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NHLBI

Decoding the Future of Precision Medicine SPECIAL FOCUS TOPMed: Trans-Omics for Precision Medicine

SPECIAL REPORT


TOPMed: Decoding the Future of Precision Medicine One of the most exciting areas of medicine to emerge in the last decade is precision medicine, an approach to disease prevention and treatment that considers the unique genes and environment of each patient. The ultimate goal of precision medicine? To provide the right treatment, at the right time, tailored to a patient’s individual needs. The National Heart, Lung, and Blood Institute (NHLBI) has been at the forefront of this new field, supporting scientists and contributing to the evidence base that will one day be used to deliver precision medicine in clinical settings. Our Institute-wide Trans-Omics for Precision Medicine (TOPMed) initiative is one of the largest initiatives of its kind and has as its goal the generation of scientific resources that will enhance our understanding of the fundamental biological processes underlying heart, lung, blood, and sleep (HLBS) disorders. Its focus on ethnic diversity is one of its greatest strengths. In fact, TOPMed’s efforts to increase racial and ethnic diversity in the program have been more successful than any other large research endeavor to date. This ensures that the research findings we have can be translated to all patients, not just those with European ancestry. Research on all racial/ethnic groups is important to ensure that all groups can receive the benefits of precision medicine, especially since some genetic variants may only appear in some groups and not in others. “TOPMed has the greatest ethnic diversity of any genetic study to date,” says James G. Wilson, MD, chair and principal investigator for TOPMed. “It includes substantial numbers of participants with African, European, Hispanic/Latino, Asian, and Pacific Islands ancestry, and the resulting data will allow us to explore health and disease in a much larger proportion of the world’s population than has previously been possible.” TOPMed contributes to the future of precision medicine through the integration of whole genome sequencing (WGS) and other –omics data (e.g., metabolic profiles, protein and RNA expression patterns) with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program seeks to uncover factors that increase or decrease the risk of disease, identify subtypes of disease, and develop more targeted and personalized treatments. In fact, since 2007, genome-wide association studies (GWAS) have identified more than one thousand genomic regions associated with HLBS diseases.


TOPMed

TOPMed Lexicon EXOME: a tiny fraction of the entire genome (1-2%)

formed by exons, the sequences which when transcribed remain within the mature RNA after introns are removed by RNA splicing EXON: a segment of a DNA or RNA molecule containing

information coding for a protein or peptide sequence GENOME: the complete set of genes or genetic material

present in a cell or organism INTRON: a segment of a DNA or RNA molecule that does

not code for proteins and interrupts the sequence of genes METABOLITE: a substance formed in or necessary

for metabolism OMICS: the suffix ‘-omics’ has been added to the names

of many fields to denote studies undertaken on a large or genome-wide scale to analyze the interactions of biological information objects in various ‘omes, e.g. proteome, metabolome. TRANS-OMICS: Trans-omic analysis is a technology

for reconstructing a global biochemical network by connecting multi-omic layers.

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TOPMed complements the activities of the National Institutes of Health (NIH) All of Us Research Program, a key component of the Precision Medicine Initiative. By sharing data and technical advice with our partners, we will not only stimulate research, but we will also get the help we need to tackle short- and long-term technical issues related to sequencing standardization, large dataset storage and access, and data commons and pilot cloud computing design. Through TOPMed, researchers now have the ability to explore genomic regions more easily because of advances in DNA sequencing and the resulting lower cost of WGS. Sequencing studies can reveal critical genetic variants, and follow-up investigations can characterize the variants’ biological functions and evaluate the variants’ clinical implications. As these studies proceed, new technologies are changing health care: mobile technologies have created new ways to monitor health, and electronic health records and cloud computing are enabling large-scale studies. The emergence of this wealth of patient-derived data and genomic information represents an unprecedented opportunity to translate genomic research into clinical practice as the NHLBI community transitions toward precision medicine for HLBS disorders. In recent years, genetic research of complex disease using GWAS and exome-sequencing approaches has resulted in an unprecedented explosion of genetic discovery. However, a large portion of heritability in complex diseases remains elusive. That’s why the Whole Genome Sequencing project is a major part of TOPMed. WGS will provide a comprehensive view of the genome, an opportunity to further understand the genetic architecture relevant to HLBS disorders, and an unprecedented resource to the scientific community. The current TOPMed project studies have a variety of study designs including family, case-control, pharmacogenomic, population cohort, founder populations, and clinical studies. We’re doing this with the help of a wide-ranging consortium of centers that support program activities such as data coordination, informatics research, whole-genome sequencing, RNA sequencing, and metabolite and methylation profiling. Two of these centers, the Data Coordination Center and the Informatics Research Center, serve the entire TOPMed program. There are multiple participating sequencing centers, with the

TOPMed by the numbers Through its first three phases, TOPMed has sequenced: • 59 studies • 783 investigators • 120,000 WGS

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TOPMed

Broad Institute of MIT and Harvard being one of the primary sites. It provides largescale whole-genome sequencing of 20,000 people along with data to support smaller transcriptome sequencing pilots and metabolite profiling. Baylor is another large provider of WGS data for TOPMed—and successfully weathered Hurricane Harvey without any loss of TOPMed samples. How NHLBI plans to grow its TOPMed program

In the coming years, NHLBI plans to expand the TOPMed program in several ways: • Grow the WGS project even further, possibly sequencing over 120,000 individual genomes. • Generate -omics data to complement the WGS project and accelerate the pace of discovery • Develop and apply new methods for data access and analysis. • Use the TOPMed program to stimulate research and improve clinical care As this effort expands, we will look for ways to include more underrepresented groups and HLBS disorders beyond what is currently in the WGS research portfolio, and we also will look for opportunities to integrate WGS and other -omics data with clinical data.

How TOPMed supports HBLS Research • Discovers molecular biomarkers that increase or decrease the risk of HLBS disorders. • Explores how environmental factors interact with genes to preserve health or contribute to our understanding of HLBS disorders. • Identifies potential drug targets. • Redefines HLBS disorders or subtypes of these disorders based on molecular signatures instead of current tissue/ organ-based approaches to medicine. • Enables clinical trials to test treatments in a targeted way, such as in patients with specific genetic markers identified in the WGS project, to help develop personalized interventions. • Accelerates systems medicine and emerging precision medicine to predict, prevent, diagnose and treat HLBS disorders based on a patient’s unique genes, environment and molecular signatures. • Increases the inclusion and representation of understudied minority populations in biomedical research, such as African Americans or Hispanics/Latinos.”

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Promising TOPMed Data Analysis Projects TOPMed is one of the most diverse and broad-reaching genetic research programs to date. Here are some of the program’s most exciting data analysis projects from leading universities and institutes around the country.

Wh SEU

Whole-genome

TANIKA KELLY, M

Tropical Medicin

Whole-genome sequencing

AMANDA SEYERLE, PHD — Divi

Community Health, Universit BRANDON COOMBES, PHD —

Whole genome allelic determinants of s

PRADEEP NATARAJAN, MD, MMSC — Director

at Massachusetts General Hospital

GINA PELOSO, PHD — School of Public Heal

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TOPMed

Computational pipeline for whole-genome analysis of complex traits HAN CHEN, PHD — School of Biomedical Informatics, University of Texas Health Science Center at Houston JENNIFER HUFFMAN, PHD — Research Scientist at the Center for Population Genomics, Boston;

VA Healthcare System

Pulmonary function and COPD ANI MANICHAIKUL, PHD — Center for Public Health Genomics MICHAEL CHO, PHD — Brigham and Women’s Hospital

Relations of mitochondrial genetic variation with cardiometabolic disease JESSICA FETTERMAN, PHD — Cardiovascular Institute (Whitaker),

Boston University School of Medicine

hole-genome sequencing for atrial fibrillation and EKG traits NG HOAN CHOI — Broad Institute

sequencing of blood pressure-related traits

MPH, PHD — School of Public Health and

ne, Tulane University

of venous thromboembolism traits

ision of Epidemiology and y of Minnesotaw Mayo Clinic

evere dyslipidemia

r of Preventive Cardiology

lth, Boston University

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TOPMed Principal Investigator Profiles

James. G. Wilson, MD Chair and Principal Investigator, TOPMed Director, Mississippi Center for Clinical and Translational Research Professor, The University of Mississippi Medical Center

What originally got you interested in genetics research?

As a postdoctoral fellow my research was focused on immunology, working in the complement system with a set of proteins designed to recognize and to help destroy

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foreign organisms and tissues that come in contact with blood. At that time, the sequence of a protein’s gene could only be studied if the gene was “cloned;” that is, isolated and produced in large amounts in the laboratory. The laboratory where I worked, which was led by Professor Doug Fearon, cloned several of these proteins, and I found that a specific variation in the gene of one of the proteins was strongly correlated with how much of the protein was expressed on the surface of red blood cells. I did this by analyzing the genetic change in what was then a large number of individuals, about 100. Because of this initial finding I became interested in how genetic variation affects biologic traits across the human population. When I moved back to my home state of Mississippi, I became interested in genetic factors that affect the health of African Americans. During this same period, methods of genetic analysis accelerated rapidly, so that now, instead of analyzing one genetic change in 100 or so people, we can analyze every nucleotide (the structural units of DNA) in the genomes of tens of thousands of people. This is truly remarkable because each person’s genome has more than 3 billion nucleotides. In the TOPMed project, we have already detected variation in about 200 million of these nucleotides. As chair of TOPMed, what has been most personally exciting for you in terms of the findings or work to come out of the program?

In addition to TOPMed having the greatest ethnic diversity of any genetic study to date, several features of TOPMed are particularly exciting. One has to do with the functional regions of the genome. About 1 to 2 percent of the genome carries the structural information used to synthesize proteins, whereas much of the rest regulates how much of each protein is produced and determines how and when production of a particular


TOPMed Principal Investigator Profiles

“TOPMed has the greatest ethnic diversity of any genetic study to date.”

protein is turned on or off in specific tissues and at specific stages of development. The TOPMed project will provide the deepest exploration of variation in this “regulatory” DNA ever achieved. Finally, in addition to substitutions at single nucleotides, people differ from each other by larger DNA changes called “structural variants,” where regions ranging from a few nucleotides to whole genes or even large regions have been either deleted or are present in multiple copies. Whole genome sequence analysis in TOPMed will provide the first comprehensive analysis of structural variation across the entire genome and in a large number of people. Structural variants undoubtedly affect many biologic traits, and we will be able to analyze these effects in great depth. Though we are just beginning to correlate our genetic findings with biologic traits, we have already found evidence, for example, of certain genetic variants that affect the risk of kidney disease and stroke in some African Americans.

are used to identify and filter out false sequencing signals and optimize true signals, as well as to make sequencing as uniform as possible across numerous groups of samples that are being sequenced in at least six different laboratories. Statistical methods are also used to analyze the evidence for structural variants, which are more difficult to detect than single nucleotide changes. After the best possible sequence is produced for each individual, the next challenge is assessing the correlation between genetic variants and biologic traits. Often the effects of individual genetic changes are subtle, and many people must be compared to be confident that a particular variant is associated with a specific trait. These analyses also require statistical methods to adjust for the effects of ancestry and of family relationships among the people being analyzed. Finally, the computational challenges are daunting. The computer files associated with the sequence data are so large that just transferring them from one storage site to another can be challenging, and the storage costs can be substantial. For this reason, it won’t be practical to keep the entire data set at multiple sites, so we are having to develop new models to store and analyze the data through large, controlled-access computing platforms that can be used by many scientists. I am happy to report that so far we have addressed all of these challenges successfully and are making rapid progress.

What’s been the greatest challenge your team has encountered with TOPMed?

There are many significant challenges, including major logistical, statistical and computational hurdles. The logistical challenges involve collecting, tracking, and sequencing the DNA of now nearly 100,000 people, correctly labeling and storing the resulting data files, and connecting them to the large number of biologic traits that have been measured in each DNA donor. We must also ensure that every analysis is performed in accordance with the consent of each DNA donor. The statistical challenges begin with analyzing the raw sequence data from the TOPMed sequencing laboratories to produce genetic sequences that are as nearly error-free as possible. Statistical approaches

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What do you think is the greatest potential of precision medicine?

What role do you anticipate the NHLBI will play in the evolution of precision medicine?

The goal of precision medicine is to treat each person with the medication(s) (including nutritional and behavioral approaches) that will be most effective for their specific condition, with the fewest adverse side effects. This can only be done by dissecting out the many pathways that can lead to human disease and then detecting, by genetic testing, which pathway(s) may be contributing to disease in each person. By identifying biologic pathways that lead to disease, we will also be able to find drug targets by which we can specifically affect those pathways. So the first big payoff will be in new drugs, followed quickly by an ability to predict which drugs will work best in which patients.

NHLBI has assumed a strong leadership role in the development of precision medicine. In addition to having made a decisive commitment by supporting the TOPMed program, the NHLBI portfolio covers many of the diseases that have the highest public health impact, particularly in developed countries. Without question, the contribution of NHLBI to precision medicine will be immense.

Could you share your thoughts on key ethical, legal, and social issues in TOPMed in particular and personalized medicine in general?

The greatest challenges in TOPMed and in personalized medicine will be determining how to share genetic data with each person. How much does each person want to know (this varies from person to person)? What about findings that predict a terrible disease for which there is no cure, but that could affect a person’s decisions about having children? What about unexpected information regarding paternity? How much responsibility do researchers or health care providers have for helping people understand every significant finding in their genome, and where would the resources come from for this sort of in-depth genetic counseling? How much information is too much? When important new discoveries are made, is there a responsibility to review existing genetic data and contact patients or study participants to discuss the implications? These are very hard questions, but an important starting point may be deciding, with each person, how to approach these questions before genetic testing is performed. Obviously, however, we are past this point in TOPMed and will have to decide how to proceed from where we are.

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What advice would you have for a medical student who’s interested in research?

First, focus on your schoolwork. The grades and standardized test scores you get will determine which opportunities are open to you after you get your degree. Second, focus on the areas that excite you the most and be confident about approaching leaders who work in those areas to discuss your interests and explore opportunities. Choose a residency program at a place with a strong research program overall. When it is time for you to begin your research training — usually during fellowship, though there may be research opportunities during medical school and residency — be very deliberate in choosing a research training program. Does the person leading the research group you are considering have a strong record of publication? Has he or she been successful in getting research grants from the NIH and other sources? Do they have a reputation for fairness and integrity? Do they have a good record of training successful investigators? Are the people who are working with them now happy and are they publishing successfully? It is important to choose wisely. You will be committing several years of your life and strongly influencing the rest of it. Research is hard, but it can be immensely rewarding. One of the most amazing feelings you can have is to be the first person on earth to know a new fact that is important to human health.


TOPMed Principal Investigator Profiles

and this alone could transform our understanding of human genetics. I also like the culture of sharing among the investigators and the focus on encouraging young investigators to take the lead. What’s been the greatest challenge your team has encountered with TOPMed?

The scale of the project! Anytime you’re taking on a project as vast as this there is much to learn and many mistakes to be made along the way.

Debbie Nickerson, PhD Professor of Genome Sciences Adjunct Professor of Bioengineering University of Washington

What originally got you interested in genetics research?

It started at the beginning: with the development of the polymerase chain reaction (PCR), which unlocked our ability to explore human genetics and analyze the human genome. What has been most personally exciting for you in terms of the findings or work to come out of your center for TOPMed?

The scale of the project. It is one of the largest human genetics studies that has ever been undertaken and focuses on common heart, lung, and blood diseases. The diversity of the samples being studied is unparalleled,

“The impact of precision medicine will be unprecedented.”

What do you think is the greatest potential of precision medicine?

Its impact will be unprecedented because we will have access to nearly all the information needed to understand the genetic factors that mediate disease and disease risk. To me, its greatest impact will be in understanding the full complement of variants that can impact our drug responsiveness, but there will be many other findings! Could you share your thoughts on key ethical, legal, and social issues in TOPMed in particular and personalized medicine in general?

The diversity of the samples is unparalleled and will open so many avenues for understanding personalized medicine in the entire US population. What role do you anticipate the NHLBI will play in the evolution of precision medicine?

Heart, lung, and blood diseases are among the most common in the population, and understanding the role of genetics in the evolution of these diseases has the potential to provide diagnostic and/or treatment avenues that could be not only individual-based, but also preventative. What advice would you have for a medical student who’s interested in research?

Never give up — research is so rewarding! You might never find the answer you are looking for, but there are so many other important things you will learn in your quest. 9


Research Supplements to Promote Diversity in Health-Related Research The Diversity Research Supplements enable principal investigators with eligible NHLBI research grants and contracts to support individuals from backgrounds underrepresented in biomedical science, including individuals from underrepresented racial and ethnic groups, individuals with disabilities, individuals from disadvantaged backgrounds and individuals who wish to re-enter research careers, on their research projects. Research supplements are available for individuals from the high school to the junior faculty level.

For program information: http://www.nhlbi.nih.gov/ research/training/application-guidelines.htm

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Research Supplement Awardees

What are you working on now?

I am leading the largest whole-genome sequencing project on bronchodilator drug response in children with asthma in the country to date. This is an important project because asthma is the most common chronic disease in children worldwide, and bronchodilator drugs, such as Albuterol, are the first line of treatment regardless of disease severity. There is a great deal of inter-individual variation in response to bronchodilator drugs among children, particularly in Puerto Rican and African American children who exhibit the lowest drug response. This fact is made more poignant because it is also these two populations that exhibit the highest asthma morbidity and mortality rates in the country. What are the most exciting aspects of the research you’ve done to date?

Marquitta White Postdoctoral Scholar Department of Medicine UCSF School of Medicine

What originally got you interested in research?

My undergraduate major was biology (pre-med), and after graduation, I planned to go to medical school to become a clinician. After taking the MCAT and beginning my secondary applications to several schools, I was invited by my molecular biology professor to work in his laboratory as a research volunteer. His work focused on the molecular mechanisms involved with prostate cancer, a disease that disproportionately affects African American men in the United States. I became really interested in research after this experience and took advantage of the NIH-sponsored MARC/RISE program to continue my research experience until I graduated. After graduation, I realized that I could effect positive changes in disease research and healthcare on a population level if I continued my involvement with research.

The most exciting aspects of the research that I have done to date have been the studies that I have done in cancer, hypertension and asthma that center on finding the environmental and genetic factors that play a role in drug response or adverse reactions to medication. I feel these studies will be the easiest to translate directly from the research lab to the clinical setting, and it is really satisfying to know that the work that I am doing has the potential to improve patient care.

“It is really satisfying to know that the work that I am doing has the potential to improve patient care.� 11


What are you working on now?

Keith Diaz, PhD Associate Research Scientist Columbia University Medical Center Department of Medicine Division of Cardiology

What originally got you interested in research?

As a graduate student, I had the opportunity to volunteer as an RA for an NHLBI-funded R01 study (PI: Dr. Michael Brown) that was examining the effects of aerobic exercise on the health of blood vessels in African Americans. As an exercise physiology major with aspirations to do clinical work in a cardiac rehabilitation setting, this exposure opened my eyes to the importance of scientific research for informing health practitioners and for creating clinical guidelines on how to prescribe healthful doses of exercise. I had an amazing mentor who fostered my scientific curiosity and provided me many opportunities to conduct research as well as attend and present at conferences. These experiences sparked a love for the science of exercise (and its health benefits), which led me to pursue a career in scientific research.

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My research focuses on the role of prolonged sedentary behavior in the pathogenesis of cardiovascular disease, with a specific focus of iteratively optimizing feasible, sustainable and cost-effective guidelines for reducing prolonged sitting. My current NHLBI-funded R01 project is a prospective cohort study evaluating prolonged sedentary behavior as a prognostic risk factor for recurring events or early death after a cardiac event. This information is vital for determining whether secondary prevention guidelines for cardiac patients should be modified to promote reductions in sedentary behavior independent from — and in addition to — exercise. What are the most exciting aspects of the research you’ve done to date?

Despite the increasing recognition that “sitting is the new smoking,” little is known about how to reduce the health risks incurred by prolonged sedentary behavior. Specifically, it is unclear whether individuals should target reducing their total sedentary time (for example, replacing one hour of their day with physical activity) or interrupting their prolonged sedentary bouts (for example, standing up and walking around for every 30 minutes of sitting) to reduce health risk. I recently published a paper in Annals of Internal Medicine wherein I analyzed data from a national cohort of over 8,000 adults and found that the total amount of sedentary time and the accumulation of sedentary time in prolonged bouts are synergistically associated with risk of death. That is, sitting for large amounts of time (for example, 11 hours) and sitting for long periods of time without moving (sitting for 60 or 90 minutes straight) in combination is linked to the greatest risk for dying. These findings highlight the importance of the total volume of sedentary time and its accumulation in prolonged, uninterrupted bouts as important health risk behaviors for which future physical activity guidelines that explicitly endorse both (1) reductions in sedentary time and (2) interruptions of prolonged sedentary bouts may be warranted.


Research Supplement Awardees

How has the NHLBI supplement you received helped you?

I have been the fortunate recipient of three diversity supplements: predoctoral, postdoctoral and investigatorlevel supplements. The funds provided by the supplement program have permitted me protected research time at every stage of my career, allowing me to dedicate 100 percent effort to my program of research. Further, the funds have permitted me to collect critical pilot data needed for the submission (and ultimate funding) of my first R01 application. These pilot data will also be used to support my future R01 applications. Finally, the training that I received from my mentors as part of the supplement program has helped me develop expertise in exercise-related research. Thus, the supplement program has been pivotal to my academic career and played a pivotal role in my transition to becoming an independent investigator.

What would be your advice to a med student who’s interested in having research be a part of his or her career?

Choose well. When deciding on what laboratory or researcher to volunteer or work for, do not base your decisions on how many grants or high-impact journal publications they have. Choose someone who looks after young scientists and is committed to their scientific and personal development. Do your homework on whether past trainees have had opportunities to publish or present their work.

“The supplement program has played a pivotal role in my transition to becoming an independent investigator.� 13


research was critical to our understanding of what the issues really were so inequities can be acknowledged and changes could be made. This also laid the groundwork for my master’s program research at North Carolina Central University and ultimately my PhD training in the Social and Personality Psychology program at the City University of New York, which passionately embraces and trains researchers with an unapologetic social justice commitment. What are you working on now?

Danielle L. Beatty Moody, Ph.D. Assistant Professor Department of Psychology University of Maryland Baltimore County

What originally got you interested in research?

As an undergraduate at North Carolina State University, I had a series of experiences that opened my eyes to the fact that an individual’s social strata shapes and determines their opportunities, decisions and even health. These experiences led me to pursue a study abroad opportunity; I spent 6 weeks towards the end of my undergraduate training in Ghana, West Africa, which showed me the importance of always considering the intergenerational processes and sociohistorical contexts of health and led me to start asking questions about the experiences of underrepresented and historically marginalized groups. This experience also clarified my decision to seek a PhD and not a JD; I felt that the 14

As a tenure-track junior professor, I am currently funded by a 5-year NIA K01 Career Development Award. My work seeks to elucidate the role of social determinants, which may underscore the earlier onset and more aggressive profile of cardiovascular and cerebrovascular disease among African Americans. During my threeyear postdoctoral fellowship in the NHLBI-funded T32 Cardiovascular Behavioral Medicine Training Program at the University of Pittsburgh (UPitt), I began to consider whether the application of a lifespanprocesses framework would help us understand the earlier onset of disease burden in African Americans. To that end, my current career award is permitting me to develop expertise in the role of early life social disadvantage in cardiovascular health, with emphasis on cerebrovascular endpoints. We have been collecting Magnetic Resonance Imaging data on communitydwelling middle-aged adults, which will allow us to better understand linkages between early life factors and brain health that may be emerging well before clinical disease or symptoms are observed. In turn, this may shed light on factors contributing to the earlier onset of poorer brain health observed in African Americans. What are the most exciting aspects of the research you’ve done to date?

Honestly, all this work has been an honor to conduct and is completely exciting to me! But the first thing that comes to mind is when I was at UPitt. I examined whether there was a linkage between exposure to everyday discrimination and ambulatory blood pressure (ABP) among adolescents (Beatty & Matthews,


Research Supplement Awardees

2009). It was surprising that not only did we observe an association, but it was most pronounced in African American adolescents from lower socioeconomic status (SES) backgrounds compared to African American adolescents from higher SES backgrounds or to White peers (irrespective of their SES). Specifically, African American adolescents with lower SES who reported greater everyday discrimination had higher ABP. These findings suggested that exposure to discrimination in interpersonal interactions in the context of more limited resources could contribute to this emerging disparate observation in African American adolescents. It was exciting because it seems plausible that these earlier experiences and challenges might account for the earlier onset we see in hypertension, but saddening because it appears that the combination of poorer treatment and fewer resources are harmful for their health, setting them on a trajectory that may not yield a positive end. Another exciting finding is my recent research into whether everyday discrimination was associated with incident metabolic syndrome (MetS) in a sample of racially/ethnically diverse women using data from the Study of Women’s Health Across the Nation (Beatty Moody, Chang, Brown, Bromberger, & Matthews, in press). Everyday discrimination exposure at baseline predicted a 33 percent increased incidence of MetS; was pronounced in Black, Hispanic, and Japanese women; and was independent of traditional risk factors. This finding was exciting because no prior studies have examined this linkage in the U.S. and it’s important because it raises the question of what are the pathways which account for these findings? Future work should

“Leverage is a critical tool for our work and the supplement taught me the value of it.”

begin to more concretely engage the implications of intergenerational transmission of exposure to adversity and inequity. How has the NHLBI supplement you received helped you?

The NHLBI Diversity Supplement provided me with access to a community of intellectual and passionate researchers, allowed me to understand the value of leveraging resources through collaboration and posi­ tioned me in a network of mentors, which is perhaps the most invaluable resource you can have as an emerging scholar. It’s shaped my trajectory and positioned me to be ready for new opportunities in three major ways: Access: The supplement provided me the access I needed to train under a sage, intellectually thoughtful and wonderful mentor (and now collaborator), Dr. Elizabeth Brondolo. It was awesome because when I contacted her and explained the mechanism to her, she immediately agreed and then asked me if I would help her also develop a Diversity Supplement application for another predoctoral trainee in her lab; we were both funded. Leverage: Leverage is really a critical tool for our work and the NHLBI Diversity Supplement taught me the value of it. I had a research question that I wanted to explore: Does racism impact hypertension

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risk among racial and ethnic minorities, and is racial identity protective? As a graduate student, acquiring the equipment, monies and other necessary resources to conduct this study, while staying on a feasible timeline towards graduation, may have been overly ambitious, if not impossible. The Diversity Supplement allowed me to come in, help with data collection and add a measure that would assess racial identity. I gained so much more from this experience with Dr. Brondolo than I would’ve gained on my own and on a very feasible timeline. Resources: The NHLBI Diversity Supplement pro­ vided resources that were vital to my development, including benefits like health care. I was able to quit other jobs and just focus on my training. I was able to present my research at national and international conferences. I was also able to purchase materials such as books and other equipment to facilitate my training. Perhaps most importantly, you could also say it provided me with access to resources in the form of a diverse network of mentors. For example, Dr. Helena Mishoe at NHLBI has been a wonderful mentor to me for over a decade, and I so value her support on both professional and research development.

Rodney Britt, PhD Research Fellow, Pediatric Lung Disease Mayo Clinic

What do you think is the importance of supporting underrepresented minorities in conducting research?

The questions we ask as researchers are often informed by observations we have made of the world and how it is or is not working. Where we are in the social strata can determine our “lens” or acuity to issues and patterns. Thus, the richness of the questions we pursue answers to is really going to be as rich as the representation of those doing the asking. We are limited when we limit our engagement of those who are from historically marginalized backgrounds. If we are truly committed to answers that will help us elucidate the issues and identify viable solutions, this requires us to be committed to training and supporting those who can shed a different light on what the problems are to begin with.

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What originally got you interested in research?

In college, I had projects that involved understanding the pharmacological properties of Ambien, a drug used for insomnia, and I also learned about prions that lead to neurodegeneration. This was the first time I examined human disease and therapeutics in depth. While working on these projects, I started to appreciate the underlying pathophysiology and complexity of human disease, leading me to pursue a career in biomedical research.


Research Supplement Awardees

What are you working on now?

My research interests lie in understanding how perinatal factors such as prematurity, allergens, and infection adversely affect the neonatal and pediatric lung. Many of these factors are known to contribute to development of wheezing and asthma in children. Presently, my research is focused on understanding how inflammation instigated by allergens and infection promotes corticosteroid resistance in pediatric asthma. We are using both in vitro and in vivo models to define mechanisms involved in corticosteroid resistance and to assess novel therapeutic strategies to improve corticosteroid sensitivity and alleviate asthmatic symptoms. What are the most exciting aspects of the research you’ve done to date?

My research has involved several aspects of cellular and molecular biology, including lung development and physiology, lipid biology, immunology, and redox biology. It’s been exciting to apply my interdisciplinary skill set and expertise toward understanding underlying mechanisms of pediatric lung disease. Additionally, I’ve enjoyed the opportunity to work and interact with physician-scientists while performing research at Nationwide Children’s Hospital and Mayo Clinic. I think it’s also exciting to be part of the discovery and preclinical phase that generates basic knowledge for development of novel therapies.

“When you consider a career in research, follow your own passion and interests.”

How has the NHLBI supplement you received helped you?

The support I’ve received from NHLBI has been pivotal for my training, maturation and success as a scientist. The NHLBI supplement provided support for me to continue my postdoctoral training and submit my K99/R00 Pathway to Independence application. The supplement also allowed me to further develop new technical skills and continue my professional development. I achieved the goals outlined in the supplement, such as my K99 application recently awarded, and I feel highly competitive for tenure-track faculty positions. What would be your advice to a med student who’s interested in having research be a part of his or her career?

There are several important things to consider for starting a career in research. Most importantly, follow your own passion and interests. Second, you should develop an ability to advocate for yourself and seek out advice and mentorship from peers and established researchers. Finally, persevere, whether it’s a thesis, grant, or manuscript — stay with it.

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Biomedical Research Training Program for Individuals from Underrepresented Groups The NHLBI established the Biomedical Research Training Program for Individuals from Underrepresented Groups (BRTPUG) to offer opportunities for underrepresented post-baccalaureate individuals to receive training in basic, translational and clinical research. The purpose of the program is to enhance career opportunities in biomedical sciences, including clinical and laboratory medicine, epidemiology and biostatistics as applied to the etiology and treatment of heart, blood vessel, lung and blood diseases. BRTPUG offers each participant the opportunity to work closely with leading research scientists in the Division of Intramural Research and extramural scientists in the Division of Cardiovascular Sciences–Prevention and Population Sciences Program. The program provides participants with hands-on training in a research environment, which will prepare them to continue their studies and advance their careers in clinical and basic research.

For program information: https://brtpug.nhlbi.nih.gov/

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Biomedical Research Training Program

How has your internship helped you?

Anderson Watson Cheyney University of Pennsylvania

How did you become interested in research?

It began during my years as an adolescent when I would experience a very sharp, stabbing pain in my chest, which is still to this day undiagnosed. Having gone through the stress of having to go from doctor to doctor and endure test after test, I developed sympathy for families going through similar situations. This unique experience also piqued my interest in research as a way to answer medical questions that would otherwise be left unknown.

This internship here at the NHLBI has helped me in ways that cannot be described. It begins with Dr. Mishoe, Director, Office of Research Training and Minority Health, who has gone above and beyond to ensure that I am comfortable and able to access all resources available. I was lucky enough to be placed in a Lab with some of the brightest and kindest people at NIH, who work as a united team rather than simply as individuals. My mentor Dr. Mark Levin, MD, and Principal Investigator, Dr. Beth Kozel, MD, PhD, have been some of the most influential presences in my career thus far. They have proven to me that performing research, having a medical practice, and maintaining a healthy relationship with family is far from impossible. They are extremely devoted to helping me achieve both my professional and personal goals. They have pro­­­vided me with the knowledge to master various techniques in the lab, all while allowing me to take time to attend lectures of interest and even take a class to help better prepare myself for the MCAT. Over the duration of my internship, I have encountered numerous obstacles, but with the help of the some of the great people at the NHLBI, I have yet to be defeated. I feel as though with this experience and networking, I am more prepared than I would have ever believed for my future endeavors.

How did you learn about the Biomedical Research Training Program for Individuals from Underrepresented Groups supported by the NHLBI?

The summer of my junior year at college, I accepted an internship at the University of Delaware, and my program advisor there introduced me to this incredible opportunity at the NHLBI. Because she was an alumnus of my alma mater, I felt comfortable asking some more in-depth and personal questions than I would have otherwise. With her and my college advisor’s extremely positive remarks toward the program, as well as my own personal research, I discovered this incredible opportunity.

“I am more prepared than I would have ever believed for my future endeavors.” 19


How did you become interested in research?

I first learned about biomedical research as a senior student at Morristown High School where I was a part of the UMDNJ Biomedical Research Honors Program. I learned much about research during my time as an honors student and I was able to understand the role that research plays in medicine. This experience fueled my interest not only in medicine, but also biomedical research. During college, I participated in research by joining NIH summer research programs. It was the culmination of these experiences that lead me to apply to the BRTPUG. How did you learn about the Biomedical Research Training Program for Individuals from Underrepresented Groups supported by the NHLBI?

Mahogany Oldham Malone University

“Through my internship, I was able to grow personally, professionally and academically.” 20

During my junior year of college, I presented my research from Brown University at the Annual Biomedical Research Conference for Minority Students (ABRCMS). It was here where I learned to communicate to other professional scientists and to share my research with students just like myself across the country. My participation with ABCRMS allowed me to network and meet leaders of research across the United States. At ABCRMS, I met the director of the BRTPUG and was encouraged to apply to the program. How has your internship helped you?

My internship has helped me to prepare for my future endeavors in many ways. Besides conducting cutting edge research at the world’s largest institution, I was able to grow personally, professionally and academically. The NIH serves as teaching institute for all levels of education and the outcome from being a fellow here is learning to be challenged to grow as a scientist and as a young professional. I have made lifelong connections here with fellow trainees as well as principal investigators. My gap year at the NIH was productive and necessary for my growth and transition into the medical field.


Biomedical Research Training Program

“It was through this internship that I decided to pursue a career in both medicine and research.”

How did you become interested in research?

My interest in research was sparked during the Summer Medical and Dental Education program at the University of Louisville in which I was exposed to the clinic. This opportunity helped me realize the key role research plays in the pursuit of treatments for diseases. It was through this experience that I decided to pursue a career in both medicine and research.

Christian Bradley Howard University

How did you learn about the Biomedical Research Training Program for Individuals from Underrepresented Groups supported by the NHLBI?

During my senior year at Howard University, I attended an informational session in the Biology Department that focused on research opportunities. I spent time comparing various post-baccalaureate programs and decided this program met all the criteria I would need for a meaningful research experience: dedicated mentorship, innovative collaborations and successful career counseling.

How has your internship helped you?

Since the beginning of my fellowship, I’ve gained great mentors, learned laboratory techniques, and further developed problem-solving skills that are essential to having a successful research experience. With the support of my mentors and colleagues, I took a lead role on my research project from planning to execution. I’ve learned to overcome challenges during the experiment process by troubleshooting unexpected problems. In addition, I’ve been fortunate to meet amazing people who share common medical and research interests in classes, seminars and meetings. Most importantly, my career goals have been supported by my mentor, Dr. Sawa Ito, and Principle Investigator, Dr. A. John Barrett. Overall, BRTPUG has afforded me the opportunity to develop my professional and personal skills. I am grateful to be able to witness and contribute to research and medicine that benefits all.

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Research Training and Career Development Programs The NHLBI supports training and career development programs to prepare individuals to become productive researchers in the prevention and treatment of heart, lung and blood diseases and sleep disorders. The following is a list of some of the research training and career development opportunities at the NIH and NHLBI-funded institutions. NIH Undergraduate Scholarship Program

Offers competitive scholarships and research training at the NIH to exceptional students from disadvantaged backgrounds who are committed to biomedical, behavioral and social science research careers. NIH Summer Internship Program in Biomedical Research

Open to high school through the graduate-level students, as well as medical and dental students with strong research interest demonstrated through coursework. Research training takes place at NHLBI laboratories for eight weeks or more during the summer. NIH Postbaccalaureate Intramural Research Training Award (IRTA) Fellowship

Supports one year of research training at the NHLBI for college graduates, within two years of graduation, who have plans to attend graduate or medical school immediately following the fellowship. Students apply to medical school or graduate school during the training period. Biomedical Research Training Program for Individuals from Underrepresented Groups

Offers opportunities for underrepresented post-baccalaureate individuals to receive training in basic, translational and clinical research. The purpose of the program is to enhance career opportunities in biomedical sciences, including clinical and laboratory

The NHLBI supports training and career development programs to prepare individuals to become productive researchers in the prevention and treatment of heart, lung, and blood diseases and sleep disorders.

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Research Training and Career Development Programs

medicine, epidemiology and biostatistics as applied to the etiology and treatment of heart, blood vessel, lung and blood diseases. Awardees work closely with leading research scientists in the Division of Intramural Research and extramural scientists in the Division of Cardiovascular Sciences – Prevention and Population Sciences Program. The program provides participants with hands-on training in a research environment, which will prepare them to continue their studies and advance their careers in clinical and basic research. For program information: http://www.nhlbi.nih.gov/research/training/programs/biomedtrain-underrepresented-groups Short-Term Research Education Program to Increase Diversity in Health-Related Research (R25)

Promotes diversity in health-related research by providing short-term support to undergraduate and health-professional students from diverse backgrounds. NIH NRSA for Individual Predoctoral MD/PhD or Other Dual-Doctoral Degree Fellowship (Parent F30)

The NHLBI supports individual predoctoral fellowships for combined MD/PhD training in research areas relevant to the mission of the NHLBI. NIH NRSA Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research (Parent F31 Diversity)

Supports individuals from backgrounds underrepresented in biomedical science, including individuals from underrepresented racial and ethnic groups, individuals with disabilities, and individuals from disadvantaged backgrounds enrolled in programs leading to a PhD, MD/PhD or other combined degree in the biomedical or behavioral sciences. NIH NRSA Individual Predoctoral Fellowship (Parent F31)

Supports predoctoral students in obtaining individualized mentored research training from outstanding faculty sponsors while conducting dissertation research. T32 Training Program for Institutions That Promote Diversity

This program provides training to predoctoral and health professional students and individuals in postdoctoral training at institutions with an institutional mission focused on serving health disparity populations not well represented in scientific research, or institutions that have been identified by federal legislation as having an institutional mission focused on these populations, with the potential to develop meritorious training programs in cardiovascular, pulmonary and hematologic diseases, and sleep disorders. The NHLBI’s T32 Training Program for Institutions That Promote Diversity is designed to expand the capability for biomedical research by providing grant support to institutions that have developed successful programs that promote diversity and serve health disparity populations and that offer doctoral degrees in the health professions or in health-related sciences.

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Loan Repayment Programs (LRP)

Information regarding the eligibility requirements and benefits for these programs may be obtained through the LRP website: www.lrp.nih.gov/. K-Award Series for Career Development

Provides research development opportunities for basic and clinical research scientists with varying levels of research experience who are committed to developing into independent investigators. http://grants.nih.gov/training/careerdevelopmentawards.htm Mentored Career Development Award to Promote Faculty Diversity in Biomedical Research (K01)

Supports investigators from diverse backgrounds underrepresented in research areas of interest to the NHLBI. It is targeted toward individuals whose basic, clinical and translational research interests are grounded in the advanced methods and experimental approaches needed to solve problems related to cardiovascular, pulmonary and hematologic diseases and sleep disorders in the general and health disparities populations. This program provides research development opportunities for non-tenured science faculty from diverse backgrounds underrepresented in research areas of interest to the NHLBI. The award will enable suitable faculty members holding doctoral degrees, such as the PhD, MD, DO, DVM or an equivalent, to undertake special study and supervised research under a mentor who is an accomplished investigator in the research area proposed and has experience in developing independent investigators. Mentored Research Scientist Development Award (Parent K01)

Supports individuals who have a research or health-professional doctoral degree and provides “protected time� (3-5 years) for an intensive, supervised career development experience. The candidate’s proposed research project must be relevant to the mission of the NHLBI and must be focused on one or more target areas specified by the NHLBI. Mentored Clinical Scientist Research Career Development Award (Parent K08)

Supports postdoctoral individuals and junior faculty members who undertake three to five years of mentored research. Candidates must have clinical doctoral degrees or equivalent and a professional license to practice in the United States. NHLBI Career Transition Award for Intramural Fellows (K22)

Provides highly qualified postdoctoral fellows with an opportunity to receive mentored research experience in the NHLBI Division of Intramural Research and to facilitate their successful transition to an extramural institution as new investigators. Mentored Patient-Oriented Research Career Development Award (Parent K23)

Provides support for the career development of investigators who have made a commitment to focus their research endeavors on patient-oriented research. This mechanism provides 24


Research Training and Career Development Programs

support for a 3 year minimum up to a 5 year period of supervised study and research for clinically trained professionals who have the potential to develop into productive clinical investigators. Mentored Quantitative Research Career Development Award (Parent K25)

Provides research and career development opportunities for scientists and engineers with little or no biomedical or behavioral research experience who are committed to establishing themselves in careers as independent biomedical or behavioral investigators. Examples of quantitative scientific and technical backgrounds outside of biology and medicine considered appropriate for this award include, but are not limited to: mathematics, statistics, computer science, informatics, physics, chemistry and engineering. This mechanism is intended for research-oriented investigators from the postdoctoral level to the level of senior faculty. Small Grant Program for NHLBI K01/K08/K23 Recipients (R03)

This program is for current or recently completed NHLBI K01, K08 and K23 awardees for grant support to expand their current research objectives or to branch out to a study that resulted from the research conducted under the K award. The R03 grant mechanism supports different types of projects, including pilot and feasibility studies; secondary analysis of existing data; small, self-contained research projects; development of research methodology; and development of new research technology. For current and previous K23 awardees, research proposed in the R03 application may or may not include patientoriented research. The R03 is, therefore, intended to support research projects that can be carried out in a short period of time with limited resources and that provide preliminary data to support a subsequent R01, or equivalent, application. Research Supplements to Promote Diversity in Health-Related Research

Enables principal investigators with eligible NHLBI research grants and contracts to support individuals from backgrounds underrepresented in biomedical science, including individuals from underrepresented racial and ethnic groups, individuals with disabilities, individuals from disadvantaged backgrounds and individuals who wish to re-enter research careers, on their research projects. Research supplements are available for individuals from the high school to the junior faculty level. For NHLBI program information: http://www. nhlbi.nih.gov/research/training/application-guidelines.htm

For Additional Information on NHLBI Training Programs: NHLBI Research Training and Career Development: http://www.nhlbi.nih.gov/research/training NHLBI Intramural Office of Education: http://www.nhlbi.nih.gov/research/intramural NIH Intramural Research and Training Opportunities: www.training.nih.gov

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NHLBI Special Report Editorial Contributions National Heart, Lung, and Blood Institute Dr. Helena O. Mishoe Dr. Cashell Jaquish Dr. Mollie Minear Dr. George Papanicolaou Helen Cox

Contacts for NHLBI Programs For academic institutions: Giuseppe Pintucci, PhD National Heart, Lung, and Blood Institute Phone: (301) 827-7969 Email: pintuccig@mail.nih.gov The NIH Campus, Bethesda, MD: Herbert Geller, PhD National Heart, Lung, and Blood Institute Phone: (301) 451-9440 Email: gellerh@nhlbi.nih.gov Jessica H. Chertow, PhD National Heart, Lung, and Blood Institute Phone: (301) 435-1859 Email: jessica.chertow@nih.gov

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NHLBI Precision Medicine Special Report  

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