Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset

Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline

Simulating Mars on Earth: Georgia Tech's Crew 47 at the Mars Desert Research Station

Presentation for the Mars Society @ Georgia Tech

Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset

Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline

Ein interdisziplinärer Ansatz zum Vorentwurf bemannter Raumfahrtsysteme

The conceptual design (project phase 0/A) of systems for long-duration manned space missions poses a significant challenge to the traditional design approach used for robotic or short-duration missions. Yet the success of planned expeditions to Mars and beyond depends on the ability of system designers to create an overall concept that maximizes crew efficiency and minimizes cost as well as the risk of catastrophic failure, while at the same time integrating a wide array of technological, crew-related and political boundary conditions. The interdisciplinary approach presented in this report proposes putting the focus on the most efficient integration of the crew into a space system as one solution to this conceptual design problem. Thus, human-rated space structures - be they inhabited orbital or planetary stations, or piloted interplanetary transfer vehicles - are treated by the designers not as 'machinery-with-attached-crew' like earlier spacecraft, but primarily as habitats, in order to assure mission success under conditions of long-term isolation, confinement and risk. The proposed approach is based on space systems engineering methodology and associated software tools, with key elements from terrestrial architectural practice added. It also provides software specifically developed for the analysis of life support systems - a crucial component of human-rated space systems - during the early phase of conceptual design. Several examples are given to demonstrate the validity of this truly interdisciplinary approach.Der Entwurf von Systemen für bemannte Langzeit-Weltraummissionen (Projektphase 0/A) stellt den herkömmlichen Entwurfsansatz, wie er für unbemannte oder Kurzzeit-Missionen verwendet wird, vor erhebliche Herausforderungen. Der Erfolg geplanter Expeditionen zum Mars und darüber hinaus hängt jedoch davon ab, ob es dem Entwurfsteam gelingt, ein Konzept zu entwickeln, welches die Produktivität der Besatzung maximiert und Kosten sowie Risiko minimiert, und das gleichzeitig eine große Anzahl technologischer, finanzieller und politischer Randbedingungen berücksichtigt. Die im vorliegenden Bericht vorgestellte interdisziplinäre Methodik zeigt einen Weg zur Lösung dieses Entwurfsproblems auf. An vorderster Stelle steht dabei die bestmögliche Integration der Besatzung in ein zu entwerfendes Raumfahrtsystem, d.h. die Behandlung bemannter Weltraumstrukturen nicht als 'Maschinen mit angegliederter Besatzung', wie oft bei früheren Raumfahrzeugen, sondern als integrierte Lebensräume. Grundannahme dabei ist, daß die Produktivität und Effizienz der Besatzung durch eine an den Menschen angepaßte Gestaltung der Umgebung erhöht wird. Der vorgestellte neue Ansatz basiert auf einer Ingenieursmethodik zum Vorentwurf von Raumfahrtsystemen samt zugehöriger Computerprogramme, die um wichtige menschenbezogene Entwurfsregeln erweitert worden ist. Hinzu kommen Elemente aus der 'irdischen' Architekturpraxis. In dieser geht es ebenfalls um den Entwurf von Lebens- und Arbeitsräumen für Menschen; sie stellt daher auch entsprechend angepaßte Entwurfswerkzeuge zur Verfügung. Ferner wurde speziell zur Analyse von Lebenserhaltungssystemen und deren synergetischen Verknüpfungspotentialen während der Vorentwurfsphase eine Software entwickelt, die eine frühzeitige Auslegung dieses für bemannte Raumfahrtsysteme unverzichtbaren Subsystems ermöglicht. Die neuentwickelte Methodik wurde in mehreren realistischen interdisziplinären Entwurfsprojekten angewendet, die im Bericht dokumentiert sind

Enhancing the Design Process for Complex Space Systems through Early Integration of Risk and Variable-Fidelity Modeling

An important enabler of the new national Vision for Space Exploration is the ability to rapidly and efficiently develop optimized concepts for the manifold future space missions that this effort calls for. The design of such complex systems requires a tight integration of all the engineering disciplines involved, in an environment that fosters interaction and collaboration. The research performed under this grant explored areas where the space systems design process can be enhanced: by integrating risk models into the early stages of the design process, and by including rapid-turnaround variable-fidelity tools for key disciplines. Enabling early assessment of mission risk will allow designers to perform trades between risk and design performance during the initial design space exploration. Entry into planetary atmospheres will require an increased emphasis of the critical disciplines of aero- and thermodynamics. This necessitates the pulling forward of EDL disciplinary expertise into the early stage of the design process. Radiation can have a large potential impact on overall mission designs, in particular for the planned nuclear-powered robotic missions under Project Prometheus and for long-duration manned missions to the Moon, Mars and beyond under Project Constellation. This requires that radiation and associated risk and hazards be assessed and mitigated at the earliest stages of the design process. Hence, RPS is another discipline needed to enhance the engineering competencies of conceptual design teams. Researchers collaborated closely with NASA experts in those disciplines, and in overall space systems design, at Langley Research Center and at the Jet Propulsion Laboratory. This report documents the results of this initial effort

A Collaborative Design Environment to Support Multidisciplinary Conceptual Systems Design

design facility supporting efficient, rapidturnaround conceptual design. The CoDE combines cost-effective, off-the-shelf information technology with advanced design methodologies and tools in a customized, user-centered physical layout that harnesses the power of creative design teams. The CoDE will enable researchers to develop, test and apply new approaches to conceptual design, and to improve modeling and simulation fidelity. It will also support sponsored design projects as well as student teams participating in national design competitions

Advancing Aeronautics: A Decision Framework for Selecting Research Agendas

Publicly funded research has long played a role in the development of aeronautics, ranging from foundational research on airfoils to development of the air-traffic control system. Yet more than a century after the research and development of successful controlled, sustained, heavier-than-air flight vehicles, there are questions over the future of aeronautics research. The field of aeronautics is relatively mature, technological developments within it have become more evolutionary, and funding decisions are sometimes motivated by the continued pursuit of these evolutionary research tracks rather than by larger factors. These developments raise questions over whether public funding of aeronautics research continues to be appropriate or necessary and at what levels. Tightened federal budgets and increasing calls to address other public demands make these questions sharper still. To help it address the questions of appropriate directions for publicly funded aeronautics research, the National Aeronautics and Space Administration's (NASA's) Aeronautics Research Mission Directorate (ARMD) asked the RAND Corporation to assess the elements required to develop a strategic view of aeronautics research opportunities; identify candidate aeronautic grand challenges, paradigms, and concepts; outline a framework for evaluating them; and exercise the framework as an example of how to use it. Accordingly, this research seeks to address these questions: What aeronautics research should be supported by the U.S. government? What compelling and desirable benefits drive government-supported research? How should the government--especially NASA--make decisions about which research to support? Advancing aeronautics involves broad policy and decisionmaking challenges. Decisions involve tradeoffs among competing perspectives, uncertainties, and informed judgment

Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset

Alzheimer’s disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline