Wendy K Chung - US grants

[unreadable] DESCRIPTION (provided by applicant): Congenital diaphragmatic hernia (CDH) is a common birth defect with a prevalence of 1 in 3000 live births, constituting 8% of all birth defects. Many cytogenetic abnormalities have been associated with CDH, and evidence is accumulating that many developmental defects can result from small genomic alternations invisible at the cytogenetic level, resulting in changes in copy number of contiguous genes. We hypothesize that in some proportion of cases of birth defects, including CDH, these genomic alternations may be mosaic and may not be readily detectable by testing lymphocytes in blood. We propose to identify changes in gene copy number by analyzing diaphragm tissue and other tissue from patients with CDH, using genome wide oligonucleotide microarrays to perform high resolution gene copy number assessment. Our long-term goal is to define a set of novel genomic aberrations important in the etiology of CDH, characterize new syndromes associated with CDH, and identify new genes implicated in diaphragm development. We believe this information will improve genetic diagnostic methods and provide more accurate clinical prognostic information that can improve genetic counseling. We will accomplish this through the following specific aims: 1) Obtain diaphragm, skin, blood, and when possible amniotic fluid samples from 250 neonates with CDH, 100 children with previously repaired CDH, and amniotic fluid on 250 cases of fetuses with prenatally diagnosed CDH and their parents for oligonucleotide microarray copy number analysis; 2) Analyze the diaphragm (neonatal), blood (pediatric) or amniotic fluid (prenatal) samples for copy number changes (CNCs) using high density oligonucleotide microarrays, filter out benign copy number polymorphisms, and determine if CNCs are de novo by comparing parents and offspring and determine tissue mosaicism; 3) Identify recurrent CNCs, define the minimal overlapping interval, identify all the genes in the minimal interval of the recurrent CNCs, and sequence positional/physiologic candidate genes and determine if there are overlapping clinical features among patients that can be used to define a genetic syndrome with associated clinical features and prognostic implications; and 4) Correlate results of genetic analyses and survival to discharge and 2 years of age, associated birth defects, severity of pulmonary hypertension at 1 and 3 months, weight and height at 2 years, and Bayley Scales of Infant Development-II and Vineland Adaptive Behavior Scale at 2 years in cases of neonatal ascertainment. PUBLIC HEALTH RELEVANCE: Congenital diaphragmatic hernia (CDH) is a common birth defect with a prevalence of 1 in 3000 live births, constituting 8% of all birth defects. Our goal is to define a set of novel genetic aberrations causing CDH, characterize new syndromes associated with CDH, and identify new genes implicated in diaphragm development. We believe this information will improve genetic diagnostic methods and provide more accurate clinical prognostic information for patients and families with CDH. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Congenital heart disease (CHD) is the most common birth defect with an incidence of 1% of all live births. Many cytogenetic abnormalities have been associated with CHD, and evidence is accumulating that many developmental defects can result from small genomic alternations invisible at the cytogenetic level, resulting in changes in copy number of contiguous genes. We propose to identify genetic contributions to CHD by screening for changes in gene copy number, using genome-wide high resolution oligonucleotide microarrays. We will also screen for genetic mutations in candidate genes in intervals of segmental aneuploidies and in candidate genes identified molecular cardiac development pathways and through model organism screens in the Cardiac Genetics Consortium using high throughput sequencing and analysis of intragenic deletions/duplications using customized oligonucleotide microarrays. Our long-term goals are to define a set of novel genetic and genomic aberrations important in the etiology of CHD, to characterize new syndromes associated with CHD, and to develop improved methods of clinical genetic diagnostics for CHD. We believe this information will provide more accurate clinical prognostic information that can improve genetic counseling and assist families in accurately determining risk of recurrence and prognosis associated with CHD RELEVANCE (See instructions): As CHD is increasingly diagnosed within the second trimester prenatally and as adults with CHD are living to reproductive age, some of the most critical clinical questions for prospective parents are whether or not the CHD in their family has an underlying genetic basis, quantifying the risk of recurrence, and determining prognosis including predictions of neurological function and systemic disease.

DESCRIPTION (provided by applicant): Our goal is to understand the molecular bases for the control of body weight by using molecular genetic and molecular physiological approaches in humans and rodents. There is growing evidence that multiple genes - each with relatively modest effect on relevant phenotypes such as food intake, energy expenditure, hedonic responses to food - interact with each other, intrauterine and early neonatal development, and the environment, to determine an individual's susceptibility to become obese within a specific environment. Deployment of reciprocal molecular genetic approaches in humans and mice provides a powerful platform by which to identify and characterize these genes. The feasibility of genome-wide association studies (GWAS) utilizing large numbers of subjects (ultimately >100,000), availability of low cost/high throughput sequencing techniques, and access to sophisticated computational approaches, will create a deluge of genes with strong statistical but virtually no physiological insight into the mechanism(s) of action with regard to obesity. Mice - that can be manipulated and studied with a wide repertoire of transgenic, neurophysiologic and bioenergetic techniques - are an optimal resource for delineating the mechanism of action of such genes. We have used these approaches fruitfully in the past, and propose to continue to do so. This proposal has 2 major Aims: 1. To identify new genes mediating the control of body weight in humans;2. To identify the molecular bases for the effects of these genes. Aim 1 will make use of our access to large collections of human subjects (New York Health Project, Yup'ik Eskimos, DNA samples selected from extremes of BMI in the NHANES, and the international GIANT consortium);a prospective study of the effects on body weight with use of second generation antipsychotic medications;and individuals with syndromic and severe, early onset obesities. Using a range of strategies, we will identify new genes for human obesity. Aim 2 will use mice to address the molecular physiology of a recently discovered pair of adjacent genes (FTO/FTM) - and a related transcription factor, CUTL1 - strongly implicated in obesity by three GWAS;and a gene (MGRN1=mahoganoid) recently cloned by us and another group which acts in the MC4R signaling pathway by unknown mechanisms. This Aim will also provide for creation and study of transgenic animals segregating for "designer" alleles of genes identified in the first specific aim. PUBLIC HEALTH RELEVANCE: Obesity is arguably the major health issue - in terms of medical morbidity and costs - now confronting developed and developing nations. Body weight and degree of fatness (adiposity) reflect the interactions of an individual's genes with developmental and environmental factors. This grant is designed to identify the genes responsible for susceptibility to obesity in humans. Success in this endeavor will impact diagnosis, treatment and prevention of obesity and its associated co-morbidities such as diabetes and heart disease.

Project Summary Genetic researchers are rapidly adopting methods of whole exome and whole genome sequencing to identify the hereditary bases for human disease as the cost of sequencing rapidly declines and the pipelines for analysis and databases of normal variation become available and more robust. Although most researchers have focused on particular diseases, comprehensive genome analysis also provides data about susceptibility to hereditary conditions beyond the original study aims. Thus, many incidental genetic findings of potential clinical relevance to research participants could be generated by the use of whole exome or whole genome sequencing. Such incidental results could have immediate implications for conditions that are avoidable and clinically actionable, such as risk of sudden cardiac death or cancer, but could also indicate hereditary predispositions for conditions for which there is no intervention, such as Alzheimer's disease. It is currently unclear whether incidental genetic findings should be offered to research participants and, if so, which ones, whether research participants will want these results, how participants will respond to their disclosure, and what is required of investigators to return results. Our goal is to collect data to address these questions. We will collect qualitative and quantitative data to investigate decision preferences for return of incidental genetic results and potential psychosocial and behavioral consequences of this information in a large sample of research participants (n=360) who have previously enrolled in research studies for specific diseases. A subset of this population (n=180) will have whole exome sequencing to attempt to identify the underlying causes of a specific disease and will be offered the option of receiving other broader genetic results of clinical relevance. Participants will undergo a re-consent process for this study and will be provided with the option of selective, comprehensive, or no return of those incidental genetic results with clinical utility. To document the medical and psychosocial impact of return of results, we will conduct surveys of participants who received incidental whole exome sequencing results at one month and 12 months following the return of results and conduct semi- structured interviews at 12 months after disclosure on a subset of 60 participants who were offered return of results. Additionally, we will conduct semi-structured interviews and collect survey data from researchers with genomic data (n=300) to determine current practices and important considerations with respect to return of incidental results. Collectively, these results will provide a more complete picture of the possible benefits and burdens of return of incidental research results to participants, differential responsibilities of the primary and secondary users of genomic data with varying degrees of access to and connection with the research participants, and the range of possible incidental findings that could be reported and the differential responsibility to report these results based upon the clinical and psychosocial implications.

MBMG Core PROJECT SUMMARY/ABSTRACT The Molecular Biology/Molecular Genetics (MBMG) Core has served the NYORC obesity research community for the past 4 cycles of this grant. The MBMG Core provides critical research support for obesity-related clinical and basic research activities in the area of molecular genetics, bioinformatics, and model organism characterization. The services are widely used and have increased productivity of NORC investigators, while curtailing costs and facilitating access to advanced genomics technologies. The primary objective of this Core is to assist investigators to apply the tools and technologies of molecular genetics and genomics to elucidate the molecular-genetic bases for the pathogenesis and medical/physiological co-morbidities of obesity. The Specific Aims of the MBMG Core are: 1) To facilitate the application of molecular genetics to problems of obesity by providing expert consultation on both study design and applicable molecular biological techniques; 2) To provide standard laboratory services to young investigators and those without formal labs for studies related to obesity; 3) To develop and make available new cutting edge research tools and reagents. To these ends, the MBMG Core offers, among others, consultation and services, including gene expression, DNA extraction, genotyping, DNA and RNA sequencing, bacterial phylogenetic characterization by 16s rRNA, mouse transgenics, stem cell derivation and differentiation, and genome editing with CRISPR Cas9, analytic tools related to these techniques. Core services are of 3 basic types: (i) On-site Direct Services. (ii) Consultative-Collaborative with Institutional Cores. (iii) Consultative-Referral. To gain access to cutting-edge technologies, avoid duplication and to maximally leverage our resources, we collaborate extensively with other local Core facilities and laboratories. Core personnel provide assistance ranging from study design to execution of studies and data interpretation. We particularly emphasize service to young investigators and holders of P&F grants. The Core has been active in developing new research tools and reagents, and has played an essential role in establishing iPS cell technology for our community. Our R&D activities are focused on developing new tools and reagents for brain research and genetic manipulations in cells and model animals. The MBMG Core has been a nexus for intellectual exchange and collaboration, and an important training venue for students, fellows and young faculty. During the past cycle, the Core responded to >3,000 service requests from 34 NORC users supported by 49 grants, in addition to 11 non-ORC members. These services helped investigators generate 35 new grants and 147 publications.

Contact PD/PI: GINSBERG, HENRY N NRSA-Training-001 (406) TL1 Precision Medicine Program Abstract Our goal is to establish the TRANSFORM TL1 Precision Medicine (PM) Program to provide training and mentoring in the methods and applications of PM to pre-docs, post-docs, junior faculty, and a wide range of research personnel. PM is the right treatment for the right patient at the right time; it offers the opportunity to increase effectiveness of health care at reduced cost with improved outcomes, decreased adverse effects, and greater patient satisfaction. Through a suite of innovative programs, we will enhance career development, translational capabilities, and collaborative skills of faculty and research team members from diverse disciplines around the theme of PM. Our goals are to: (i) develop innovative education and career development programs, building on and extending our many successful existing programs, that will build competency in our scholars and trainees to engage in interdisciplinary teamwork, make new discoveries, and translate those discoveries to clinical practice/patient benefit; (ii) demonstrate the effectiveness of those programs through continuous monitoring and assessment for quality improvement, using key metrics to evaluate the impact of our educational programs on research output, career trajectories, and continued engagement in biomedical research; and (iii) To disseminate findings on novel educational delivery approaches, new methods for assessing student learning, and best practices in enhancing interdisciplinary team science skills to our partners at Columbia, the members of the CTSA consortium, and educational programs throughout the nation. Columbia University is a significant contributor, nationally and world-wide, to research in genetics, genomics, data science, phenotyping and risk prediction, biomarker development, and the molecular basis of human disease; as well as to interdisciplinary team science training. These strengths will allow us to offer new and enhanced coursework in PM; create pre-doc and post-doc programs to increase competency in PM; develop short-term training that allows pre-docs to gain facility with PM strategies and methods; and evaluate our educational efforts in an ongoing way to improve programming. In 2013, Columbia's President, Lee Bollinger, announced the University-wide PM Initiative aimed at bringing together all units within Columbia to address the full spectrum of research, education, and implementation sciences in this field. Thus, this is the ideal time to undertake these goals. We are confident we can achieve these goals because of the outstanding CUMC research portfolio, the momentum provided by the new, University-wide PM initiative, our 10+ years of experience in administering successful training and mentoring programs, and the personnel and infrastructure provided by our Irving Institute resources. Through all these means, we are poised to contribute substantially to NIH's goal of building a larger and exceptionally well-prepared biomedical research workforce prepared to advance health through the potential of PM. Project Summary/Abstract Page 1015 Contact PD/PI: GINSBERG, HENRY N NRSA-Training-001 (406) J. Training Core References 1. Levinson DJ. The Seasons of a Man's Life. New York: Alfred A. Knopf, Inc.1978. 363p. 2. Pincus HA, Haviland MG, Dial TH, Hendryx MS. The relationship of postdoctoral research training to current research activities of faculty in academic departments of psychiatry. Am J Psychiatry. 1995 Apr;152(4):596-601. PMID: 7694910. 3. Leibenluft E, Dial TH, Haviland MG, Pincus HA. Sex differences in rank attainment and research activities among academic psychiatrist. Arch Gen Psychiatry. 1993 Nov;50(11):896-904. PMID:8215815. 4. Keyser DJ, Lakoski JM, Lara-Cinisomo S, Schultz DJ, Williams VL, Zellers DF, Pincus HA. Advancing institutional efforts to support research mentorship: a conceptual framework and self-assessment tool. Acad Med. 2008 Mar;83(3):217-25. PMID: 18316865. 5. Pfund C, House SC, Asquith P, Fleming MF, Buhr KA, Burnham EL, Eichenberger Gilmore JM, Huskins WC, McGee R, Schurr K, Shapiro ED, Spencer KC, Sorkness CA. Training mentors of clinical and translational research scholars: a randomized controlled trial. Acad Med. 2014 May;89(5):774-82. PMID: 24667509. 6. Hall KL, Stokols D, Moser RP, Taylor BK, Thornquist MD, Nebeling LC, Ehret CC, Barnett MJ, McTiernan A, Berger NA, Goran MI, Jeffery RW. The collaboration readiness of transdisciplinary research teams and centers: findings from the National Cancer Institute's TREC Year-One evaluation study. Am J Prev Med. 2008 Aug;35(2 Suppl):S161-72. PMCID: PMC3292855. 7. Masse LC, Moser RP, Stokols D, Taylor BK, Marcus SE, Morgan GD, Hall KL, Croyle RT, Trochim WM. Measuring collaboration and transdisciplinary integration in team science. Am J Prev Med. 2008 Aug;35(2 Suppl):S151-60. PMCID: PMC3292855. 8. Porter AL, Cohen AS, Roessner JD, Perreault M. Measuring researcher interdisciplinarity. Scientometrics. 2007 Jul;72(1): 117-47. 9. Greenhaus JH, Parasuraman S, Wormley WM. Effects of race on organizational experiences, job performance evaluations, and career outcomes. Acad Manage J. 1990 Mar;33(1): 64-86. References Cited Page 1016

Project Summary Obesity is an extremely costly health problem, largely unresponsive to current therapeutic and prophylactic measures. Heritability estimates indicate that 30-50% of the likelihood of becoming obese is conveyed by genes, and over 100 genes leading to susceptibility to obesity have been identified in rodents and humans. However, the genes so far identified in the aggregate account for no more than ~5% of this risk. Genome wide association studies for obesity are inherently designed to detect common alleles present in 5% or more of the population. We hypothesize that some or most of the ?missing heritability? for obesity is due to rare variants. In Aim 1 we will sequence the exomes (and possibly entire genomes) of individuals and their families in which severe, early-onset obesity is segregating. Multi-tiered bioinformatics filters and pathway analysis will be used to examine the biological functions, molecular networks, and canonical energy homeostasis pathways represented by the prioritized novel variants. In Aim 2?the implicated genes will be characterized in: 1. hypothalamic neurons (and possibly other cell types) created from somatic cells of affected individuals as compared to their isogenic controls (generated using CRISPR); 2. Mice manipulated by direct injection of candidate gene constructs into the brain and mice segregating for knock-in alleles of the candidate gene. These animals will be studied using sophisticated measures of energy homeostasis and food intake, including studies of hedonic aspects of the quantity and quality of good intake. The stem cell-derived neurons will enable study of the developmental, structural, cellular, biochemical/molecular and functional phenotypes of not otherwise accessible for this type of analysis. Success in generating patient-specific hypothalamic neurons from human iPSCs will create a cellular ?reagent? likely to be extremely useful in molecular physiology and drug discovery. The combining of three elements of analysis: exome sequencing/pathway analysis, iPSC- derived hypothalamic neurons/other cells, and creation of animal models subjected to sophisticated metabolic and behavioral phenotyping provides a powerful platform for the identification of novel molecular mechanisms for human obesity. .

Project Summary Whole exome and whole genome sequencing (WGS) have expanded our ability to determine the genetic etiology of previously undiagnosed disorders. We propose a multicenter prospective cohort study to evaluate the emerging technology of WGS for the management of fetuses with structural anomalies. We hypothesize that a significant subset of fetal structural anomalies has a genetic etiology identifiable by whole genome sequencing (WGS) and that prenatal knowledge of this information will improve perinatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve quality of life for both the child and the family. Our aims are to investigate these multiple aspects of prenatal sequencing in a single study with an innovative integrated prospective design, which will permit a robust evaluation of the benefits and risks of delivering diagnostic and prognostic genetic testing results in a prenatal setting. To certify sufficient funds to accomplish all goals, we have secured significant industry support for the cost of WGS. The study will determine, in a sequential population of women with pregnancies with unselected fetal structural anomalies, the frequency of pathogenic, likely pathogenic, and uncertain genomic variants identifiable by WGS. To determine the impact of this information on clinical care we will prospectively recruit a control population of women with unsequenced pregnancies with similar structural anomalies and follow the infants from both cohorts up to 1 year of age. This study component will evaluate differences in healthcare management and cost. The educational, counseling and psychosocial impact of WGS data during the prenatal period, in the nursery and through 1 year of life will also be evaluated. Since the analytical and clinical tools needed for the full translation of WGS into care are still developing, we will investigate and optimize bioinformatic tools to improve identification of pathogenic and likely pathogenic mutations associated with prenatal phenotypes of established disease genes, as well as identification of new genes associated with presently undiagnosed fetal/neonatal phenotypes. Accomplishing the aims that address our study hypotheses will require the establishment of a tightly integrated team with collective expertise in diagnosis of fetal anomalies, interpretation of WGS data, clinical genetics, cost effectiveness analysis, and ethical, legal and psychosocial outcomes. The assembled team has expertise in each of these areas as well as a track record of prior productive collaboration. This study will provide an in-depth evaluation of the prenatal diagnostic value of WGS prior to its responsible introduction into practice and will provide independent data to guide its translation.

Project Abstract As genomic sequence data are being produced faster and at lower cost, the most significant challenge in clinical genetic testing today is variant classification. Currently, there are marked differences in variant classification among clinical laboratories, with clinically significant discrepancies in 29% of variants interpreted. Variants that were previously categorized as pathogenic are now known to be benign with the increasing availability of more ethnically diverse reference data, and this is issue is more common for individuals of non-European ancestry. At the same time, a substantial percentage of variants are classified as of unknown significance (VUS), with inadequate data to prove or disprove a pathogenic association with a medical condition. Progress in interpreting genomic data, however, will lead to greater agreement on how to call variants that are currently subject to discrepant classifications and the question arises about how will that information about reclassification of variants reach patients and their health care providers. There is currently no definitive guidance from professional organizations or opinion leaders about how to handle variant reclassification, and the field seems uncertain how to respond. Stakeholders including laboratories, providers, patients, and payers likely have different perspectives and opinions. To provide an empirical foundation for this critical discussion and develop guidance for the field, we will conduct a series of activities including focus groups and online surveys with 3 key stakeholder groups: patients, providers, and the laboratories. We will have three working groups to define the legal, ethical, and economic aspects to consider and develop possible solutions. We will host an annual meeting with experts on genetics, clinical laboratory operations, reimbursement, health economists, regulatory and legal issues, and ethics, along with clinicians and patient advocates, to provide guidance for the project, to review the data and develop a set of options and a final set of recommendations to address this issue. We will seek input on possible solutions from stakeholders through an online survey and arrive at final recommendations that we will present to the genomics community and to board of the American College of Medical Genetics and Genomics to guide the adoption of an acceptable and responsible policy in for this rapidly changing area.

CANCER RESEARCH CAREER ENHANCEMENT (CRCE) CORE: SUMMARY The CRCE Core leads, facilitates, and coordinates cancer research education and training. It provides educational opportunities throughout the training pipeline from high school to junior faculty. This is achieved through a rich research environment, numerous training grants, and the conduct of scientific seminars, journal clubs, workshops, networking, and mentoring activities; all part of HICCC membership activities. A new initiative will be the CRCE Core?s emphasis on unique training opportunities in precision medicine and health disparities for basic, clinical, and population scientists. The CRCE Core works with the Community Outreach and Education (COE) Core to ensure that training is focused on enhancing our deep commitment to the HICCC?s catchment area (CA), which is racially, ethnically, and socioeconomically diverse. The CRCE Core coordinates and collaborates with other institutional efforts including Columbia?s NIH Clinical Translation Science Award (CTSA) and the Columbia University Precision Medicine initiative in order to maximize impact while reducing overlap. Wendy K. Chung, MD, PhD leads the CRCE Core, and she is also a member of the Cancer Genomics and Epigenomics (CGE) Program. Chung, Kennedy Family Professor of Pediatrics and Medicine, is a clinical and molecular geneticist who directs the clinical cancer genetics program at Columbia University and has led fellowship programs in molecular and cytogenetics. A CRCE committee and program manager support Chung. As Associate Director of Education and Training in the HICCC, Chung plays critical roles in the strategic plan of the HICCC. The CRCE Core has interrelated Specific Aims that span all training stages and promote patient focused and transdisciplinary, collaborative research. Aim 1: High school and undergraduate students: Provide engaging exposure to cancer research with the HICCC mentors for a diverse community of high school and undergraduate students in New York City. Aim 2: Graduate and health professional students: Provide integrated, interdisciplinary cancer research education, training, and mentoring opportunities for graduate (Master and PhD in the medical, nursing, dental and public health schools) and medical, nursing and dental students. Aim 3: Postgraduate fellows and faculty: Enhance career development for postgraduate trainees and faculty at all levels by supporting continuing education and training, developing critical thinking, grant writing, and presentation skills, and providing mentorship support to mentors and mentees. The CRCE core trains a transdisciplinary workforce, recruits and retains underrepresented minority trainees and faculty, and uses a data-driven approach to develop and refine enduring educational resources across the pipeline of trainees. The CRCE Core facilitates the training of the next generation of cancer researchers for successful careers in diverse settings. Testimony to the equivocal support from the HICCC will be investment of at least $2.4M administrative support ($.5M) from non-CCSG sources.

PROJECT SUMMARY/ABSTRACT Recently, large-scale genome-wide association studies (GWAS) provide evidence for a substantial polygenic contribution to the risk of many common complex diseases. However, most of these studies were performed in Europeans, and new data and methods are necessary to tailor polygenic risk prediction to non-Europeans, to ensure that genomic stratification does not further exacerbate health disparities. The overarching goal of the eMERGE-IV network is to leverage genetic and electronic health record (EHR) data for diverse populations to design, validate and test the clinical utility of ancestry-tailored polygenic risk scores for common diseases. As a current member of the eMERGE network, Columbia University has significantly advanced its goals, having recruited over 2,500 diverse patients for sequencing and return of actionable findings, leading the effort to transition the network to the OMOP Common Data Model to improve the efficiency, accuracy, reproducibility and portability of electronic phenotypes, and contributing a widely-adopted XML parser for structuring genetic test reports. Since our last application, the Columbia Precision Medicine Initiative has also grown and now includes participation in several national initiatives, such as the All-of-Us program, in which we have demonstrated our ability to rapidly recruit patients under-represented in biomedical research. Our scientific expertise combined with our strong tradition of patient-centered research and community engagement in a socioeconomically, racially, and ethnically diverse community of Northern Manhattan, positions us to successfully contribute as the Enhanced Diversity Clinical Site of the eEMERGE-IV network. We will leverage our prior experience with eMERGE, scientific expertise, and knowledge gained from participation in other national precision medicine initiatives to develop, optimize, validate and disseminate ancestry-tailored genomic risk assessment and clinical management tools. In Aim 1, we will continue to advance electronic phenotyping by contributing sharable natural language processing tools for converting clinical text into OMOP-based discrete data and facilitating phenotype interoperability. In Aim 2, we will develop and optimize accurate ancestry-tailored genome-wide polygenic predictors, integrate them with clinical risk predictions, and test their performance in diverse populations. In Aim 3, we will investigate ELSI issues related to the return of health risk predictions to diverse patients by ascertaining patients?, clinicians?, and IRB members? views through focus groups. In Aim 4, we will develop portable EHR plug-ins to facilitate prospective risk communication and management using integrated genomic data, family history, and clinical data. In Aim 5, we will recruit 2,500 diverse patients and use a randomized controlled trial design to assess the impact of return of genomic prediction on the accuracy of risk perception, health surveillance, and risk reducing measures. This proposal will address major knowledge gaps in genetic risk assessment for diverse populations, and the solutions and knowledge gained will be broadly applicable to precision medicine for common complex traits across many clinical specialties.

Project Summary Improvements in the surgical and medical care of children with congenital heart disease (CHD) have increased survival. Among survivors, however, there is a high prevalence and significant long term impact of cognitive and behavioral problems and medical complications including heart failure and problems with growth. We hypothesize that in some cases of CHD, there are genes that have pleiotropic effects on development and function of other systems including the brain. The goal of this study is to determine the genetic contributions to clinical outcomes in individuals with CHD and to begin to use this information in clinical care and to design better clinical trials of treatments for CHD. Through these studies, we will determine major genetic contributors to CHD outcomes, expand the scientific evidence through additional case finding outside of PCGC to increase the number of confirmed CHD genes and clinically characterize these genetic conditions to improve the ability to anticipate and prevent medical problems in those CHD patients. By identifying individuals with pathogenic variants from previous clinical trials, we will determine whether integration of genomic data would improve power and precision for CHD treatment trials by eliminating groups of patients unlikely to respond. All of these efforts are focused on translating the findings from PCGC into clinical care.

Mutations in the human kinesin gene KIF1A cause a variety of neurological defects. This syndrome has remained poorly defined because of the rarity of the condition. This proposal brings together the very different, but highly complementary expertise of Dr. Wendy Chung at Columbia University Medical School, a specialist in human genetic disease; Dr. Richard Vallee, also at Columbia, an expert in the role of Kif1a in neuronal development and physiology; and Dr. Arne Gennerich, at Albert Einstein College of Medicine, an expert in motor protein biophysics. Dr. Chung's lab has developed clinical and computational methods to compile information from patients locally and worldwide on the range, severity, and variety of symptoms associated with this condition, which her lab has termed KAND KIF1A Associated Neurological Disorders. This is a heterogeneous group of severe neurodegenerative conditions, including spastic paraplegia, peripheral neuropathy, optic nerve atrophy, cerebral and cerebellar atrophy, cognitive impairment, and seizures. The condition available. The over-all goals of this project are to obtain sufficient clinical information to understand the full-range of KAND symptoms; to determine how mutations at diverse sites within the Kif1a motor domain impact clinical outcome; to understand the cellular and developmental causes of the syndrome; and to identify small molecule reagents to treat it. Aim 1 will be to define the natural history of KAND based on a rapidly increasing patient database and correlate clinical severity and rate of progression with KIF1A genotype. Aim 2 will be to use advanced single molecule biophysical and in vivo axonal transport approaches to determine the molecular and cellular consequences of the Kif1a mutations. Aim3 will be to use Kif1a mutant mice to determine the longitudinal and cross-sectional effects of the condition in a model organism, and to test more completely the role of BDNF in KAND and the value of small molecule BDNF mimetics as KAND therapeutic agents. These studies are of great importance for a number of reasons. They will dramatically extend our capability to identify and characterize rare diseases. They will provide detailed insight into the molecular basis of a motor protein-associated disease. They will provide extensive new information on the progression of the disease and the relationship of mutation site to prognosis. And, they will take advantage of our new molecular and physiological insights into gene function to develop targeted therapies. can be fatal, and there is at present no treatment