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  • “Big data” gets personal | Science Translational Medicine
    Boston MA 02115 U S A Broad Institute of MIT and Harvard Boston MA 02115 U S A Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text Abstract A woman at risk for a rare fatal prion disease retrained in science with her husband and joined a bioinformatics team to analyze shared data providing insights about variant penetrance and possible treatments Minikel et al this issue Copyright 2016 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 8 Issue 322 20 January 2016 Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them with commas You are going to email the following Big data gets personal Message Subject Your Name has forwarded a page to you from Science Translational Medicine Message Body Your Name thought you would like to see this page from the Science Translational Medicine web site Your Personal Message Send Message Download Powerpoint Print Save to my folders User Name Password Remember my user name password Submit Alerts Please log in to add an alert for this article Username Enter your Sciencemag org username Password Enter the password that accompanies your username Log in Request Permissions Citation tools Big data gets personal By Matthew S Lebo Sheila Sutti Robert C Green Science Translational Medicine

    Original URL path: http://stm.sciencemag.org/content/8/322/322fs3 (2016-02-10)
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  • “Big data” gets personal | Science Translational Medicine
    and even in some sense less explicable than before the specter of inheriting a fatal mutation has been mitigated for her for her children and for their children to come Download high res image Open in new tab Download Powerpoint Patient empowerment and unconventional activism A physician explains the concept of penetrance to a patient and informs her that she has a pathogenic mutation that will result in a rare incurable and fatal genetic disorder The patient ponders her fate and and in a rare form of patient activism becomes a medical genomics researcher dedicated to seeking new treatments for her disease MASSIVELY SCALABLE DATA MEET ARTISANAL ANNOTATION The collection and sharing of case level data through the goodwill of more than 16 000 families affected by prion diseases and the generosity of the clinicians and scientists who diagnosed and submitted the data were crucial to the success of Minikel et al study 1 So too was the startling power of the ExAC database http biorxiv org content early 2015 10 30 030338 created through an international consortium by rigorously collating ancestry specific variant frequencies in more than 60 000 individuals from which extremely rare variant frequencies could for the first time be estimated For this analysis where consents permitted contributors of individual cohorts to ExAC were able to reach back into individual case histories and provide enough phenotypic information to determine the case status or family history of individuals with exceedingly rare PRNP variants thus adding to the power of the control data As demonstrated by the multinational authors and cohorts the power for such in depth studies can only be amassed by pooling cases across continents The rise of federated sharing will enhance the utility of such collections for example the Global Alliance for Genomics and Health has made the linkage and sharing of case level data one of its initial objectives through its newly formed Matchmaker Exchange www matchmakerexchange org The Minikel et al paper also highlights the precarious state of variant classification for most rare variants and diseases and the limitations of existing literature 5 Clinical laboratories must parse previously published reports and try to detect misclassifications in existing databases as they struggle to classify incompletely penetrant variants especially when estimates of penetrance begin to resemble odds ratios below 3 or 2 typically associated with more common complex risk alleles Even when databases are accurate about variant disease associations existing estimates of penetrance have been determined almost exclusively among affected families and are likely much lower for suspected variants in families without a robust family history The resulting classification paradigms make the best predictions that they can but often the hours of literature analysis translate into only the vague and frustrating category of variant of uncertain significance or VUS Our own work has shown that even for hypertrophic cardiomyopathy one of the most commonly tested for dominant genetic conditions 42 of variants identified in patients are VUSs which represents almost 20 of cases 6 This highlights the need for large case control populations and for unbiased phenotyping and family histories of general population cohorts such as that envisioned by President Obama s Precision Medicine Initiative www whitehouse gov precision medicine The increased use of automation combined with large scale data will enable laboratorians and geneticists to better determine the pathogenicity of variants The findings of Minikel et al 1 emphasize the complex nature of low penetrance alleles which because of their relatively high frequency in the general population may not be classified as pathogenic without strong additional evidence It is important to note that while the work of Minikel and colleagues demonstrates the power of statistical approaches and large datasets the authors were able to make strong assertions only about the pathogenicity and penetrance on 10 of the 63 variants that they studied Although these variants are some of the most common in their cohort in 15 of genotype positive individuals the prognosis remains unclear Clinical laboratories currently identify VUSs twice as often as pathogenic variants and the vast majority of variants are observed only once or a handful of times in clinical laboratories Therefore much more data such as those housed in ClinGen and other resources www clinicalgenome org are needed to make approaches such as the one described herein more broadly applicable ACTIONABILITY AND PATIENT EMPOWERMENT More than just teasing out PRNP variant pathogenicity and demonstrating an important framework for rare diseases this work speaks to the confusing concept of actionability in genomic testing In the strictest sense Sonia s test results would never have been considered medically actionable as prion disease is rapidly progressive universally fatal and completely untreatable at this time By many published standards and expert perspectives Sonia should have been heavily counseled if not dissuaded about the potential psychological damage of learning whether or not she carried this mutation with the underlying assumption that no medical good could result from such knowledge But the notion of actionability has proven to be far less parochial than current conventions would suggest Accumulating evidence from disclosure of genetic risk for a single condition 7 for panels of genetic risk markers 8 9 and for potentially devastating unanticipated findings 10 suggest that when individuals wish to know their genetic risks they largely manage the information in highly constructive ways The power of sharing of such knowledge with patients might in some cases be exaggerated by genetic testing companies in the emerging bioindustrial complex but patient empowerment also appears to be a tangible quantifiable construct that can stir fundamental personal changes and breakthrough science Eric Minikel and Sonia Vallabh have re defined the notion of actionability for prion disease in a way that could lead to treatment and prevention It seems both naïve and patronizing to suggest that anyone who is properly informed should not be permitted access if they wish to any genetic information about themselves regardless of whether treatments are currently available Eric Sonia and their colleagues have given us a shining example

    Original URL path: http://stm.sciencemag.org/content/8/322/322fs3.full (2016-02-10)
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  • A cybersecurity primer for translational research | Science Translational Medicine
    this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text Abstract Virtually all health care organizations have had at least one data breach since 2012 Most of the largest data breaches and Health Care Information Privacy and Accountability Act fines could have been prevented by the simplest of strategies Each researcher must clearly understand his or her responsibilities and liability Copyright 2016 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 8 Issue 322 20 January 2016 Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them with commas You are going to email the following A cybersecurity primer for translational research Message Subject Your Name has forwarded a page to you from Science Translational Medicine Message Body Your Name thought you would like to see this page from the Science Translational Medicine web site Your Personal Message Send Message Download Powerpoint Print Save to my folders User Name Password Remember my user name password Submit Alerts Please log in to add an alert for this article Username Enter your Sciencemag org username Password Enter the password that accompanies your username Log in Request Permissions Citation tools A cybersecurity primer for translational research By Eric D Perakslis Martin Stanley Science Translational Medicine 20 Jan 2016 322ps2 Researchers have responsibilities

    Original URL path: http://stm.sciencemag.org/content/8/322/322ps2 (2016-02-10)
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  • A cybersecurity primer for translational research | Science Translational Medicine
    technology life cycle as systems are acquired used and discarded Regulations and standards are typically updated and assessed on an annual basis whereas the landscape of security threats and necessary protections changes so rapidly that security controls often must be updated daily and even hourly Security and compliance officers often report to different organizations and their levels of accountability may be unclear Similarly both are best managed in a data driven and risk based approach but this can be difficult if a compliance driven culture is already established and is exclusively focusing the security resources on compliance efforts Last in complex research organizations scientists frequently assume that security and compliance are someone else s job and are often over documented and under tested Last compliance can actually be a competitive advantage for research institutions when it comes to federal grants and industry collaborations With increasing federal requirements for research grants such as the ability of a research institution to ensure that their technology infrastructure can comply with Federal Information Security Management Act FISMA standards organizations that can demonstrate high levels of compliance will have greater opportunities for funding and data centric collaborations One example of this is the Coordinating Center grant for the NIH Undiagnosed Diseases Network at Harvard Medical School HMS The successful implementation of this program which involves the sharing of sensitive data across multiple research institutions required that HMS implement a FISMA compliant solution Organizations that have poor compliance histories will be at a disadvantage despite the merits of their research ENSURING SECURITY There are qualitative and quantitative assessment methodologies that represent cyber risk in dollar values as well as the potential impact on an organization or mission These methodologies are well documented in the National Institute of Standards and Technology NIST Risk Management Framework and the NIST Cybersecurity Framework summarized in supplementary materials and provide model approaches for assessing cyber risk and determining a budget for protecting IT systems and data 13 14 Effective risk management requires that business owners such as scientific researchers remain involved in all phases of the risk management process because they intuitively understand what is most important to them and can most effectively direct what information must be protected and to what extent All data are not equal and the necessary first step to determining where to focus cybersecurity efforts is knowing which data and systems are sensitive and most essential to an organization s mission This knowledge then leads directly to the second step which is to ensure that only users with a genuine need one that supports the institute s mission are granted access to sensitive data In the case of collaborative translational medical research in which highly specific phenotypic traits and molecular profiling information must be shared and discussed researchers must take due care to deidentify and share using proper encryption only the minimum amount of PII and or PHI required to conduct the study In addition although one size does not fit all there are basic risk based protections that form the cornerstone of good cybersecurity 15 Implementing basic cybersecurity protections virtually mitigates the most common cyber vulnerabilities such as a lost laptop or phone and affords the same advantages as securing one s home with a system that is superior to one s neighbors systems Intruders will often opt for an easier break in Researchers should not count on others to implement these critical basic protections instead they should be well versed in their organization s security and privacy policies as well as the important security contacts at their institutions such as the chief information security officer CISO who can help researchers to understand and implement protections The CISO is essential for the protection of data and of biomedical research operations 16 and if an organization lacks an internal CISO the role should be contracted out Data protection depends on a well functioning cooperative and collaborative partnership among scientists clinicians computer scientists and security officers First virtually all research data are input manipulated and accessed via some form of device that represents an endpoint to the network Laptops cell phones tablets desktop computers and even medical devices are all types of endpoints and must be highly protected Failures in endpoint security are the most common causes of data loss and theft and most are completely avoidable Single passwords are ineffective once a device falls into malicious hands 17 Researchers should rely on the organizational CISO to provide a federated identity management solution that ensures that users are securely authenticated for access to any and all devices and systems at a minimum all IT systems must support two factor authentication for systems that use sensitive data 15 Further all endpoints should be adequately encrypted so that the device becomes useless to any unauthorized user Some institutions have implemented such security measures but many research institutions lag behind The real challenge here is that the technology and policy infrastructure in use at most institutions was put into place years ago long before many of the current threats existed and it is impossible to fix everything quickly and simultaneously The online guide at the University of Washington UW Medicine provides an excellent example of how a basic but comprehensive cybersecurity program can be used effectively to secure data and be integrated in a complex research and clinical environment 18 There also are many commercial encryption tools and services available The best approach is to work with the information security office at your institution to select the tools that will be most effective in your particular technology environment The second line of defense in research data protection is the computing network to which these endpoints connect Network firewall and antivirus technologies are limited because they are only capable of detecting and protecting against threats that they have seen before There is great debate about the utility of protection via firewalls and sole reliance on a strong network perimeter however these tools serve well as part of a systematic application of

    Original URL path: http://stm.sciencemag.org/content/8/322/322ps2.full (2016-02-10)
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  • Quantifying prion disease penetrance using large population control cohorts | Science Translational Medicine
    Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alison Boyd Australian National Creutzfeldt Jakob Disease Registry The University of Melbourne Parkville Victoria 3010 Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Robert G Will National Creutzfeldt Jakob Disease Research Surveillance Unit Western General Hospital Edinburgh EH4 2XU UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Richard Knight National Creutzfeldt Jakob Disease Research Surveillance Unit Western General Hospital Edinburgh EH4 2XU UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Claudia Ponto National Reference Center for the Surveillance of Human Transmissible Spongiform Encephalopathies Georg August University Goettingen 37073 Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Inga Zerr National Reference Center for the Surveillance of Human Transmissible Spongiform Encephalopathies Georg August University Goettingen 37073 Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Theo F J Kraus Center for Neuropathology and Prion Research ZNP Ludwig Maximilians University Munich 81377 Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sabina Eigenbrod Center for Neuropathology and Prion Research ZNP Ludwig Maximilians University Munich 81377 Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Armin Giese Center for Neuropathology and Prion Research ZNP Ludwig Maximilians University Munich 81377 Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Miguel Calero Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos III Madrid 28031 Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jesús de Pedro Cuesta Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos III Madrid 28031 Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stéphane Haïk INSERM U 1127 CNRS UMR 7225 Sorbonne Universités Pierre and Marie Curie University Paris 06 UMR S 1127 Institut du Cerveau et de la Moelle Epinière 75013 Paris France Assistance Publique Hôpitaux de Paris AP HP Cellule Nationale de Référence des Maladies de Creutzfeldt Jakob Groupe Hospitalier Pitié Salpêtrière F 75013 Paris France Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jean Louis Laplanche AP HP Service de Biochimie et Biologie Moléculaire Hôpital Lariboisière 75010 Paris France Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elodie Bouaziz Amar AP HP Service de Biochimie et Biologie Moléculaire Hôpital Lariboisière 75010 Paris France Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jean Philippe Brandel INSERM U 1127 CNRS UMR 7225 Sorbonne Universités Pierre and Marie Curie University Paris 06 UMR S 1127 Institut du Cerveau et de la Moelle Epinière 75013 Paris France Assistance Publique Hôpitaux de Paris AP HP Cellule Nationale de Référence des Maladies de Creutzfeldt Jakob Groupe Hospitalier Pitié Salpêtrière F 75013 Paris France Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sabina Capellari Istituto di Ricovero e Cura a Carattere Scientifico Institute of Neurological Sciences Bologna 40123 Italy Department of Biomedical and Neuromotor Sciences University of Bologna Bologna 40126 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Piero Parchi Istituto di Ricovero e Cura a Carattere Scientifico Institute of Neurological Sciences Bologna 40123 Italy Department of Biomedical and Neuromotor Sciences University of Bologna Bologna 40126 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anna Poleggi Department of Cell Biology and Neurosciences Istituto Superiore di Sanità Rome 00161 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anna Ladogana Department of Cell Biology and Neurosciences Istituto Superiore di Sanità Rome 00161 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anne H O Donnell Luria Program in Medical and Population Genetics Broad Institute of Massachusetts Institute of Technology MIT and Harvard Cambridge MA 02142 USA Analytical and Translational Genetics Unit Massachusetts General Hospital Boston MA 02114 USA Division of Genetics and Genomics Boston Children s Hospital Boston MA 02115 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Konrad J Karczewski Program in Medical and Population Genetics Broad Institute of Massachusetts Institute of Technology MIT and Harvard Cambridge MA 02142 USA Analytical and Translational Genetics Unit Massachusetts General Hospital Boston MA 02114 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jamie L Marshall Program in Medical and Population Genetics Broad Institute of Massachusetts Institute of Technology MIT and Harvard Cambridge MA 02142 USA Analytical and Translational Genetics Unit Massachusetts General Hospital Boston MA 02114 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael Boehnke Department of Biostatistics and Center for Statistical Genetics University of Michigan School of Public Health Ann Arbor MI 48109 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Markku Laakso Department of Medicine University of Eastern Finland and Kuopio University Hospital Kuopio 70210 Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Karen L Mohlke Department

    Original URL path: http://stm.sciencemag.org/content/8/322/322ra9.editor-summary (2016-02-10)
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  • Quantifying prion disease penetrance using large population control cohorts | Science Translational Medicine
    fatal and transmissible prion disease 108 109 By contrast the N terminal truncating variants that we observed retain only residues dispensable for prion propagation and are likely to cause a total loss of protein function DISCUSSION More than 100 000 genetic variants have been reported to cause Mendelian disease in humans 56 57 Many such reports do not meet current standards for assertions of pathogenicity 58 59 and if all such reports were believed the cumulative frequency of these variants in the population would imply that most people have a genetic disease 27 It is generally unclear how much of the excess burden of purported disease variants in the population results from benign variants falsely associated and how much results from variants with genuine association but incomplete penetrance Here we leveraged newly available large genomic reference data sets to reevaluate reported disease associations in a dominant disease gene PRNP We identify some missense variants as likely benign and show that others span a spectrum from 0 1 to 100 penetrance Our analyses provide quantitative estimates of lifetime risk for hundreds of asymptomatic individuals who have inherited incompletely penetrant PRNP variants Available data sets are only now approaching the size and quality required for such analyses resulting in limitations for our study The confidence intervals CIs on our lifetime risk estimates span more than an order of magnitude and our inability to perfectly control for population stratification injects additional uncertainty We have been unable to reclassify those PRNP variants that are very rare both in cases and in controls Supplementary Discussion We have avoided analysis of large insertions that are poorly called with short sequencing reads although we note that existing literature on these insertions is consistent with a spectrum of penetrance similar to the spectrum that we observe for missense variants 28 32 Penetrance estimation in Mendelian disease will be improved by the collection of larger case series particularly with genome wide SNP data to allow more accurate population matching This coupled with continued large scale population control sequencing and genotyping efforts should reveal whether the dramatic variation in penetrance that we observe here is a more general feature of dominant disease genes Because PrP is required for prion pathogenesis and reduction in gene dosage slows disease progression 53 60 62 several groups have sought to therapeutically reduce PrP expression using RNA interference 63 65 antisense oligonucleotides 66 or small molecules 67 68 Our discovery of heterozygous loss of function variants in three healthy older humans provides the first human genetic data regarding the effects of a 50 reduction in gene dosage for PRNP Both the number of individuals and the depth of available phenotype data are limited and lifelong heterozygous inactivation of a gene is an imperfect model of the effects of pharmacological depletion of the gene product With those limitations our data provide preliminary evidence that a reduction in PRNP dosage if achievable in patients is likely to be tolerated Increasingly large control sequencing data sets will soon enable researchers to test whether the same is true of other genes currently being targeted in substrate reduction therapeutic approaches for other protein folding disorders Together our findings highlight the value of large reference data sets of human genetic variation for informing both genetic counseling and therapeutic strategy MATERIALS AND METHODS Study design We sought to estimate the penetrance of variants reported to cause genetic prion disease We reasoned that fully penetrant variants should not be any more common in the general population than genetic prion disease is and that by comparing allele frequencies in cases versus population controls we could estimate penetrance for individual variants This approach does not require controls that are certified to be free of prion disease but instead only requires that controls not be enriched for prion disease We carried out a retrospective analysis of existing data from three sources prion surveillance centers ExAC and 23andMe research participants which are described in detail below Prion disease case series Prion disease is considered a notifiable diagnosis in most developed countries with mandatory reporting of all suspect cases to a centralized surveillance center Surveillance was carried out broadly according to established guidelines 69 70 with specifics as described previously for Australia 71 France 72 Germany 73 75 Italy 76 Japan 22 and the Netherlands 77 Sanger sequencing of the PRNP open reading frame was performed as described 78 We included only prion disease cases classified as definite autopsy confirmed or probable according to published guidelines 70 Criteria for genetic testing vary between countries and over the years of data collection with testing offered only on indication of family history in some times and places and testing of all suspect cases with tissue available in other instances Summary statistics on the total number and proportion of cases sequenced are presented in table S1 Exome sequencing and analysis The ascertainment sequencing and joint calling of the ExAC data set have been described previously 27 We extracted all rare 0 1 coding variant calls in PRNP with genotype quality GQ 10 alternate allele depth AD 3 and alternate allele balance AB 20 Read level evidence was visualized using Integrative Genomics Viewer IGV 79 for manual review Because most ExAC exomes were sequenced with 76 base pair bp reads and the PRNP octapeptide repeat region codons 50 to 90 inclusive is 123 bp long it was impossible to determine whether genotype calls in this region were correct and they were not considered further After review of IGV screenshots 87 of genotype calls were judged to be correct and were included in table S3 Of the genotype calls judged to be correct 99 had GQ 95 99 had AB between 30 and 70 and 97 had AD 10 All participants provided informed consent for exome sequencing and analysis The ExAC s aggregation and release of exome data have been approved by the Partners Healthcare Institutional Research Board 2013P001339 ExAC data have been publicly released at http exac broadinstitute org and IGV screenshots of the rare PRNP variants deemed to be genuine and included in this study are available at https github com ericminikel prnp penetrance tree master supplement igv 23andMe research participants and genotyping Participants were drawn from the customer base of 23andMe Inc a personal genetics company accessed 6 February 2015 All participants provided informed consent under a protocol approved by an external Association for the Accreditation of Human Research Protection Programs accredited institutional review board Ethical Independent Review Services DNA extraction and genotyping were performed on saliva samples by the National Genetics Institute a Clinical Laboratory Improvement Amendments licensed clinical laboratory and a subsidiary of Laboratory Corporation of America Samples were genotyped on one of four Illumina platforms V1 to V4 as described previously 80 Of the PRNP SNPs considered 2 P105L and E200K were genotyped on all four platforms whereas the other 14 were genotyped only on V3 and V4 resulting in differing numbers of total samples genotyped table S5 Genotypes were called with Illumina GenomeStudio A 98 5 call rate was required for all samples As with all 23andMe research participants individuals whose genotyping analyses failed to reach the desired call rate repeatedly were recontacted to provide additional samples A maximal set of unrelated individuals was chosen on the basis of segmental identity by descent IBD estimation 81 Individuals were defined as related if they shared more than 700 centimorgan IBD about the minimal expected sharing between first cousins Allele counts between one and five were rounded up to five to protect individual privacy table S5 Rounding down to one instead would raise our estimates of penetrance for V180I to 7 7 95 CI 1 2 to 50 and for P102L A117V D178N and E200K collectively to 100 95 CI 100 to 100 but the CI would still overlap those based on ExAC allele frequencies and the overall conclusions of our study would remain unchanged 23andMe ancestry composition Ancestral origins of chromosomal segments were assigned on a continental level European Latino African and East Asian and on a country level Japanese as described by Durand et al 82 Briefly after phasing genotypes using an out of sample implementation of the Beagle algorithm 83 a string kernel support vector machine classifier assigns tentative ancestry labels to local genomic regions Then an autoregressive pair hidden Markov model was used to simultaneously correct phasing errors and produce reconciled local ancestry estimates and confidence scores based on the initial assignment Finally isotonic regression models were used to recalibrate the confidence estimates Europeans and East Asians were defined as individuals with more than 97 of chromosomal segments predicted as being from the respective ancestries Because African Americans and Latinos are highly admixed no single threshold of genome wide ancestry is sufficient to distinguish them However segment length distributions of European African and Native American ancestries are different between African Americans and Latinos because of the distinct admixture timing in the two ethnic groups Thus a logistic classifier based on segment length of European African and Native American ancestries was used to distinguish between African Americans and Latinos At the country level individuals were classified as Japanese based on the fraction of the respective local ancestry using a threshold of 90 for classifying Japanese ancestry This threshold is based on the average fraction of local ancestry in the reference population 23andMe research participants with all four grandparents from the reference country 94 5 SD n 533 for Japanese Using the same approach we were unable to obtain a confident set of Italian individuals for analysis of V210I because of extensive admixture 23andMe research participants with all four grandparents from Italy only have 66 18 SD n 2090 Italian ancestry and only 60 participants have 90 Italian ancestry ExAC ancestry inference We computed 10 principal components based on 5800 common SNPs as described 27 84 A centroid in eigenvalue weighted principal component space was generated for each HapMap population based on 1000 Genomes individuals in ExAC The remaining individuals in ExAC were assigned to the HapMap population with the nearest centroid according to eigenvalue weighted Euclidean distance Ancestries of all individuals including those with reportedly pathogenic variants are summarized in tables S7 and S8 Prion disease incidence and baseline risk The reported incidence of prion disease varies between countries and between years with much of the variability explained by the intensity of surveillance as measured by the number of cases referred to national surveillance centers 13 Rates of about one case per million population per year have been reported for instance in the United States 85 and in Japan 22 however the countries with the most intense surveillance greatest number of referrals per capita such as France and Austria observe incidence figures as high as two cases per million population per year 13 Only in small countries where the statistics are dominated by a particular genetic prion disease founder mutation such as Israel and Slovakia 23 26 has an incidence higher than two per million been consistently observed 86 We therefore accepted two cases per million as an upper bound for the true incidence of prion disease Assuming an all causes death rate of 10 per 1000 annually 87 this incidence corresponds to prion disease accounting for 0 02 of all deaths which we accepted as the baseline disease risk in the general population Lifetime risk estimation By Bayes theorem the probability of disease given a genotype penetrance or lifetime risk P D G is equal to the proportion of individuals with the disease who have the genotype genotype frequency in cases P G D times the prevalence of the disease baseline lifetime risk in the general population P D divided by the frequency of the genotype in the general population here population control allele frequency P G The use of this formula to estimate disease risk dates back at least to Cornfield s estimation of the probability of lung cancer in smokers 88 with later contributions by Woolf 89 and a synthesis by Li 90 with application to genetics We used an allelic rather than a genotypic model such that lifetime risk in an individual with one allele is equal to case allele frequency based on the number of prion disease cases that underwent PRNP sequencing times baseline risk divided by population control allele frequency P D A P A D P D P A Note that we assumed that our population control data sets include individuals who will later die of prion disease thus enabling direct use of the ExAC and 23andMe allele frequencies as the denominator P A Following Kirov et al 11 we computed Wilson 95 CI on the binomial proportions P A D and P A and calculated the upper bound of the 95 CI for penetrance using the upper bound on case allele frequency and the lower bound on population control allele frequency and vice versa for the lower bound on penetrance Statistical analysis and source code availability Error bars in Fig 3 are as described in the previous section Data processing analysis and figure generation used custom scripts written in Python 2 7 6 and R 3 1 2 These scripts along with vector graphics of all figures and tab delimited text versions of all supplementary tables are available online at https github com ericminikel prnp penetrance and are sufficient to reproduce the figures and the analyses described in this paper SUPPLEMENTARY MATERIALS www sciencetranslationalmedicine org cgi content full 8 322 322ra9 DC1 Discussion Table S1 Allele counts of rare PRNP variants in 16 025 definite and probable prion disease cases in nine countries Table S2 Rare PRNP variants reported in peer reviewed literature to cause prion disease Table S3 Allele counts of rare PRNP variants in 60 706 individuals in ExAC Table S4 Summary of rare PRNP variants by functional class in ExAC Table S5 Allele counts of 16 reportedly pathogenic PRNP variants in 500 000 23andMe research participants Table S6 Phenotypes investigated in studies in which ExAC individuals with reportedly pathogenic PRNP variants were ascertained Table S7 Inferred ancestry and codon 129 genotypes of ExAC individuals with reportedly pathogenic variants Table S8 Inferred ancestry of all ExAC individuals Table S9 Inferred ancestry of 23andMe research participants Table S10 Details of Japanese prion disease cases Table S11 Phenotypes of individuals with N terminal PrP truncating variants Fig S1 Age of ExAC individuals with reportedly pathogenic PRNP variants versus all individuals in ExAC Fig S2 Sanger sequencing results for individuals with N terminal truncating variants References 110 179 REFERENCES AND NOTES L R Brunham M R Hayden Hunting human disease genes Lessons from the past challenges for the future Hum Genet 132 603 617 2013 OpenUrl CrossRef Medline J Amberger C Bocchini A Hamosh A new face and new challenges for Online Mendelian Inheritance in Man OMIM Hum Mutat 32 564 567 2011 OpenUrl CrossRef Medline Web of Science J X Chong K J Buckingham S N Jhangiani C Boehm N Sobreira J D Smith T M Harrell M J McMillin W Wiszniewski T Gambin Z H Coban Akdemir K Doheny A F Scott D Avramopoulos A Chakravarti J Hoover Fong D Mathews P D Witmer H Ling K Hetrick L Watkins K E Patterson F Reinier E Blue D Muzny M Kircher K Bilguvar F López Giráldez V R Sutton H K Tabor S M Leal M Gunel S Mane R A Gibbs E Boerwinkle A Hamosh J Shendure J R Lupski R P Lifton D Valle D A Nickerson Centers for Mendelian Genomics M J Bamshad The genetic basis of Mendelian phenotypes Discoveries challenges and opportunities Am J Hum Genet 97 199 215 2015 OpenUrl CrossRef Medline J F Crow Hardy Weinberg and language impediments Genetics 152 821 825 1999 OpenUrl FREE Full Text C B Begg On the use of familial aggregation in population based case probands for calculating penetrance J Natl Cancer Inst 94 1221 1226 2002 OpenUrl Abstract FREE Full Text S Goldwurm M Zini L Mariani S Tesei R Miceli F Sironi M Clementi V Bonifati G Pezzoli Evaluation of LRRK2 G2019S penetrance Relevance for genetic counseling in Parkinson disease Neurology 68 1141 1143 2007 OpenUrl CrossRef Medline D N Cooper M Krawczak C Polychronakos C Tyler Smith H Kehrer Sawatzki Where genotype is not predictive of phenotype Towards an understanding of the molecular basis of reduced penetrance in human inherited disease Hum Genet 132 1077 1130 2013 OpenUrl CrossRef Medline G M Cooper B P Coe S Girirajan J A Rosenfeld T H Vu C Baker C Williams H Stalker R Hamid V Hannig H Abdel Hamid P Bader E McCracken D Niyazov K Leppig H Thiese M Hummel N Alexander J Gorski J Kussmann V Shashi K Johnson C Rehder B C Ballif L G Shaffer E E Eichler A copy number variation morbidity map of developmental delay Nat Genet 43 838 846 2011 OpenUrl CrossRef Medline A G Bick J Flannick K Ito S Cheng R S Vasan M G Parfenov D S Herman S R DePalma N Gupta S B Gabriel B H Funke H L Rehm E J Benjamin J Aragam H A Taylor Jr E R Fox C Newton Cheh S Kathiresan C J O Donnell J G Wilson D M Altshuler J N Hirschhorn J G Seidman C Seidman Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts Am J Hum Genet 91 513 519 2012 OpenUrl CrossRef Medline J Flannick N L Beer A G Bick V Agarwala J Molnes N Gupta N P Burtt J C Florez J B Meigs H Taylor V Lyssenko H Irgens E Fox F Burslem S Johansson M J Brosnan J K Trimmer C Newton Cheh T Tuomi A Molven J G Wilson C J O Donnell S Kathiresan J N Hirschhorn P R Njølstad T Rolph J G Seidman S Gabriel D R Cox C E Seidman L Groop D Altshuler Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes Nat Genet 45 1380 1385 2013 OpenUrl CrossRef Medline G Kirov E Rees J T R Walters V Escott Price L Georgieva A L Richards K D Chambert G Davies S E Legge J L Moran S A McCarroll M C O Donovan M J Owen The penetrance of copy number variations for schizophrenia and developmental delay Biol Psychiatry 75 378 385 2014 OpenUrl CrossRef Medline Web of Science S B Prusiner Prions Proc Natl Acad Sci U S A 95 13363 13383 1998 OpenUrl Abstract FREE Full Text G M J A Klug H Wand M Simpson A Boyd M Law C L Masters R Matěj R Howley M Farrell M Breithaupt I Zerr C van Duijn C Ibrahim Verbaas J Mackenzie R G Will J P Brandel A Alperovitch H Budka G G Kovacs G H Jansen M Coulthard S J Collins Intensity of human prion disease surveillance predicts observed disease incidence J Neurol Neurosurg Psychiatry 84 1372 1377 2013 OpenUrl Abstract FREE Full Text U S National Prion Disease Pathology Surveillance Center Centers for Disease Control and Prevention CJD Creutzfeldt Jakob Disease Classic http web archive org web 20150202162606 http www cdc gov ncidod dvrd cjd U K National Creutzfeldt Jakob Disease Research and Surveillance Unit Creutzfeldt Jakob disease in the UK http web archive org web 20150330211505 http www cjd ed ac uk documents figs pdf K Hsiao H F Baker T J Crow M Poulter F Owen J D Terwilliger D Westaway J Ott S B Prusiner Linkage of a prion protein missense variant to Gerstmann Sträussler syndrome Nature 338 342 345 1989 OpenUrl CrossRef Medline Web of Science K Hsiao Z Meiner E Kahana C Cass I Kahana D Avrahami G Scarlato O Abramsky S B Prusiner R Gabizon Mutation of the prion protein in Libyan Jews with Creutzfeldt Jakob disease N Engl J Med 324 1091 1097 1991 OpenUrl CrossRef Medline Web of Science R Medori H J Tritschler A LeBlanc F Villare V Manetto H Y Chen R Xue S Leal P Montagna P Cortelli P Tinuper P Avoni M Mochi A Baruzzi J J Hauw J Ott E Lugaresi L Autilio Gambetti P Gambetti Fatal familial insomnia a prion disease with a mutation at codon 178 of the prion protein gene N Engl J Med 326 444 449 1992 OpenUrl CrossRef Medline Web of Science E V Minikel I Zerr S J Collins C Ponto A Boyd G Klug A Karch J Kenny J Collinge L T Takada S Forner J C Fong S Mead M D Geschwind Ascertainment bias causes false signal of anticipation in genetic prion disease Am J Hum Genet 95 371 382 2014 OpenUrl CrossRef Medline J Owen J Beck T Campbell G Adamson M Gorham A Thompson S Smithson E Rosser P Rudge J Collinge S Mead Predictive testing for inherited prion disease Report of 22 years experience Eur J Hum Genet 22 1351 1356 2014 OpenUrl CrossRef Medline G G Kovács M Puopolo A Ladogana M Pocchiari H Budka C van Duijn S J Collins A Boyd A Giulivi M Coulthart N Delasnerie Laupretre J P Brandel I Zerr H A Kretzschmar J de Pedro Cuesta M Calero Lara M Glatzel A Aguzzi M Bishop R Knight G Belay R Will E Mitrova Genetic prion disease The EUROCJD experience Hum Genet 118 166 174 2005 OpenUrl CrossRef Medline Web of Science I Nozaki T Hamaguchi N Sanjo M Noguchi Shinohara K Sakai Y Nakamura T Sato T Kitamoto H Mizusawa F Moriwaka Y Shiga Y Kuroiwa M Nishizawa S Kuzuhara T Inuzuka M Takeda S Kuroda K Abe H Murai S Murayama J Tateishi I Takumi S Shirabe M Harada A Sadakane M Yamada Prospective 10 year surveillance of human prion diseases in Japan Brain 133 3043 3057 2010 OpenUrl Abstract FREE Full Text J Chapman J Ben Israel Y Goldhammer A D Korczyn The risk of developing Creutzfeldt Jakob disease in subjects with the PRNP gene codon 200 point mutation Neurology 44 1683 1686 1994 OpenUrl CrossRef Medline S Spudich J A Mastrianni M Wrensch R Gabizon Z Meiner I Kahana H Rosenmann E Kahana S B Prusiner Complete penetrance of Creutzfeldt Jakob disease in Libyan Jews carrying the E200K mutation in the prion protein gene Mol Med 1 607 613 1995 OpenUrl Medline Web of Science M D Alessandro R Petraroli A Ladogana M Pocchiari High incidence of Creutzfeldt Jakob disease in rural Calabria Italy Lancet 352 1989 1990 1998 OpenUrl CrossRef Medline Web of Science E Mitrová G Belay Creutzfeldt Jakob disease with E200K mutation in Slovakia Characterization and development Acta Virol 46 31 39 2002 OpenUrl Medline Web of Science Exome Aggregation Consortium M Lek K Karczewski E Minikel K Samocha E Banks T Fennell A O Donnell Luria J Ware A Hill B Cummings T Tukiainen D Birnbaum J Kosmicki L Duncan K Estrada F Zhao J Zou E Pierce Hoffman D Cooper M DePristo R Do J Flannick M Fromer L Gauthier J Goldstein N Gupta D Howrigan A Kiezun M Kurki A L Moonshine P Natarajan L Orozco G Peloso R Poplin M Rivas V Ruano Rubio D Ruderfer K Shakir P Stenson C Stevens B Thomas G Tiao M Tusie Luna B Weisburd H H Won D Yu D Altshuler D Ardissino M Boehnke J Danesh E Roberto J Florez S Gabriel G Getz C Hultman S Kathiresan M Laakso S McCarroll M McCarthy D McGovern R McPherson B Neale A Palotie S Purcell D Saleheen J Scharf P Sklar S Patrick J Tuomilehto H Watkins J Wilson M Daly D MacArthur Analysis of protein coding genetic variation in 60 706 humans bioRxiv 10 1101 030338 2015 Q Kong W K Surewicz R B Petersen S G Chen P Gambetti P Parchi S Capellari L Goldfarb P Montagna E Lugaresi P Piccardo B Ghetti in Prion Biology and Diseases Cold Spring Harbor Laboratory Press Cold Spring Harbor 2004 J A Beck M Poulter T A Campbell G Adamson J B Uphill R Guerreiro G S Jackson J C Stevens H Manji J Collinge S Mead PRNP allelic series from 19 years of prion protein gene sequencing at the MRC prion unit Hum Mutat 31 E1551 E1563 2010 OpenUrl CrossRef Medline Web of Science J A Mastrianni The genetics of prion diseases Genet Med 12 187 195 2010 OpenUrl CrossRef Medline M S Palmer A J Dryden J T Hughes J Collinge Homozygous prion protein genotype predisposes to sporadic Creutzfeldt Jakob disease Nature 352 340 342 1991 OpenUrl CrossRef Medline Web of Science S Mead Prion disease genetics Eur J Hum Genet 14 273 281 2006 OpenUrl CrossRef Medline Web of Science S Capellari R Strammiello D Saverioni H Kretzschmar P Parchi Genetic Creutzfeldt Jakob disease and fatal familial insomnia Insights into phenotypic variability and disease pathogenesis Acta Neuropathol 121 21 37 2011 OpenUrl CrossRef Medline Web of Science S Mead M M Reilly A new prion disease Relationship with central and peripheral amyloidoses Nat Rev Neurol 11 90 97 2015 OpenUrl CrossRef Medline R C Moore F Xiang J Monaghan D Han Z Zhang L Edström M Anvret S B Prusiner Huntington disease phenocopy is a familial prion disease Am J Hum Genet 69 1385 1388 2001 OpenUrl CrossRef Medline Web of Science H Zhang M Wang L Wu H Zhang T Jin J Wu L Sun Novel prion protein gene mutation at codon 196 E196A in a septuagenarian with Creutzfeldt Jakob disease J Clin Neurosci 21 175 178 2014 OpenUrl CrossRef Medline M C Tartaglia J N Thai T See A Kuo R Harbaugh B Raudabaugh I Cali M Sattavat H Sanchez S J DeArmond M D Geschwind Pathologic evidence that the T188R mutation in PRNP is associated with prion disease J Neuropathol Exp Neurol 69 1220 1227 2010 OpenUrl CrossRef Medline K Peoc h P Manivet P Beaudry F Attane G Besson D Hannequin N Delasnerie Lauprêtre J L Laplanche Identification of three novel mutations E196K V203I E211Q in the prion protein gene PRNP in inherited prion diseases with Creutzfeldt Jakob disease phenotype Hum Mutat 15 482 2000 OpenUrl Medline J Beck J Collinge S Mead Prion protein gene M232R variation is probably an uncommon polymorphism rather than a pathogenic mutation Brain 135 e209 2012 OpenUrl FREE Full Text I Nozaki K Sakai T Kitamoto M Yamada Reply Prion protein gene M232R variation is probably an uncommon polymorphism rather than a pathogenic mutation Brain 135 e210 2012 OpenUrl FREE Full Text S Capellari F Cardone S Notari M E Schininà B Maras D Sità A Baruzzi M Pocchiari P Parchi Creutzfeldt Jakob disease associated with the R208H mutation in the prion protein gene Neurology 64 905 907 2005 OpenUrl CrossRef Medline L Ripoll J L Laplanche M Salzmann A Jouvet B Planques M Dussaucy J Chatelain P Beaudry J M Launay A new point mutation in the prion protein gene at codon 210 in Creutzfeldt Jakob disease Neurology 43 1934 1938 1993 OpenUrl CrossRef Medline C L Masters J O Harris D C Gajdusek C J Gibbs Jr C Bernoulli D M Asher Creutzfeldt Jakob disease Patterns of worldwide occurrence and the significance of familial and sporadic clustering Ann Neurol 5 177 188 1979 OpenUrl CrossRef Medline Web of Science H S Lee N Sambuughin L Cervenakova J Chapman M Pocchiari S Litvak H Y Qi H Budka T del Ser H Furukawa P Brown D C Gajdusek J C Long A D Korczyn L G Goldfarb Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt Jakob disease Am J Hum Genet 64 1063 1070 1999 OpenUrl CrossRef Medline Web of Science A Ladogana M Puopolo A Poleggi S Almonti V Mellina M Equestre M Pocchiari High incidence of genetic human transmissible spongiform encephalopathies in Italy Neurology 64 1592 1597 2005 OpenUrl CrossRef Medline S Shibuya J Higuchi R W Shin J Tateishi T Kitamoto Codon 219 Lys allele of PRNP is not found in sporadic Creutzfeldt Jakob disease Ann Neurol 43 826 828 1998 OpenUrl CrossRef Medline Web of Science M T Bishop C Pennington C A Heath R G Will R S G Knight PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non synonymous polymorphism BMC Med Genet 10 146 2009 OpenUrl CrossRef Medline S Mead J Uphill J Beck M Poulter T Campbell J Lowe G Adamson H Hummerich N Klopp I M Rückert H E Wichmann D Azazi V Plagnol W H Pako J Whitfield M P Alpers J Whittaker D J Balding I Zerr H Kretzschmar J Collinge Genome wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP Hum Mol Genet 21 1897 1906 2012 OpenUrl Abstract FREE Full Text H Büeler M Fischer Y Lang H Bluethmann H P Lipp S J DeArmond S B Prusiner M Aguet C Weissmann Normal development and behaviour of mice lacking the neuronal cell surface PrP protein Nature 356 577 582 1992 OpenUrl CrossRef Medline Web of Science J A Richt P Kasinathan A N Hamir J Castilla T Sathiyaseelan F Vargas J Sathiyaseelan H Wu H Matsushita J Koster S Kato I Ishida C Soto J M Robl Y Kuroiwa Production of cattle lacking prion protein Nat Biotechnol 25 132 138 2007 OpenUrl CrossRef Medline Web of Science G Yu J Chen Y Xu C Zhu H Yu S Liu H Sha J Chen X Xu Y Wu A Zhang J Ma G Cheng Generation of goats lacking prion protein Mol Reprod Dev 76 3 2009 OpenUrl CrossRef Medline Web of Science S L Benestad L Austbø M A Tranulis A Espenes I Olsaker Healthy goats naturally devoid of prion protein Vet Res 43 87 2012 OpenUrl CrossRef Medline M Fischer T Rülicke A Raeber A Sailer M Moser B Oesch S Brandner A Aguzzi C Weissmann Prion protein PrP with amino proximal deletions restoring susceptibility of PrP knockout mice to scrapie EMBO J 15 1255 1264 1996 OpenUrl Medline Web of Science J Bremer F Baumann C Tiberi C Wessig H Fischer P Schwarz A D Steele K V Toyka K A Nave J Weis A Aguzzi Axonal prion protein is required for peripheral myelin maintenance Nat Neurosci 13 310 318 2010 OpenUrl CrossRef Medline Web of Science K E Samocha E B Robinson S J Sanders C Stevens A Sabo L M McGrath J A Kosmicki K Rehnström S Mallick A Kirby D P Wall D G MacArthur S B Gabriel M DePristo S M Purcell A Palotie E Boerwinkle J D Buxbaum E H Cook Jr R A Gibbs G D Schellenberg J S Sutcliffe B Devlin K Roeder B M Neale M J Daly A framework for the interpretation of de novo mutation in human disease Nat Genet 46 944 950 2014 OpenUrl CrossRef Medline M J Landrum J M Lee G R Riley W Jang W S Rubinstein D M Church D R Maglott ClinVar Public archive of relationships among sequence variation and human phenotype Nucleic Acids Res 42 D980 D985 2014 OpenUrl Abstract FREE Full Text P D Stenson M Mort E V Ball K Shaw A D Phillips D N Cooper The human gene mutation database Building a comprehensive mutation repository for clinical and molecular genetics diagnostic testing and personalized genomic medicine Hum Genet 133 1 9 2014 OpenUrl CrossRef Medline D G MacArthur T A Manolio D P Dimmock H L Rehm J Shendure G R Abecasis D R Adams R B Altman S E Antonarakis E A Ashley J C Barrett L G Biesecker D F Conrad G M Cooper N J Cox M J Daly M B Gerstein D B Goldstein J N Hirschhorn S M Leal L A Pennacchio J A Stamatoyannopoulos S R Sunyaev D Valle B F Voight W Winckler C Gunter Guidelines for investigating causality of sequence variants in human disease Nature 508 469 476 2014 OpenUrl CrossRef Medline Web of Science S Richards N Aziz S Bale D Bick S Das J Gastier Foster W W Grody M Hegde E Lyon E Spector K Voelkerding H L Rehm ACMG Laboratory Quality Assurance Committee Standards and guidelines for the interpretation of sequence variants A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med 17 405 424 2015 OpenUrl CrossRef Medline H Büeler A Aguzzi A Sailer R A Greiner P Autenried M Aguet C Weissmann Mice devoid of PrP are resistant to scrapie Cell 73 1339 1347 1993 OpenUrl CrossRef Medline Web of Science G Mallucci A Dickinson J Linehan P C Klöhn S Brandner J Collinge Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis Science 302 871 874 2003 OpenUrl Abstract FREE Full Text J G Safar S J DeArmond K Kociuba C Deering S Didorenko E Bouzamondo Bernstein S B Prusiner P Tremblay Prion clearance in bigenic mice J Gen Virol 86 2913 2923 2005 OpenUrl CrossRef Medline Web of Science M D White M Farmer I Mirabile S Brandner J Collinge G R Mallucci Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease Proc Natl Acad Sci U S A 105 10238 10243 2008 OpenUrl Abstract FREE Full Text B Pulford N Reim A Bell J Veatch G Forster H Bender C Meyerett S Hafeman B Michel T Johnson A C Wyckoff G Miele C Julius J Kranich A Schenkel S Dow M D Zabel Liposome siRNA peptide complexes cross the blood brain barrier and significantly decrease PrP C on neuronal cells and PrP RES in infected cell cultures PLOS One 5 e11085 2010 OpenUrl CrossRef Medline M Ahn K Bajsarowicz A Oehler A Lemus K Bankiewicz S J DeArmond Convection enhanced delivery of AAV2 PrPshRNA in prion infected mice PLOS One 9 e98496 2014 OpenUrl CrossRef Medline K Nazor Friberg G Hung E Wancewicz K Giles C Black S Freier F Bennett S J Dearmond Y Freyman P Lessard S Ghaemmaghami S B Prusiner Intracerebral infusion of antisense oligonucleotides into prion infected mice Mol Ther Nucleic Acids 1 e9 2012 OpenUrl CrossRef Y E Karapetyan G F Sferrazza M Zhou G Ottenberg T Spicer P Chase M Fallahi P Hodder C Weissmann C I Lasmézas Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents Proc Natl Acad Sci U S A 110 7044 7049 2013 OpenUrl Abstract FREE Full Text B M Silber J R Gever S Rao Z Li A R Renslo K Widjaja C Wong K Giles Y Freyman M Elepano J J Irwin M P Jacobson S B Prusiner Novel compounds lowering the cellular isoform of the human prion protein in cultured human cells Bioorg Med Chem 22 1960 1972 2014 OpenUrl CrossRef Global Surveillance Diagnosis and Therapy of Human Transmissible Spongiform Encephalopathies Report of a WHO Consultation Geneva Switzerland 9 11 February 1998 World Health Organization Geneva 1998 www who int csr resources publications bse whoemczdi989 pdf WHO Manual for Surveillance of Human Transmissible Spongiform Encephalopathies Including Variant Creutzfeldt Jakob Disease World Health Organization Geneva 2003 www who int bloodproducts TSE manual2003 pdf S Collins A Boyd J S Lee V Lewis A Fletcher C A McLean M Law J Kaldor M J Smith C L Masters Creutzfeldt Jakob disease in Australia 1970 1999 Neurology 59 1365 1371 2002 OpenUrl CrossRef Medline J P Brandel A Welaratne D Salomon I Capek V Vaillant A Aouba A Aouaba S Haïk A Alpérovitch Can mortality data provide reliable indicators for Creutzfeldt Jakob disease surveillance A study in France from 2000 to 2008 Neuroepidemiology 37 188 192 2011 OpenUrl CrossRef Medline O Windl A Giese W Schulz Schaeffer I Zerr K Skworc S Arendt C Oberdieck M Bodemer S Poser H A Kretzschmar Molecular genetics of human prion diseases in Germany Hum Genet 105 244 252

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  • CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival | Science Translational Medicine
    20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Amanda L Collar Fungal Pathogenesis Unit Laboratory of Clinical Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Brett G Fischer Fungal Pathogenesis Unit Laboratory of Clinical Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health NIH Bethesda MD 20892 USA Molecular Signaling Section Laboratory of Molecular Immunology National Institute of Allergy and Infectious Diseases NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Chyi Chia Richard Lee Laboratory of Pathology Center for Cancer Research National Cancer Institute NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site John R Perfect Duke University School of Medicine Durham NC 27708 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Barbara D Alexander Duke University School of Medicine Durham NC 27708 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bart Jan Kullberg Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center Nijmegen 6500HB Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mihai G Netea Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center Nijmegen 6500HB Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site Philip M Murphy Molecular Signaling Section Laboratory of Molecular Immunology National Institute of Allergy and Infectious Diseases NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michail S Lionakis Fungal Pathogenesis Unit Laboratory of Clinical Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the editor s summary View Full Text Username Enter your Sciencemag org username Password Enter the password that accompanies your username Forgot your username or password Log in Join Subscribe Purchase Article Activate Member Account Renew Subscription Recommend a subscription to your library Help for librarians Candida camera The yeast Candida albicans can live symbiotically in human gut and skin but when it penetrates the mucosal barrier and enters the bloodstream it can cause life threatening systemic infection Now Swamydas et al provide a look at how neutrophils control Candida They show that the neutrophil selective chemokine receptor Cxcr1 plays a critical

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  • CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival | Science Translational Medicine
    Sinai NY 10029 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nathaniel M Green Fungal Pathogenesis Unit Laboratory of Clinical Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Amanda L Collar Fungal Pathogenesis Unit Laboratory of Clinical Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Brett G Fischer Fungal Pathogenesis Unit Laboratory of Clinical Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health NIH Bethesda MD 20892 USA Molecular Signaling Section Laboratory of Molecular Immunology National Institute of Allergy and Infectious Diseases NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Chyi Chia Richard Lee Laboratory of Pathology Center for Cancer Research National Cancer Institute NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site John R Perfect Duke University School of Medicine Durham NC 27708 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Barbara D Alexander Duke University School of Medicine Durham NC 27708 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bart Jan Kullberg Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center Nijmegen 6500HB Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mihai G Netea Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center Nijmegen 6500HB Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site Philip M Murphy Molecular Signaling Section Laboratory of Molecular Immunology National Institute of Allergy and Infectious Diseases NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michail S Lionakis Fungal Pathogenesis Unit Laboratory of Clinical Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health NIH Bethesda MD 20892 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF Log in to view full text Username Enter your Sciencemag org username Password Enter the password that accompanies your username Forgot your username or password Log in Join Subscribe Purchase Article Activate Member Account Renew Subscription Recommend a subscription to your library Help for librarians Science Translational Medicine Vol 8 Issue 322 20 January 2016 Table of Contents Article

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