Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Bhakta N, Liu Q, Yeo F, et al. Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin s lymphoma: an analysis from the St Jude Lifetime Cohort Study. Lancet Oncol 2016; published online July 25. http://dx.doi.org/10.1016/s1470-2045(16)30215-7.
1 Appendix Text Multiple Imputation for Non-SJLIFE survivors For each of the 348 non-sjlife survivors without a SJLIFE clinical, we borrowed empirical sets of actual cardiovascular conditions from 10 survivors randomly selected from a pool of SJLIFE survivors who had complete SJLIFE clinical s, matched on gender, age at diagnosis (±5 years), treatment era (±10 years), anthracycline cumulative dose category, and heart radiation dose category (see Table 2 for dose categories). This multiple imputation generates 10 complete datasets. The 10 sets of cardiovascular conditions reflect the range and uncertainty of plausible sets of cardiovascular conditions the survivor in question might have had. This is a hot-deck multiple imputation method that is valid under the assumption of "missing at random" (i.e., conditioned on observed data, whether cardiovascular condition data of a survivor are missing or not does not depend on true cardiovascular conditions the survivor had). Approximate Bayesian Bootstrap was applied to make the multiple imputation properly reflect the entire uncertainty associated with missing data. 1 All analyses were performed for each of the 10 imputed datasets and 10 sets of results were summarized using the specific standard statistical method into a single set, combining the uncertainty estimates of each quantity of interest (e.g., cumulative burden at a given time point) within each of, and between, the 10 analyses. 1 Reference: 1 Molenberghs G, Fitzmaurice G, Kenward MG, Tsiatis A, Verbeke G. Handbook of Missing Data Methodology. CRC Press, 2014.
2 Appendix Tables and Figures Appendix Figure 1: Grade 3-5 Cumulative burden among SJLIFE Eligible Participants (Without the Imputation Cohort) alone and All SJLIFE Eligible HL (With the Imputation Cohort)
Appendix Figure 2: Sensitivity Analysis excluding Dyslipidemia and Essential Hypertension for both the Control and Entire SJLIFE Survivor cohort 3
4 Appendix Table 1: Cardiovascular Chronic Health Conditions Grade Definitions Using a Modified Common Terminology Criteria for Adverse Events (CTCAE) Grading Rubric Chronic Health Condition Acute myocardial infarction Grouped Category Myocardial Infarction Grading Source/Event Type Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Acute coronary syndrome Not applicable Asymptomatic and cardiac enzymes minimally abnormal and no evidence of ischemic ECG changes Severe symptoms; cardiac enzymes abnormal; hemodynamically stable; ECG changes consistent with infarction (Q waves) hemodynamically unstable (CABG or angioplasty) Atrioventricular Heart Block Arrhythmias AV Heart Block Complete Asymptomatic, not Non-urgent Symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker) urgent Conduction abnormalities Arrhythmias Modified First Degree Heart Block AND MERGE WITH Conduction disorder Asymptomatic or mild symptoms; not Moderate symptoms: nonurgent Severe symptoms; urgent Prolonged QT interval Arrhythmias Modified Investigations: Electrocardiogram QT corrected interval prolonged QTc 460-480 ms (men); 470-480 ms (women) QTc 481-500 ms QTc >= 501 ms on >= two separate ECGs QTc >= 501 or >60 ms change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Not applicable Cardiac dysrhythmia Arrhythmias Cardiac Disorders:Atrial fibrillation; Atrial flutter; Paroxysmal atrial tachycardia; Supraventricular tachycardia Asymptomatic, not Non-urgent medical Symptomatic and incompletelycontrolled medically, or controlled with device (e.g., pacemaker), or ablation urgent
5 Sinus bradycardia Arrhythmias Modified Sinus bradycardia Asymptomatic, not Symptomatic, medical Severe, medically significant, medical urgent Sinus tachycardia Arrhythmias Modified Sinus tachycardia Asymptomatic, not Symptomatic; nonurgent medical Urgent medical Not applicable Cardiomyopathy Cardiovascular dysfunction Modified Investigations: Ejection fraction decreased AND Left ventricular systolic dysfunction Not applicable Resting EF <50-40%; 10-19% drop from baseline Resting EF 39-20%; 20% drop from baseline or or initiated Resting EF<20% or with a history of EF<20% that has improved on subsequent ECHO after initiated. Interventions may include: ventricular assist devices, intravenous vasopressor support, or heart transplant Not applicable Right ventricular systolic dysfunction Cardiovascular dysfunction Modified Right ventricular dysfunction Asymptomatic cardiac imaging abnormalities Symptoms with mild to moderate activity or exertion Severe symptoms, associated with hypoxemia, right heart failure; oxygen urgent (e.g., ventricular assist device); heart transplant Cor pulmonale Cardiovascular dysfunction Modified Right ventricular dysfunction Asymptomatic with laboratory (e.g., BNP) or cardiac imaging abnormalities Symptoms with mild to moderate activity or exertion Severe symptoms, associated with hypoxemia, right heart failure; oxygen urgent (e.g., ventricular assist device); heart transplant
6 Pulmonary hypertension Cardiovascular dysfunction Other, specify Asymptomatic or mild symptoms; clinical or diagnostic observations only; not Moderate; minimal, local or noninvasive ; limiting age appropriate instrumental ADL Severe or medically significant but not immediately life threatening; hospitalization or prolongation of existing hospitalization ; disabling; limiting self-care ADL urgent Heart valve disorder Structural defects Modified CTCAE v4.03 Aortic valve disease; mitral valve disease; pulmonary valve disease; tricuspid valve disease Asymptomatic valvular thickening with or without mild valvular regurgitation or stenosis by imaging Asymptomatic; moderate regurgitation or stenosis by imaging Symptomatic; severe regurgitation or stenosis by imaging; symptoms controlled with medical urgent (e.g., valve replacement, valvuloplasty) Pericarditis Structural defects Modified CTCAE v4.03 Pericarditis Asymptomatic, ECG or physical findings (e.g., rub) c/w pericarditis Symptomatic pericarditis (e.g., chest pain) Pericarditis with physiologic consequences (e.g., pericardial constriction) urgent (cardiac tamponade) Aortic root aneurysm Structural defects Modified Other, specify Asymptomatic or mild symptoms; clinical or diagnostic observations only; not (aortic root >= 3.5 cm to < 4 cm) Moderate; minimal, local or noninvasive ; limiting age appropriate instrumental ADL (aortic root > = 4 cm) Severe or medically significant but not immediately life threatening; hospitalization or prolongation of existing hospitalization ; disabling; limiting self-care ADL urgent Atrial myxoma Structural defects Other, specify Asymptomatic or mild symptoms; clinical or diagnostic observations only; not Moderate; minimal, local or noninvasive ; limiting age appropriate instrumental ADL Severe or medically significant but not immediately life threatening; hospitalization or prolongation of existing hospitalization ; disabling; limiting self-care ADL urgent
7 Arteriovenous malformation Vascular disease Other, specify Asymptomatic or mild symptoms; clinical or diagnostic observations only; not Moderate; minimal, local or noninvasive ; limiting age appropriate instrumental ADL Severe or medically significant but not immediately life threatening; hospitalization or prolongation of existing hospitalization ; disabling; limiting self-care ADL urgent Raynaud phenomenon Vascular disease CTCAE v4.03 Vascular Disorders: Other, specify Asymptomatic or mild symptoms; clinical or diagnostic observations only; not Moderate; minimal, local or noninvasive ; limiting age appropriate instrumental ADL Severe or medically significant but not immediately life threatening; hospitalization or prolongation of existing hospitalization ; disabling; limiting self-care ADL urgent Not applicable Thrombus Vascular disease Vascular Disorders: Thromboembolic event Venous thrombosis (e.g., superficial thrombosis) Venous thrombosis (e.g., uncomplicated deep vein thrombosis), medical Thrombosis (e.g., uncomplicated pulmonary embolism [venous], non-embolic cardiac mural [arterial] thrombus), medical (e.g., pulmonary embolism, cerebrovascular event, arterial insufficiency); hemodynamic or neurologic instability; urgent Stenosis/occlusion of vessel Vascular disease Other, specify Asymptomatic or mild symptoms; clinical or diagnostic observations only; not Moderate; minimal, local or noninvasive ; limiting age appropriate instrumental ADL Severe or medically significant but not immediately life threatening; hospitalization or prolongation of existing hospitalization ; disabling; limiting self-care ADL urgent
8 Hypertension Dyslipidemia/ Essential Hypertension Modified Vascular Disorders:Hypertension Prehypertension (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) from resting BP in HPL Stage 1 hypertension (systolic BP 140-159 mm Hg or diastolic BP 90-99 mm Hg); medical or initiated; recurrent or persistent (>=24 hrs); symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously WNL; monotherapy or initiated Pediatric: recurrent or persistent (>=24 hrs) BP >ULN; monotherapy or initiated Stage 2 hypertension (systolic BP >=160 mm Hg or diastolic BP >=100 mm Hg); medical ; more than one drug or more intensive therapy than previously used or initiated Pediatric: Same as adult consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent Pediatric: Same as adult Hypertriglyceridemia Dyslipidemia/ Essential Hypertension Modified Metabolism and Nutrition Disorders : Hypertriglyceridemia 150 mg/dl - 300 mg/dl >300 mg/dl - 500 mg/dl; or treatment with one lipid lowering agent >500 mg/dl - 1000 mg/dl; or treatment with >=2 lipid lowering agents >1000 mg/dl; lifethreatening consequences Not applicable Hypercholesterolemia Dyslipidemia/ Essential Hypertension Modified Investigations: Cholesterol high >200 mg/dl - 300 mg/dl >300-400 mg/dl; or treatment with one lipid lowering agent >400-500 mg/dl; or treatment with >=2 lipid lowering agents >500 mg/dl Not applicable
9 Appendix Table 2: Cardiovascular Chronic Health Conditions Grade Definitions and Cumulative Burden Grading Rules Chronic Health Condition Grouped Category Definition Source Data Event Type Grades Recurrent Pre-5 year Inclusion Acute myocardial infarction Myocardial Infarction Clinically determined and consistent CTCAE definition Prineas RJ, Crow RS, Zhang ZM: The Minnesota code manual of electrocardiographic findings. 2009 Medical record abstraction: emergency department visits and hospitalizations Centrally reviewed electrocardiogram (for evidence of asymptomatic/old infarcts) Chronic/Recurrent 2,3,4 No Atrioventricular Heart Block Arrhythmias Prineas RJ, Crow RS, Zhang ZM: The Minnesota code manual of electrocardiographic findings. 2009 Minnesota Codes: 6-1, 6-2-1; 6-2-2; 6-2-3; 6-3 Centrally reviewed electrocardiogram at SJLIFE visit Chronic/Recurrent 3,4 No Conduction abnormalities Arrhythmias Prineas RJ, Crow RS, Zhang ZM: The Minnesota code manual of electrocardiographic findings. 2009 Minnesota Codes: 6-4-1; 7-* Centrally reviewed electrocardiogram at SJLIFE visit Chronic/Recurrent 3,4 No Prolonged QT interval Arrhythmias Prineas RJ, Crow RS, Zhang ZM: The Minnesota code manual of electrocardiographic findings. 2009 Rautaharju P, Rautaharju F. Investigative Electrocardiography in Epidemiological Studies and Clinical Trials First ed: Springer Science & Business Media 2007. Centrally reviewed electrocardiogram at SJLIFE visit Chronic/Recurrent 4 No Cardiac dysrhythmia Arrhythmias Prineas RJ, Crow RS, Zhang ZM: The Minnesota code manual of electrocardiographic findings. 2009Minnesota Codes: 8-2-1; 8-2-2; 8-2-3; 8-3-1; 8-3-2; 8-3-3; 8-3-4; 8-4-1; 8-4-2; 8-5-1; 8-5-2; 8-6-1; 8-6-2; 8-6-3; 8-6-4 Centrally reviewed electrocardiogram at SJLIFE visit Chronic/Recurrent 3,4 No Sinus bradycardia Arrhythmias Heart rate < 50 (sustained after resting for 10 minutes in the Human Performance Lab) Centrally reviewed electrocardiogram at SJLIFE visit Chronic/Recurrent 3,4 No
10 Sinus tachycardia Arrhythmias Heart rate > 110 (sustained after resting for 10 minutes in the Human Performance Lab) Centrally reviewed electrocardiogram at SJLIFE visit Chronic/Recurrent 3,4 No Cardiomyopathy Cardiovascular dysfunction EF < 50%, SF < 28% (by echocardiography and/or MUGA) Centrally reviewed echocardiogram Chronic/Recurrent 4 Yes Right ventricular systolic dysfunction Cardiovascular dysfunction Clinically and radiographically determined and consistent CTCAE definition Centrally reviewed echocardiogram Chronic/Recurrent 4 Yes Cor pulmonale Cardiovascular dysfunction Clinically, labortory and radiographically determined and consistent CTCAE definition Centrally reviewed echocardiogram Chronic/Recurrent 4 Yes Pulmonary hypertension Cardiovascular dysfunction Determined by cardiac catheterization and consistent CTCAE definition Medical record abstraction of cardiac catheterization reports Chronic/Not Recurrent None Yes Heart valve disorder Structural defects Radiographically determined and consistent CTCAE definition Centrally reviewed echocardiogram Chronic/Recurrent 4 Yes Pericarditis Structural defects Radiographically determined and consistent CTCAE definition Centrally reviewed echocardiogram Chronic/Recurrent 4 No Aortic root aneurysm Structural defects Radiographically determined and consistent CTCAE definition Centrally reviewed echocardiogram Chronic/Recurrent 4 Yes Atrial myxoma Structural defects Radiographically determined and consistent CTCAE definition Centrally reviewed echocardiogram Review of echocardiogram records from outside cardiology practice Medical record abstraction: emergency department visits and hospitalizations Chronic/Recurrent 4 Yes
11 Arteriovenous malformation Vascular disease Radiographically determined and consistent CTCAE definition Medical record abstraction Chronic/Recurrent 4 Yes Raynaud phenomenon Vascular disease Clinically determined and consistent CTCAE definition Medical record abstraction Chronic/Not Recurrent None Yes Thrombus Vascular disease Clinically and radiographically determined and consistent CTCAE definition Medical record abstraction Single/Recurrent 1,2,3,4 No Stenosis/occlusion of vessel Vascular disease Clinically and radiographically determined and consistent CTCAE definition. Medical record abstraction Chronic/Recurrent 2,3,4 Yes Hypertension Dyslipidemia/ Essential Hypertension Clinically and diagnostically determined and consistent CTCAE definition Based on 2 resting blood pressure measurements with at least one in the Human Performance Lab Medical record abstraction Chronic/Recurrent 4 Yes Hypertriglyceridemia Dyslipidemia/ Essential Hypertension Diagnostically determined and consistent CTCAE definition Laboratory: triglyceride value (fasting minimum 8 hours) Medical record abstraction Chronic/Not Recurrent None No Hypercholesterolemia Dyslipidemia/ Essential Hypertension Diagnostically determined and consistent CTCAE definition Laboratory: total cholesterol value (fasting minimum 8 hours) Medical record abstraction Chronic/Not Recurrent None No
12 Appendix Table 3: Prevalence of Maximum Grades by Individually Graded Chronic Cardiovascular Health Condition Among St. Jude Lifetime Cohort Study (SJLIFE) Hodgkin Lymphoma Cardiovascular Conditions SJLIFE Modified CTCAE Grade No Event 1 2 3 4 Total Aortic Root Aneurysm 324 21 3 0 0 348 Arteriovenous malformation (AVM) 347 1 0 0 0 348 Atrial myxoma 347 0 0 1 0 348 Atrioventricular Heart Block 331 9 3 5 0 348 Cardiac Dysrhythmia 327 7 6 3 5 348 Cardiomyopathy 281 0 39 22 6 348 Conduction Abnormality 262 75 9 2 0 348 Cor pulmonale (right heart failure) 348 0 0 0 0 348 Dyslipidemia - Hypercholesterolemia 155 131 59 3 0 348 Dyslipidemia - Hypertriglyceridemia 223 97 23 5 0 348 Heart Valve Disorder 113 182 29 6 18 348 Hypertension 123 114 74 37 0 348 Myocardial Infarction 299 0 0 27 22 348 Pericarditis 340 0 2 4 2 348 Prolonged QT Interval 283 34 26 5 0 348 Pulmonary Hypertension 338 2 3 5 0 348 Raynaud's phenomenon 343 4 1 0 0 348 Right ventricular systolic dysfunction 344 3 1 0 0 348 Sinus Bradycardia 344 4 0 0 0 348 Sinus Tachycardia 316 28 4 0 0 348 Thrombus 340 0 8 0 0 348 Vascular Disease 305 31 5 0 7 348 Total 6433 743 295 125 60 7656
13 Appendix Table 4: Grade 1-5 Cumulative Incidence [%] of Overall and Six Groups of Chronic Cardiovascular Health Conditions by Attained Age with 95% Confidence Intervals in Hodgkin Lymphoma and Community-Controls Condition 25 30 35 40 45 50 55 60 Community-Controls Overall 11 3 (7 4-15 2) 22 3 (17 0-27 5) 39 7 (33 2-46 1) 57 4 (50 4-64 4) 76 4 (69 8-83 0) 85 8 (80 1-91 6) 93 0 (88 7-97 4) 98 3 (95 9-100 6) Myocardial Infarction 0 0 0 0 1 6 (0 0-4 6) 1 6 (0 0-4 6) 1 6 (0 0-4 6) 9 8 (0 0-25 4) Dyslipidemia and Essential Hypertension 9 8 (6 1-13 4) 18 3 (13 4-23 2) 35 2 (28 8-41 6) 51 3 (44 1-58 5) 70 0 (62 6-77 5) 80 5 (73 6-87 5) Arrhythmias 1 7 (0 0-3 3) 4 1 (1 5-6 8) 7 1 (3 5-10 7) 12 1 (6 6-17 5) 14 9 (8 3-21 5) 23 5 (12 4-34 6) 88 8 (82 9-94 8) 27 8 (14 5-41 0) 96 7 (92 5-100 9) 42 2 (21 4-63 0) Cardiovascular Dysfunction 0 4 (0 0-1 2) 0 4 (0 0-1 2) 0 4 (0 0-1 2) 0 4 (0 0-1 2) 0 4 (0 0-1 2) 0 4 (0 0-1 2) 0 4 (0 0-1 2) 8 7 (0 0-24 3) Structural Defects 1 3 (0 0-2 7) 3 8 (1 2-6 3) 10 2 (5 8-14 5) 15 9 (10 1-21 8) 23 2 (15 0-31 4) 33 1 (21 5-44 7) 49 8 (34 3-65 2) 77 7 (60 9-94 4) Vascular Disease 0 0 0 0 9 (0 0-2 8) 0 9 (0 0-2 8) 0 9 (0 0-2 8) 0 9 (0 0-2 8) 9 2 (0 0-24 8) Overall 40 3 (19 6-61 1) 55 6 (39 9-71 3) 66 2 (54 3-78 1) 76 9 (68 5-85 2) 85 0 (79 5-90 5) 89 2 (85 3-93 2) Myocardial Infarction 3 1 (0 0-14 9) 4 5 (0 0-16 1) 6 4 (0 0-17 9) 11 1 (0 0-22 2) 17 1 (6 1-28 0) 24 9 (14 3-35 6) Dyslipidemia and Essential Hypertension 23 6 (5 2-41 9) 37 5 (22 5-52 5) 48 8 (36 5-61 1) Arrhythmias 10 5 (0 0-22 2) 18 4 (7 3-29 5) 23 9 (13 8-34 0) 61 9 (52 3-71 4) 31 7 (22 5-40 9) 71 3 (64 0-78 6) 42 2 (34 2-50 3) 78 6 (72 7-84 4) 51 7 (44 3-59 0) Cardiovascular Dysfunction 7 4 (0 0-24 4) 9 9 (0 0-26 7) 12 1 (0 0-28 8) 17 1 (0 8-33 4) 22 7 (7 1-38 4) 28 4 (13 1-43 6) Structural Defects 17 1 (5 0-29 2) 26 9 (15 9-37 9) 37 2 (27 6-46 8) 50 2 (42 4-57 9) 62 0 (55 3-68 7) 71 2 (65 8-76 5) Vascular Disease 2 7 (0 0-10 2) 4 3 (0 0-12 1) 5 3 (0 0-13 1) 8 8 (1 0-16 7) 15 8 (8 2-23 4) 20 5 (12 5-28 6) 91 4 (88 1-94 7) 30 2 (19 9-40 6) 83 3 (78 3-88 3) 61 8 (54 8-68 7) 40 5 (26 5-54 5) 77 1 (72 3-81 9) 28 0 (19 1-37 0) 38 5 (26 3-50 8) 85 6 (81 0-90 1) 67 4 (60 2-74 7) 47 4 (33 3-61 5) 80 0 (75 2-84 9) 29 1 (19 5-38 7)
14 Appendix Table 5: Grade 3-5 Cumulative Incidence [%] of Overall and Six Groups of Chronic Cardiovascular Health Conditions by Attained Age with 95% Confidence Intervals in Hodgkin Lymphoma and Community-Controls Condition 25 30 35 40 45 50 55 60 Community-Controls Overall 0 1 1 (0 0-2 5) 2 5 (0 1-4 9) 5 7 (1 4-9 9) 13 5 (5 7-21 2) 15 7 (7 0-24 4) 26 0 (10 5-41 6) 32 2 (13 8-50 6) Myocardial infarction 0 0 0 0 1 6 (0 0-4 6) 1 6 (0 0-4 6) 1 6 (0 0-4 6) 9 8 (0 0-25 4) Dyslipidemia and Essential Hypertension 0 1 1 (0 0-2 5) 1 8 (0 0-3 8) 2 8 (0 0-5 6) 9 1 (2 4-15 9) 11 4 (3 5-19 3) 22 3 (6 4-38 1) 28 8 (9 8-47 7) Arrhythmias 0 0 0 7 (0 0-2 0) 2 9 (0 0-6 2) 2 9 (0 0-6 2) 2 9 (0 0-6 2) 2 9 (0 0-6 2) 2 9 (0 0-6 2) Cardiovascular dysfunction 0 0 0 0 0 0 0 8 3 (0 0-24 0) Structural defects 0 0 0 0 0 0 0 0 Vascular disease 0 0 0 0 0 0 0 0 Overall 8 3 (0 0-21 0) 11 5 (0 0-23 6) 15 4 (3 9-26 9) 22 9 (12 2-33 6) 34 8 (24 9-44 8) 45 5 (36 6-54 3) 56 1 (47 4-64 9) 62 5 (53 1-72 0) Myocardial infarction 3 1 (0 0-14 9) 4 5 (0 0-16 1) 6 4 (0 0-17 9) 11 1 (0 0-22 2) 17 1 (6 1-28 0) 24 9 (14 3-35 6) 30 2 (19 9-40 6) 38 5 (26 3-50 8) Dyslipidemia and Essential Hypertension 1 1 (0 0-2 8) 2 1 (0 2-4 0) 3 4 (1 1-5 7) 5 9 (3 2-8 5) 8 7 (5 4-12 0) 16 0 (11 2-20 7) 21 4 (15 2-27 5) 24 5 (16 6-32 3) Arrhythmias 0 2 (0 0-1 0) 0 6 (0 0-1 7) 0 9 (0 0-2 1) 1 9 (0 2-3 6) 3 2 (0 8-5 6) 4 1 (1 4-6 8) 6 9 (2 5-11 3) Cardiovascular dysfunction 0 7 (0 0-2 7) 1 5 (0 0-3 7) 3 0 (0 8-5 2) 5 9 (2 8-9 0) 9 2 (5 6-12 9) 12 3 (7 4-17 3) 23 2 (15 2-31 2) 27 8 (17 9-37 7) Structural defects 3 1 (0 0-8 1) 3 4 (0 0-8 5) 4 0 (0 0-9 0) 5 4 (0 2-10 6) 10 1 (4 5-15 7) 15 6 (8 9-22 3) 19 9 (12 4-27 3) 27 3 (17 0-37 6) Vascular disease 0 8 (0 0-2 1) 1 0 (0 0-2 3) 1 1 (0 0-2 5) 1 7 (0 0-3 5) 2 7 (0 5-4 9) 3 8 (1 0-6 7) 4 6 (1 4-7 8)
15 Appendix Table 6: Grade 1-5 Cumulative Burden [mean number of events per 100 survivors] of Chronic Cardiovascular Health Conditions by Attained Age with 95% Confidence Intervals in Hodgkin Lymphoma, Overall and by Gender and Treatment Exposures, and Community-Controls Group CB25 CB30 CB35 CB40 CB45 CB50 CB55 CB60 Community-Controls 15 3 (10 0-21 6) 31 3 (23 9-40 0) 65 4 (52 6-81 2) 111 6 (90 5-134 1) 167 4 (142 2-196 2) 227 4 (192 7-267 5) 284 9 (244 8-334 1) 393 1 (315 3-501 2) 79 4 (23 9-134 9) 130 2 (78 1-182 3) 177 9 (127 9-227 8) 252 6 (204 8-300 4) 341 8 (296 5-387 0) 430 6 (380 7-480 6) 525 9 (471 2-580 6) 603 3 (542 0-664 6) Gender Male 76 8 (18 6-135 0) 129 6 (71 9-187 4) 179 0 (124 9-233 1) 271 9 (218 7-325 2) 360 8 (306 2-415 5) 439 1 (375 7-502 5) 531 9 (455 5-608 4) 592 4 (501 7-683 1) Female 68 4 (0 0-137 8) 117 1 (53 3-180 8) 163 5 (106 3-220 8) 215 9 (160 4-271 5) 306 4 (251 5-361 3) 409 5 (349 4-469 7) 507 6 (435 8-579 4) 593 0 (507 9-678 1) Anthracycline Exposure No Anthracycline 27 0 (0 0-61 8) 34 5 (0 0-72 4) 51 9 (10 1-93 7) 113 9 (70 3-157 4) 213 4 (165 2-261 5) 318 1 (262 7-373 6) 427 1 (362 6-491 7) 518 7 (443 0-594 3) Anthracycline 1-249 mg 128 9 (31 2-226 6) 210 4 (129 5-291 3) 276 1 (207 3-344 8) 381 0 (317 5-444 5) 486 6 (419 2-554 1) 572 5 (483 8-661 2) Anthracycline 250+ mg 94 5 (0 0-212 4) 160 1 (39 8-280 3) 250 1 (129 2-371 0) 329 7 (217 3-442 1) 375 9 (265 6-486 2) 440 9 (304 1-577 8) 556 4 (411 8-701 0) (Anthracycline any dose) 130 2 (31 7-228 8) 207 9 (123 4-292 4) 277 5 (204 9-350 1) 375 6 (310 1-441 1) 469 1 (403 9-534 3) 556 1 (471 5-640 7) 660 0 (549 5-770 6) Cardiac Radiation Exposed 76 6 (26 6-126 6) 125 3 (79 4-171 2) 173 2 (130 9-215 6) 250 8 (209 6-292 0) 342 8 (302 2-383 4) 435 9 (388 6-483 1) 531 8 (476 2-587 3) 613 4 (548 9-677 8) Not exposed 79 9 (0 0-220 7) 156 3 (20 3-292 2) 202 0 (59 9-344 2) 232 5 (82 6-382 3) 284 7 (132 7-436 7) 334 8 (183 8-485 7) 435 3 (282 6-588 1) 460 7 (316 3-605 1)
16 Appendix Table 7: Grade 3-5 Cumulative Burden [mean number of events per 100 survivors] of Chronic Cardiovascular Health Conditions by Attained Age with 95% Confidence Intervals in Hodgkin Lymphoma, Overall and by Gender and Treatment Exposures, and Community-Controls Group CB25 CB30 CB35 CB40 CB45 CB50 CB55 CB60 Community-Controls 0 1 1 (0 0-2 7) 2 5 (0 5-5 1) 6 8 (1 9-13 0) 14 7 (7 0-24 3) 17 0 (8 4-27 5) 28 1 (12 2-47 9) 51 2 (16 6-105 8) 11 0 (0 0-26 3) 15 9 (0 6-31 2) Male 8 0 (0 0-25 1) 13 8 (0 0-30 6) Female 9 6 (0 0-26 4) 12 5 (0 0-30 2) No Anthracycline 9 2 (0 0-31 0) 11 6 (0 0-34 2) Anthracycline 1-249 6 4 (0 0-16 9) 12 1 (0 0-24 3) Anthracycline 250+ 6 6 (0 0-28 2) 16 0 (0 0-46 1) Anthracycline Exposed Cardiac Radiation 12 6 (0 0-25 2) 6 7 (0 0-16 2) 13 2 (2 0-24 3) 17 6 (4 0-31 2) No Cardiac Radiation 4 0 (0 0-14 9) 13 7 (0 0-37 6) 22 5 (7 5-37 4) 22 0 (5 3-38 7) 16 1 (0 0-34 6) 15 1 (0 0-37 5) 22 0 (6 9-37 1) 21 4 (0 0-51 3) 22 0 (9 3-34 8) 22 8 (9 4-36 3) 25 8 (0 0-62 0) 39 7 (23 9-55 5) 44 4 (24 3-64 4) 65 8 (47 4-84 1) 100 8 (77 3-124 3) 68 5 (43 5-93 5) 100 9 (65 8-135 9) 140 6 (110 9-170 4) 176 4 (138 2-214 6) 132 0 (85 8-178 2) 151 1 (96 0-206 2) 24 8 (5 7-43 9) 47 1 (22 8-71 3) 82 9 (53 3-112 5) 123 2 (83 0-163 5) 164 5 (112 2-216 8) 25 6 (2 6-48 7) 46 1 (20 3-71 9) 76 5 (40 1-112 8) 105 8 (60 3-151 2) 138 1 (77 9-198 3) 52 2 (31 4-73 0) 88 6 (52 1-125 1) 132 6 (74 1-191 1) 33 0 (2 8-63 3) 43 4 (11 2-75 6) 51 4 (11 9-91 0) 117 3 (51 9-182 7) 47 9 (29 8-66 0) 40 9 (25 3-56 5) 79 3 (48 3-110 2) 117 7 (66 9-168 4) 67 8 (48 9-86 7) 105 2 (81 2-129 2) 197 2 (117 1-277 3) 147 5 (115 3-179 8) 188 5 (148 1-228 8) 31 7 (0 0-74 1) 51 2 (4 2-98 3) 73 7 (15 1-132 3) 101 9 (32 8-171 0) 101 9 (32 8-171 0)
17 Appendix Table 8: Grade 1-5 Cumulative Burden [mean number of events per 100 survivors] of Overall and Six Groups of Chronic Cardiovascular Health Conditions by Attained age with 95% Confidence Intervals in Hodgkin Lymphoma and Community Controls Grade 1-5 CB25 CB30 CB35 CB40 CB45 CB50 CB55 CB60 Overall Community- Controls 15 3 (10 0-21 6) 31 3 (23 9-40 0) 65 4 (52 6-81 2) 111 6 (90 5-134 1) 167 4 (142 2-196 2) 227 4 (192 7-267 5) 284 9 (244 8-334 1) 393 1 (315 3-501 2) 79 4 (23 9-134 9) 130 2 (78 1-182 3) 177 9 (127 9-227 8) 252 6 (204 8-300 4) 341 8 (296 5-387 0) 430 6 (380 7-480 6) 525 9 (471 2-580 6) 603 3 (542 0-664 6) Myocardial Infarction Physiologic Community- Controls Community- Controls Arrhythmias Community- Controls Cardiovascular Dysfunction Structural Defects Community- Controls Community- Controls Vascular Disease Community- Controls 0 0 0 0 1 6 (0 0-5 0) 1 6 (0 0-5 0) 1 6 (0 0-5 0) 9 8 (0 0-30 0) 3 4 (0 0-15 5) 5 1 (0 0-16 8) 7 3 (0 0-18 9) 12 9 (1 5-24 3) 19 5 (8 2-30 8) 30 3 (18 3-42 2) 38 6 (26 4-50 8) 47 1 (33 5-60 7) 11 9 (7 8-16 8) 22 9 (17 1-29 7) 47 5 (37 8-58 2) 79 3 (64 3-94 6) 122 8 (105 2-144 1) 35 0 (0 0-73 8) 58 9 (23 8-93 9) 80 6 (48 5-112 7) 109 8 (81 1-138 5) 137 3 (112 6-162 0) 162 4 (138 5-187 7) 162 6 (140 0-185 1) 195 3 (169 6-224 8) 185 4 (164 6-206 2) 221 9 (195 9-251 5) 198 7 (179 2-218 3) 1 7 (0 4-3 5) 4 2 (1 8-7 3) 7 3 (3 7-11 5) 13 6 (7 2-20 7) 16 6 (9 1-24 4) 26 1 (14 7-40 3) 31 0 (16 8-50 0) 48 8 (23 2-83 4) 11 5 (0 0-24 9) 21 5 (7 7-35 2) 29 1 (16 2-42 1) 42 2 (29 6-54 9) 62 9 (49 6-76 2) 85 4 (70 6-100 2) 118 8 (99 0-138 5) 146 3 (121 8-170 8) 0 4 (0 0-1 3) 0 4 (0 0-1 3) 0 4 (0 0-1 3) 0 4 (0 0-1 3) 0 4 (0 0-1 3) 0 4 (0 0-1 3) 0 4 (0 0-1 3) 8 7 (0 0-28 6) 7 7 (0 0-24 6) 10 3 (0 0-27 1) 13 1 (0 0-29 9) 19 1 (2 2-36 0) 26 6 (9 7-43 5) 34 2 (16 8-51 6) 48 3 (31 5-65 1) 58 2 (41 0-75 4) 1 3 (0 0-3 0) 3 8 (1 4-6 5) 10 3 (6 3-14 7) 16 2 (10 5-22 5) 24 0 (15 2-33 1) 35 0 (22 4-48 2) 54 6 (36 6-75 9) 93 7 (66 5-124 1) 18 3 (5 2-31 4) 29 1 (16 7-41 6) 40 8 (29 2-52 4) 57 2 (46 1-68 3) 75 4 (64 7-86 2) 91 8 (79 6-104 0) 100 2 (87 4-113 0) 115 9 (99 4-132 5) 0 0 0 2 0 (0 0-6 7) 2 0 (0 0-6 7) 2 0 (0 0-6 7) 2 0 (0 0-6 7) 10 3 (0 0-30 8) 3 4 (0 0-11 3) 5 3 (0 0-13 6) 6 9 (0 0-15 2) 11 3 (2 5-20 2) 20 0 (10 9-29 2) 26 4 (16 1-36 7) 34 7 (23 0-46 3) 37 0 (23 9-50 2)
18 Appendix Table 9: Grade 3-5 Cumulative Burden [mean number of events per 100 survivors] of Overall and Six Groups of Chronic Cardiovascular Health Conditions by Attained age with 95% Confidence Intervals in Hodgkin Lymphoma and Community Controls Grade 3-5 CB25 CB30 CB35 CB40 CB45 CB50 CB55 CB60 Overall Community-Controls 0 1 1 (0 0-2 7) 2 5 (0 5-5 1) 6 8 (1 9-13 0) 14 7 (7 0-24 3) 17 0 (8 4-27 5) 28 1 (12 2-47 9) 51 2 (16 6-105 8) Myocardial Infarction 11 0 (0 0-26 3) 15 9 (0 6-31 2) 22 5 (7 5-37 4) 39 7 (23 9-55 5) 65 8 (47 4-84 1) 100 8 (77 3-124 3) 140 6 (110 9-170 4) 176 4 (138 2-214 6) Community-Controls 0 0 0 0 1 6 (0 0-5 0) 1 6 (0 0-5 0) 1 6 (0 0-5 0) 9 8 (0 0-30 0) Physiologic 3 4 (0 0-15 5) 5 1 (0 0-16 8) 7 3 (0 0-18 9) 12 9 (1 5-24 3) 19 5 (8 2-30 8) 29 8 (18 0-41 5) 38 1 (26 1-50 1) 46 6 (33 2-60 0) Community-Controls 0 1 1 (0 0-2 7) 1 8 (0 0-3 9) 2 8 (0 5-5 9) 9 2 (3 2-16 4) 11 5 (3 9-19 8) 22 5 (8 3-41 0) 29 1 (10 9-49 4) Arrhythmias 1 7 (0 0-4 1) 2 9 (0 3-5 4) 4 2 (1 2-7 1) 7 1 (3 7-10 4) 9 9 (5 9-13 9) 17 4 (12 2-22 7) 22 9 (16 6-29 2) 26 1 (18 1-34 1) Community-Controls 0 0 0 7 (0 0-2 2) 4 0 (0 0-9 8) 4 0 (0 0-9 8) 4 0 (0 0-9 8) 4 0 (0 0-9 8) 4 0 (0 0-9 8) Cardiovascular Dysfunction 0 2 (0 0-1 0) 0 7 (0 0-2 3) 1 2 (0 0-3 0) 2 7 (0 0-5 8) 7 0 (1 3-12 8) 10 4 (2 8-18 1) 19 1 (6 3-31 8) 26 7 (11 1-42 2) Community-Controls 0 0 0 0 0 0 0 8 3 (0 0-28 6) Structural Defects 0 9 (0 0-3 6) 1 8 (0 0-4 7) 3 5 (0 6-6 5) 7 4 (3 5-11 3) 11 9 (7 0-16 8) 15 1 (9 1-21 1) 27 1 (18 1-36 0) 31 1 (21 1-41 1) Community-Controls 0 0 0 0 0 0 0 0 Vascular Disease 3 4 (0 0-9 3) 3 8 (0 0-9 7) 4 5 (0 0-10 4) 6 7 (0 0-13 4) 12 8 (5 3-20 3) 21 6 (11 2-31 9) 26 4 (15 6-37 1) 37 0 (22 6-51 4) Community-Controls 0 0 0 0 0 0 0 0 1 3 (0 0-3 5) 1 6 (0 0-4 0) 1 7 (0 0-4 2) 3 0 (0 0-6 2) 4 6 (0 9-8 4) 6 5 (1 6-11 3) 7 1 (2 1-12 0) 9 0 (3 1-14 8)
19 Appendix Table 10: Comparison of age-sex-race standardized Prevalence between NHANES and SJLIFE Controls for Selected Cardiovascular Conditions NHANES 2013-14 SJLIFE Controls Hypercholesterolemia 9.68% 7.35% Hypertension 16.30% 16.54% Myocardial infarction 0.60% 0.74%