 Okay, well, once again, I want to welcome all of you to this open session. And that includes all of you in this room, and those of you who are joining us remotely. As Rudy pointed out, all things associated with this open session are archived, but in particular, a lot of effort goes into my director's report. It's not only being videotaped, as the rest of the open session is being videotaped, but it also includes other materials related to it that will be permanently archived on our website, genome.gov. For those of you who are new to our council meetings, this is the website you would go to if you would go to the particular web page whose URL is shown here. This is essentially a supplemental materials or a electronic resource that reflects supplemental materials associated with director's report. The slides that I'm going to be showing are available. You can download them, either as PDF or as PowerPoint files. And if you notice throughout my talk, if you see a document number in the bottom right corner of a slide, it reflects materials that you can download from this site or access, either it's a website or it's a document. And all of these materials, the website and all these documents will be permanently archived as a historic record of this council meeting. Now there's going to be a number of other presentations that will take place during the open session of this council meeting. I will try to tell, my presentation is tailored around those presentations, so I'm not going to discuss in detail things that other people are going to cover. But here are the presentations you'll hear in the open session. Immediately after my director's report will be joined by Hunt Willard of Geisinger National Precision Health, who's going to give a presentation entitled, A Clinical Imperative Genomics Population Health and Precision Health at Geisinger. After lunch, Terry Minolio will present a concept clearance on the electronic medical records in genomics or a merge comprehensive genomic risk assessment and management. That will be followed by a second concept clearance that Joe Boyer will give on Centers of Excellence in LC Research. Following those two concept clearances, there's going to be four reports today. Council Member Trey Eideker is going to present a report from Council's Data Science Working Group. And then Gwen Darien will be here to present a report from Council's Community Engagement and Genomics Working Group. Erin Ramos will be joined by Council Member Sharon Plan, and together they're going to give a report on the clinical genomics or ClinGen resource. And finally, Christine Chang will present a summary of NHGRI Triennial Inclusion Report. So that's our plan for the open session. My director's report will go through these seven areas that we have found provide a convenient framework for summarizing material I want to tell you about today. And we'll start off with some NHGRI updates. And the first one is mixed news. As far as I'm concerned, it's really with mixed feelings that I tell you that Laura Rodriguez will be leaving NHGRI and her position as Director of our Institute's Division of Policy Communications and Education in April. Laura will be joining, there's a theme here, Geisinger National Precision Health to become their Director for Genome Policy and National Engagement. After joining NHGRI in 2002, Laura's held a number of different positions, spearheaded numerous initiatives, and worked closely with several NHGRI directors, both acting and permanent. As a division director, she has worked to develop and implement policies, design communication and outreach strategies, and prepare the public and healthcare professionals for the future of genomic medicine. As a leader in the development of the NIH policy for data sharing in genome-wide association studies, and then the follow-up, follow-on NIH genomic data sharing policy, Laura helped shape the agency's approach for sharing NIH-supported genomic research data. Laura has been a key member of my leadership team for my entire time as NHGRI Director, and I will certainly miss her wide-ranging contributions and her wise advice. Her shoes will not be easily filled, and indeed several of us, specifically me, Larry Brody, and Vince Bottom, are stepping in to collectively help oversee the Division of Policy Communications and Education on an interim basis until permanent leadership is identified. Nonetheless, we're very happy for Laura, and we wish her all the best in her role at Geisinger. She will no doubt continue to push the field of genomics forward. We also have a retirement that's pending. Jeff Struing, NHGRI Extramural Program Director, will retire at the end of April. Jeff came to NIH in 1991. He studied inherited factors in cancer, first in the genetic epidemiology branch, and then in the laboratory of population genetics at the National Cancer Institute. Then in 2007, Jeff came to NHGRI as a program director, at which time he conceived and initiated the electronic medical records in genomics or eMERGE network. He also conceived and helped lead the NIH Common Fund's Genotype Tissue Expression, or G-TEX project. He has continued to be an influential contributor or a number of NHGRI extramural programs and a valued advisor to both junior and senior staff alike. While he has threatened to do some ad hoc contract consulting with NIH after retirement, we actually suspect that he will most enjoy his woodworking and volunteer work with Luminous Studio Theater and Lucky Dog Animal Rescue. So we certainly wish Jeff all the best in his retirement, and I think he also deserves it. That's it for departures. Just don't want to think this is a trend here. So as I hope you're all aware, NHGRI is in the midst of an important genomics 2020 strategic planning process, one that will yield a new strategic plan in the fall of 2020. To date, NHGRI has held 30 events to gather input for various communities. Recent events have included a town hall at Morehouse School of Medicine in Atlanta, Georgia, and nine satellite meetings and sessions at various annual conferences and consortium meetings. Shown on this slide are photographs from the most recent event, a major workshop entitled From Genome to Phenotype, Genomic Variation Identification Association and Function in Human Health and Disease that was held three weeks ago. The recorded video cast from the workshop is now available on our Genome TV channel on YouTube. As we approach the halfway point of the genomics 2020 strategic planning process, NHGRI is beginning to pivot from gathering open input from the community to seeking feedback on the general themes and ideas that are emanating from the process. In 2019 and then early 2020, we will be holding additional town halls, workshops, and sessions that will aim to gather that feedback and help us craft the new strategic plan. And the details of those future events will be forthcoming. NHGRI and the National Institute on Minority Health and Health Disparities, or NIMHD, are working together to examine and support research into how populations are described in research and how this translates into the scientific literature and ultimately into clinical care. In October of 2018, NIMHD's director, Elisao Perez-Stable, Vence Bonham and I co-authored a perspective in the Journal of the American Medical Association on this topic, which actually summarizes the key discussion that took place at a recent NIH workshop that we convened on this general topic. This published perspective highlights some of the complexities of this area and also calls on researchers to increase the scientific rigor in collecting data describing participants, especially in clinical settings, and ensure the collected data reflect the multidimensional nature of person's identity, for example, race, ethnicity, socioeconomic status, and geographic ancestry. emanating from the recent workshop and now this perspective, NHGRI and NIMHD have embarked on stimulating more conversations on this topic, specifically looking into what NIH institutes and centers should do to guide appropriate uses of race and ethnicity as population descriptors in biomedical and genomics research. One step in that direction has been the establishment of a new trans-NIH working group led by NHGRI and NIMHD that will identify next steps and carry this discussion forward in the coming months. Moving on then to some general NIH updates. On a sad note, in late December, NIH lost one of its most beloved leaders, Steve Katz, the longtime director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, or NIMS. Steve was an outstanding physician, scientist, leader, and NHGRI friend. A world-renowned expert in investigative dermatology, Steve was responsible for training a large number of the immunodermatologists now practicing in the United States and around the world. At a personal level, when I was first appointed NHGRI director, Steve was assigned the role of serving as my mentor. This is actually a routine followed for all newly appointed NIH Institute directors. I recall the valuable insights that Steve provided me during our regular meetings over the ensuing months. He was truly a man of many talents, a distinguished physician, scientist, an outstanding administrator, and a devoted public servant. And the NIH and the biomedical research community have benefited immensely from his many contributions. While NIH conducts a search for a new NIMS director, the Institute's deputy director, Bob Carter, will serve as acting director. In January, Bruce Tromburg became the new director of the National Institute of Biomedical Imaging and Bioengineering, or N-I-B-I-B. Bruce comes to NIH from the University of California at Irvine, where he has had dual appointments in the Department of Biomedical Engineering and Surgery. He was also director of the university's Beckman Laser Institute and Medical Clinic in Interdisciplinary Research, Teaching, and Clinical Center for Optics and Photonics in Biology and Medicine. And earlier last month, Kevin Drogener was confirmed by the Senate to lead the White House Office of Science and Technology Policy. A former professor of meteorology and vice president for research at the University of Oklahoma, he was previously appointed by President George W. Bush and had his term extended by President Barack Obama to serve on the National Science Board, which guides the National Science Foundation and advises Congress and the President on policy matters related to science and engineering. Moving on to genomic data sharing issues. A year ago, I provided an update about the proposed data management update that would change the access procedures for genomic summary results, or GSR. In November 2018, NIH updated the access procedures for GSR under the genomic data sharing policy to allow for unrestricted access to GSR for most studies deposited in NIH-designated data repositories, such as the database for genotypes and phenotypes, or DBGAP. This means that beginning in May of 2019, GSR for most genomic studies will be possible through open access. GSR from studies designated as sensitive by the submitting institution will remain in controlled access, as they are currently. Genomic studies already registered in DBGAP that wish to designate their genomic summary results as sensitive have until May 1st, 2019, to consult with their institutional review boards and submit an updated institutional certification. NIH has made this policy update to provide researchers and other stakeholders, for example, clinical laboratories, with more proportional controls for access to genomic data in the hope that it will support the advancement of research while continuing to protect participants' privacy and respect the informed consent. NIH released a guide notice in early January that provides NIH grantees with guidance on the implementation of the common rule, which began on January 21st, 2019. Provisions that apply to NIH grantees include changes to institutional review board, or IRB review, and a requirement to post-clinical trial informed consent forms. Another provision of the revised common rule directs the departments and agencies, too, within one year and subsequently every four years, evaluate technologies and techniques on whether they generate, quote, identifiable private information, end of quote. The preamble to the revised common rule specifically notes that whole genome sequencing is expected to be one of the first technologies to be evaluated and is, therefore, an area for NHGRI to monitor. Last summer, NIH held a workshop that brought together leaders in innovation and science to explore the opportunities for artificial intelligence and machine learning to accelerate medical advances from biomedical research. Recently, a report from the workshop entitled Harnessing Artificial Intelligence and Machine Learning to Advanced Biomedical Research was released. One of the presentations at that workshop was made by an encode investigator, Anshul Konduzhai, who gave a talk entitled Deciphering Genome Function with Functional Genomics and Machine Learning. One of the outcomes of the workshop was the establishment of a new working group of the advisor committed to the NIH director, specifically focusing on artificial intelligence and biomedical research. I expect there will, therefore, be more NIH developments in this area to report in the coming months as this new working group becomes established. Finally, at the NIH level, a summary about the budget circumstance. I think as you're all aware, part of the government was recently closed, but fortunately, during that time, the vast majority of NIH was open, as it has been since the beginning of fiscal year 2019, which started on October 1st, 2018. So we're now operating at fiscal year 19, and for this fiscal year, the NIH appropriation that emanated from the budgeting process resulted in roughly $2 billion increase over fiscal year 2018, as seen in the second column from the right. Of that, NHGRI received a roughly $19 million increase, bringing the institute's overall budget to around $575 million. As seen in the far right column, NIH's overall increase was about 5.1%, while NHGRI's increase was about 3.3%. The major reason for the differences between these two percentages is the set aside of about $800 million of the $2 billion increase for targeted areas, such as Alzheimer's disease research, cancer research, the brain initiative, and the All of Us research program. Moving on to some general genomics updates, NHGRI was saddened to learn that Ray White passed away in October. Ray, along with David Botstein, Ron Davis, and Mark Skolnick published a seminal American Journal of Human Genetics paper that proposed the systematic development of human genetic markers and their placement into human chromosomal maps. Later, Ray and others genetic markers and maps became valuable assets for the successful completion of the Human Genome Project. His efforts to collect human samples for use in research resulted in the well-known CEPH collection, which has been used by thousands of researchers performing genetics research. The American Society of Human Genetics, or ASHG, gave awards to five members of the genomics community at its 2018 annual meeting. Eric Lander received the William Allen Award, which recognizes scientists for substantial and far-reaching scientific contributions to human genetics. Zach Cathreson received the Kurt Stern Award, which recognizes genetics and genomics researchers who have made significant scientific contributions during the past decade. Jim Lopsky received the Victor Amy Kuzik Leadership Award, which recognizes individuals who have fostered and enriched the development of human genetics and its assimilation into the broader context of science, medicine, and health. Mayor Claire King received the Advocacy Award, which recognizes individuals or groups who have exhibited excellence and achievement in applications of human genetics for the common good. And Andy AD received the Early Career Award for his contributions to genetics and genomics in the past and the first 10 years of his career as an independent investigator. So congratulations to these five individuals. And congratulations is also in order for new members or newly elected members of National Academy of Medicine, who recently announced the election of their new members that have particular relevance to the genomics community and to NIH and to NHGRI, such as those individuals that are listed on this slide. I mean, in particular, we extend our heartfelt congratulations to everyone, but specifically we wanna give a special shout out to Bill Gall and Charles Rotimi, both from the NHGRI Intramural Research Program. Also, congratulations, go to an impressive group of geneticists and genomicists, who as well as NHGRI friends who are recently elected to be Fellows of the American Association for the Advancement of Science or AAAS, with their names listed here. Congratulations to these colleagues as well, but especially former council member Jay Shenduri and also Andy Baxavanas from the NHGRI Intramural Research Program. The Human Proteome Organization in conjunction with Elsevier have awarded the 2018 Proteomics Discovery Prize to the work of the human SMR Atlas, which will be given to the lead author Ulrike Kusabak. The human SRM Atlas is a comprehensive database of quantitative assays, including selective reaction monitoring or SRM assays for essentially all human proteins. This is a particular relevance to us as this work was supported by a 2009 American Recovery and Reinvestment Act, or AERA grant, from NHGRI. And then moving on to year-end accolades, three genomics-related efforts were named. Science's 2018 breakthrough of the year runners up, particularly forensic genealogy comes of age, gene silencing drug approved, and how cells marshal their contents. And then when the scientist came out with its top 10 innovations of 2018, genomic technologies once again appeared on the list. Five genomic innovations were included as listed here. Each of these innovations involved some aspect of genome sequencing or genome editing. And in terms of genomes in the news, the genome sequencing of creatures just never stops. There have been a number of recently generated genome sequences reported since the last council meeting, just since September, including opium poppy, the cane toad, the fall web worm, not to be confused with the gypsy moth, the small hive beetle, snap dragon, sugar cane, Venice-throated parrot bill, the blue-fronted Amazon parrot, the Hawaiian bobtail squid, sea lettuce, and orange clownfish. Yes, just like Nemo. And a bottle nose dolphin named Sandy. And particularly interesting, Lonesome George. Now remember, Lonesome George was the last giant pinta tortoise from the Galapagos Islands, who sadly died in 2012. Who by the way, I met in person in 2002 when I was in the Galapagos Islands. Although that's not my photo, I could have probably pulled my photo out. Okay, moving on then to our extramural research program. And as often the case, we'll start with our genome sequencing program, which is composed of the centers for Mendelian genomics, the centers for common disease genomics, a coordinating center, and several analysis centers. As a reminder, this program is supported by NHGRI, as well as other organizations, including the National Heart, Lung, and Blood Institute, the National Institute of Aging, National Eye Institute, and the Simons Foundation. Starting off with the centers for Mendelian genomics, they are committed to sharing their discoveries with the broader community. One way that they do this is through the Matchmaker Exchange Network, which is a federated platform that matches patients, researchers, clinicians, and families that encounter similar genotypes and phenotypes. The centers contribute to three nodes of this network. So first, the Baylor Hopkins node called Gene Machine has facilitated over 98,000 matches in 81 countries. A total of 10,590 genes have been entered into Gene Matcher, 51% of which have been matched to other users. Next, the Broad node recently published a manuscript about their Matchbox program, which functions as an open-source portable bridge that allows interested researcher to make their data available through Matchmaker Exchange. Matchmaker uses human phenotype ontology to record and analyze the phenotype data. Finally, the University of Washington node has developed MyGene2, which also contains Yale's nodes' data. MyGene2 is more patient-focused than the other nodes and helps families to obtain genetic diagnoses and to connect other patients diagnosed with similar conditions. Moving on then to our Centers for Common Disease Genomics. To date, they have sequenced almost 76,000 genomes and 78,000 exomes in three disease areas, listed along the left, cardiovascular, immune-mediated, and neuropsychiatric. These Centers have plans to generate over 125,000 genome sequences and over 250,000 exome sequences by the time the program concludes in December of 2020. Two recent publications from this program are worth highlighting. Zalazik, at all, demonstrated the high error rates in single molecule, long-grain DNA sequencing that can be ameliorated by using two open-source tools, the NGMLR alignment method and the Sniffles method for identifying structural variants. These tools increase the sensitivity and precision of genomic variant detection, even in complex regions of the genome. Both tools can be used with low coverage data so their use has potential to reduce costs for generating long-read sequence data in clinical and research settings. Second, representatives from this program develop processing standards for whole genome sequencing, allowing different groups to produce functionally-equivalent results. The resulting pipelines yield similar genomic variant calls with less variability than simple replicates. These pipelines will allow for joint genomic variant calling, increasing the statistical power and sample sizes of whole genome data analyses. Note that the Centers for Common Disease Genomics and NHLBI's Trans-omics for Precision Medicine, or TopMed, and the NIMH's whole genome sequencing and psychiatric disorders programs all use this pipeline. Data from the 1,000 genomes, the haplotype reference consortium, and NOMAD are also compatible with this pipeline. The Harvard Analysis Center hosted a conference entitled BioBanks, Study Design, and Data Analysis in November 2018 that focused on how the genomics community might best use BioBanks as a resource of genomic epidemiological phenotypic and medical record data. The discussion focused on quantitative issues, including methods and study designs for increasing scale and statistical power. The Genome Sequencing Program's analysis centers have published two exciting manuscripts in recent months. Wojcik, at all, published a novel framework for selecting tagged single nucleotide polymorphisms. This method has the potential to increase imputation accuracy for rare variants and large-scale multi-ethnic populations and to inform the development of new single nucleotide polymorphism assays. Gazel, at all, reported their new mathematical models for using UK Biobank data and demonstrated negative selection patterns in both coding and non-coding annotations for low-frequency and common variants associated with human diseases and common traits. These methods can be used to improve the design of rare variant association studies. And finally, the Genome Sequencing Program's Coordinating Center recently created a Twitter account for the program, which provides updates on manuscripts, tools, and upcoming meetings. The funding opportunity announcements for the new Human Genome Reference Program have been released and HRI is currently soliciting applications for three components, a Human Genome Reference Center, a High Quality Human Reference Genomes, and a Research and Development for Genome Reference Representations. Applicants will be, or applications will be accepted from March 2nd to April 2nd, 2019, and there will be a webinar addressing frequently asked questions on March 8th from 11 a.m. to 1 o'clock p.m. Eastern Time. In the meantime, potential applicants are encouraged to reach out to NHGRI's Adam Felsenfeld and Heidi Sophia with questions. NHGRI's Technology Development Program continues to develop new and improved technologies to enable genomic discoveries and facilitate the adoption of genomics in medicine. Applications for the novel nucleic acid sequencing technology development request for applications are due on June 27th of this year. And then meanwhile, an Advanced Genomic Technology Development Meeting will again be held at Northeastern University in late May, at which novel nucleic acid sequencing and genomic technology grantees from the program will meet to communicate, collaborate, and interact. But in addition to that, there'll be an adjacent public meeting on May 31st that will allow for the broader community to participate and interact with NHGRI grantees and staff. Moving on to ENCODE, the goal of the Encyclopedia of DNA Elements or ENCODE project is to create catalogs of all functional elements in the human and mouse genomes and to make those catalogs available as a resource to the biomedical research community. The ENCODE consortium held its annual meeting last month in the DC area. Participants shared scientific progress, discussed challenges and plans to overcome them and then laid out plans through 2021. The meeting also featured a session on NHGRI strategic planning process. ENCODE continues to make its resource accessible to a wide range of researchers. For example, on October ENCODE held a half day workshop as an ancillary event at the American Society of Human Genetics annual meeting on the accessibility and utilization of ENCODE data. The workshop included an introduction to the ENCODE project and the resources available for accessing ENCODE data as well as specific research applications that have used ENCODE data. This coming July, the ENCODE consortium will hold its third research and application users meeting in Seattle, Washington. The meeting will feature hands-on workshops for learning to navigate, analyze and integrate ENCODE data into data users research and details about this meeting will be forthcoming on genome.gov. Now, Psyche ENCODE is a national institute on mental health funded consortium with ties to ENCODE and it's a collaborative effort among 15 research institutions that aim to characterize the functional genome of the human brain. The Psyche ENCODE project has performed unbiased multi-omic molecular profile of over 2,000 human post-mortem brains across neurodevelopmental time periods and psychiatric disorders, including schizophrenia, autism spectrum disorder and bipolar disease. There was a special issue on the Psyche ENCODE project that was recently published in Science along with a series of additional papers that were published in other science journals. The collection of 11 publications, three of which are shown on the right, provide insight into the gene regulatory architecture driving human brain development and neuropsychiatric disorders. Moving on to our Centers of Excellence in Genomic Science or SEGS program, which supports interdisciplinary research teams to develop highly innovative approaches in genomics research. Here, I highlight a recent study to develop genomic recorders to track the lineage of cells in a mammal. This work was funded in part by the SEGS program and the NHGRI technology development program, specifically involving grants to George Church and Prasant Mali. These researchers engineered mice with multiple CRISPR homing guide RNA loci, then crossed these mice with another line expressing Cas9. During development, the Cas9 induced changes and the homing guide RNA loci functioned as genomic recorders. DNA from adult mice were sequenced and the combinatorial recording pattern from single cells was used to infer cell lineage. This is the first time such a feat was achieved in the mammal. This approach has the potential to provide important new insights into the cellular basis of development. The Electronic Medical Records and Genomics or Emerge Network conducts genomic discovery and clinical implementation research by leveraging data from large biorepositories linked to electronic medical records. Recently, Emerge Investigators published two major articles. The first article entitled Parents' Attitudes Towards Consent and Data Sharing in Biobanks, a multi-site experimental survey, found that 55% of parents were willing to allow their youngest child to participate in a hypothetical biobank. The paper also reported that factors such as lower educational attainment, higher religiosity, lower trust, and worries about privacy were independently associated with less willingness to allow their child to participate. The second article entitled the Emerge Genotype Set of 83,717 subjects imputed to 40 million variants genome-wide and association with the herpes zoster medical record phenotype, describes the imputation of Emerge results and methods to create the unified imputed merge set of genome-wide variant genotype data. The graph on the right shows the principal components analysis of 83,717 participants examining the ancestry of Emerge phase one through three imputation. All Emerge array data were imputed against the haplotype reference consortium reference panel using the Michigan imputation server. To test the merged imputed genotype set, the investigators replicated a previously reported chromosome six HLAB herpes zoster association and discovered a novel zoster associated loci in an epigenetic site near the terminus of chromosome three. The clinical genome resource or ClinGen evaluates and disseminates the clinical relevance of genes and genomic variants for use in precision medicine and research. The journal Human Mutation published a special issue highlighting the advances in both ClinGen and the NCBI-led ClinVar. The special issue was published this past October and involved the efforts of three guest editors who are all ClinGen principal investigators, Jonathan Berg, Heidi Rehm, and Sharon Plon. The 25 paper issue touched on various relevant topics, including gene and genomic variants curation, clinical actionability data sharing, and the use of ancestry and diversity data in the context of clinical genomics. And then in December of 2018, the U.S. Food and Drug Administration or FDA announced that they were recognizing ClinGen's expert curated genomic variant pathogenicity interpretations through their new public human variant database program. The program is part of an FDA effort to provide genetic test developers access to consistent expert validated evidence that they can cite when seeking FDA approval of their tests with the hopes of reducing regulatory burdens and sparing advancements in the evaluation and implementation of precision medicine. ClinGen is the first curation effort to receive this FDA recognition. And the genomic variant interpretations are available in ClinVar and are identified with the quote FDA recognized database and a quote label as shown in the upper right of this slide. And later this afternoon, Erin Ramos and Sharon Plon will give you an update on ClinGen's activities during which they will touch on the FDA recognition and also address curation progress, collaborations and other aspects of the ClinGen resource. The clinical sequencing evidence generating research or CSER program aims to generate evidence related to the clinical utility of genome sequencing with a major emphasis on recruiting ancestrally diverse and medically underserved populations. The six clinical sites are currently working to sequence the genomes of roughly 6,500 participants over the next two and a half years, reaching recruitment goals of at least 60% of participants from non-European populations, underserved populations or populations known to experience poor medical outcomes. CSER participants are being recruited from a variety of clinical settings, including medical centers, intensive care units, outpatient clinics, community hospitals and a federally qualified health center. CSER is still early in its recruitment efforts. The focus on increasing diversity comes with unique challenges. And some of the lessons learned during the process include the importance of engaging recruiter providers who know their patients well and the finding that some, but not all sites are reporting potentially lower decline rates than expected, perhaps because of the increased emphasis on recruiting diverse populations. And then in January of this year, the CSER and Emerge programs actually met together for the third time in six years to discuss important topics and identify collaborative opportunities that are relevant to both groups. The investigators discussed topics such as selection and performance of harmonized measures and outcomes, cascade testing of relatives, provider engagement, tools for variant classification, outcomes and healthcare utilization, scalable approaches to patient or provider interactions and LC issues among others. As a next step, some of the more promising opportunities such as an updated variant bake-off comparing variant classifications among CSER and Emerge groups will be discussed with the leadership of both consortia. Moving on to IGNITE. IGNITE-1 is the first phase of the implementing genomics in practice or IGNITE network. And as its one-year extension ends, it is a good time to actually look back and reflect on some of the program's accomplishments. While the program's reach has far exceeded the six funded IGNITE-1 institutions, this map shows the 18 affiliate institutions represented by 64 individual members who have joined and strengthened the network by collaborating rating with IGNITE-1 investigators. To date, IGNITE has published 133 papers with an additional 41 manuscripts submitted for publication. The network has also created the Spark Toolbox, which houses numerous resources for clinicians and researchers working to implement genomic medicine, including a custom implementation guide. IGNITE-1 has made great strides in the implementation of genomic medicine, tackling issues such as recruitment, information technology, education, and policy. Their innovations include increased stakeholder engagement, the use of an open standards platform based for electronic health record interoperability, and pragmatic lessons about reimbursement and genomic medicine test adoption. And the final steering committee meeting of the IGNITE network will be held in April of this year. Well, with IGNITE-1 ramping down, the second phase of IGNITE, that is IGNITE-2, is ramping up. In their grant application, each IGNITE-2 clinical site proposed a protocol for implementing genomics into practice using a pragmatic clinical trial. A protocol review committee made up of expert stakeholders met to assess the feasibility and impact of the proposed protocols this past October and then again in December. NHGRI is proposing to implement one or more of these protocols at all five IGNITE-2 clinical sites. The first is a harmonized pharmacogenomics protocol that was proposed jointly by Indiana University, Vanderbilt University, and the University of Florida. It aims to study the clinical utility of pharmacogenomics in patients suffering from depression, chronic pain, or post-surgery acute pain. The second is the Guard U.S. protocol or a genetic testing to understand renal disease disparities U.S. protocol proposed by Mount Sinai, which aims to study the impact of disclosing APOL-1 renal risk information to African American patients with hypertension and kidney disease. The third protocol was proposed by Duke University. It aims to build and deploy a genomic medicine risk assessment model for diverse primary care populations, which it calls the GRACE protocol. NHGRI staff will soon establish a data safety monitoring board, which will observe and advise the network for the duration of the program. IGNITE-2 aims to begin recruitment for the first pragmatic clinical trial in mid to late 2019. The newborn sequencing and genomic medicine of public health or our N-site program is funded jointly with the Unis Kennedy Shriver National Institute on Child Health and Human Development. This program explores an unlimited but deliberative manner of the implications, challenges, and opportunities associated with the possible use of genome sequence information in the care of newborns. In January, the baby seek project published results from their insight study of healthy and ill newborns in the American Journal of Human Genetics. Exome sequencing revealed a risk of childhood onset disease in 9% of newborns, none of which were anticipated based on the newborn's known clinical or family histories. Carrier status was also reported for pharmacogenomic variants in 5% of newborns and recessive clinical childhood onset disorders in about 88% of newborns. Moving on, the NSURI Computational Genomics and Data Science program supports research and development of data science methods, resources, and tools that maximize the integration of genomics data into biomedical research. In November, the program received the first round of applications in response to funding opportunity announcements, or FOAs, for the R01 and R21 grant mechanisms. These FOAs aim to increase the pool of investigator-initiated applications for a broad range of innovative research efforts in computational genomics, data science, statistics, and bioinformatics. The next receipt date for new applications to both FOAs is July 16th of this year. In addition, we have released a small business innovation research, or SBIR funding opportunity announcement, which aims to support commercial product development in computational genomics, data science, statistics, and bioinformatics. The next receipt deadline for these SBIR applications is April 5th of this year. Now, our NSURI Computational Genomics and Data Science program also supports a number of genomic resources, including the Alliance of Genome Resources, or AGR. Now, recall that the AGR was founded in 2016 as a collaboration among six model organism databases and the Gene Ontology Resource. AGR's goals are to establish an integrated resource that provides enhanced support for comparative genome biology, including human, and to develop shared modular infrastructure to reduce the costs of resource development and maintenance. Following its initial release in 2017, the AGR continues to work on harmonizing model organism data to develop the AGR into a premier comparative genomics research. Now, the AGR consortium held its annual All Hands Meeting last November, as shown in this photo. The meeting highlighted recent accomplishments with a focus on work products that are available through the AGR web resource. This includes a common ontology set, uniform representations of gene-to-human disease associations across model organisms, and a display of harmonized gene function, expression, and interaction data. Now, the Gene Ontology, or GO resource, is one of the founding members of the just-mentioned AGR, recently celebrated its 20th anniversary. This milestone was commemorated by a recent publication in nucleic acid research. Now, GO provides structured, computable knowledge regarding the functions of genes and gene products and has been widely adopted in the life sciences community. The original GO publication, which was published in 2000, has been cited over 10,000 times, placing it in the 99.9 percentile of NIH-funded publications. The 2019 publication, shown here, outlines some of the current efforts of the GO resource. These include implementing an approved framework for gene function models, revision of the GO resource, and improved integration with external ontologies, and development of the GO ribbon, which is a configurable tool for visualizing GO annotations. The fifth I-DASH genomic privacy challenge was held this past October in San Diego. The I-DASH genomic privacy challenge brings together leaders in biomedical informatics, computer science, and cryptography to test cutting-edge solutions to work with and share sensitive data while preserving privacy. Now, in its fifth year, the challenge has grown to include 64 registered teams and has gained international visibility. This year, the three challenge tasks included one, blockchain to create an audit trial for tracking use of distributed genomic data that may be hosted in different places and to ensure that users are complying with the policy. Second, secure parallel genome-wide association studies, or GWAS, using homomorphic encryption to protect data during analysis. And three, secure search of DNA segments and genomic databases. Now, this third task aims to help protect the privacy of genealogical searches by reporting relatedness without exposing either the query or the database sequences themselves. The Institute's Ethical, Legal, and Social Applications, or ELSI Research Program, supports research that anticipates, explores, and addresses the implications of genomics for individuals, families, and communities. ELSI-funded projects have investigated topics such as forensics and gene editing since the founding of the program in 1990. Now, many ELSI-funded publications can be found in an online searchable database, including a number of timely papers by current ELSI-funded investigators. I will now briefly summarize several 2018 ELSI publications. So in June, Marcia Michee and Megan Elise published an assessment of the views of families with Down syndrome regarding potential gene modification interventions. In October, Christie Guriri and colleagues published preliminary data on individual perspectives on police access to genetic genealogical websites and customer information for director-consumer genetic testing companies. And finally, in December, Eric Junst and council member Gail Henderson, along with other colleagues, described the need to carefully consider the intersection between prevention and enhancement in the gene editing context. This last paper was published just as news about the first gene-edited child was being reported. NHGRI's Small Business Innovation Research, or SBIR, and Small Business Technology Transfer STTR program continues to thrive. In total, the institute funded $15 million in small business grants in fiscal 2018, last year. Those recent SBIR and STTR grants reflect 19 phase one proof of principal awards and five phase two pre-commercialization awards. Of note, these new phase two awards are supporting work at five companies in the following areas, development of a device for sizing DNA, integrated single cell imaging and RNA-seq analysis, designing urine DNA isolation methods, and two companies generating computational genomics data analysis technologies. These small business grants are drawn from an increasingly strong application pool. The NHGRI Research Training and Career Development program provides a wide range of programs aimed at advancing the professional training and career development of students, health professionals, and research scientists. The institute funds research training and career development activities through individual and institutional awards, supports a diverse workforce through diversity and re-entry supplements, and supports the reduction of education debt by way of the loan repayment program. Our program offers opportunities at the undergraduate, graduate, postdoctoral, and faculty levels. Since 2002, NHGRI supported programs focused on exposing underrepresented minority students to research experiences in genomics through our Diversity Action Plan, or DAP, awards. More recently, the DAP program has been open to genomic medicine and ELSI research. In fiscal year 2018, NHGRI funded six new DAP programs, doubling the total number of supported programs to 12. Shown in this table are the new programs specifically at the universities of Utah, Pennsylvania, Alabama, Oklahoma, and Utah, as well as Johns Hopkins University. To further strengthen NHGRI's effort to train a diverse workforce, the institute published a notice last December that encourages NHGRI grantees to apply for research supplements to promote diversity and health-related research. These supplements provide funds for recruiting and supporting students, postdoctoral fellows, and eligible investigators from diverse backgrounds, including those from groups that have been shown to be underrepresented in health-related research. The activities proposed in the supplement application must fall within the scope and advance the objectives of the parent grant, as well as support the research training and professional development of the supplement candidate. Applicants are encouraged to provide detailed information in a timeline describing the candidate's expected progression to the next stage in their research career. Funds can be requested for up to two years of support beginning in fiscal year 2019. These supplements must be submitted at least 90 days prior to the anticipated need and no later than May 15th of 2019. Finally, I would like to provide some highlights emanating from NHGRI's Investigator Initiated Awards. So this first paper by James Hazel and Christopher Slobogen reports on a survey of the privacy policies of 90 direct-to-consumer genetic testing companies operating in the United States. They provide a detailed analysis of whether and to what extent those policies inform consumers about their genetic information, how they'll be used and secured and whom it will be shared and a host of other issues. In this second paper by Elena Kuzmin and colleagues, the Investigator studied complex genetic interactions in triple mutants in yeast by measuring fitness. They estimated that the global tri-genic interaction map is a hundred times as large as the global di-genic network and bridges distant biological processes. This work provides significant interactions and I'm sorry, provides significant insights into higher-order genetic interactions and has implications for interpretation of human genomic variants, understanding genotype to phenotype connections and explaining missing heritability. So moving beyond NHGRI to NIH Common Fund and trans-NIH efforts, we'll start with the Knockout Mouse Phenotyping Project or COMP-2. COMP-2 will create a phenotype about 3,000 strains of knockout mice using CRISPR technology between 2016 and 2021. The project is on track to meet its spring 2019 goals. COMP-2, of course, is part of a larger international mouse phenotyping consortium or IMPC. In October of 2018, NIH staff convened a successful COMP-2 collaboration meeting that included several human disease consortia, including the Centers for Mendelian Genomics, the Transomics for Precision Medicine or TopMed, Gabriella Miller's Kids First, and ClinGen, the meeting focused on the utility of mouse data for human disease research, the challenges in integrating mouse data into clinical settings and also the future opportunities for collaborations between COMP and other human disease consortia. In December of 2018, there was a joint meeting between the IMPC and also Infra Frontier, which is the European Research Infrastructure for the Generation Phenotyping, archiving, and distribution of model mammalian genomes. This meeting focused on advancing rare disease research and gene therapy applications using animal models. And then recently, the IMPC published a paper reporting the generation of 347 gene knockouts with eye-related phenotypes. 75% of the knocked out genes were not previously associated with eye function. The goal of the Gabriella Miller Kids First pediatric research or Kids First program is to alleviate suffering from childhood cancer and structural birth defects by fostering a collaborative research to uncover the etiology of these diseases and supporting data sharing within the pediatric research community. Returning to the theme of collaborations between COMP2 and the human disease consortia, the NIH Common Fund is providing supplemental funding for COMP2 to collaborate with the Kids First program. Specifically, Kids First and COMP2 are collaborating on a pilot project entitled Precision Modeling of Pediatric Conditions that will develop mouse strains to study phenotype and validate coding and non-coding genomic variants. For this pilot collaborative project, the Kids First program is accepting nominations of disease alleles identified through the Kids First genome sequencing projects. Selected alleles will then undergo mouse modeling, production, and phenotyping. And nominations are being accepted on a semi-rolling basis with the upcoming 2019 due dates listed here. Alleles will be prioritized based on the strength and breadth of the supporting evidence. And so far, two human disease alleles have been accepted and will be added to the COMP2 phenotyping pipeline. Another NIH Common Fund project is the Human Heredity and Health in Africa or H3Africa program. The central goal of H3Africa is to develop a sustainable and collaborative African genomics research enterprise. Program is currently in its seventh year and the consortium now supports 48 projects across 34 African countries involving over 54,000 research participants to date. Samples for more than half of those participants are now deposited in the three H3Africa biorepositories. Genomic data is stored in the H3A BioNet for eventual sharing through the European Genome Phenome Archive. Recent publications include a 50,000 participant research cohort to study genomic and environmental contributions to cardiovascular disease, insights into the recent LASA virus, outbreaks, overall and sex specific determinants of cardiometabolic disease and four bioinformatic workflows optimized for genomic data generated on the African continent. Additionally, H3Africa investigators have increased their visibility and the consortium's visibility by presenting the conferences such as the annual meeting of the American Society of Human Genetics, the fourth Global Genomic Medicine Collaborative Conference and the sixth plenary meeting of the Global Alliance for Genomics and Health. And lastly, H3Africa investigators are looking to build bridges with other NIH initiatives with various H3Africa working groups now in discussions with the Undiagnosed Diseases Network with the Centers for Mendelian Genomics and with the Phoenix Toolkit. Speaking of the Undiagnosed Diseases Network, or UDN, the UDN aims to develop, to improve the level of diagnosis and care for patients with undiagnosed diseases, facilitate research into the etiology of these diseases and promote an integrated and collaborative community to investigate these difficult to diagnose disorders. And recently, the UDN published a manuscript in the New England Journal of Medicine describing the first 1,519 applicants to the UDN. For the 382 patients who have had complete evaluations, the diagnosis rate was 35%, with 31 new syndromes defined. To apply to the UDN, access the UDN gateway by clicking on the applied button, which appears on all UDN One Pages. You can also find real-time research updates by following the UDN on social media at UDN Connect. The Human Biomolecular Atlas Program, or HubMap, is a new NIH Common Fund program that started in late 2018. This program aims to catalyze the development of an open global framework for comprehensively mapping the human body at cellular resolution. HubMap's promise is that better insights into the principles governing organization-function relationships will lead to better understanding of the significance of inter-individual variability, changes across the lifespan, tissue engineering, and the emergence of disease at the biomolecular level. HubMap held its first all-hands meeting this past November, and outcomes of the meeting include a draft of a manuscript describing the goals and structure of the program. And then in January, HubMap released a new funding opportunity announcement, or FOA, aiming to support the rapid implementation of technologies for mapping the human body at high resolution. The goals of this FOA are to broaden and deepen HubMap's consortium's range of technologies and expertise in tissue collection and preservation, also implementing new methods for data collection analysis to supplement existing HubMap efforts. This FOA has a focus on the extracellular environment and matrix composition, and the applications for this FOA are due on March 14th. The Sematic Cell Genome Editing, or SGE program, is another NIH Common Fund that aims to develop quality tools to perform effective and safe genome editing in human patients. The program elements include improved delivery systems in genome editors, as well as in vitro and in vivo assay platforms to test safety and efficacy. The information and materials will constitute a genome editing toolkit that will be disseminated through a data coordination center. A kickoff meeting of this new program was held in December of 2018, and NHGRI specifically is managing the Data Coordination Center, which was awarded to the Medical College of Wisconsin. And the second round of applications have been received for this program and are now under review. These applications include novel editors and delivery systems, tissue platform initiatives, and an in vivo cell monitoring initiative. And finally, trans-NIH program, the All of Us Research Program, aims to build a community of a million or more participants to gather health information for the acceleration of research and the improvement of healthcare for a variety of conditions affecting the diversity of populations in the United States. To date, more than 150,000 individuals have registered with the program, and over 90,000 people have completed all the requirements for inclusion. Of relevance or particular relevance for NHGRI, in September of this past year, All of Us awarded funds to three genome centers for generating both array-based genotyping data and whole genome sequencing data using biosamples from the program participants. The first center is at the Baylor College of Medicine in conjunction with the Johns Hopkins University and the University of Texas. The second center is at the Broad Institute with Color Genomics and Partners Healthcare. And the third center is at the University of Washington. To handle the return of genomic results in a responsible manner, All of Us solicited applications for a genetic counseling resource, and the closing date for applications was earlier this month with awards expected later this spring. So moving on then to our Division of Policy, Communications and Education. To continue diversifying how the institute reaches the many important audience that NHGRI serves, the Communications and Public Liaison Branch has been collaborating with various parts of the institute on new video projects. The first of these new videos has been now posted on our Genome TV channel of YouTube and promotes the research of one of our intramural investigators, Chuck Venditti. Chuck is a senior investigator and the video that describes his work, which involves a focus on patients afflicted with methamelonic acidemia or MMA, and how research by the Venditti Laboratories providing important new insights about this devastating disease of the molecular level. The video will be part of a set of educational materials designed to support upcoming clinical trials to test several new treatments for this disorder. And then the NHGRI Smithsonian Exhibition Genome Unlocking Life's Code will make several more stops across North America as it continues to travel in 2019 and into 2020. The exhibition completed its stay at the Orange County History Museum in Florida in early January and is now open in Birmingham, Alabama for a run at the McWayne Science Center. When it leaves Alabama, the exhibition will travel to the Da Vinci Science Center in Allentown, Pennsylvania. Please continue to check the exhibition's website and follow it on social media for the most up-to-date program information. NHGRI's Education and Community Involvement Branch continues to participate in various public outreach activities that highlight the Institute and current topics in genomics. NHGRI is partnering with the National Academies of Science LabX program to organize programming focused on genomic information, privacy, policing, and social justice. This past December, representatives from the community organizations and the science policy and criminal justice fields came together to discuss benefits and concerns associated with these issues. In January, NHGRI engaged with the Washington DC community at the free NBC4 Health and Fitness Expo with 257 exhibitors and more than 70,000 visitors attending, actually despite an unexpected snowstorm that occurred at that time. NHGRI staff and genetic counselors from the Genetic and Rare Diseases Program at NIH's National Center for Advancing Translational Sciences interacted with nearly 200 people. In addition, on the main stage, NHGRI's Julie Segre participated in a panel discussion about DNA and what it can tell us. And finally, this year will mark the 16th anniversary of National DNA Day, which will occur on April 25th. NHGRI will be wrapping up activities to celebrate the completion of the Human Genome Project and the discovery of the double helical structure of DNA in the coming months. I encourage you to visit the National DNA Day website on genome.gov for more information on the planned events and the resources that are available for supporting local DNA day activities. And then in September of this past year, NHGRI's Education and Community Involvement Branch invited 25 healthcare providers, including physicians, nurses, pharmacists, physicians, assistants and genetic counselors to a meeting at NIH that discussed what is needed to enhance genomics education of healthcare providers. The meeting concluded with a set of recommendations for improving genomics education for providers. These recommendations included, one, increasing funding for genomics education, two, working with underserved communities and increasing the diversity of investigators and providers, three, continuing to support existing NHGRI tools, four, fostering genomic and genetic awareness with an ambassador network and or social media campaign, and five, providing training opportunities for train the trainer courses for healthcare professionals. The Education and Community Involvement Branch will convene a group of providers from this meeting to begin addressing this set of recommendations. And finally, the My Family Health Portrait is a web-based public tool that was launched in 2004 by NHGRI in partnership with the Surgeon General and other federal partners, including the Centers for Disease Control and Prevention. Now over the past few years, the tool has been updated by NHGRI to improve its use, add functionality, and also to increase accessibility by the public. NHGRI continues to support family health history initiatives through the Family Health History Day on Thanksgiving each year, as well as by hosting bimonthly calls of clinicians, educators, and industry through the National Family Health History Group. To increase exposure and use of the My Family Health Portrait tool by the public, genomic educators, and clinicians, the tool was actually moved to a new home at the Centers for Disease Control and Prevention this past September. The core capabilities of the tool remain the same. That is a convenient way to gather family health history as a pedigree or a chart to share with family members and providers. And last, but by no means least, moving on to NHGRI's Intramural Research Program, let me just provide you a few updates. First, a really remarkable update. In October of this past year, Dan Kastner, which is NHGRI's scientific director, was named the Federal Employee of the Year as part of the 2018 Samuel J. Hyman Service to America Metals Program, also known as the SAMHIs. Now the SAMHIs are a highly respected and highly competitive set of honors given each year to government employees for their outstanding contributions. This is across the entire federal government. Dan was recognized as the Federal Employee of the Year for his work to uncover the genomic causes of multiple rare and debilitating auto-inflammatory diseases and identifying and treating previously undiagnosed illnesses, efforts that have alleviated the suffering of thousands of patients in the United States and around the world. We were extremely proud of Dan's winning this award. And then Charles Rotimi, a senior investigator in NHGRI's Intramural Research Program, a director of NIH's Center for Research of Genomics and Global Health, has been named one of the Quartz Africa Innovators of 2018. Each year, this award highlights the work of 30 African leaders that are making an impact on their communities, countries, and ultimately the continent. Charles was recognized for his work in understanding how the information coded in our DNA can shed light on human migration history within and outside of Africa. And then in terms of transitions, after 16 years of being clinical director within NHGRI's Intramural Research Program, Bill Gaul is stepped down from this important leadership position where he stepped down at the end of 2018. Bill has developed an outstanding track record as both a physician and a scientist with many accomplishments and many honors. And although he has stepped down as clinical director to spend full time on his research, he certainly will remain at NHGRI and continue to be an important part of our Intramural Research Program. Now, NHGRI scientific director, Dan Kastner, will serve as acting clinical director while NHGRI launches a search for a new clinical director. And more information about that recruitment will be forthcoming in the coming weeks and months. And lastly, just a few highlights from NHGRI's Intramural Research Program. As always, they are incredibly productive, but a few highlights from the past four months or so. Vence Bonham and colleagues found that patients, parents, and physicians were optimistic about the use of CRISPR-Cas9 to reverse sickle cell disease, but concerned about treatment risk and transparency of the research enterprise. Chuck Venditti, who you heard about in the video that was made about one of the diseases that he studies, he discovered a, his lab discovered a hormone in a mouse study that can be used immediately to help doctors predict the severity of symptoms in patients with the rare disease, methamyelonic acidemia. And then finally, Narasu and colleagues found that North Asians, including Mongolians and other Siberian ethnic groups, may be more closely related to Eastern and Northern Europeans, including the people of Finland, than previously thought. And that brings me to my, nearly the second or last, or end of the slides. Before ending director's report, I will always put in a shameless plug to say anyone who wants to receive my monthly email update called the Genomics Landscape can simply go to NHGRI's website, genome.gov, and subscribe under email updates. And then a big thanks to everyone. Thanks to the 50 or 60 people sitting in the back of the room mostly who contributed to the slides and associated materials for this director's report. It's a Herculean effort pulling these slides together, but it's a group effort that I greatly appreciate everyone's effort on. Of course, thanks to the communications group as well for helping make the video conference possible, and also for helping to make my director's report into electronic resource. And none of this is possible getting the document together without Chris Watterstrand's central role as ring leader, shown here, she's at the podium at the recent genome to phenotype strategic workshop where many heads were put together to develop ideas for the future of genomics. And I will stop there and happy to take any questions. Now, we can switch the slides. Any questions? And now we're gonna move on to our speaker. Going once, going twice. Sharon? There are really 90 direct-to-consumer genetic testing countries? Is that what you said? That paper? The fire room. Wow, that's amazing. I don't know the details. I don't know what. Well, yeah. I don't know. Does anybody know the details of that paper? It depends how I guess it's defined. There's a lot of, as you know, there's a lot out there. So.