PTD_JAN2014_MAIN. Primary Address

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1 PTD_JAN2014_MAIN Confirmation of Yes Reporting Requirements: Confirmation of Programmatic Requirements. By checking Yes below, you confirm your acceptance of programmatic requirements if you receive a RAPtr yearlong or short-term grant. If your project is funded, you will be notified of the source of your funding in your award letter. First Name Shalini Last Name Dixit Primary Address shalini.dixit@ucsf.edu (must be UCSF ) Date of Birth Sep 21, 1988 Current Mailing 637 Frederick Street Address San Francisco, CA Primary Phone Number (925) Permanent Mailing 20 Brookbank Road Address Orinda, CA Personal dixit.shal@gmail.com Address (permanent) Emergency Contact Rashmi First Name Emergency Contact Dixit Last Name Emergency Contact dixit.rb@gmail.com Address Emergency Contact (925) Phone Number Emergency Contact Mother Relationship To You Gender Female Citizenship US Citizen or US Noncitizen National Are you Hispanic (or No Latino)? Race Asian Disability: Do you have No any physical or mental impairments that limit your life activities? Page 1 of 12

2 Are you from a disadvantaged background? Applicant School School of Medicine Level Expected Date of Graduation/Program Completion Application Type What Pathway are you applying for? I confirm that I have reviewed and agree to complete the above requirements for my Pathway No Medicine SOM3 May 15, 2015 Yearlong Funding Clinical and Translational Research Confirmed If you have already I received funding for a Curriculum Ambassador Project in the summer of applied for and received funding from RAPtr for this project, specify precisely what you have accomplished with your previous support and what you intend to accomplish in the next quarter if you receive this award. Please also list all grants you have received to support research or related experiences during medical school. Type of Project: Check Basic, Biomedical or Clinical and Translational Research the one that best describes your project. If you are doing a curriculum development or advocacy project that also includes hypothesis-driven research, select one of the research options. (Make sure you've reviewed eligibility and funding amounts on the RAPtr website before you make your selections) Is this an international No experience? Project Title Identification of Environmental Influences that Mediate the Association Between European Ancestry and Atrial Fibrillation Page 2 of 12

3 Project Summary: Research, Project, or Trip Plan Summary. Please describe briefly: 1) your objectives or hypothesis, 2) a brief description of your plan, 3) if applicable, its relevance to the field. (max: 250 words) Prior studies have shown that African Americans exhibit significantly less atrial fibrillation (AF) than whites despite the increased incidence of AF risk factors. Furthermore, Dr. Marcus, the primary mentor, has shown that increasing European ancestry within African Americans is an independent risk factor for AF using genetic ancestry informative markers (AIMs) in the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study. Our objective is to determine if particular modifiable environmental exposures, specifically diet, physical activity, smoking, alcohol or socioeconomic status (SES), mediate the association between European ancestry and AF. RESEARCH QUESTION OR HYPOTHESIS: In 300 words or less, describe the specific research question you will undertake and your objectives. For CHS and ARIC, both NIH-funded cohort studies, genotyping has already been performed, and AF has been ascertained by serial electrocardiograms and incident hospitalizations. In addition, Dr. Marcus and his colleagues have already performed the steps necessary to determine the percent European ancestry in all African Americans in both cohorts. First, we will investigate the relationship between environmental exposures as potential mediators between self-identified race (whites or African Americans) and AF; then, as a means to validate significant associations, we will determine if the candidate environmental exposures mediate the association between genotype-derived European ancestry and AF. In each case, we will use a multi-step assessment of each environmental exposure before incorporating potential confounders into a multivariable mediation model in order to identify independent mediators of the European ancestry-af association. If an important mediator can be identified, this may represent an easily modifiable exposure or behavior that could influence the risk of AF in the general population. African Americans exhibit significantly less atrial fibrillation (AF) than whites despite the increased incidence of AF risk factors (1-3). Furthermore, increasing European ancestry within African Americans has been identified as an independent risk factor for AF (4). However, the mechanisms underlying this paradox remain unknown, and understanding those mechanisms may reveal important clues regarding the origins of all AF regardless of race. We therefore seek to determine if particular modifiable environmental exposures mediate the association between European ancestry and AF. Specifically, does diet, physical activity, smoking, alcohol or socioeconomic status (SES) mediate the relationship between European ancestry and AF? If an important mediator can be identified, this may represent an easily modifiable exposure or behavior that could influence the risk of AF in the general population. Page 3 of 12

4 BACKGROUND AND REVIEW OF LITERATURE: In 700 words or less, describe the rationale for your research question through a review of relevant literature and any preliminary studies. AF affects millions of Americans and is growing in incidence and prevalence (5). It causes substantial morbidity, is one of the most common causes of stroke, and nearly doubles mortality (6,7). Though the cause of AF remains largely unknown, several risk factors have been identified including hypertension, heart failure, diabetes, and obesity. Interestingly, although African Americans display more of these risk factors than whites, they have substantially lower rates of AF. Thus far there is no explanation for this paradox; however, understanding the basis of this discrepancy could uncover novel insights into the mechanisms of AF. If we can determine why African Americans have less AF, perhaps we can discover why individuals, regardless of race, are more or less prone to AF independent of established risk factors. As African Americans represent a population of mixed African and European ancestry, the study of genetic ancestry informative markers (AIMs) can be used to help explain observed differences. Ancestryinformative markers are sets of polymorphisms for a particular DNA sequence that appear in substantially different frequencies between populations from different geographical regions of the world. Using AIMs in the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study, Dr. Marcus (the primary mentor) and his colleagues have shown that increasing European ancestry within African Americans is an independent risk factor for AF. Using data from the ARIC and CHS trials, Dr. Marcus performed analyses showing that the risk of AF in Africans Americans increases with increasing European ancestry. In each cohort, African Americans exhibited a significantly lower risk of AF compared to whites. After multivariable adjustment, African Americans had a 40% lower risk of AF (HR 0.60, 95% CI , p<0.001) in CHS and a 56% lower risk of AF (HR 0.44, 95% CI , p=0.001) in ARIC. This is despite the fact that African Americans in both cohorts had a larger average body mass index and more hypertension, diabetes, heart failure, and left ventricular hypertrophy. Dr. Marcus used 1,747 AIMs from the ITMAT- Broad-CARe array (the IBC array ) to estimate the percent European ancestry in 822 African Americans in CHS and 3,517 African Americans in ARIC using the Structure software. In addition, he used 3,192 AIMs on the Affymetrix 6.0 genome-wide genotyping platform to estimate the percent European ancestry in the African Americans in ARIC using the ANCESTRYMAP program. After multivariable adjustment, African Americans in each cohort alone and in a meta-analysis of the two cohorts had a 12-13% higher risk of AF for every 10% increase in European ancestry by the IBC array. Using the Affymetrix 6.0 array, every 10% increase in European ancestry was associated with a 20% increased risk of AF (95% CI , p=0017). For the proposed project, it is important to review how other groups have used the CHS and ARIC data to assess diet, physical activity, smoking, alcohol and SES. The measurements chosen have been rigorously obtained and recorded in each cohort, with data readily available for secondary analyses. Furthermore, high-quality research using these measurements has been published in several peer-reviewed journals (8-11). The measurements are summarized in Table 1. Page 4 of 12 CHS diet assessment was through a 99-item interview-administered food frequency questionnaire (FFQ) in year 1 (12) followed by a 131-item self-administered FFQ in year 5 (13). ARIC diet assessment was through two interviewer-administered, 66-item semi-quantitative FFQs completed approximately six years apart (14).

5 Physical activity in CHS was assessed at baseline and at the 3rd and 7th annual visits using a modified Minnesota Leisure-Time Activities questionnaire. Similarly, in ARIC, physical activity was assessed by a Modified Baecke questionnaire administered at years one and seven (15). Smoking exposure was assessed in CHS and ARIC via questionnaires (16). Self-reported alcohol consumption in CHS and ARIC was ascertained at baseline through an interviewer-administered dietary questionnaire (17,18). Subjects reported the frequency and amount of alcohol consumed both currently and in the past, as well as type of alcohol in ARIC. Socioeconomic status (SES) in CHS was assessed by self-reported level of education, occupation and income (19). Similarly, in ARIC SES was assessed by parental level of education, participant level of education, occupation, and income to create a cumulative SES score (20). Page 5 of 12

6 PROJECT OR RESEARCH PLAN: For the Yearlong Fellowship. In 1000 words or less, discuss your project design including appropriate methods, number and type of subjects, and data analysis. This project is part of a larger study by Dr. Marcus to understand why African Americans have less AF despite having more risk factors. He and his colleagues are currently 1) performing an admixture mapping scan to identify potentially novel genetic associations with AF and 2) examining whether differences in left atrial structure identified by echocardiography explain why more European ancestry leads to more AF. The current proposed project will attempt to identify factors aside from genetics and left atrial changes that are potential mediators between European ancestry and AF, using comprehensive data already available on thousands of cohort study participants. The focus will be on diet, physical activity, socioeconomic status, smoking and alcohol. Even if parallel investigations into genetics and/or atrial size are positive, these additional environmental analyses will be important to determine if more than one process is occurring, if there are gene-environment interactions, and potentially to better understand causal relationships (e.g. does a particular dietary component lead to more AF via an increase in left atrial size?). Basic characteristics of the cohorts to be utilized are shown in Table 2. Differences according to European Ancestry will be assessed in two ways. First, self-identified whites will be compared to self-identified African Americans. Previous studies have shown that self-identified whites have = 95% European ancestry (23), while African Americans typically have a mean 70-80% African ancestry (Figure 1). Therefore, comparisons by self-identified race are useful. Furthermore, the observation that self-identified African Americans have less AF has been consistent across multiple studies. Second, when possible, among African Americans alone, covariates will be compared to the degree of European ancestry determined by data from the genome-wide arrays using the program ADMIXTURE. This approach takes advantage of nearly all of the single nucleotide polymorphisms (SNPs) on the arrays rather than relying only on pre-selected AIMs, providing a more powerful method for estimating European ancestry. Figure 1 illustrates that in selfidentified African Americans, the degree of European ancestry takes on a nearly normal and quite wide distribution, facilitating the power to detect associations among African Americans. Page 6 of 12 Though we will pursue associations based on biological plausibility and previous literature, such as the potential protective effect of fish consumption against AF (26), one of the primary goals of this project is to reveal new causal pathways. Thus, we plan to make several comparisons within the categories of diet, physical activity, socioeconomic status, smoking, and alcohol use. We will use the race/european ancestry association to implement an algorithm with multistep criteria (Figure 2). First, measurements examined as an outcome (such as amount of a particular dietary component or amount of a certain type of physical activity) must be significantly different between African Americans and whites and associated with European ancestry in African Americans. In Step 2, the measurement now as a predictor must be associated with incident AF either as a time varying (or instantaneous ) covariate, or, if relevant, as a cumulative covariate. In Step 3, that measurement will then be tested for mediation between self-identified race and incident AF and between increasing European ancestry within African Americans and incident AF. In Step 4, covariates fulfilling all of these criteria as well as potential confounders will be added to a multivariable mediation model in order to identify independent mediators of the European ancestry-af association. Of note, while Dr. Marcus is formally trained in epidemiology and biostatistics and can guide me through the majority of these analyses, Dr. Charles McCulloch, head of

7 PROJECT TIMELINE: for the Yearlong Fellowship: Develop a timeline including projected completion of preparations (including animal and human subjects protocol approvals); travel; preliminary studies; data collection; data analysis; write-up. the Biostatistics Division of the Department of Epidemiology and Biostatistics at UCSF and consultant on this project, will assist in performing the more complex analyses. In keeping with the studies referenced in the literature review, we will break diet into food categories and nutrient intake, calculate weekly alcohol intake and cigarette years, and also assess physical activity by leisure-time activity, exercise intensity, and walking habits. With regards to SES, we will look at education level, assessed as greater than or equal to twelve years of education, median annual income, and urban versus suburban or rural residence. As serial food frequency questionnaires, physical activity, smoking, alcohol, and SES information are available on nearly all participants, we expect to have sufficient power to detect differences that would be clinically relevant. For example, using CHS (the smaller cohort) to derive conservative power calculations and assuming a standard deviation in alcohol consumption of 40 g/week (27), we estimate that we will be able to detect a difference of 2 g/week change for every 10% increase in European ancestry in 800 African Americans, assuming power of 0.80 and a twotailed alpha of In mediation analysis, using a two-tailed alpha of 0.05 and assuming 120 incident AF cases among CHS African Americans only, we anticipate we will have 80% power to detect a hazard ratio of 1.1 per standard deviation of alcohol consumption for every 10% increase in European ancestry as a mediator of incident AF. This project will be realizable within the time frame of one year, given that we already have approval from both CHS and ARIC to perform these analyses and that, as part of grants previously awarded to Dr. Marcus, we already have the data sets to perform these analyses. Furthermore, Dr. Marcus and his colleagues have already performed the analyses necessary to determine the percent European ancestry in all African Americans in both cohorts. Finally, Dr. Marcus has published multiple peer-reviewed manuscripts using both CHS and ARIC data primarily with mentees as first author, which gives us both confidence that this work can lead to a successful manuscript. -Data cleaning and organization: 1 month -Diet analyses: 2 months -Physical activity analyses: 2 months -Socioeconomic status and habits analyses: 2 months -Validation analyses: 1 month -European ancestry analyses: 1 month -Final mediation analysis: 1 month -Abstract and manuscript preparation: 2 months Page 7 of 12

8 PERSONAL STATEMENT: 700 words or less, please explain why you want to do research or undertake this project. I would like to pursue a career in academic medicine that includes elements of patient care, teaching, and research. Through my rotations I am gaining the clinical skills that will carry me on to residency. From high school, college, a Fulbright teaching fellowship, and a UCSF curriculum ambassador project, I have acquired substantial teaching and curriculum development experience. Lastly, in college I gained a glimpse into the world of research that has inspired me to now take on new research endeavors. While at Northwestern University, I led weekly biology workshops for undergraduate students, as well as worked at a laboratory science camp for children. In the year prior to medical school, I was awarded a Fulbright scholarship to teach English to adolescents at a public school in Madrid. This experience allowed me to hone my teaching skills over a full year and gave me practice in lesson planning and classroom problem solving. Then, the summer after first year, I pursued a project to revise the UCSF School of Medicine tobacco cessation curriculum. This involved assessing how tobacco cessation is taught in medical schools across the country, deciding what knowledge is crucial for medical students to learn, and devising a more innovative learning platform. In the end, the final product was a series of video-based online modules that will be used by our medical students, other health professions students, and eventually by other schools and the general public. My prior research was in basic science, where I spent two summers in Dr. Mary Nakamura s laboratory at UCSF assisting with research examining the role of membrane-associated signaling adapters LAT and LAB in normal osteoclastogenesis. This experience was an invaluable introduction to research and allowed me to develop laboratory skills that would aid me in my undergraduate studies. However, I quickly realized that my research interests were more geared towards the clinical and translational realm, where the results can be more readily applied to clinical practice. At this point in my training, I need more hands-on experience in the design, implementation, and statistical interpretation of research. In addition to participating in the research project described in this application, I plan to enroll in the Advanced Training in Clinical Research program in order to develop a strong foundation in epidemiology, biostatistics, and study design that will pave the way for a more successful research year and future career. Our project examining the association between atrial fibrillation (AF) and European ancestry fits closely with my interests both prior to medical school and going forward. In college, I majored in molecular biology and genetics and was especially fascinated by medical genomics. In medical school, I have been drawn to the field of internal medicine, especially cardiology, and would like to gain a better understanding of the clinical and research aspects of this discipline. This particular research would allow me to combine my interests in genomics and clinical cardiology while serving as a stepping-stone for acquiring statistical knowledge and skills. Page 8 of 12 Furthermore, AF is a condition that has perplexed me since the first year of medical school. Though I came to identify its appearance on electrocardiogram and know the drugs with which to treat it, I was frustrated by not understanding what caused it. On my internal medicine and neurology rotations, I was surprised by the frequency of AF in the hospitalized population and by the serious consequences of both untreated AF and of the anticoagulants we give patients with this affliction.

9 Related Coursework. Please list any preparatory coursework you have or will have completed by your project start date I am confident that this particular project and this mentor will provide me with a rewarding year. Dr. Marcus has mentored past students and fellows undergoing the ATCR program and is therefore aware of the specific coursework and how to help students take full advantage of the training. In addition, because the data sets are already populated, I will have sufficient time to struggle with these complex, multi-faceted analyses while learning new techniques in study design and biostatistics. Having ready data will also allow me time to draft abstracts and manuscripts for submission to national meetings and peer-reviewed manuscripts. I am excited and hopeful about this opportunity to step out of the hospital and delve into research on a specific and pertinent topic. From my undergraduate education, an introduction to statistics course as well as several courses in genetics will be of benefit to me. With regards to medical school, the coursework in epidemiology, biostatistics, and cardiology from the first two years have been excellent preparation, as well as my more recent internal medicine rotation. Page 9 of 12

10 Literature Cited: Not to exceed 700 words or approximately one single-spaced page Page 10 of Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. Jama 2001;285: Alonso A, Agarwal SK, Soliman EZ, Ambrose M, Chamberlain AM, Prineas RJ, Folsom AR. Incidence of atrial fibrillation in whites and African-Americans: the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J 2009;158: Marcus GM, Olgin JE, Whooley M, Vittinghoff E, Stone KL, Mehra R, Hulley SB, Schiller NB. Racial differences in atrial fibrillation prevalence and left atrial size. Am J Med 2010;123:375 e Marcus GM, Alonso A, Peralta CA, Lettre G, Vittinghoff E, Lubitz SA, Fox ER, Levitzky YS, Mehra R, Kerr KF, Deo R, Sotoodehnia N, Akylbekova M, Ellinor PT, Paltoo DN, Soliman EZ, Benjamin EJ, Heckbert SR. European Ancestry as a Risk Factor for Atrial Fibrillation in African Americans. Circulation 2010;122: Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol. 2009;104: Fuster V, Ryden LE, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary. J Am Coll Cardiol 2006;48: Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol 2001;37: Mozaffarian D, Furberg CD, Psaty BM, Siscovick D. Physical Activity and Incidence of Atrial Fibrillation in Older Adults: The Cardiovascular Health Study. Circulation 2008; 118(8): Nettleton JA, Steffen LM, Loehr LR, Rosamond WD, Folsom AR. Incident Heart Failure Is Associated with Lower Whole-Grain Intake and Greater High-Fat Dairy and Egg Intake in the Atherosclerosis Risk in Communities (ARIC) Study. Journal of the American Dietetic Association 2008; 108(11): Volcik KA, Ballantyne CM, Fuchs FD, Sharrett AR, Boerwinkle E. Relationship of alcohol consumption and type of alcoholic beverage consumed with plasma lipid levels: differences between Whites and African Americans of the ARIC study. Annals of Epidemiology 2008; 18(2): Carson AP, Rose KM, Catellier DJ, et al. Cumulative socioeconomic status across the life course and subclinical atherosclerosis. Ann Epidemiol 2007;17: Kumanyika S, Tell GS, Shemanski L, Polak J, Savage PJ. Eating patterns of community-dwelling older adults: the Cardiovascular Health Study. Ann Epidemiol1994;4: Feskanich D, Rimm EB, Giovannucci EL, et al. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. J Am Diet Assoc 1993;93: Steffen LM, Jacobs DR, Jr., Stevens J, Shahar E, Carithers T, Folsom AR. Associations of whole-grain, refined-grain, and fruit and vegetable consumption with risks of all-cause mortality and incident coronary artery disease and ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 2003;78: Richardson MT, Ainsworth BE, Wu HC, Jacobs DR, Jr., Leon AS. Ability of the Atherosclerosis Risk in Communities (ARIC)/Baecke Questionnaire to assess leisure-time physical activity. Int J Epidemiol 1995;24: Zhang L, Samet J, Caffo B, Punjabi NM. Cigarette smoking and nocturnal sleep architecture. Am J Epidemiol 2006;164:

11 Human Subjects Protections: Does your project require CHR approval? 17. Mukamal KJ, Psaty BM, Rautaharju PM, et al. Alcohol consumption and risk and prognosis of atrial fibrillation among older adults: the Cardiovascular Health Study. Am Heart J 2007;153: Eigenbrodt ML, Mosley TH, Jr., Hutchinson RG, Watson RL, Chambless LE, Szklo M. Alcohol consumption with age: a cross-sectional and longitudinal study of the Atherosclerosis Risk in Communities (ARIC) study, Am J Epidemiol 2001;153: Peralta CA, Ziv E, Katz R, et al. African ancestry, socioeconomic status, and kidney function in elderly African Americans: a genetic admixture analysis. J Am Soc Nephrol 2006;17: Chichlowska KL, Rose KM, Diez-Roux AV, Golden SH, McNeill AM, Heiss G. Life course socioeconomic conditions and metabolic syndrome in adults: the Atherosclerosis Risk in Communities (ARIC) 21. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. American journal of epidemiology 1989;129: Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA, Kuller LH, Manolio TA, Mittelmark MB, Newman A, et al. The Cardiovascular Health Study: design and rationale. Annals of epidemiology 1991;1: Halder I, Yang BZ, Kranzler HR, Stein MB, Shriver MD, Gelernter J. Measurement of admixture proportions and description of admixture structure in different U.S. populations. Hum Mutat 2009;30: Marcus GM, Alonso A, Peralta CA, Lettre G, Vittinghoff E, Lubitz SA, Fox ER, Levitzky YS, Mehra R, Kerr KF, Deo R, Sotoodehnia N, Akylbekova M, Ellinor PT, Paltoo DN, Soliman EZ, Benjamin EJ, Heckbert SR. European Ancestry as a Risk Factor for Atrial Fibrillation in African Americans. Circulation 2010;122: Keating BJ, Tischfield S, et al. Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PloS one 2008;3:e Mozaffarian D, Psaty BM, Rimm EB, Lemaitre RN, Burke GL, Lyles MF, Lefkowitz D, Siscovick DS. Fish intake and risk of incident atrial fibrillation. Circulation 2004;110: Eigenbrodt ML, Mosley TH et al. Alcohol consumption with age: a cross-sectional and longitudinal study of the Atherosclerosis Risk in Communities (ARIC) study, Am J Epidemiol 2001;153: No Describe briefly why The cohort data have already been collected, and given that the data is you believe your project all de-identified, the CHR no longer reviews these research proposals. does not require CHR approval. IRB/CHR Policy I understand that if I don't have IRB/CHR approval in place by the beginning of my research/project, I am liable to lose my funding. UCSF Primary Project Greg or Research Mentor First Name UCSF Primary Project Marcus or Research Mentor Last Name Primary UCSF Project marcusg@medicine.ucsf.edu or Research Mentor Page 11 of 12

12 Mentor Institutional Affiliation Mentor Department Secondary Mentor Institutional Affiliation Confirmation I have read the eligibility criteria for the PROF-PATH program and would like to be considered for PROFPATH funding Letter of Reference #1 (must be PDF) Letter of Reference #2 (must be PDF) Transcripts (must be PDF) Figures (optional-must be PDF) Medicine Cardiology Medicine By checking this box, I confirm that I have notified my mentor(s) of their responsibility to submit their endorsement by 5:00 on the application deadline. See information at the beginning of this survey for submission instructions No dation_jms.pdf dation_mn.pdf pdf Page 12 of 12