Background/Objective Phenotyping Family History of Coronary Heart Disease to Inform Risk Assessment for Cardiovascular Events in MESA  Jaideep Patel1,2, Mahmoud Al Rifai1,3, Pradeep Patel4, Maren Scheuner5, Steven Shea6, Roger S Blumenthal1, Khurram Nasir1,7, Michael J Blaha1, John W McEvoy1 1Johns Hopkins Ciccarone Center for the Prevention of Heart Disease; 2Division of Internal Medicine, VCU Medical Center; 3The University of Kansas, School of Medicine; Department of Cardiology, 4University of Florida; 5Veterans Administration, Greater Los Angeles Healthcare System; 6Department of Medicine and Epidemiology, Columbia University; 7Center for Prevention and Wellness Research, Baptist Health Medical Group. Background/Objective Results The relationships between various subtypes of family history (FH) of CHD and CVD events have not been fully explored. We sought to determine: 1) which FH subtypes predict risk of ASCVD events (both composite and the individual events of CHD, angina, stroke/TIA, PAD, and HF); and 2) whether risk differs by FH subtype (FH at any age in a parent, sibling, or child; FH at any age in spouse; FH premature in a parent, sibling, or child; FH premature in spouse; and, finally, by Familial risk strata: weak, moderate, or strong). Table 1. Baseline characteristics of the study population stratified by FH status. Total (N= 6200) No FH (N= 3989) Any FH (N= 2211) Premature FH N= (983) p-value* p-value** Age, years 62 (10) 61 (10) 0.64 0.003 Males+ 2950 (48) 1984 (50) 970 (44) 406 (41) <0.001 Race/Ethnicity+ White 2499 (40) 1378 (35) 1075 (49) 433 (44)   Black 1669 (27) 1092 (27) 581 (26) 305 (31) Hispanic 1347 (22) 890 (22) 457 (21) 216 (22) Chinese 727 (12) 629 (16) 98 (4) 29 (3) BMI, kg/m2 28.3 (5.4) 28.0 (5.3) 28.9 (5.6) 29.4 (5.7) LDL, mg/dL 117 (31) 116 (31) 119 (31) 118 (31) 0.002 0.19 HDL, mg/dL 51 (15) 0.10 0.57 SBP, mmHg 126 (21) 127 (21) 126 (20) 0.12 0.73 DM+ 740 (12) 478 (12) 263 (12) 130 (13) 0.93 Cigarette Smoking Status+ Never 3121 (51) 2077 (52) 1047 (47) 459 (47) Former 2280 (37) 1417 (36) 866 (39) 367 (37) Current 774 (13) 482 (12) 294 (13) 155 (16) Lipid-lowering therapy+ 1006 (16) 585 (15) 423 (19) 191 (19) Antihypertensive therapy+ 2275 (37) 1397 (35) 880 (40) 395 (40) 0.02 Baseline characteristics expressed as means (SD) for continuous variables and numbers, %’s for categorical variables. *p-value comparing presence of any FH to no FH;** p-value comparing presence of premature FH to no FH; + expressed at percentage (%). P-value was calculated using  ANOVA or Wilcoxon rank sum test for continuous variables  depending on normality, and chi-square for discrete variables. Table 2. Hazard ratios (95% CI) for events (note that associations with stroke, PAD and FH were non-significant)   CHD Angina Composite ASCVD Unadjusted Model 1 Model 2 Family History Status No FH (ref) 1.00 Any 1.4 (1.1,1.8) 1.7 (1.3,2.2) 1.8 (1.4,2.3) 1.6 (1.2,2.1) 1.4 (1.2,1.6) 1.3 (1.2,1.6) 1.3 (1.1,1.5) Premature 1.3 (0.9,1.7) 1.3 (0.9,1.8) 1.5 (1.1,2.0) 1.7 (1.2,2.2) 1.3 (1.1,1.6) Familial Risk Weak (ref) Moderate 1.4 (0.9,1.9) 1.4 (1.0,2.0) 1.5 (1.1,2.1) 1.3 (0.9,1.9) 1.2 (1.0,1.5) 1.2 (0.9,1.5) Strong 1.4 (1.0,1.9) 1.9 (1.4,2.5) 2.0 (1.5,2.6) 1.8 (1.4,2.4) 1.5 (1.2,1.7) 1.4 (1.2,1.7) Model 1: Adjusted for age, sex, race/ethnicity, education, and MESA site; Model 2: Adjusted for Model 1 covariates + body mass index, diabetes mellitus, cigarette smoking status, systolic blood pressure, low density lipoprotein cholesterol, high density lipoprotein cholesterol, lipid-lowering therapy, and anti-hypertensive medication use. Bold items are significant Figure 1. Incidence rates of cardiovascular disease outcomes by familial risk stratification. Table 3. Net reclassification improvement analysis for incident CVD events with addition of FH domains to model adjusted for FRS in the entire study population. FH Variable  CHD Composite ASCVD NRI (95%CI) FRS+ FH Any 0.162 (0.061-0.264) 0.159 (0.027-0.279) FH Premature 0.069 (-0.106-0.179) 0.051 (-0.094-0.137) FH Risk Strata 0.164 (0.067-0.260) 0.163 (0.027-0.282) FRS – Framingham Risk Score; FH – family history; NRI – net reclassification index; . Bold items are significant Methods MESA Prospective, community-based, multi-ethnic cohort of 6,814 asymptomatic men & women aged 45-84 from six US field centers. Study Population and Analysis 6,200 adults with information on FH were included. Any FH was defined as 1st degree relative with a CHD event [fatal or nonfatal MI, or cardiac procedure (CABG, balloon angioplasty, & intracoronary stenting)] at any age. Premature FH was defined as having at least one 1st degree relative with CHD occurring ≤55 years (males) or ≤65 years (females). Familial risk stratification rules considered the number and age of 1st degree relatives with CHD, stroke, and DM and was classified as weak, moderate, or strong. Events were ascertained over a median of 10.1 years. Cox models were use to examined the association of FH (status and risk) with CVD events. Multiplicative interaction testing was performed for race/ethnicity & FH (race/ethnicity*FH). The likelihood ratio test was used to assess the prognostic impact of FH for discrimination of CVD when added to elements of the 2013 ACC/AHA ASCVD risk estimate. NRI was used to assess the incremental contribution of FH status for reclassification of CVD events when added to elements of the Framingham CVD Risk Score (calibrated for individual CVD outcomes), plus race/ethnicity Figure 2. Receive operator curve for incident composite ASCVD. AUC: (1) = 0.7403; (2) = 0.7430; (3) = 0.7417; (4) = 0.7435 Summary of Results FH Status (Any/Premature) is associated with CHD, angina, and composite ASCVD, but not stroke, PAD, or HF. Any Parental FH was associated with CHD, angina and composite ASCVD; Premature Parent and Child FH were significantly associated with angina and composite ASCVD, respectively (adjusted models). Strong Familial risk is associated with CHD, angina and composite ASCVD. Any FH predicts CHD and composite ASCVD risk. FH Status (Any/Premature)/FH Risk improve discrimination of composite ASCVD; FH Risk score discriminates over and above premature FH for composite ASCVD. Any FH and FH Risk score improved reclassification of CHD and composite ASCVD. P-value comparing (1) and (2) = 0.0004 P-value comparing (1) and (3) = 0.0051 P-value comparing (1) and (4) = 0.001 P-value: FH risk+(PCE+FH Any) = 0.45 P-value: FH risk+(PCE+FH Premature) = 0.051 Conclusion The association between FH and ASCVD risk differs depending on the number of affected family members, suggesting the value of detailed FH information to refine risk. Any FH and Family Risk Score may be used to improve discrimination and reclassification of CHD and ASCVD risk suggesting their potential value in refining risk assessment. The predictive value of Any/Premature FH of CHD for non-coronary events appears to be limited.