ADD.
| S-EPMC9278752 | biostudies-literature
Project description:Background There are no risk scores designed specifically for mortality risk prediction in unselected cardiac intensive care unit (CICU) patients. We sought to develop a novel CICU-specific risk score for prediction of hospital mortality using variables available at the time of CICU admission. Methods and Results A database of CICU patients admitted from January 1, 2007 to April 30, 2018 was divided into derivation and validation cohorts. The top 7 predictors of hospital mortality were identified using stepwise backward regression, then used to develop the Mayo CICU Admission Risk Score (M-CARS), with integer scores ranging from 0 to 10. Discrimination was assessed using area under the receiver-operator curve analysis. Calibration was assessed using the Hosmer-Lemeshow statistic. The derivation cohort included 10 004 patients and the validation cohort included 2634 patients (mean age 67.6 years, 37.7% females). Hospital mortality was 9.2%. Predictor variables included in the M-CARS were cardiac arrest, shock, respiratory failure, Braden skin score, blood urea nitrogen, anion gap and red blood cell distribution width at the time of CICU admission. The M-CARS showed a graded relationship with hospital mortality (odds ratio 1.84 for each 1-point increase in M-CARS, 95% CI 1.78-1.89). In the validation cohort, the M-CARS had an area under the receiver-operator curve of 0.86 for hospital mortality, with good calibration (P=0.21). The 47.1% of patients with M-CARS <2 had hospital mortality of 0.8%, and the 5.2% of patients with M-CARS >6 had hospital mortality of 51.6%. Conclusions Using 7 variables available at the time of CICU admission, the M-CARS can predict hospital mortality in unselected CICU patients with excellent discrimination.
| S-EPMC6755843 | biostudies-other
Project description:OBJECTIVES:To derive and validate a score that correlates with an objective measurement of a child's effort of breathing. DESIGN:Secondary analysis of a previously conducted observational study. SETTING:The pediatric and cardiothoracic ICUs of a quaternary-care children's hospital. PATIENTS:Patients more than 37 weeks gestational age to age 18 years who were undergoing extubation. INTERVENTIONS:Effort of breathing was measured in patients following extubation using esophageal manometry to calculate pressure rate product. Simultaneously, members of a multidisciplinary team (nurse, physician, and respiratory therapist) assessed respiratory function using a previously validated tool. Elements of the tool that were significantly associated with pressure rate product in univariate analysis were identified and included in a multivariate model. An Effort of Breathing score was derived from the results of the model using data from half of the subjects (derivation cohort) and then validated using data from the remaining subjects (validation cohort) by calculating the area under the receiver operator characteristic curve for pressure rate product greater than 90th percentile and for the need for reintubation. MEASUREMENTS AND MAIN RESULTS:Among 409 subjects, the median age was 5 months, and nearly half were cardiac surgery patients (49.1%). Retractions, stridor, and pulsus paradoxus were included in the Simple Score. Area under the receiver operator characteristic curve for pressure rate product greater than 90th percentile was 0.8359 (95% CI, 0.7996-0.8722) in the derivation cohort and 0.7930 (0.7524-0.8337) in the validation cohort. Area under the receiver operator characteristic curve for reintubation was 0.7280 (0.6807-0.7752) when all scores were analyzed individually and was 0.7548 (0.6644-0.8452) if scores from three clinicians from different disciplines were summated. Results were similar regardless of provider discipline or training. CONCLUSIONS:A scoring system was derived and validated, performed acceptably to predict increased effort of breathing or need for advanced respiratory support and may function best when used by a team.
| S-EPMC6322953 | biostudies-literature
Project description:ObjectiveTo determine whether a polygenic risk score for Alzheimer's disease (AD) predicts dementia probability and memory functioning in non-Hispanic black (NHB) and non-Hispanic white (NHW) participants from a sample not used in previous genome-wide association studies.MethodsNon-Hispanic white and NHB Health and Retirement Study (HRS) participants provided genetic information and either a composite memory score (n = 10,401) or a dementia probability score (n = 7690). Dementia probability score was estimated for participants' age 65+ from 2006 to 2010, while memory score was available for participants age 50+. We calculated AD genetic risk scores (AD-GRS) based on 10 polymorphisms confirmed to predict AD, weighting alleles by beta coefficients reported in AlzGene meta-analyses. We used pooled logistic regression to estimate the association of the AD-GRS with dementia probability and generalized linear models to estimate its effect on memory score.ResultsEach 0.10 unit change in the AD-GRS was associated with larger relative effects on dementia among NHW aged 65+ (OR = 2.22; 95% CI: 1.79, 2.74; P < 0.001) than NHB (OR=1.33; 95% CI: 1.00, 1.77; P = 0.047), although additive effect estimates were similar. Each 0.10 unit change in the AD-GRS was associated with a -0.07 (95% CI: -0.09, -0.05; P < 0.001) SD difference in memory score among NHW aged 50+, but no significant differences among NHB (β = -0.01; 95% CI: -0.04, 0.01; P = 0.546). [Correction added on 29 July 2014, after first online publication: confidence intervalshave been amended.] The estimated effect of the GRS was significantly smaller among NHB than NHW (P < 0.05) for both outcomes.ConclusionThis analysis provides evidence for differential relative effects of the GRS on dementia probability and memory score among NHW and NHB in a new, national data set.
| S-EPMC4107377 | biostudies-literature
Project description:This study builds the first translational model of biological sensitivity to context. In order to determine gene expression patterns that underlie environmental responsivity, we conduct RNA sequencing of ventral dentate gyrus in C57BL6/J mice exposed to two distinctly divergent contexts: environmental enrichment or chronic social defeat stress. Differential expression analysis revealed 18 genes that were commonly regulated in response to these contexts compared to control and were thus considered environmentally responsive irrespective of the valance of the environment. Using the human orthologs, we build a polygenic score of environmental responsivity (ER-ePRS). We then tested whether this ER-ePRS moderated the relationship between the quality of the prevailing environment and anxiety-like or depression problems in four culturally distinctive human cohorts. Results reveal that the molecular underpinnings responsible for environmental responsivity in mice predict a greater propensity to develop psychopathological symptoms in humans in a context and sex dependent manner.
2020-05-20 | GSE150812 | GEO
Project description:ObjectivesTo determine whether there are clinically relevant and reproducible Vasoactive Inotrope Score (VIS) trajectories in children with shock during the acute phase of critical illness.DesignRetrospective, observational cohort study.SettingTwo tertiary, academic PICUs.PatientsChildren (< 18 yr old) who required vasoactive infusions within 24 hours of admission to the PICU. Those admitted post cardiac surgery were excluded.InterventionsNone.Measurements and main resultsAn hourly VIS was calculated for the first 72 hours after initiation of vasoactives. Group-based trajectory modeling (GBTM) was applied to a derivation set (75% of encounters) and compared with the trajectories in a validation set (25% of encounters) using the same variables. The primary outcome was in-hospital mortality, and the secondary outcome was multiple organ dysfunction syndrome (MODS) on day 7. A total of 1,828 patients met inclusion criteria, and 309 (16.9%) died. GBTM identified four subgroups that were reproducible in the validation set: "Mild, fast resolving shock" ( n = 853 [47%]; mortality 9%), "Moderate, slow resolving shock" ( n = 422 [23%]; mortality 15%), "Moderate, prolonged shock" ( n = 312 [17%]; mortality 21%), and "Severe, prolonged shock" ( n = 241 [13%]; mortality 40%). There was a significant difference in mortality, MODS on day 7, and suspected infection ( p < 0.001) across groups. The "Mild, fast resolving shock" and "Severe, prolonged shock" groups were identifiable within the first 24 hours. The "Moderate, slow resolving" and "Moderate, prolonged shock" groups were indistinguishable in the first 24 hours after initiation of vasoactives but differed in in-hospital mortality and MODS on day 7. Hydrocortisone administration was independently associated with poor outcomes in the "Mild, fast resolving shock" group.ConclusionsWe uncovered four distinct and reproducible VIS trajectory groups that were associated with different risk factors, response to therapy, and outcomes in children with shock. Characterizing VIS trajectory groups in the acute phase of critical illness may enable better prognostication and more targeted management.
| S-EPMC9722555 | biostudies-literature