NHLBI TOPMed: Heart and Vascular Health Study (HVH)

Objectives The Heart and Vascular Health Study (HVH) is a case-control study of risk factors for the development of myocardial infarction (MI), stroke, venous thrombosis (VT), and atrial fibrillation (AF). The study setting is Group Health, an integrated health care delivery system in Washington State. Only VT cases and early-onset AF cases are included as part of TOPMed. Background The HVH study originated in 1988 with the examination of risk factors for MI. Over the ensuing years, the study has been funded by a series of grants which have added case subjects with stroke, VT, and AF. Study aims focused on the associations of medication use with cardiovascular events, and starting in 1997, the study aims expanded to include genetic associations with cardiovascular disease. Participants recruited in 2009 or later who provided blood samples for genetic analysis were asked for consent to deposit genetic and phenotypic data in dbGaP. Design As part of the HVH study, case subjects were identified by searching for ICD-9 codes consistent with MI, stroke, VT, or AF, and medical records were reviewed to confirm the diagnosis. Control subjects were identified at random from the Group Health enrollment and were matched to MI cases. All subjects have an index date. For cases, the index date was assigned as the date that the cardiovascular event (MI, stroke, VT, or AF) came to clinical attention. For controls, the index date was a random date within the range of the case index dates. For both cases and controls, information was collected from the inpatient and outpatient medical record, by telephone interview with consenting survivors, and from the Group Health pharmacy and laboratory databases. Consenting participants provided a blood specimen. Subjects Only VT and early-onset AF cases from HVH are included in TOPMed. Within the HVH study, VT and AF cases were diagnosed in both inpatient and outpatient settings, and only incident cases are eligible for inclusion in TOPMed. Genetic Research Genetic factors underlying cardiovascular disease are studied using DNA isolated from the blood samples. Phenotype data for HVH study participants are available through dbGaP phs001013.]]>
TOPMed Whole Genome Sequencing Methods: Freeze 8TOPMed Whole Genome Sequencing Methods: Freeze 9Early Onset AF The AF study identified early onset AF cases with a date of clinically recognized AF onset between January 2005 and June 2007. Early onset AF is defined as AF first recognized at ages 30-65 in a person with no known heart disease, and includes both AF and atrial flutter. First-time episodes of AF diagnosed in inpatient and outpatient settings were included. AF and its date of onset were verified by review of the inpatient and outpatient medical records. First-time episodes of AF that occurred during or after a surgical procedure and had resolved by the time of hospital discharge were not included. However, if a person had surgery-related AF that resolved, and later in time had AF that occurred in the absence of surgery, that second event was eligible as a first lifetime episode of non-surgery-related AF. If the onset of AF was recognized in a subject who already had clinically recognized heart disease, including heart failure, myocardial infarction, probable or definite angina, coronary bypass, coronary angioplasty, moderate or severe valvular heart disease, severe left ventricular hypertrophy, congenital heart disease, implanted pacemaker/AICD, or poor left ventricular systolic function, the AF case was not included. If a diagnosis of hyperthyroidism, pneumonia, active alcoholism, or another specific condition was identified as precipitating the AF, the AF case was not included. Idiopathic Venous Thrombosis (VT) The TOPMed VT project included idiopathic VT events identified between January 2002 and December 2012. Idiopathic events were those whose VT was diagnosed in the absence of precipitating factors such as cancer or surgery. ]]>
1988 - Study originates1997 - Study aims expand to include genetic associations with cardiovascular disease2009 - Participants who provided blood samples for genetic analysis are asked for consent to deposit genetic and phenotype data in dbGaP]]>

研究目标
心脏与血管健康研究（Heart and Vascular Health Study, HVH）是一项针对心肌梗死（myocardial infarction, MI）、卒中、静脉血栓栓塞（venous thrombosis, VT）及心房颤动（atrial fibrillation, AF）发病危险因素的病例对照研究。本研究的实施场景为华盛顿州的整合式医疗服务系统健康集团（Group Health）。本研究仅将VT病例与早发性AF病例纳入精准医学跨组学计划（Trans-Omics for Precision Medicine, TOPMed）。

研究背景
HVH研究起源于1988年，最初聚焦于心肌梗死的危险因素探究。后续十余年间，该研究获得多项资助，陆续新增了卒中、VT及AF的病例受试者。研究初始旨在阐明药物使用与心血管事件的关联；自1997年起，研究方向拓展至心血管疾病的遗传关联领域。2009年及之后招募的、提供血液样本用于遗传分析的参与者，被要求签署知情同意书，将其遗传与表型数据存入遗传与表型数据库（Database of Genotypes and Phenotypes, dbGaP）。

研究设计
作为HVH研究的组成部分，病例受试者通过检索匹配心肌梗死、卒中、VT或AF的国际疾病分类第9版（ICD-9）编码进行初筛，并经病历审阅确认诊断。对照受试者从健康集团的注册人群中随机抽取，并与心肌梗死病例进行匹配。所有受试者均设有索引日期：对于病例组，索引日期为该心血管事件（心肌梗死、卒中、VT或AF）进入临床关注的日期；对于对照组，索引日期为病例组索引日期范围内的随机选取日期。无论病例组还是对照组，研究数据均来源于住院与门诊病历、经知情同意的幸存者的电话访谈，以及健康集团的药房与实验室数据库。签署知情同意的受试者提供了血液标本。

受试者
本研究仅将HVH研究中的VT与早发性AF病例纳入TOPMed。在HVH研究中，VT与AF病例在住院及门诊场景下均完成确诊，且仅新发病例符合TOPMed的纳入标准。

遗传研究
研究人员通过分离血液样本中的DNA，探究心血管疾病的潜在遗传因素。HVH研究参与者的表型数据可通过dbGaP数据库（phs001013）获取。

TOPMed全基因组测序方法：第8冻存批次
TOPMed全基因组测序方法：第9冻存批次

早发性心房颤动
本研究纳入的早发性AF病例，其临床确诊AF的发病日期介于2005年1月至2007年6月之间。早发性AF的定义为：在无已知心脏病史的人群中，首次确诊AF时年龄为30~65岁，涵盖心房颤动与心房扑动两种心律失常类型。纳入住院及门诊环境下首次确诊的AF发作。AF及其发病日期需通过审阅住院与门诊病历进行验证。手术期间或术后发生、且在出院前已缓解的首次AF发作不予纳入统计。但若受试者曾出现手术相关性AF且已缓解，后续在无手术诱因的情况下再次发生AF，则该次后续事件可被视为非手术相关性AF的首次终生发作。若受试者在确诊AF时已存在临床确认的心脏病（包括心力衰竭、心肌梗死、确诊或疑似心绞痛、冠状动脉旁路移植术、冠状动脉成形术、中重度瓣膜性心脏病、重度左心室肥厚、先天性心脏病、植入式起搏器/自动植入式心脏复律除颤器（AICD），或左心室收缩功能低下），则该AF病例不予纳入。若AF发作由甲状腺功能亢进症、肺炎、活动性酒精中毒或其他特定诱因引发，则该AF病例不予纳入。

特发性静脉血栓栓塞（VT）
TOPMed的VT研究项目纳入2002年1月至2012年12月期间确诊的特发性VT事件。特发性事件指在无癌症或手术等明确诱因的情况下确诊的VT。

1988年 - 研究启动
1997年 - 研究拓展至心血管疾病遗传关联方向
2009年 - 提供血液样本用于遗传分析的参与者被要求签署知情同意书，将遗传与表型数据存入dbGaP数据库