The prediction of HLA genotypes from next generation sequencing and genome scan data

Genome-wide association studies have very successfully found highly significant disease associations with single nucleotide polymorphisms (SNP) in the Major Histocompatibility Complex for adverse drug reactions, autoimmune diseases and infectious diseases. However, the extensive linkage disequilibrium in the region has made it difficult to unravel the HLA alleles underlying these diseases. Here I present two methods to comprehensively predict 4-digit HLA types from the two types of experimental genome data widely available. The Virtual SNP Imputation approach was developed for genome scan data and demonstrated a high precision and recall (96% and 97% respectively) for the prediction of HLA genotypes. A reanalysis of 6 genome-wide association studies using the HLA imputation method identified 18 significant HLA allele associations for 6 autoimmune diseases: 2 in ankylosing spondylitis, 2 in autoimmune thyroid disease, 2 in Crohn's disease, 3 in multiple sclerosis, 2 in psoriasis and 7 in rheumatoid arthritis. The EPIGEN consortium also used the Virtual SNP Imputation approach to detect a novel association of HLA-A*31:01 with adverse reactions to carbamazepine. For the prediction of HLA genotypes from next generation sequencing data, I developed a novel approach using a naïve Bayes algorithm called HLA-Genotyper. The validation results covered whole genome, whole exome and RNA-Seq experimental designs in the European and Yoruba population samples available from the 1000 Genomes Project. The RNA-Seq data gave the best results with an overall precision and recall near 0.99 for Europeans and 0.98 for the Yoruba population. I then successfully used the method on targeted sequencing data to detect significant associations of idiopathic membranous nephropathy with HLA-DRB1*03:01 and HLA-DQA1*05:01 using the 1000 Genomes European subjects as controls. Using the results reported here, researchers may now readily unravel the association of HLA alleles with many diseases from genome scans and next generation sequencing experiments without the expensive and laborious HLA typing of thousands of subjects. Both algorithms enable the analysis of diverse populations to help researchers pinpoint HLA loci with biological roles in infection, inflammation, autoimmunity, aging, mental illness and adverse drug reactions

Investigating the Solid-Liquid Phase Transition of Water Nanofilms Using the Generalized Replica Exchange Method

This is the author's accepted manuscript. The final version is available from AIP at http://scitation.aip.org/content/aip/journal/jcp/141/18/10.1063/1.4896513.The Generalized Replica Exchange Method (gREM) was applied to simulate a solid-liquid phase transition in a nanoconfined bilayer water system using the monatomic water (mW) model. Merging an optimally designed non-Boltzmann sampling weight with replica exchange, gREM is particularly well suited for the effective simulation of first-order phase transitions characterized by S-bends (“backbending”) in the statistical temperature and a bimodal structure in the canonical probability density function. The effective temperatures of gREM were designed to form unique crossing points with the statistical temperature, thereby facilitating sampling of energy states across the transition region. Statistical Temperature Weighted Histogram Analysis Method (ST-WHAM) was used to reweight gREM simulation results into canonical ensemble averages, including the Helmholtz free energy, internal energy, and heat capacity. The minimized structures of bilayer water systems with varying sizes were obtained through basin-hopping global optimization using the GMIN package, and ice structures composed of pentagons, hexagons and heptagons were observed

Introduction, dispersal and naturalisation of the Manila clam Ruditapes philippinarum in British estuaries, 1980-2010

The introduction of the Manila clam into British coastal waters in the 1980s was contested by conservation agencies. While recognizing the value of the clam for aquaculture, the government decided that it posed no invasive risk, as British sea temperatures would prevent naturalization. This proved incorrect. Here we establish the pattern of introduction and spread of the species over the first 30 years of its presence in Britain. We report archival research on the sequence of licensed introductions and examine their relationship in time and space to the appearance of wild populations as revealed in the literature and by field surveys. By 2010 the species had naturalized in at least 11 estuaries in southern England. These included estuaries with no history of licensed introduction. In these cases activities such as storage of catch before market or deliberate unlicensed introduction represent the probable mechanisms of dispersal. In any event naturalization is not an inevitable consequence of introduction and the chances of establishment over the period in question were finely balanced. Consequently in Britain the species is not currently aggressively invasive and appears not to present significant risk to indigenous diversity or ecosystem function. However it is likely to gradually continue its spread should sea surface temperatures rise as predicted

Knee Injuries in NFL Lineman -- A Correlation with BMI

Knee Injuries in NFL Linemen - Correlation with BMI Dr. Michael Lem, MD; Dr. John Bianchi, DO; Austin Irwin, OMS II; Dr. Robert Farrell, MD; Cole Siegenfeld, OMS II Purpose: Knee injuries are among the most common injuries suffered in the NFL which in turn can decrease a player\u27s playing time in a given season and thus negatively impact future performance. Understanding characteristics like BMI can help modify and identify players at risk for knee injuries. Methods and Study Design: Data collected for this study was extracted from the official NFL database of injuries. Reported knee injuries for offensive and defensive lineman were collected and organized by week during the 2009-2022 seasons; final data was calculated for players with a BMI over 39.95. Pro-football-reference.com was cited for height, weight, career length and draft status. BMI was calculated based on height and weight. Comparisons were made between BMI and game status. Results: Among the players collected, offensive tackles were the most likely to appear on the injury report. Players with a BMI above 40 appeared most commonly as Probable (n=182), followed by Questionable (157), Out (134) then Doubtful (26). The average BMI for the players listed as probable was x=42.4 (SD=2.69); questionable x=41.2 (1.37); doubtful x=41.0 (.856); out x=40.9 (.991). There is a significant difference in the player’s BMI between “probable” game status and both “questionable” (p=.023) and “out” (p\u3c .001). Players with a BMI= +37 appeared as either out or doubtful 30.07% total. Players with a BMI under 37 appeared as either out or doubtful 30.81%. Conclusions: Based on our data, BMI may play a protective role on injury report placement for knee injuries. The abundance of “probable” game status also supports the notion that the injuries studied are lower-grade. More players appear on the injury list towards the end of the season, which may indicate there is a persisting effect to the injuries

Comparison of the diagnostic accuracy of three current guidelines for the evaluation of asymptomatic pancreatic cystic neoplasms.

Asymptomatic pancreatic cysts are a common clinical problem but only a minority of these cases progress to cancer. Our aim was to compare the accuracy to detect malignancy of the 2015 American Gastroenterological Association (AGA), the 2012 International Consensus/Fukuoka (Fukuoka guidelines [FG]), and the 2010 American College of Radiology (ACR) guidelines.We conducted a retrospective study at 3 referral centers for all patients who underwent resection for an asymptomatic pancreatic cyst between January 2008 and December 2013. We compared the accuracy of 3 guidelines in predicting high-grade dysplasia (HGD) or cancer in resected cysts. We performed logistic regression analyses to examine the association between cyst features and risk of HGD or cancer.A total of 269 patients met inclusion criteria. A total of 228 (84.8%) had a benign diagnosis or low-grade dysplasia on surgical pathology, and 41 patients (15.2%) had either HGD (n = 14) or invasive cancer (n = 27). Of the 41 patients with HGD or cancer on resection, only 3 patients would have met the AGA guideline\u27s indications for resection based on the preoperative cyst characteristics, whereas 30/41 patients would have met the FG criteria for resection and 22/41 patients met the ACR criteria. The sensitivity, specificity, positive predictive value, negative predictive value of HGD, and/or cancer of the AGA guidelines were 7.3%, 88.2%, 10%, and 84.1%, compared to 73.2%, 45.6%, 19.5%, and 90.4% for the FG and 53.7%, 61%, 19.8%, and 88% for the ACR guidelines. In multivariable analysis, cyst size \u3e3 cm, compared to ≤3 cm, (odds ratio [OR] = 2.08, 95% confidence interval [CI] = 1.11, 4.2) and each year increase in age (OR = 1.07, 95% CI = 1.03, 1.11) were positively associated with risk of HGD or cancer on resection.In patients with asymptomatic branch duct-intraductal papillary mucinous neoplasms or mucinous cystic neoplasms who underwent resection, the prevalence rate of HGD or cancer was 15.2%. Using the 2015 AGA criteria for resection would have missed 92.6% of patients with HGD or cancer. The more inclusive FG and ACR had a higher sensitivity for HGD or cancer but lower specificity. Given the current deficiencies of these guidelines, it will be important to determine the acceptable rate of false-positives in order to prevent a single true-positive

A preconditioner for the Ohta-Kawasaki equation

We propose a new preconditioner for the Ohta-Kawasaki equation, a nonlocal Cahn-Hilliard equation that describes the evolution of diblock copolymer melts. We devise a computable approximation to the inverse of the Schur complement of the coupled second-order formulation via a matching strategy. The preconditioner achieves mesh independence: as the mesh is refined, the number of Krylov iterations required for its solution remains approximately constant. In addition, the preconditioner is robust with respect to the interfacial thickness parameter if a timestep criterion is satisfied. This enables the highly resolved finite element simulation of three-dimensional diblock copolymer melts with over one billion degrees of freedom

Finding help for OCD in Australia : development and evaluation of a clinician directory

Objective: People tend to live with obsessive-compulsive disorder (OCD) for many years before receiving evidence-based treatment. This delay is partly due to a lack of access to information about which healthcare providers offer evidence-based treatment for OCD. This information was not easily accessible online for people in Australia. Methods: In this study, we describe how an online directory of clinicians was developed and evaluated. We report on a needs analysis and survey of treatment-seeking histories among consumers and carers impacted by OCD. We describe the key features of the directory developed, and present survey feedback on its usability and utility. Results: The results validated the need for a directory specific to clinicians who offer evidence-based treatment for OCD, and that it meets essential usability standards. Areas for improvement and further developments were identified. Conclusion: This directory contributes to broader efforts invested to improve the treatment-seeking process for people living with OCD in Australia

First geodetic observations using new VLBI stations ASKAP-29 and WARK12M

We report the results of a successful 7 hour 1.4 GHz VLBI experiment using two new stations, ASKAP-29 located in Western Australia and WARK12M located on the North Island of New Zealand. This was the first geodetic VLBI observing session with the participation of these new stations. We have determined the positions of ASKAP-29 and WARK12M. Random errors on position estimates are 150-200 mm for the vertical component and 40-50 mm for the horizontal component. Systematic errors caused by the unmodeled ionosphere path delay may reach 1.3 m for the vertical component.Comment: 11 pages, 6 flgures, 4 table