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In cancer genomics research, gene expressions provide clues to gene regulations implicating patients’ risk of survival. Gene expressions, however, fluctuate due to noises arising internally and externally, making their use to infer gene associations, hence regulation mechanisms, problematic. Here, we develop a new regression approach to model gene association networks while considering uncertain biological noises. In a series of simulation experiments accounting for varying levels of biological noises, the new method was shown to be robust and perform better than conventional regression methods, as judged by a number of statistical measures on unbiasedness, consistency and accuracy. Application to infer gene associations in germinal-center B cells led to the discovery of a three-by-two regulatory motif gene expression and a three-gene prognostic signature for diffuse large B-cell lymphoma.

The optimal treatment for vitreoretinal lymphoma (VRL) remains a challenge, as central nervous system (CNS) relapse occurs frequently, leading to the worst impact on survival. We previously proposed combined intravitreal methotrexate and systemic high-dose methotrexate therapy for this disease. This study aimed to report the long-term outcomes of patients with VRL using this combination treatment.We conducted a retrospective cohort study on patients with VRL at a tertiary referral center between 2003 and 2018.Thirty-two patients were included, of whom 23 had primary VRL (PVRL) and nine had concurrent intraocular and CNS diseases. The treatment was well tolerated. Twenty-six (81.3%) patients achieved complete response (CR). After a median follow-up time of 103.5 months, the 5-year survival rate was 73.3%, whereas the 5-year progression-free survival (PFS) rate was 29.9%. Twenty-four (75%) patients relapsed, including 12 with isolated intraocular relapses at first relapse and a total of 17 with CNS/systemic relapses. The development of CNS/systemic relapse negatively affected survival, but intraocular relapse did not. The median CNS/systemic PFS was 69.5 months, but the risk of CNS/systemic relapse increased steadily with a cumulative incidence rate at 2, 5, and 10 years being 22.6%, 44.2%, and 65%, respectively. Multivariate analysis identified concurrent CNS disease at diagnosis as the only poor-risk factor for CNS/systemic relapse.This study confirms good efficacy and acceptable toxicities of the combination approach. However, incorporation of further intensive consolidation strategies into the treatment protocol to effectively prevent subsequent CNS/systemic relapse deserves to be considered.

The increased expression of programmed death-ligands 1 and 2 (PD-L1 and PD-L2, respectively) on tumour cells contributes to immune evasion, suggesting that these proteins are attractive therapeutic targets. This study aimed to evaluate the validity of cerebrospinal fluid (CSF) soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2) as biomarkers for primary central nervous system lymphoma (PCNSL). We determined the CSF concentrations of sPD-L1 and sPD-L2 in 46 patients with PCNSL using enzyme-linked immunosorbent assays (ELISAs). A control group comprised 153 patients with other brain tumours, inflammatory/infectious status, or neurodegenerative diseases. Only CSF sPD-L1 levels were significantly higher in patients with PCNSL relative to the controls. CSF sPD-L1 also exhibited superior overall discrimination performance compared to CSF sPD-L2 in diagnosing PCNSL. Compared with patients with PCNSL with low CSF sPD-L1 levels, more patients with high levels had high serum lactate dehydrogenase levels, leptomeningeal involvement, and deep-brain involvement. Furthermore, CSF sPD-L1 could predict poor survival in PCNSL but CSF sPD-L2 could not. Intriguingly, CSF sPD-L1 levels were correlated with disease status and their dynamic changes post treatment could predict time to relapse. In conclusion, this study identified CSF sPD-L1 as a promising prognostic biomarker, indicating a therapeutic potential of PD-L1 blockade in PCNSL.

Studies have reported a positive association between hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection and follicular lymphoma (FL). Nevertheless, clinical information concerning chronic HBV infection in FL is sparse. This retrospective cohort study investigated the prognostic impact of HBsAg in immunocompetent patients with FL treated with frontline rituximab-containing chemoimmunotherapy in an HBV-endemic area between 2006 and 2016. Among the 149 analyzed patients, 32 (21.5%) were HBsAg-positive. HBsAg positivity was positively associated with symptomatic splenomegaly, significant serous effusions, and peritreatment hepatic dysfunction. HBsAg-positive patients had a trend of lower complete remission rate (59.4% vs. 76.9%, P = 0.07), significantly poorer overall survival (hazard ratio for death, 2.68; 95% confidence interval, 1.21–5.92), and shorter progression-free survival than had HBsAg-negative patients. Multivariate analysis revealed that HBsAg is an independent adverse prognostic factor for overall survival. Intriguingly, HBsAg-positive patients had a higher incidence of progression of disease within 24 months (POD24) than had HBsAg-negative patients (cumulative incidence rate, 25.8% vs. 12.4%, P = 0.045). This study revealed that patients with FL and chronic HBV infection represent a distinct subgroup with a markedly poor prognosis. HBsAg was positively associated with POD24 and might serve as a new prognostic predictor of the survival of FL patients in endemic regions for HBV infection.

The use of penalized least squares based estimations in high dimensional linear regression has been received a great deal of attention during past decades and applied to variable selections under s...

The impacts of outliers and Berkson-type uncertainties with additive and multiplicative errors in linear regression are investigated. The work is motivated by a common biological phenomenon in which outlying observations and Berkson-type uncertainties may lie partly in the data, causing incorrect estimations and inferences. In this article, we use Wald-type estimator to combat these uncertainties due to its merits, including large sample properties especially for asymmetric errors, as well as its simplicity without nuisance parameters. The severity of the neglect of uncertainty effects will be examined by Monte Carlo simulations and real data examples through comparison with residual-based methods and the proposed estimate.

Dementia frequently occurs in Down syndrome (DS) patients, and early intervention is important in its management. We have previously demonstrated a positive correlation of plasma β-amyloid Aβ42 levels and negative correlations of Aβ40 and tau levels with dementia in DS. In this study, we examined more cases and constructed composite scores with both tau and amyloids to correlate with dementia in DS. Plasma Aβ42, Aβ40, and tau proteins were measured by an immunomagnetic reduction assay in DS patients. Data were randomly and repeatedly split into training and validating sets, and logistic regression was applied to calculate the area under the curve (AUC) for each biomarker. A total of 73 DS patients (among them, 23 had neurodegeneration) and 77 controls were recruited. In DS patients without dementia, plasma Aβ40 and tau levels were highly elevated, but Aβ42 levels were lower than those of the healthy controls. DS patients with dementia, compared with DS patients with no dementia, had a large decline in Aβ40 and tau but a rise in Aβ42. For biomarker scores correlating with dementia, Aβ40 revealed an AUC of 0.912; the composite score of Aβ40 × tau revealed an AUC of 0.953; and a combined composite score of 0.1 for Aβ40 × Tau +0.9 Tau × Aβ40/Aβ42 achieved the highest AUC of 0.965. Therefore, composite biomarker scores including both plasma tau and β-amyloid levels correlate with dementia in DS better than using individual biomarker scores. The pattern of tau decline and Aβ42 rise in DS patients with dementia are also different from previous findings in Alzheimer's disease.

Background Patients with diffuse large B-cell lymphoma (DLBCL) with concurrent hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection have distinct clinical features. Nevertheless, the prognostic value of HBsAg in DLBCL in the rituximab era remains unclear. Materials and Methods We conducted a retrospective cohort study to investigate the clinical relevance of HBsAg in immunocompetent patients with DLBCL treated with homogeneous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone between 2002 and 2016. Results Among 416 analyzed patients, 98 (23.6%) were HBsAg positive. HBsAg positivity was associated with a younger age and more advanced stage at diagnosis, more frequent hepatic impairment during perichemotherapy, and a trend of higher National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score at diagnosis. Compared with the HBsAg-negative patients, the HBsAg-positive patients had a lower overall response rate (76.5% vs. 85.5%, p = .043), poorer 5-year overall survival (OS) rate (57.2% vs. 73.5%, p < .001), and shorter 5-year progression-free survival (PFS) rate (47.2% vs. 60.7%, p = .013). Multivariate analyses showed that HBsAg positivity was an independent unfavorable prognostic indicator for OS and PFS. A scoring system incorporating HBsAg positivity, the NCCN-IPI score, and serum albumin levels proved to be useful for stratifying prognostically relevant subgroups of patients with DLBCL. Conclusion This study demonstrated that HBV infection is uniquely relevant to DLBCL. HBsAg might serve as a novel biomarker to improve clinical risk stratification of patients with DLBCL in areas with high prevalence of HBV infection. Further research investigating the etiopathogenesis of HBV infection in DLBCL is imperative. Implications for Practice A considerable disparity exists regarding the prognostic relevance of hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection in patients with diffuse large B-cell lymphoma (DLBCL). In this large, retrospective cohort study from an area with high prevalence of HBV infection, the authors demonstrated that HBsAg was an independent unfavorable factor significantly associated with survival, highlighting its potential as a novel prognostic indicator to improve the risk stratification of patients with DLBCL in the rituximab era.

This article proposes a consistent estimation approach in linear regression models for the case when the predictor variables are subject to collinearities and Berkson-type measurement errors simultaneously. Our presented procedure does not rely on ridge regression (RR) methods that have been widely addressed in the literature for ill-conditioned problems resulted from multicollinearity. Instead, we review and propose new consistent estimators due to Wald (1940) so that, except finite fourth moments assumptions, no prior knowledge of parametric settings on observations and errors is used, and there is no need to solve estimating equations for coefficient parameters. The performance of the estimation procedure is compared with that of RR based estimators by using a variety of numerical experiments through Monte Carlo simulation under estimated mean squared error (EMSE) criterion.

Interval-censored survival data arise often in medical applications and clinical trials [Wang L, Sun J, Tong X. Regression analyis of case II interval-censored failure time data with the additive hazards model. Statistica Sinica. 2010;20:1709–1723]. However, most of existing interval-censored survival analysis techniques suffer from challenges such as heavy computational cost or non-proportionality of hazard rates due to complicated data structure [Wang L, Lin X. A Bayesian approach for analyzing case 2 interval-censored data under the semiparametric proportional odds model. Statistics & Probability Letters. 2011;81:876–883; Banerjee T, Chen M-H, Dey DK, et al. Bayesian analysis of generalized odds-rate hazards models for survival data. Lifetime Data Analysis. 2007;13:241–260]. To address these challenges, in this paper, we introduce a flexible Bayesian non-parametric procedure for the estimation of the odds under interval censoring, case II. We use Bernstein polynomials to introduce a prior for modeling the odds and propose a novel and easy-to-implement sampling manner based on the Markov chain Monte Carlo algorithms to study the posterior distributions. We also give general results on asymptotic properties of the posterior distributions. The simulated examples show that the proposed approach is quite satisfactory in the cases considered. The use of the proposed method is further illustrated by analyzing the hemophilia study data [McMahan CS, Wang L. A package for semiparametric regression analysis of interval-censored data; 2015. http://CRAN.R-project.org/package=ICsurv.

This article discusses a consistent and almost unbiased estimation approach in partial linear regression for parameters of interest when the regressors are contaminated with a mixture of Berkson and classical errors. Advantages of the presented procedure are: (1) random errors and observations are not necessarily to be parametric settings; (2) there is no need to use additional sample information, and to consider the estimation of nuisance parameters. We will examine the performance of our presented estimate in a variety of numerical examples through Monte Carlo simulation. The proposed approach is also illustrated in the analysis of an air pollution data.

The 6-minute walking test (6MWT) is a simple method used to evaluate exercise capacity in adults and children with cardiac diseases. Normal reference values in pediatric populations have been reported, but significant variations in the walking distance (6MWD) were noted among different studies. We aimed to provide and validate normal reference values of the 6MWD for healthy Taiwanese pediatric population between 7 and 17 years of age.Healthy children and adolescents were recruited from 13 randomly selected schools in Kaohsiung City. From that recruitment effort, 762 participants (50.1% male) were included, and the 6MWT was conducted using standardized protocols. The main outcome measure utilized was the 6MWD, which was used to construct centile charts and Z score equations. Data from additional 64 healthy volunteers recruited from the National Taiwan University Children's Hospital were used to validate these standards.There was an overall linear trend of increase in the 6MWD between 7 and 17 years of age (p0.001). Males covered significantly more distance than females after the age of 14 years, when the 6MWD essentially plateaued in female adolescents. Upon multivariate analysis, height was the most significant positive predictor of the 6MWD, while body mass index negatively correlated with the 6MWD. The height-based normal reference values of the 6MWD, derived from the 6MWT conducted in the school settings, were validated by a second cohort who received 6MWT inside the hospital.Normal reference values of the 6MWD in healthy Taiwanese children and adolescents may serve as useful references for future clinical and research studies.Adolescents; Children; Six-minute walking test; Taiwan.

Objective To explore the role of transcription-coupled repair (TCR) pathway in the UVC-induced SupF gene mutation in Tet-on 293 cell line, we designed and constructed a Tet-responsive plasmid DNA pTCR-C1, and utilized this pTCR-C1 plasmid to obtain the mutation frequency of SupF reporter gene induced by UVC in Tet-on 293 cell line. Methods SupF gene was cloned into a Tet-responsive plamid pBI-L, which include a bidirectional Tet-responsive promoter, and was named pTCR-C1. The pTCR-C1 plasmid was transfected into Tet-on 293 cell line, and the mutation frequency of SupF reporter gene was detected in the presence and absence of DOX. Results The pTCR-C1 plasmid was identified with the methods of restriction digestion and DNA sequencing. The mutation frequency of SupF reporter gene in the presence of DOX was higher than in the absence of DOX. Conclusion The TCR pathway takes part in the UVC-induced SupF gene mutation in Tet-on 293 cell line.