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The Dallas Heart Study

The Dallas Heart Study. Donald W. Reynolds Cardiovascular Clinical Research Center. Amit Khera, MD, MSc. 1980. 1986. 1992. 1998. Ethnic Gap in Heart Disease Deaths in Dallas County. Deaths from Heart Disease. African-American men. African-American women. per 100,000. Caucasian men.

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The Dallas Heart Study

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  1. The Dallas Heart Study Donald W. Reynolds Cardiovascular Clinical Research Center Amit Khera, MD, MSc

  2. 1980 1986 1992 1998 Ethnic Gap in Heart Disease Deaths in Dallas County Deaths from Heart Disease African-American men African-American women per 100,000 Caucasian men Caucasian women CDC Wonder, 2002

  3. Translational Research Basic Science Discoveries -Cardiomyocyte differentiation - Cardiac development - Lipid metabolism - Human genetics Clinical Science Discoveries Dallas Heart Study Prevention and Rx of Heart Disease

  4. The Dallas Heart Study The Human Biology Laboratory Exquisite Phenotyping + Extensive Genotyping + Genetic Diversity FOCUS ON LOCAL EXPERTISE

  5. inclusive representative Community Advisory Board Reverend Zan Holmes Richard Meyers Elizabeth Flores-Velasquez Rubin Esquivel Myra Hollins Dallas Heart Study - 2000 Community Sample Years 1-5 Dallas County Prevention & Treatment Ethics Committee Tom Mayo Al Silva Fred Grinnell Years 5-10

  6. Dallas Heart Study- Sampling Probability- based sample n = 15,000 addresses 10 Geographic Strata

  7. Distribution of Participant Homes: Visit 1 Dallas County UT Southwestern Black White Hispanic Other

  8. Three Phases ofthe DHS Phase 1: n = 6,000 HOME Ages 30-65; 50% African American Phase 2 : n = 3,400 HOME - Blood and urine samples Phase 3 : n = 3,000 - Imaging studies UTSWMC

  9. Visit 1: In-Home Survey n= 6101 (18-65 years) 50%: African-American 50%: women • Structured interview • Blood pressure X 5 • Weight DuWayne Willett Patrice Vaeth Computer-assisted interveiw

  10. Visit 2: Home Phlebotomy n= 3,398 (30-65 y) • Blood pressure X 5 • Serum • Plasma • Urine • Genomic DNA • Lymphocytes

  11. Visit 3: Clinic Tests n = 2,971 (30-65 y) DXA EBCT MRI Coronary Ca++ Cardiac size/function Aortic compliance Abdominal fat Liver fat: 1H-MRS Fat distribution Bone density

  12. DHS: Critical Design Features • Multiethnic: identification of race-specific variants • Single site: availability of families • Extensive phenotyping: provides insights into • - mechanism of action • - feasibility as drug target • - safety concerns • Scientific focus: local expertise

  13. Community Relations & Ethics Center for Biostatistics & Clinical Science Dallas Heart Study Clinical specimen lab Data & Cohort Manage- ment Integrated relational database Imaging & analysis CV Clinical trials Human genetics lab

  14. MODULE 1: PERSONAL HISTORY/SOCIODEMOGRAPHICS MODULE 2: FAMILY HISTORY MODULE 3: MEDICAL HISTORY: ATHEROSCLEROTIC HEART DISEASE MODULE 4: HEART DISEASE BELIEFS MODULE 5: MEDICAL HISTORY: DYSLIPIDEMIA MODULE 6: HIGH CHOLESTEROL BELIEFS MODULE 7: MEDICAL HISTORY: DIABETES MODULE 8: DIABETES BELIEFS MODULE 9: MEDICAL HISTORY: HIGH BLOOD PRESSURE/HYPERTENSION MODULE 10: HIGH BLOOD PRESSURE/HYPERTENSION BELIEFS MODULE 11: WOMEN’S HEALTH MODULE 12: SYMPTOMS MODULE 13: COMORBID CONDITIONS/GENERAL HEALTH MODULE 14: HEALTH CARE ACCESS AND UTILIZATION MODULE 15: PHYSICAL ACTIVITY MODULE 16: WEIGHT HISTORY MODULE 17: DRINKING PATTERNS MODULE 18: TOBACCO USE MODULE 19: SOCIAL SUPPORT MODULE 20: ACCULTURATION MODULE 21: NEIGHBORHOOD QUESTIONNAIRE MODULE 22: DISCRIMINATION MODULE 23: INCOME/SOCIOECONOMICS MODULE 24: BLOOD PRESSURE AND PULSE MEASUREMENT MODULE 25: HEIGHT & WEIGHT MEASUREMENT DHS Survey

  15. Major DHS Phenotypes Imaging Coronary Ca++ Cardiac MRI (structure/fnct) Aortic Plaque Aortic Compliance Abdominal MRI Pelvic MRI Proton MRS liver DXA (fat, BMD) EKG Plasma Lipid levels (noncholesterol sterols) Lipoproteins ApoB Lipoprotein sizes (NMR) Chem 20 Insulin/leptin CRP Troponin T ANP, BNP Oxidized LDL Lp(a) Apo(a) isoforms CD40 ANA FSH/LH/Testosterone… Urine Microalbumin Electrolytes, Cr

  16. Sequencing & Genotyping in the Dallas Heart Study 1. Sequencing extremes: LDL: 12 lipid genes: high (>95%) & low (<5%) LDL >32 men + >32 women (both blacks +whites) HDL: 6 genes Fatty liver: 6 genes Triglycerides: 6 genes 2. SNP and haplotype analysis ~ 10,000 SNPs in 146 lipid genes in entire DHS 3. Nonsynonoymous SNPs in genome ~ 10,000 SNPs in entire DHS

  17. Return to DHS: 2007-2009 Convert to a Longitudinal Study Repeat Imaging and Blood Measures Progression of Disease Focus on Prevention 2005 2006 2007 2008 2009 10/04 6 7 8 9 10 Year Imaging Workgroup DHS-2 Pilot / Validation Aims Defined Outside Review Final Protocols

  18. Return to DHS DHS 2 DHS 1 Updated Survey Survey Blood samples Blood samples EKG EKG ABI Clinical Outcomes

  19. Return to DHS- Imaging DHS 2 DHS 1 Cor Ca++ EBCT Cor Ca++ MDCT Aorta 1.5 T MRI Aorta 3 T MRI Cardiac 1.5 T MRI Cardiac 3 T MRI

  20. Potential Collaborations Coordination of phenotyping • Imaging • Other new phenotypes Replication studies • Genetic association • Biomarkers

  21. Dallas Heart Study INVESTIGATORS ADMINISTRATION Cardiology James de Lemos Mark Drazner Amit Khera Darren McGuire Ronald Victor Genetics Jonathan Cohen Helen Hobbs Imaging Ronald Peshock Lipids/Metabolism Scott Grundy Gloria Vega Other Richard Auchus Wanpen Vongpatanasin Patrice Vaeth Biostatistics David Leonard Director Helen Hobbs Project Manager Donald Hammons Cohort Management Teresa Eversole Database DuWayne Willett Mereeja Varghese www.ReynoldsCenters.org

  22. Postal Addresses in Dallas County n=841,943 23,518 residential PO Boxes 5,402 not geocoded 1,046 multidrop addresses 962 in census tracts with n<50 Step 1. Selection of address sample Addresses on Sampling Frame n=811,015 Stratified Random Sample of Addresses n=15,088 1,308 refusals 913 not available 336 other 219 access denied Step 2. Address screening Successfully Screened Addresses n=12,312 (81.6%) 2,517 no eligible resident 1,165 vacant Screened and Eligible Addresses n=8,630 Step 3. Selection of eligible subjects 807 not selected 147 no longer at address 48 incapable 25 ineligible 10 language barrier 6 incarcerated 1 deceased Sampled Subjects n=7,823 Eligible for Interview n=7,586 1,001 refusals 417 not available 67 other Step 4. Interviews Completed Interview n=6,101 (80.4%) 1,576 ages 18-29 Eligible for Phlebotomy and Clinic n=4,525 Step 5. Phlebotomy 1,127 non-participants Completed Phlebotomy Visit n=3,398 (75.1%) Step 6. Clinic 427 non-participants Completed Clinic Visit n=2,971 (87.4%)

  23. Survey Sample Design Sampled Addresses 15,000 U.S. Postal Service Lists (over-sampled AA census tracts) 12,000 Occupied Residences 8,500 Screening Completed Ages 18-65 (over-sampled AA participants) 6,000 Household Interview Ages 18-65

  24. Stratified Random Sample: 15,088 Steps 2 & 3: Address & Subject Selection 219 access denied 893 never home 356 other 1308 refusal 2776 not screened Successfully Screened Addresses: 12,312 1218 vacant 2462 no one eligible Screened and Eligible Addresses: 8630 807 not selected Eligible Subjects (18-65Y): 7823 425 unavailable 147 moved 6 incarcerated 1 deceased 25 ineligible 58 in capable 10 language barrier 1001 refusal Step 4: Interviews 1722 non- participants Completed Interviews: 6101

  25. Completed Interviews (18-65Y): 6101 1576: Ages 18-29Y Eligible for Phlebotomy & Clinic (30-65Y): 4525 Step 5: Phlebotomy Blacks: 75% 1127 non participants Others: 85% Completed Phlebotomy Visits: 3398 Blacks: 85% Step 6: Clinic 427 non participants Others: 92% Completed Clinic Visits: 2971

  26. Electron Beam Computer Tomography (EBCT) Heart Low Coronary artery Moderate High Ron Peshock Aorta Coronary arteries Coronary calcium Indicates the amount of atherosclerosis in the coronary arteries

  27. Normal Hypertrophy Magnetic Resonance Imaging (MRI) Subject 1 Blood: R heart Blood: L heart Wall: L heart Subject 2 Blood: R heart Blood: L heart Wall: L heart Ron Peshock

  28. Dual Xray Absorptiometry (DXA) Muscle mass Fat mass Bone mineral density %Fat = 23.1% %Fat = 3.2% %Fat = 48.1% Gloria Vega Scott Grundy

  29. Translational Research Basic Science Discoveries Donald W. Reynolds Cardiovascular Clinical Research Center Clinical Science Discoveries Prevention and Rx of Heart Disease

  30. Progression of Heart Disease LVH Risk Factors Events ASHD Death Southwestern

  31. Imaging Tests DXA scan Fat distribution EBCT Atherosclerosis MRI Heart size, function %Fat: 3.2% 23.1% 48.1%

  32. Hepatic Fat Content by Proton Magnetic Resonance Spectroscopy – Spectral Images Subject 1 Subject 2 Subject 3 Tracing 1 Tracing 2 Hepatic Fat%: WATER FAT 1% 5% 45%

  33. Survey Sample Design Sampled Addresses 15,000 U.S. Postal Service Lists (over-sampled AA census tracts) 12,000 Occupied Residences 8,500 Screening Completed Ages 18-65 (over-sampled AA participants) 6,000 Household Interview Ages 18-65

  34. DHS: Critical Design Features • Multi-ethnic, population-based sample • Single site with proximity to UTSW • State-of-the-art phenotyping/genotyping • State-of-the-art sample storage • Scientific focus: local expertise

  35. New Genotyping in DHS: Admixture SNPs 2,400 SNPs (Reich et. al. AJHG, 2004) Partitioning of SNPs (n=1,057) in DHS: Relationship to Self-assigned Race AFRICAN-AMERICAN n=150 WHITES n=150 HISPANICS n=150 % 100 80 60 40 20 0 1 150 1 150 1 150 Individuals =Black =White =Other

  36. Causes of Death-Dallas County(1999-2001) 20,000 15,688 9,561 10,000 Number of deaths 1,348 1,001 1,000 561 0 Motor Vehicle Heart/ Vessels Cancer AIDS Crime CDC Wonder.gov

  37. Coronary Artery Calcium DHS-2 DHS-1 EBCT MDCT • MDCT: validated & established (MESA) • Transition protocols: Standard phantom used in DHS-1 Calibration & comparison with DHS-2 • Pilot validation study Calcium calibration phantom

  38. Cardiac Morphology and Function - MRI DHS-1 DHS-2 Sensitivity encoding Turbo Field Echo (85%) 3.0 T 1.5 T Steady State Free Precession (15%) ImprovedImagingEfficiency • Validation study: 1.5 vs 3T

  39. Carotid Atherosclerosis: 3.0T MRIMeasure Plaque Volume & Composition • Predictive for coronary atherosclerosis • Provides detailed plaque composition • Next step: direct coronary plaque imaging

  40. 2005 2006 2007 2008 2009 10/04 6 7 8 9 10 Year Imaging Workgroup Aims Defined Review (Joao Lima) Pilot Studies/ Validation DHS-2 Review (Peter Wilson) Final protocols Commitment by Dean

  41. Dallas County Random Population Sample n = 45,000 Probability- based sample n = 15,000 addresses

  42. Dallas Heart Study Translational Research DNA Cell Tissue Organ Individual Population Heart Disease

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