Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition

The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker—which quantifies the neutralization potency of antibodies in an individual’s serum against an HIV-1 isolate—can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT80 <200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT80 biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe

Analysis of gamma-ray spectra from foils activated in a range-thick lead target by 800-MeV protons. Final technical report

Approximately 400 gamma-ray spectra have been analyzed to obtain the types and quantities of radioisotopes produced when 800-MeV protons interact with a range-thick lead target. These spectra were obtained from the radioactive decay of product isotopes in lead disks placed at various depths and radial positions within the target. These spectra were analyzed with the computer code HYPERMET and the photopeak areas were reduced to nuclei produced per incident proton per cubic centimeter of material. Product nuclei ranged from atomic mass 160 to mass 206 and over a range of half lives from a few minutes to several weeks. The results of this analysis have been outlined in this report and transmitted on computer disk to Los Alamos National Laboratory. The consistency of these analyses have been confirmed by a comparison of photopeak areas obtained at LANL with the computer code GAMANAL with those from HYPERMET for two gamma-ray spectra. Also, the nuclear production per proton per cm{sub 3} obtained from these two spectra analyzed both at LANL and at EKU have been found to agree to within the statistical accuracy of the peak-fitting programs. This analysis of these 400 gamma-ray spectra has determined the nuclear production per incident proton per cm{sub 3} at five regularly-spaced radial positions and depths up to 40 cm into a range-thick lead target

Comparative reasoning in constitutional litigation: functions, methods and selected case law of the German Federal Constitutional Court

The German Federal Constitutional Court: History, Jurisdiction and Composition.Structure and Style of the Judgments. Comparative Reasoning in Constitutional Litigation: Comparative Law as a “fifth” Method of Interpretation, numbers and statistics and selcted case law. The Affirmative Function of Foreign Case Law. The Dismissive or Distinguishing Function of Foreign Case Law. The Implicit or “hidden” Use of Comparative Reasoning. Questions of Methodology