Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Rabies Vaccination Compliance and Reasons for Incompletion

Introduction: Rabies is a fatal disease with a 91% mortality rate in the United States. Current treatment of rabies consists of post-exposure prophylaxis treatment involving a complicated vaccination regimen. Studies conducted in other countries have found that patients do not complete their rabies vaccination treatment due to forgetting about their treatment, lack of time for visits, and the financial burden of treatment. However, little is known about why patients do not complete the rabies series in the US. The objective of this study was to determine the reasons why patients in the US do not complete rabies treatment.Methods: We performed a retrospective study to evaluate rabies post-exposure prophylaxis completion in the emergency department of an academic suburban hospital between June 2014–  July 2017. Further review was performed for patients who received inadequate vaccination to determine the cause of treatment incompletion. We conducted additional follow-up by phone survey for those patients who did not complete their rabies treatment but had no explanation for discontinuation available in the medical chart review.Results: Results indicated 198 patients received rabies post-exposure treatment during the inclusion period. Of these, 145 patients completed the rabies vaccination regimen. Reasons for treatment incompletion were found for 29 patients, and 24 patients were lost to follow-up. Of the 29 patients for which discontinuation was assessed, 23 patients (79.3%) stopped treatment due to appropriate reasons – either the animal involved tested negative for the rabies virus or the patient had prior rabies treatment and only required two booster shots. Reasons for not completing the series when medically indicated included the patient deciding to not return for treatment, lack of awareness of the full vaccination regimen, and the patient declining initiation of rabies vaccination.Conclusion: Most patients in the US discontinue their rabies vaccination treatment for appropriate reasons; however, there is a proportion of patients who discontinue rabies vaccination when further treatment is medically indicated. This subset of patients is particularly at risk of rabies-related mortality, and additional measures need to be taken to ensure increased treatment compliance

Rabies Vaccination Compliance and Reasons for Incompletion

Introduction: Rabies is a fatal disease with a 91% mortality rate in the United States. Current treatment of rabies consists of post-exposure prophylaxis treatment involving a complicated vaccination regimen. Studies conducted in other countries have found that patients do not complete their rabies vaccination treatment due to forgetting about their treatment, lack of time for visits, and the financial burden of treatment. However, little is known about why patients do not complete the rabies series in the US. The objective of this study was to determine the reasons why patients in the US do not complete rabies treatment.Methods: We performed a retrospective study to evaluate rabies post-exposure prophylaxis completion in the emergency department of an academic suburban hospital between June 2014–  July 2017. Further review was performed for patients who received inadequate vaccination to determine the cause of treatment incompletion. We conducted additional follow-up by phone survey for those patients who did not complete their rabies treatment but had no explanation for discontinuation available in the medical chart review.Results: Results indicated 198 patients received rabies post-exposure treatment during the inclusion period. Of these, 145 patients completed the rabies vaccination regimen. Reasons for treatment incompletion were found for 29 patients, and 24 patients were lost to follow-up. Of the 29 patients for which discontinuation was assessed, 23 patients (79.3%) stopped treatment due to appropriate reasons – either the animal involved tested negative for the rabies virus or the patient had prior rabies treatment and only required two booster shots. Reasons for not completing the series when medically indicated included the patient deciding to not return for treatment, lack of awareness of the full vaccination regimen, and the patient declining initiation of rabies vaccination.Conclusion: Most patients in the US discontinue their rabies vaccination treatment for appropriate reasons; however, there is a proportion of patients who discontinue rabies vaccination when further treatment is medically indicated. This subset of patients is particularly at risk of rabies-related mortality, and additional measures need to be taken to ensure increased treatment compliance

Keeping Track of your Research in the Archives Workshop Materials

Getting ready for a research trip? This workshop will teach you strategies for taking and keeping track notes, images, and other outputs from your trip to the archives, techniques for working with many files and file names, and how to organize your research processes. Within this deposit are PDFs and powerpoints of slide decks used within the archive.Ope

Mathematical Computations in the Management of Public Construction Work in Mesopotamia (End of the Third and Beginning of the Second Millennium BCE)

The aim of this chapter is to examine what types of computations Mesopotamian scribes were trained when dealing with building activities. Its aim is also to try to determine how far these calculation methods were actually used in practice. In order to do this we examine mathematical and administrative texts dealing with construction activities as well as archaeological and ethnographical data. Two types of texts provide the information on mathematical calculations for construction on which we draw: mathematical texts and practical administrative texts. We distinguish between three different steps in these computations. The first is the use of labor norms. In this category we find the daily tasks (called iškarum) expected from unskilled workers. The second step is the use of coefficients to calculate a magnitude on the basis of other magnitudes (determining a volume from a given weight, for instance). The last step consists of exercises dealing with several types of tasks, using combined coefficients. Finally, by drawing on some administrative construction texts, we try to check whether or not these computations were actually used in practice

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection

Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Abstract: Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers