Detection of Parent-of-Origin Effects for the Variants Associated With Behavioral Disinhibition in the MCTFR Data.

Behavioral disinhibition is one of the important characteristics of many mental diseases. It has been reported in literature that serious behavioral disinhibition will affect people's health and greatly reduce people's quality of life. Meanwhile, behavioral disinhibition can easily lead to illegal drug abuse and violent crimes, etc., which will bring great harm to the society. At present, large-scale genome-wide association analysis has identified many loci associated with behavioral disinhibition. However, these studies have not incorporated the parent-of-origin effects (POE) into analysis, which may ignore or underestimate the genetic effects of loci on behavioral disinhibition. Therefore, in this article, we analyzed the five phenotypes related to behavioral disinhibition in the Minnesota Center for Twin and Family Research data (nicotine, alcohol consumption, alcohol dependence, illicit drugs, and non-substance use related behavioral disinhibition), to further explore the POE of variants on behavioral disinhibition. We applied a linear mixed model to test for the POE at a genome-wide scale on five transformed phenotypes, and found nine SNPs with statistically significant POE at the significance level of 5 × 10-8. Among them, SNPs rs4141854, rs9394515, and rs4711553 have been reported to be associated with two neurological disorders (restless legs syndrome and Tourette's syndrome) which are related to behavioral disinhibition; SNPs rs12960235 and rs715351 have been found to be associated with head and neck squamous cell carcinoma, skin cancer and type I diabetes, while both SNPs have not been identified to be related to behavioral disinhibition in literature; SNPs rs704833, rs6837925, rs1863548, and rs11067062 are novel loci identified in this article, and their function annotations have not been reported in literature. Follow-up study in molecular genetics is needed to verify whether they are surely related to behavioral disinhibition.

Prediction of hepatic inflammation in chronic hepatitis B patients with a random forest-backward feature elimination algorithm.

BACKGROUND: Persistent liver inflammatory damage is the main risk factor for developing liver fibrosis, cirrhosis, and even hepatocellular carcinoma in chronic hepatitis B (CHB) patients. Thus, accurate prediction of the degree of liver inflammation is a high priority and a growing medical need. AIM: To build an effective and robust non-invasive model for predicting hepatitis B-related hepatic inflammation. METHODS: A total of 650 treatment-naïve CHB (402 HBeAg-positive and 248 HBeAg-negative) patients who underwent liver biopsy were enrolled in this study. Histological inflammation grading was assessed by the Ishak scoring system. Serum quantitative hepatitis B core antibody (qAnti-HBc) levels and 21 immune-related inflammatory factors were measured quantitatively using a chemiluminescent microparticle immunoassay. A backward feature elimination (BFE) algorithm utilizing random forest (RF) was used to select optional features and construct a combined model. The diagnostic abilities of the model or variables were evaluated based on the estimated area under the receiver operating characteristics curve (AUROC) and compared using the DeLong test. RESULTS: Four features were selected to predict moderate-to-severe inflammation in CHB patients using the RF-BFE method. These predictive features included qAnti-HBc, ALT, AST, and CXCL11. Spearman's correlation analysis indicated that serum qAnti-HBc, ALT, AST, and CXCL11 levels were positively correlated with the histology activity index (HAI) score. These selected features were incorporated into the model to establish a novel model named I-3A index. The AUROC [0.822; 95% confidence interval (CI): 0.790-0.851] of the I-3A index was significantly increased compared with qAnti-HBc alone (0.760, 95%CI: 0.724-0.792, P < 0.0001) in all CHB patients. The use of an I-3A index cutoff value of 0.41 produced a sensitivity of 69.17%, specificity of 81.44%, and accuracy of 73.8%. Additionally, the I-3A index showed significantly improved diagnostic performance for predicting moderate-to-severe inflammation in HBeAg-positive and HBeAg-negative CHB patients (0.829, 95%CI: 0.789-0.865 and 0.810, 95%CI: 0.755-0.857, respectively). CONCLUSION: The selected features of the I-3A index constructed using the RF-BFE algorithm can effectively predict moderate-to-severe liver inflammation in CHB patients.

Selected Cytokines Serve as Potential Biomarkers for Predicting Liver Inflammation and Fibrosis in Chronic Hepatitis B Patients With Normal to Mildly Elevated Aminotransferases.

Previous studies of small cohorts have implicated several circulating cytokines with progression of chronic hepatitis B (CHB). However, to date there have been no reliable biomarkers for assessing histological liver damage in CHB patients with normal or mildly elevated alanine aminotransferase (ALT). The aim of the present study was to investigate the association between circulating cytokines and histological liver damage in a large cohort. Also, this study was designed to assess the utility of circulating cytokines in diagnosing liver inflammation and fibrosis in CHB patients with ALT less than 2 times the upper limit of normal range (ULN). A total of 227 CHB patients were prospectively enrolled. All patients underwent liver biopsy and staging by Ishak system. Patients with at least moderate inflammation showed significantly higher levels of CXCL-11, CXCL-10, and interleukin (IL)-2 receptor (R) than patients with less than moderate inflammation (P < 0.001). Patients with significant fibrosis had higher levels of IL-8 (P = 0.027), transforming growth factor alpha (TGF-α) (P = 0.011), IL-2R (P = 0.002), and CXCL-11 (P = 0.032) than the group without significant fibrosis. In addition, 31.8% and 29.1% of 151 patients with ALT < 2 × ULN had at least moderate inflammation and significant fibrosis, respectively. Multivariate analysis demonstrated that CXCL-11 was independently associated with at least moderate inflammation, and TGF-α and IL-2R independently correlated with significant fibrosis in patients with ALT < 2 × ULN. Based on certain cytokines and clinical parameters, an inflammation-index and fib-index were developed, which showed areas under the receiver operating characteristics curve (AUROC) of 0.75 (95% CI 0.66-0.84) for at least moderate inflammation and 0.82 (95% CI 0.75-0.90) for significant fibrosis, correspondingly. Compared to existing scores, fib-index was significantly superior to aspartate aminotransferase (AST) to platelet ratio index (APRI) and FIB-4 score for significant fibrosis. In conclusion, CXCL-11 was independently associated with at least moderate inflammation, whereas IL-2R and TGF-α were independent indicators of significant fibrosis in both, total CHB patients and patients with normal or mildly elevated ALT. An IL-2R and TGF-α based score (fib-index) was superior to APRI and FIB-4 for the diagnosis of significant fibrosis in patients with normal or mildly elevated ALT.