Identification and characterization of a nonbiological small-molecular mimic of a Zika virus conformational neutralizing epitope.

Antigenic similarities between Zika virus (ZIKV) and other flaviviruses pose challenges to the development of virus-specific diagnostic tools and effective vaccines. Starting with a DNA-encoded one-bead-one-compound combinatorial library of 508,032 synthetic, non-natural oligomers, we selected and characterized small molecules that mimic ZIKV epitopes. High-throughput fluorescence-activated cell sorter-based bead screening was used to select molecules that bound IgG from ZIKV-immune but not from dengue-immune sera. Deep sequencing of the DNA from the "Zika-only" beads identified 40 candidate molecular structures. A lead candidate small molecule "CZV1-1" was selected that correctly identifies serum specimens from Zika-experienced patients with good sensitivity and specificity (85.3% and 98.4%, respectively). Binding competition studies of purified anti-CZV1-1 IgG against known ZIKV-specific monoclonal antibodies (mAbs) showed that CZV1-1 mimics a nonlinear, neutralizing conformational epitope in the domain III of the ZIKV envelope. Purified anti-CZV1-1 IgG neutralized infection of ZIKV in cell cultures with potencies comparable to highly specific ZIKV-neutralizing mAbs. This study demonstrates an innovative approach for identification of synthetic non-natural molecular mimics of conformational virus epitopes. Such molecular mimics may have value in the development of accurate diagnostic assays for Zika, as well as for other viruses.

Left ventricular remodeling in end-stage liver disease and post-transplant mortality assessed using end-diastolic pressure-volume relation analysis: Observational retrospective study.

BACKGROUND: Diastolic dysfunction is regarded as an important predictor of outcome after liver transplantation (LT). We investigated the influence of liver disease severity on left ventricular diastolic properties using end-diastolic pressure-volume relationship (EDPVR) analysis in patients with end-stage liver disease (ESLD). Association between alterations of the EDPVR and mortality after LT was evaluated. METHODS: In this observational retrospective cohort study, 3,211 patients who underwent LT for ESLD were included in analysis. Variables derived from single-beat EDPVR (diastolic stiffness-coefficient [ß] and end-diastolic volume at an end-diastolic pressure of 20 mmHg [EDVI20] indicating ventricular capacitance) were estimated using preoperative echocardiographic data. Alterations in EDPVR with increased stiffness (ß > 6.16) were categorized into 3 groups; leftward-shifted (EDVI20 <51 mL/m2), rightward-shifted (EDVI20 > 69.7 mL/m2), and intermediate (EDVI20 51-69.7 mL/m2). RESULTS: As the model for ESLD score increases, both EDVI20 and ß gradually increased, which indicated ventricular remodeling with larger capacitance and higher diastolic stiffness. Among patients with increased stiffness (ß > 6.16, n = 1,090), survival rates after LT were lower in leftward-shifted EDPVR than in rightward-shifted EDPVR (73.7% vs 82.9%; log-rank P = 0.002). In the adjusted Cox proportional hazard model, risk of cumulative all-cause mortality at 11 years was the highest in leftward-shifted EDPVR (hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.27-2.92), followed by intermediate EDPVR (HR: 1.55; 95% CI: 1.12-2.26), compared with rightward-shifted EDPVR. The SHapley Additive exPlanation model revealed that the variables associated with leftward-shifted EDPVR were diabetes, female sex, old age, and hypertension. CONCLUSIONS: As ESLD advances, diastolic ventricular properties are characterized by increased EDVI20 and ß on rightward-shifted EDPVR, indicating larger capacitance and higher stiffness. However, leftward-shifted EDPVR with left ventricle remodeling failure is associated with poor post-LT survival.

Relationship between Preoperative Echocardiographic Parameters and the Incidence of Postoperative Complications in Patients Undergoing Clipping of Unruptured Intracranial Aneurysms: A Retrospective Cohort Study.

Background and Objectives: Preoperative echocardiography is widely performed in patients undergoing major surgeries to evaluate cardiac functions and detect structural abnormalities. However, studies on the clinical usefulness of preoperative echocardiography in patients undergoing cerebral aneurysm clipping are limited. Therefore, this study aimed to investigate the correlation between preoperative echocardiographic parameters and the incidence of postoperative complications in patients undergoing clipping of unruptured intracranial aneurysms. Materials and Methods: Electronic medical records of patients who underwent clipping of an unruptured intracranial aneurysm from September 2018 to April 2020 were retrospectively reviewed. Data on baseline characteristics, laboratory variables, echocardiographic parameters, postoperative complications, and hospital stays were obtained. Univariable and multivariable logistic regression analyses were performed to identify independent variables related to the occurrence of postoperative complications and prolonged hospital stay (≥8 d). Results: Among 531 patients included in the final analysis, 27 (5.1%) had postoperative complications. In multivariable logistic regression, the total amount of crystalloids infused (1.002 (1.001-1.003), p = 0.001) and E/e' ratio (1.17 (1.01-1.35), p = 0.031) were significant independent factors associated with the occurrence of a postoperative complication. Additionally, the maximal diameter of a cerebral aneurysm (1.13 (1.02-1.25), p = 0.024), total amount of crystalloids infused (1.001 (1.000-1.002), p = 0.031), E/A ratio (0.22 (0.05-0.95), p = 0.042), and E/e' ratio (1.16 (1.04-1.31), p = 0.011) were independent factors related to prolonged hospitalization. Conclusions: Echocardiographic parameters related to diastolic function might be associated with postoperative complications in patients undergoing clipping of unruptured intracranial aneurysms.

MethylSeqDesign: a framework for Methyl-Seq genome-wide power calculation and study design issues.

Bisulfite DNA methylation sequencing (Methyl-Seq) becomes one of the most important technologies to study methylation level difference at a genome-wide scale. Due to the complexity and large scale of methyl-Seq data, power calculation and study design method have not been developed. Here, we propose a "MethylSeqDesign" framework for power calculation and study design of Methyl-Seq experiments by utilizing information from pilot data. Differential methylation analysis is based on a beta-binomial model. Power calculation is achieved using mixture model fitting of p-values from pilot data and a parametric bootstrap procedure. To circumvent the issue of existing tens of millions of methylation sites, we focus on the inference of pre-specified targeted regions. The performance of the method was evaluated with simulations. Two real examples are analyzed to illustrate our method. An R package "MethylSeqDesign" to implement this method is publicly available.

Solitary osteolytic skull metastasis as the only recurrence of advanced gastric cancer: a case report and literature review.

Bone metastases from gastric cancer are very rare, and skull metastases develop in only 11.2% among patients who develop bone metastases from gastric cancer. We report a case of solitary osteolytic skull metastasis as the only recurrence of advanced gastric cancer. A 67-year-old man was referred to us with a two-month history of headache and progressive scalp swelling in the left parietal region. A right hemiparesis developed a week before admission. Thirteen months previously, he had undergone radical total gastrectomy with Roux-en-Y reconstruction. Pathological analysis indicated well-differentiated adenocarcinoma of the gastric cardia (stage IIIA: pT3N2M0). Brain magnetic resonance imaging showed a large skull metastasis in the left parietal region (approximately 65 × 54 mm). An extensive search did not reveal any other tumors. Gross total tumor resection was performed, and the biopsy revealed an adenocarcinoma, suggesting metastasis of the gastric cancer.

[Network Meta-analysis of six Chinese patent medicines for replenishing Qi and activating blood in treatment of chronic heart failure].

The efficacy of six commonly used Chinese patent medicines for replenishing Qi and activating blood in the treatment of chronic heart failure was evaluated systematically by network Meta-analysis. Randomized controlled trials(RCTs) about the treatment of chronic heart failure were searched against CNKI, Wanfang, SinoMed, PubMed, and Cochrane library. Network Meta-analysis was performed in Stata 16. A total of 154 RCTs involving 15 620 patients were eventually included. The network Meta-analysis showed that Qili Qiangxin Capsules+conventional western medicine had the highest total effective rate, followed by Tongxinluo Capsules+conventional western medicine, Qishen Yiqi Drop Pills+conventional western medicine, Naoxintong Capsules+conventional western medicine, Shexiang Tongxin Drop Pills+conventional western medicine, Yangxinshi Tablets+conventional western medicine, and conventional western medicine. As for left ventricular ejection fraction(LVEF), Yangxinshi Tablets+conventional western medicine had the highest value, followed by Shexiang Tongxin Drop Pills+conventional western medicine, Qili Qiangxin Capsules+conventional western medicine, Tongxinluo Capsules+conventional western medicine, Qishen Yiqi Drop Pills+conventional western medicine, Naoxintong Capsules+conventional western medicine, and conventional western treatments. As for N-terminal pro-B type natriuretic peptide(NT-proBNP), Qishen Yiqi Drop Pills+conventional western medicine was the most effective treatment, followed by Yangxinshi Tablets+conventional western medicine, Shexiang Tongxin Drop Pills+conventional western medicine, Qili Qiangxin Capsules+conventional western medicine, Tongxinluo Capsules+conventional western medicine, and conventional the most effective treatment was. As for left ventricular end-diastolic diameter(LVEDD), Naoxintong Capsules+conventional western medicine was the best therapy, followed by Tongxinluo Capsules+conventional western medicine, Shexiang Tongxin Drop Pills+conventional western medicine, Yangxinshi Tablets+conventional western medicine, Qili Qiangxin Capsules+conventional western medicine, Qishen Yiqi Drop Pills+conventional western medicine, and conventional western medicine. In summary, the combination of Chinese patent medicines for replenishing Qi and activating blood with western medicines is superior to conventional western medicine alone in the treatment of chronic heart failure. It effectively improves cardiac function indicators such as LVEF, NT-proBNP, and LVEDD, and thus is worthy of popularization in clinical practice. The results of this study provide evidence-based options for the clinical treatment of chronic cardiac failure by combining the Chinese patent medicines for replenishing Qi and activating blood with western medicine.

P-value evaluation, variability index and biomarker categorization for adaptively weighted Fisher's meta-analysis method in omics applications.

MOTIVATION: Meta-analysis methods have been widely used to combine results from multiple clinical or genomic studies to increase statistical powers and ensure robust and accurate conclusions. The adaptively weighted Fisher's method (AW-Fisher), initially developed for omics applications but applicable for general meta-analysis, is an effective approach to combine P-values from K independent studies and to provide better biological interpretability by characterizing which studies contribute to the meta-analysis. Currently, AW-Fisher suffers from the lack of fast P-value computation and variability estimate of AW weights. When the number of studies K is large, the 3K - 1 possible differential expression pattern categories generated by AW-Fisher can become intractable. In this paper, we develop an importance sampling scheme with spline interpolation to increase the accuracy and speed of the P-value calculation. We also apply bootstrapping to construct a variability index for the AW-Fisher weight estimator and a co-membership matrix to categorize (cluster) differentially expressed genes based on their meta-patterns for intuitive biological investigations. RESULTS: The superior performance of the proposed methods is shown in simulations as well as two real omics meta-analysis applications to demonstrate its insightful biological findings. AVAILABILITY AND IMPLEMENTATION: An R package AWFisher (calling C++) is available at Bioconductor and GitHub (https://github.com/Caleb-Huo/AWFisher), and all datasets and programing codes for this paper are available in the Supplementary Material. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Appraisal of Cardiac Ejection Fraction With Liver Disease Severity: Implication in Post-Liver Transplantation Mortality.

BACKGROUND AND AIMS: Enhanced sympathetic nervous activation and peripheral vasodilation in end-stage liver disease (ESLD) may limit the importance of left ventricular ejection fraction (LVEF) as an influential prognosticator. We sought to understand the LVEF and cardiac dimensions in ESLD patients in order to define the LVEF threshold to predict all-cause mortality after liver transplantation (LT). APPROACH AND RESULTS: Data were collected prospectively from the Asan LT Registry between 2008 and 2016, and outcomes were retrospectively reviewed. LVEF, end-diastolic volume index (EDVI), and end-diastolic elastance (Eed) were measured by preoperative echocardiography. Of 2,799 patients, 452 (16.2%) had LVEF ≤ 60%, with 29 (1.0%) having LVEF < 55% and 269 (9.6%) had LVEF ≥ 70%. Over a median of 5.4-year follow-up, 329 (11.8%) patients died: 104 (3.7%) died within 90 days. LVEF (range, 30%-81%) was directly proportionate to Model for End-stage Liver Disease (MELD) scores, an index of liver disease severity, in survivors but showed a fixed flat-line pattern in nonsurvivors (interaction P = 0.004 between groups), with lower EDVI (P = 0.013) and higher Eed (P = 0.001) in the MELD ≥ 20 group. Patients with LVEF ≤ 60% had higher 90-day (13% vs. 7.4%; log rank, P = 0.03) and median 5.4-year (26.7% vs. 16.2%; log rank, P = 0.003) mortality rates in the MELD ≥ 20 group, respectively, compared to those with LVEF > 60%. Specifically, in the MELD > 35 group, median 5.4-year mortality rate was 53.3% in patients with LVEF ≤ 60% versus 24% in those with LVEF > 60% (log rank P < 0.001). By contrast, mortality rates of LVEF ≤ 60% and > 60% were similar in the MELD < 20 group (log rank P = 0.817). CONCLUSIONS: LVEF ≤ 60% is strongly associated with higher post-LT mortality rates in the MELD ≥ 20 group, indicating the need to appraise both LVEF and liver disease severity simultaneously. Enhanced diastolic elastance with low EDVI provides insights into pathogenesis of low LVEF in nonsurvivors with MELD ≥ 20.

MetaOmics: analysis pipeline and browser-based software suite for transcriptomic meta-analysis.

SUMMARY: The rapid advances of omics technologies have generated abundant genomic data in public repositories and effective analytical approaches are critical to fully decipher biological knowledge inside these data. Meta-analysis combines multiple studies of a related hypothesis to improve statistical power, accuracy and reproducibility beyond individual study analysis. To date, many transcriptomic meta-analysis methods have been developed, yet few thoughtful guidelines exist. Here, we introduce a comprehensive analytical pipeline and browser-based software suite, called MetaOmics, to meta-analyze multiple transcriptomic studies for various biological purposes, including quality control, differential expression analysis, pathway enrichment analysis, differential co-expression network analysis, prediction, clustering and dimension reduction. The pipeline includes many public as well as >10 in-house transcriptomic meta-analytic methods with data-driven and biological-aim-driven strategies, hands-on protocols, an intuitive user interface and step-by-step instructions. AVAILABILITY AND IMPLEMENTATION: MetaOmics is freely available at https://github.com/metaOmics/metaOmics. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Intramuscular dexmedetomidine and oral chloral hydrate for pediatric sedation for electroencephalography: A propensity score-matched analysis.

BACKGROUND: Intramuscular dexmedetomidine can be used for pediatric sedation without requiring intravenous access and has advantages for electroencephalography by inducing natural sleep pathway, but only a limited number of studies compared the efficacy of intramuscular dexmedetomidine with oral chloral hydrate. AIMS: To compare the efficacy and safety of intramuscular dexmedetomidine and oral chloral hydrate used for sedation during electroencephalography in pediatric patients. METHODS: We reviewed the medical records of pediatric patients who underwent sedation for electroencephalography between January 2015 and December 2016. Initial doses of dexmedetomidine and chloral hydrate were 3 mcg/kg and 50 mg/kg, respectively; second doses (1 mcg/kg and 50 mg/kg, respectively) were administered if adequate sedation was not achieved. Demographic data, time of sedative administration, time of sedation and awakening, and time of arrival at recovery room and discharge were analyzed. RESULTS: Out of a total of 1239 patients, 125 patients had received dexmedetomidine and 1114 had received chloral hydrate. After 1:1 propensity score matching, the dexmedetomidine and chloral hydrate groups each had 118 patients. Testing completion rate with a single dose of medication was higher in the dexmedetomidine group (91.5% vs 71.2%; mean difference [95% CI] 20.3 [10.8-29.9]; P < .0001; Pearson chi-square value = 16.09). Sedation onset time was shorter in the dexmedetomidine group as well (16.6 ± 13.0 minutes vs 41.5 ± 26.8 minutes; mean difference [95% CI] 24.8 [19.1-30.6]; P < .0001; T = 8.27). On the contrary, the duration of recovery was longer in the dexmedetomidine group (35.5 ± 40.2 minutes vs 18.5 ± 30.7 minutes; mean difference [95% CI] 18.6 [8.8-28.5]; P = .0002; T = -2.82). Total residence time was not significantly different between the two groups (125.8 ± 40.6 minutes vs 122.1 ± 42.2 minutes, mean difference [95% CI] 5.21 [6.1-16.5], P = .3665 T = 0.04). CONCLUSIONS: Intramuscular dexmedetomidine showed higher sedation success rate and shorter time to achieving the desired sedation level compared with oral chloral hydrate and thus may be an effective alternative for oral chloral hydrate in pediatric patients requiring sedation for electroencephalography.

Real-Time Monitoring of Blood Pressure Using Digitalized Pulse Arrival Time Calculation Technology for Prompt Detection of Sudden Hypertensive Episodes During Laryngeal Microsurgery: Retrospective Observational Study.

BACKGROUND: Laryngeal microsurgery (LMS) is often accompanied by a sudden increase in blood pressure (BP) during surgery because of stimulation around the larynx. This sudden change in the hemodynamic status is not immediately reflected in a casual cuff-type measurement that takes intermittent readings every 3 to 5 min. OBJECTIVE: This study aimed to investigate the potential of pulse arrival time (PAT) as a marker for a BP surge, which usually occurs in patients undergoing LMS. METHODS: Intermittent measurements of BP and electrocardiogram (ECG) and photoplethysmogram (PPG) signals were recorded during LMS. PAT was defined as the interval between the R-peak on the ECG and the maximum slope on the PPG. Mean PAT values before and after BP increase were compared. PPG-related parameters and the correlations between changes in these variables were calculated. RESULTS: BP surged because of laryngoscopic manipulation (mean systolic BP [SBP] from 115.3, SD 21.4 mmHg, to 159.9, SD 25.2 mmHg; P<.001), whereas PAT decreased significantly (from mean 460.6, SD 51.9 ms, to 405.8, SD 50.1 ms; P<.001) in most of the cases. The change in SBP showed a significant correlation with the inverse of the PAT (r=0.582; P<.001). Receiver-operating characteristic curve analysis indicated that an increase of 11.5% in the inverse of the PAT could detect a 40% increase in SBP, and the area under the curve was 0.814. CONCLUSIONS: During LMS, where invasive arterial catheterization is not always possible, PAT shows good correlation with SBP and may, therefore, have the potential to identify abrupt BP surges during laryngoscopic manipulations in a noninvasive manner.

Risk stratification of myocardial injury after liver transplantation in patients with computed tomographic coronary angiography-diagnosed coronary artery disease.

We aimed to determine if the severity of computed tomographic coronary angiography (CTCA)-diagnosed coronary artery disease (CAD) is associated with postliver transplantation (LT) myocardial infarction (MI) within 30 days and early mortality. We retrospectively evaluated 2118 consecutive patients who underwent CAD screening using CTCA. Post-LT type-2 MI, elicited by oxygen supply-and-demand mismatch within a month after LT, was assessed according to the severity of CTCA-diagnosed CAD. Obstructive CAD (>50% narrowing, 9.2% prevalence) was identified in 21.7% of patients with 3 or more known CAD risk factors of the American Heart Association. Post-LT MI occurred in 60 (2.8%) of total patients in whom 90-day mortality rate was 16.7%. Rates of post-LT MI were 2.1%, 3.1%, 3.4%, 4.3%, and 21.4% for normal, nonobstructive CAD, and 1-, 2-, and 3-vessel obstructive CAD, respectively. Two-vessel or 3-vessel obstructive CAD showed a 4.9-fold higher post-LT MI risk compared to normal coronary vessels. The sensitivity and negative predictive value of obstructive CAD in detecting post-LT MI were, respectively, 20% and 97.5%. In conclusion, negative CTCA finding in suspected patients can successfully exclude post-LT MI, whereas proceeding with invasive angiography is needed to further risk-stratify in patients with significant CTCA-diagnosed CAD. Prognostic role of CTCA in predicting post-LT MI needs further research.

Meta-analytic principal component analysis in integrative omics application.

Motivation: With the prevalent usage of microarray and massively parallel sequencing, numerous high-throughput omics datasets have become available in the public domain. Integrating abundant information among omics datasets is critical to elucidate biological mechanisms. Due to the high-dimensional nature of the data, methods such as principal component analysis (PCA) have been widely applied, aiming at effective dimension reduction and exploratory visualization. Results: In this article, we combine multiple omics datasets of identical or similar biological hypothesis and introduce two variations of meta-analytic framework of PCA, namely MetaPCA. Regularization is further incorporated to facilitate sparse feature selection in MetaPCA. We apply MetaPCA and sparse MetaPCA to simulations, three transcriptomic meta-analysis studies in yeast cell cycle, prostate cancer, mouse metabolism and a TCGA pan-cancer methylation study. The result shows improved accuracy, robustness and exploratory visualization of the proposed framework. Availability and implementation: An R package MetaPCA is available online. (http://tsenglab.biostat.pitt.edu/software.htm). Contact: ctseng@pitt.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

Neutrophil-to-lymphocyte ratio is a predictor of early graft dysfunction following living donor liver transplantation.

BACKGROUND & AIMS: Early allograft dysfunction (EAD) is predictive of poor graft and patient survival following living donor liver transplantation (LDLT). Considering the impact of the inflammatory response on graft injury extent following LDLT, we investigated the association between neutrophil-to-lymphocyte ratio (NLR) and EAD, 1-year graft failure, and mortality following LDLT, and compared it to C-reactive protein (CRP), procalcitonin, platelet-to-lymphocyte ratio and the Glasgow prognostic score. METHODS: A total of 1960 consecutive adult LDLT recipients (1531/429 as development/validation cohort) were retrospectively evaluated. Cut-offs were derived using the area under the receiver operating characteristic curve (AUROC), and multivariable regression and Cox proportional hazard analyses were performed. RESULTS: The risk of EAD increased proportionally with increasing NLR, and the NLR AUROC was 0.73, similar to CRP and procalcitonin and higher than the rest. NLR ≥ 2.85 (best cut-off) showed a significantly higher EAD occurrence (20.5% vs 5.8%, P < 0.001), higher 1-year graft failure (8.2% vs 4.9%, log-rank P = 0.009) and higher 1-year mortality (7% vs 4.5%, log-rank P = 0.039). NLR ≥ 2.85 was an independent predictor of EAD (odds ratio, 1.89 [1.26-2.84], P = 0.002) after multivariable adjustment, whereas CRP and procalcitonin were not. Increasing NLR was independently associated with higher 1-year graft failure and mortality (both P < 0.001). Consistent results in the validation cohort strengthened the prognostic value of NLR. CONCLUSIONS: Preoperative NLR ≥ 2.85 predicted higher risk of EAD, 1-year graft failure and 1-year mortality following LDLT, and NLR was superior to other parameters, suggesting that preoperative NLR may be a practical index for predicting graft function following LDLT.

Integrative clustering of multi-level omics data for disease subtype discovery using sequential double regularization.

With the rapid advances in technologies of microarray and massively parallel sequencing, data of multiple omics sources from a large patient cohort are now frequently seen in many consortium studies. Effective multi-level omics data integration has brought new statistical challenges. One important biological objective of such integrative analysis is to cluster patients in order to identify clinically relevant disease subtypes, which will form basis for tailored treatment and personalized medicine. Several methods have been proposed in the literature for this purpose, including the popular iCluster method used in many cancer applications. When clustering high-dimensional omics data, effective feature selection is critical for better clustering accuracy and biological interpretation. It is also common that a portion of "scattered samples" has patterns distinct from all major clusters and should not be assigned into any cluster as they may represent a rare disease subcategory or be in transition between disease subtypes. In this paper, we firstly propose to improve feature selection of the iCluster factor model by an overlapping sparse group lasso penalty on the omics features using prior knowledge of inter-omics regulatory flows. We then perform regularization over samples to allow clustering with scattered samples and generate tight clusters. The proposed group structured tight iCluster method will be evaluated by two real breast cancer examples and simulations to demonstrate its improved clustering accuracy, biological interpretation, and ability to generate coherent tight clusters.

Acute Pancreatitis Has a Long-term Deleterious Effect on Physical Health Related Quality of Life.

BACKGROUND & AIMS: It is not clear how acute pancreatitis (AP) affects health related quality of life (HRQOL). We aimed to determine the long-term independent effect of AP on physical and mental HRQOL. METHODS: We analyzed data from 91 patients (mean 52 years of age, 54% women) admitted with AP to the University of Pittsburgh Medical Center from 2011 to 2015 who responded to telephone surveys at a median of 14 months after hospital discharge (interquartile range, 12-16 months). Individuals who did not answer the telephone survey were sent a questionnaire by regular mail. Patients answered questions from the 12-Item Short-Form Survey, and answers were used to calculate mental component summary (MCS) and physical component summary (PCS) scores with norm-based scoring (normal ≥50). HRQOL for these subjects was compared with that of age- and sex-matched individuals without pancreatitis (1:2) identified from the North American Pancreatitis Study. We controlled for other covariates using multivariable regression analysis. RESULTS: At follow-up, individuals with AP had a significantly lower PCS score (46.2 ± 11.8) than did control subjects (51.1 ± 9.5; P < .01), but a similar MCS score. A 4-point reduction of the PCS was attributed to AP after controlling for sociodemographic factors and medical comorbidities. The only pancreatitis-related factor associated with low PCS score was multisystem organ failure. Presence of abdominal pain, analgesic use, disability, and current smoking at the time of follow-up were also associated with lower PCS scores. Etiology of AP, disease severity (by Revised Atlanta classification), use of nutritional support, and performance of pancreatic interventions did not affect HRQOL at follow-up. CONCLUSIONS: In a 14-month follow-up of patients hospitalized with AP, we found a meaningful, independent, and deleterious effect of AP in the physical HRQOL of these patients, compared to individuals without AP. Further research is needed to determine the duration of this impairment and to evaluate the effects of modifying risk factors.

Differential methylation analysis for BS-seq data under general experimental design.

MOTIVATION: DNA methylation is an epigenetic modification with important roles in many biological processes and diseases. Bisulfite sequencing (BS-seq) has emerged recently as the technology of choice to profile DNA methylation because of its accuracy, genome coverage and higher resolution. Current statistical methods to identify differential methylation mainly focus on comparing two treatment groups. With an increasing number of experiments performed under a general and multiple-factor design, particularly in reduced representation bisulfite sequencing, there is a need to develop more flexible, powerful and computationally efficient methods. RESULTS: We present a novel statistical model to detect differentially methylated loci from BS-seq data under general experimental design, based on a beta-binomial regression model with 'arcsine' link function. Parameter estimation is based on transformed data with generalized least square approach without relying on iterative algorithm. Simulation and real data analyses demonstrate that our method is accurate, powerful, robust and computationally efficient. AVAILABILITY AND IMPLEMENTATION: It is available as Bioconductor package DSS. CONTACT: yongpark@pitt.edu or hao.wu@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MethylSig: a whole genome DNA methylation analysis pipeline.

MOTIVATION: DNA methylation plays critical roles in gene regulation and cellular specification without altering DNA sequences. The wide application of reduced representation bisulfite sequencing (RRBS) and whole genome bisulfite sequencing (bis-seq) opens the door to study DNA methylation at single CpG site resolution. One challenging question is how best to test for significant methylation differences between groups of biological samples in order to minimize false positive findings. RESULTS: We present a statistical analysis package, methylSig, to analyse genome-wide methylation differences between samples from different treatments or disease groups. MethylSig takes into account both read coverage and biological variation by utilizing a beta-binomial approach across biological samples for a CpG site or region, and identifies relevant differences in CpG methylation. It can also incorporate local information to improve group methylation level and/or variance estimation for experiments with small sample size. A permutation study based on data from enhanced RRBS samples shows that methylSig maintains a well-calibrated type-I error when the number of samples is three or more per group. Our simulations show that methylSig has higher sensitivity compared with several alternative methods. The use of methylSig is illustrated with a comparison of different subtypes of acute leukemia and normal bone marrow samples. AVAILABILITY: methylSig is available as an R package at http://sartorlab.ccmb.med.umich.edu/software. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

CONFIDENCE INTERVALS UNDER ORDER RESTRICTIONS.

In this paper, we consider the problem of constructing confidence intervals (CIs) for G independent normal population means subject to linear ordering constraints. For this problem, CIs based on asymptotic distributions, likelihood ratio tests and bootstraps do not have good properties particularly when some of the population means are close to each other. We propose a new method based on defining intermediate random variables that are related to the original observations and using the CIs of the means of these intermediate random variables to restrict the original CIs from the separate groups. The coverage rates of the intervals are shown to exceed, but be close to, the nominal level for two groups, when the ratio of the variances is assumed known. Simulation studies show that the proposed CIs have coverage rates close to nominal levels with reduced average widths. Data on half-lives of an antibiotic are analyzed to illustrate the method.

Association between De Ritis ratio and intraoperative blood transfusion in patients undergoing surgical clipping of unruptured intracranial aneurysms: a single center, retrospective, propensity score-matched study.

BACKGROUND: Although elective surgery for unruptured intracranial aneurysms (UIA) has increased, few studies have evaluated the risk factors for transfusion during UIA surgery. We evaluated the association between the preoperative De Ritis ratio (aspartate transaminase/alanine transaminase) and the incidence of intraoperative transfusion in patients who had undergone surgical UIA clipping. METHODS: Patients who underwent surgical clipping of UIA were stratified into two groups according to the preoperative De Ritis ratio cutoff levels (< 1.54 and ≥ 1.54), and the propensity score (PS)-matching analysis was performed to compare the incidence of intraoperative transfusion. Logistic regression analyses were performed to determine the risk factors for intraoperative transfusion. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were performed to verify the improvement in the intraoperative transfusion predictive model upon addition of the De Ritis ratio. RESULTS: Intraoperative transfusion incidence was 15.4% (77/502). We observed significant differences in the incidence of intraoperative transfusion (16.2% vs. 39.7%, P = 0.004) between the groups after matching. In the logistic regression analyses, the De Ritis ratio ≥ 1.54 was an independent risk factor for transfusion (odds ratio [OR]: 3.04, 95% CI [1.53, 6.03], P = 0.002). Preoperative hemoglobin (Hb) value was a risk factor for transfusion (OR: 0.33, 95% CI [0.24, 0.47], P < 0.001). NRI and IDI analyses showed that the De Ritis ratio improved the intraoperative blood transfusion predictive models (P = 0.031 and P = 0.049, respectively). CONCLUSIONS: De Ritis ratio maybe a significant risk factor for intraoperative transfusion in UIA surgery.